Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:12]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[C:4](N)[N:3]=1.NC1N=C2C(N=CN2[C@@H]2O[C@H](CO)[C@@](CCCCN3C=CN=C3)(O)[C@H]2[OH:42])=C(N)N=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O>CS(C)=O>[N:18]1([CH2:17][CH2:16][CH2:15][CH2:14][O:13][C@@H:12]2[C@H:23]([OH:24])[C@@H:25]([CH2:27][OH:28])[O:26][C@H:11]2[N:8]2[C:9]3[N:10]=[C:2]([NH2:1])[NH:3][C:4](=[O:42])[C:5]=3[N:6]=[CH:7]2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@](O)(CCCCn4ccnc4)[C@H]3O)c2n1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3OCCCCn3ccnc3)c2n1
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CS(C)=O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCCn2ccnc2)c(=O)[nH]1

Procedure:
A mixture of the 2,6-diamino-9-[2′-O-(imidazol-1-yl)butyl-β-D-ribofuranosyl]purine and 2,6-diamino-9-[3′-(imidazol-1-yl)butyl-β-D-ribofuranosyl]purine isomers in 0.1 M tris buffer (pH 7.4), 0.1 M NaSO4 buffer (pH 7.4) and DMSO is treated with adenosine deaminase at RT for 5 days as per the procedure of Example 3. The product containing fractions are purified by silica gel chromatography and the product containing fraction evaporated to give the product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:15][C:16]([O:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(OCC)(=O)C>CN(C)C=O>[CH:19]([O:18][C:16]([CH2:15][N:5]1[CH:6]=[CH:7][C:2](=[O:1])[CH:3]=[CH:4]1)=[O:17])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CCl)OC(c1ccccc1)c1ccccc1
Reactant: Oc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cn1ccc(=O)cc1)OC(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
4 g (42.06 mmol) of 4-hydroxypyridine was dissolved in 80 ml of N,N-dimethylformamide, and 8.7 g (62.92 mmol) of potassium carbonate and 16.45 g (63 mmol) of benzhydryl 2-chloroacetate were added thereto. The mixture was stirred at 60° C. for 4 hours. 200 ml of ethyl acetate was added to the reaction solution. The ethyl acetate layer was washed with water and with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and then treated with active carbon. The solvent was distilled off under reduced pressure, and the crystalline residue was washed with diethyl ether to obtain 9.8 g (yield: 73%) of 1-benzhydryloxycarbonylmethyl-4-pyridone.
Reaction SMILES: [CH3:1][C:2]([SH:5])([CH3:4])[CH3:3].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](F)[C:8]=1[C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=1.[H-].[Na+]>C1COCC1>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:5][C:2]([CH3:4])([CH3:3])[CH3:1])[C:8]=1[C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=1
Reactant: CC(C)(C)S
Reactant: CC1(C)COC(c2c(F)cccc2F)=N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)COC(c2c(F)cccc2SC(C)(C)C)=N1
Yield: 82.9 %

Procedure:
A mixture of 2-methyl-2-propanethiol (2.7 g, 30 mmol), the compound of example g (3.17 g, 15 mmol), and NaH (0.79 g, 33 mmol) in THF (100 mL) was stirred at RT for 1d, then at reflux for 1d. This was then quenched with sat aq NaHCO3 (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried (MgSO4), concentrated, and purified by HPLC with 1:4 EtOAc/hexanes to afford 3.5 g of 2-[2-fluoro-6-(1,1-dimethylethylthio)phenyl]-4,4-dimethyl-2-oxazoline as a yellow oil, an 83% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])[CH2:14][C:13]2[C:8](=[C:9]([O:21][CH3:22])[C:10]([O:19][CH3:20])=[C:11]([O:17][CH3:18])[C:12]=2[O:15][CH3:16])[CH2:7]1)=[O:5])[CH3:2].Cl>C1COCC1>[OH:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:14][C:13]2[C:8](=[C:9]([O:21][CH3:22])[C:10]([O:19][CH3:20])=[C:11]([O:17][CH3:18])[C:12]=2[O:15][CH3:16])[CH2:7]1
Reactant: CCOC(=O)C1(CCCCCCCC(=O)O)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCCCCCCCO)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A THF solution of borane complex (1 M, 3.74 ml, 3.74 mmols) was added to a THF (9.0 ml) solution of 8-(2-ethoxycarbonyl-4,5,6,7-tetramethoxyindan-2-yl)octanoic acid (847 mg, 1.87 mmol), with cooling with ice. The reaction mixture was allowed to warm to room temperature, and then stirred for 2 hours. 1N hydrochloric acid was added and the reaction mixture was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the entitled compound (713 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:10]([O-])=O.[Na+].[Sn](Cl)Cl.C(=O)([O-])O.[Na+]>Cl.O>[Cl:8][C:6]1[CH:5]=[C:4]([OH:9])[CH:3]=[C:2]([NH:1][NH2:10])[CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1cc(O)cc(Cl)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: O
Product: NNc1cc(O)cc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.1 g (14.3 mmol) 3-amino-5-chloro-phenol are dissolved in 20 ml of conc. hydrochloric acid and 20 ml of water and cooled to 0° C. 1.0 g (15.0 mmol) sodium nitrite in 4 ml of water are added. Then a solution of 12.1 g (53.5 mmol) tin(II)-chloride in 16 ml hydrochloric acid is slowly added dropwise at −5° C. It is stirred for 1 hour at 0° C., then adjusted to pH7 with sodium hydrogen carbonate. The precipitate formed is suction filtered and washed with water. The filtrate is extracted with diethyl ether. The organic phase is dried and evaporated to dryness. The residue is extracted with hexane.
Reaction SMILES: C([Li])CCC.[Si:6]([O:13][C:14]1[CH:22]=[CH:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH:15]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C.O>CCCCCC.O1CCCC1>[Si:6]([O:13][C:14]1[CH:22]=[CH:21][C:17]2[CH:18]=[C:19]([B:23]([OH:28])[OH:24])[S:20][C:16]=2[CH:15]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2ccsc2c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(B(O)O)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
2.5 M n-butyllithium (23 mL, 57.5 mmol) in hexane was slowly added to the 6-(t-butyldimethylsilyloxy)benzothiophene (23, 13.6 g, 51.0 mmol) dissolved in anhydrous tetrahydrofuran (150 mL) at −78° C. under nitrogen atmosphere. 15 minutes later, the mixture was agitated at room temperature for 1 hour. After cooling again to −78° C., triisopropyl borate ((i-PrO)3B; 14.0 mL, 62.0 mmol) was slowly added. Then, after slowly heating to room temperature and agitating for 3 hours, water was added to quench the reaction. After extracting the organic compound with ethyl acetate and removing water using sodium sulfate, column chromatography yielded the target compound 6-(t-butyldimethylsilyloxy)benzothiophene-2-boronic acid (24, 9.75 g, 62%).
Reaction SMILES: ClC[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]2[CH:13]=[N:14][CH:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.BrCCCC[Cl:21]>>[Cl:21][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]2[CH:13]=[N:14][CH:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1
Reactant: ClCCCCCc1cccc2cncn12
Reactant: ClCCCCBr
Product: ClCCCCc1cccc2cncn12

Procedure:
5-(4-Chlorobutyl)-imidazo[1,5-a]pyridine is prepared by the procedure described for the preparation of 5-(5-chloropentyl)imidazo[1,5-a]pyridine of Example 4 using 1-bromo-3-chloropropane as reagent instead of 1-bromo-4-chlorobutane therein.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:2]=1.Br[C:14]1[S:18][C:17]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:16]=2[C:15]=1[CH3:24].N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:23][C:21]1[CH:20]=[CH:19][C:17]2[S:18][C:14]([N:9]3[CH2:10][CH2:11][N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[C:8]3=[O:12])=[C:15]([CH3:24])[C:16]=2[CH:22]=1
Reactant: Cc1c(Br)sc2ccc(F)cc12
Reactant: O=C1NCCN1c1cccnc1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1c(N2CCN(c3cccnc3)C2=O)sc2ccc(F)cc12
Yield: 61.1 %

Procedure:
Using the same reaction conditions as in Example 1, 1-pyridin-3-yl-imidazolidin-2-one (I-1b: 73 mg, 0.45 mmol) was reacted with 2-bromo-5-fluoro-3-methyl-benzo[b]thiophene (110 mg, 0.45 mmol), 1,4-dioxane (5 mL), copper iodide (8 mg, 0.045 mmol), trans-1,2-diamino cyclohexane (7 mg, 0.0675 mmol) and potassium carbonate (124 mg, 0.9 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform), afforded 90 mg of the product (61.64% yield).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][CH2:22]O)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:29]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>O1CCCC1.O>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][CH2:22][I:29])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: II
Reactant: CS(=O)(=O)Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCO)CS3)cc2c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCI)CS3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
The compound (178 mg, 0.42 mmol) prepared in Example 70 was dissolved in tetrahydrofuran (10 ml). Iodine (161 mg, 0.63 mmol), triphenylphosphine (166 mg, 0.63 mmol) and imidazole (86 mg, 1.23 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and separated by column chromatography to give the title compound (120 mg, Yield 54%).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[NH:16][N:17]=[CH:18][CH:19]=3)=[N:12][C:11]=2[CH3:20])=[O:9])=[CH:4][CH:3]=1.Cl[CH2:24][C:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:19]=[CH:18][N:17]([CH2:24][C:25]([CH3:27])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH3:26])[N:16]=3)=[N:12][C:11]=2[CH3:20])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccc(F)cc1
Reactant: CC(C)(CCl)c1ccccc1
Product: Cc1nc(-c2ccn(CC(C)(C)c3ccccc3)n2)sc1C(=O)NCc1ccc(F)cc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)thiazole-5-carboxylic acid 4-fluoro-benzylamide and (2-chloro-1,1-dimethyl-ethyl)-benzene as describe in Example 83 and isolated as a white solid (0.046 g, 33% yield). 1H NMR (400 MHz, CDCl3) δ 7.22-7.35 (m, 7H), 7.02-7.08 (m, 1H), 6.69 (d, J=2 Hz, 1H), 6.62 (d, J=2 Hz, 1H), 5.96-6.03 (bm, 1H), 4.57 (d, J=4 Hz, 2H), 4.28 (s, 2H), 2.73 (s, 3H), 1.40 (s, 6H); MS (M+H)+=449.2; Rt=1.64 min; HRMS (M+H)+=449.18.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[C:21]([F:28])[C:3]=1[O:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([CH3:11])[C:6]=1[C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=1[F:20].[Cl-].[NH4+].O>C(O)C.C(OCC)(=O)C.[Fe]>[CH3:10][N:9]1[C:5]([O:4][C:3]2[C:2]([F:1])=[CH:24][C:23]([NH2:25])=[CH:22][C:21]=2[F:28])=[C:6]([C:12]2[C:13]([F:20])=[CH:14][C:15]([F:19])=[CH:16][C:17]=2[F:18])[C:7]([CH3:11])=[N:8]1
Reactant: Cc1nn(C)c(Oc2c(F)cc([N+](=O)[O-])cc2F)c1-c1c(F)cc(F)cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(Oc2c(F)cc(N)cc2F)c1-c1c(F)cc(F)cc1F
Reaction time: 0.5 h

Procedure:
5-(2,6-Difluoro-4-nitrophenoxy)-1,3-dimethyl-4-(2,4,6-trifluorophenyl)-1H-pyrazole (i.e. the product of Synthesis Example 8) (0.780 g, 1.95 mmol) was combined with iron powder (325 mesh, 0.58 g, 10 mmol) and ammonium chloride (64 mg, 1.2 mmol) in ethanol (27 mL) to which water (3 mL) had been added. The mixture was heated at reflux for 1.25 h and then allowed to cool. The reaction mixture was diluted with an equal volume of ethyl acetate and filtered through Celite filter aid. The filtrate was dried with MgSO4 and concentrated. Analysis by LC/MS showed the major component (93%) to have mass 370 amu (AP+). The residue was dissolved in anhydrous dimethyl sulfoxide (8 mL), and a commercial solution of sodium methoxide in methanol (0.45 mL of 25% solution) was added. This solution was stirred under nitrogen and heated at reflux for 1 h. Additional sodium methoxide/methanol solution (0.20 mL) was added, and heating was continued for an additional 30 minutes. The reaction mixture was allowed to cool, and it was then treated with aqueous citric acid solution (1 M, 5 mL), diluted with water (50 mL) and extracted with ethyl acetate (2×25 mL). The organic phase was washed with water (3×) and with brine, dried over MgSO4, and concentrated to leave the title product, a compound of the present invention, as a viscous oil (0.52 g).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:18]([CH3:29])=[C:17]2[CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1)=O)C1C=CC=CC=1>O1CCCC1.[Pd]>[NH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:18]([CH3:29])=[C:17]2[CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: COC(=O)CCn1c(C)c(Cn2ccnc2)c2cc(CCNC(=O)OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)CCn1c(C)c(Cn2ccnc2)c2cc(CCN)ccc21
Yield: 79.5 %

Procedure:
A solution of methyl 5-(2-benzyloxycarbonylaminoethyl)-3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole-1-propanoate (0.57 g) in tetrahydrofuran (50 ml) was hydrogenated at room temperature and 4.5 atm. pressure in the presence 10% palladium on carbon (50 mg) for 20 hours. The mixture was filtered and the residue was washed with methanol. The filtrate and washings were combined and evaporated to give a gum which was chromatographed on silica gel. Elution with dichloromethane/methanol (19:1) gave impurity, and then further elution with dichloromethane/methanol/0.880 ammonia solution (95:5:1) gavepure product. The product fractions were evaporated to give the title compound as a gum (0.325 g), Rf. 0.4 (SS3). The product was used directly for further reaction.
Reaction SMILES: CC[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]2[C@@H:15]3[CH:16]=[C:17](C)[CH2:18][CH2:19][C@H:14]3C(C)(C)O[C:10]=2[CH:11]=1.C([O-])(=[O:26])C.[Na+].C(#N)C.C(O)(C(F)(F)F)=O>C(O)C.O>[CH:18]1[CH:19]=[CH:14][C:15](/[CH:9]=[C:8]2/[C:7]([C:6]3[C:5]([O:23]/2)=[CH:4][CH:3]=[CH:10][CH:11]=3)=[O:26])=[CH:16][CH:17]=1
Reactant: CC(=O)[O-]
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC#N
Product: O=C1/C(=C/c2ccccc2)Oc2ccccc21

Procedure:
The reaction was started by adding 5 μl of THC, having an absorbance of 462 at 366 nm in ethanol, to 50 μl of 1 M sodium acetate buffer (pH 5.0) and 350 μl of crude enzyme solution diluted with water. After allowing to react for 1 hour at 30° C., and adding 100 μl of an aqueous solution of 90% (v/v) acetonitrile containing 1% (v/v) TFA to stop the reaction, activity was measured by HPLC. The crude enzyme solution in each purification step described later in Example 4 was measured.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([CH:42]=[CH:43][CH:44]=1)[CH2:7][O:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10]1)=[O:3].[CH3:45][O:46][CH2:47][CH2:48][NH2:49]>>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][O:25][CH2:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH:14]2[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10][CH:9]2[O:8][CH2:7][C:6]2[CH:42]=[CH:43][CH:44]=[C:4]([C:2](=[O:3])[NH:49][CH2:48][CH2:47][O:46][CH3:45])[CH:5]=2)=[CH:16][CH:17]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc(C(=O)Cl)c2)cc1
Reactant: COCCN
Product: COCCNC(=O)c1cccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)c1

Procedure:
Analogously to Example 127a, 0.355 g of tert-butyl 3-(3-chlorocarbonylbenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 106b) and 0.087 g of 2-methoxyethylamine are reacted. The title compound is obtained as a colourless oil. Rf=0.10 (1:1 EtOAc-heptane); Rt=5.51.
Reaction SMILES: [H-].[Na+].C(O[C:6]([C:8]1[C:12]([C:13]2[CH:18]=[C:17]([Br:19])[C:16]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:15]([Br:28])[CH:14]=2)=[CH:11][S:10][C:9]=1[NH:29][C:30](=[O:34])[CH2:31][C:32]#[N:33])=[O:7])C.Cl>C1COCC1>[CH2:21]([O:20][C:16]1[C:17]([Br:19])=[CH:18][C:13]([C:12]2[C:8]3[C:6]([OH:7])=[C:31]([C:32]#[N:33])[C:30](=[O:34])[NH:29][C:9]=3[S:10][CH:11]=2)=[CH:14][C:15]=1[Br:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1c(-c2cc(Br)c(OCc3ccccc3)c(Br)c2)csc1NC(=O)CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(O)c2c(-c3cc(Br)c(OCc4ccccc4)c(Br)c3)csc2[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of NaH (275 mg, 6.87 mmol) in THF (50 mL) was added 4-(4-benzyloxy-3,5-dibromo-phenyl)-2-(2-cyano-acetylamino)-thiophene-3-carboxylic acid ethyl ester from Example 36D (1.8 g, 3.12 mmol) in THF (50 mL). The reaction stirred at room temperature for 18 h. It was acidified with 1M HCl and concentrated in vacuo. The resulting orange solid was taken up in H2O and filtered, rinsing with H2O (2×20 mL) and CH2Cl2 (3×20 mL). The titled compound was isolated as a yellow solid (940 mg, 1.76 mmol, 56% yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([NH:10][C:11]2[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O1CCCC1.[Cl-].[NH4+]>[Zn].O>[NH2:17][C:16]1[C:11]([NH:10][C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(Nc2ncccc2N)cc1F
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-fluoro-4-[(3-nitropyridin-2-yl)amino]benzonitrile (C14) (5.4 g, 21 mmol) in a 1:1 mixture of tetrahydrofuran and water (40 mL) was added ammonium chloride (8.9 g, 170 mmol), followed by zinc (10.8 g, 165 mmol). The mixture was stirred at 60° C. for 30 minutes, whereupon it was filtered through a pad of Celite. The organic layer from the filtrate was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo; the residue was washed with heptane to afford the product as a brown solid. Yield: 4.2 g, 18 mmol, 86%. LCMS m/z 229.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (br s, 1H), 7.82 (dd, J=13.6, 2.0 Hz, 1H), 7.66 (dd, J=8.4, 8.3 Hz, 1H), 7.61 (dd, J=4.8, 1.6 Hz, 1H), 7.37 (dd, J=8.8, 2.0 Hz, 1H), 7.03 (dd, J=7.8, 1.6 Hz, 1H), 6.82 (dd, J=7.8, 4.8 Hz, 1H), 5.24 (br s, 2H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(N(C(C)C)CC)(C)C>C1COCC1.C(OCC)(=O)C>[CH2:5]([O:4][C:2]([N:28]1[CH2:29][CH2:30][CH:25]([NH:24][S:21]([C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=2)(=[O:23])=[O:22])[CH2:26][CH2:27]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)NC2CCNCC2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.7 %

Procedure:
Benzyl chloroformate (0.7 ml, 4.9 mmol) was added drop wise to a cool (0° C.) solution of 4-nitro-N-piperidin-4-yl-benzenesulfonamide (1.4 g, 4.9 mmol) and diisopropylethylamine (1.6 ml, 9.8 mmol) in THF (10 ml). The resulting mixture was warmed to room temperature and stirred under a nitrogen atmosphere for 18 hours. After this time, the mixture was diluted with ethyl acetate (50 ml), washed with water (50 ml), the organic layer was separated and dried (MgSO4), filtered and concentrated under vacuum. The resulting residue was purified by flash column chromatography (elution: 50% heptane, 50% ethyl acetate) to give the title compound (0.98 g, 48% yield) as a white solid. Tr=2.04 min m/z (ES+) (M+H+) 420.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:9]=2[N:8]=[CH:7]1)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:37]12[NH:44][CH:41]([CH2:42][CH2:43]1)[CH2:40][CH:39]([OH:45])[CH2:38]2.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:1]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:44]3[CH:37]4[CH2:43][CH2:42][CH:41]3[CH2:40][CH:39]([OH:45])[CH2:38]4)=[O:17])=[CH:14][C:9]=2[N:8]=[CH:7]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCn1cnc2cc(C(=O)O)ccc21
Reactant: OC1CC2CCC(C1)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=NCCn1cnc2cc(C(=O)N3C4CCC3CC(O)C4)ccc21
Temperature: 0 °C
Reaction time: 15 h
Yield: 90.5 %

Procedure:
To a solution of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid (0.82 g, 0.00357 mol) in dry DMF (8.0 mL) was added with stirring HOBt (0.578 g, 0.00428 mol), DIPEA (1.9 mL, 0.0107 mol), 8-azabicyclo[3.2.1]octan-3-ol (0.5 g, 0.00393 mol) and the mixture was cooled to 0° C. To the resulting mixture was added EDCl (0.82 g, 0.00428 mol) and stirred for 15 h at ambient temperature. The reaction mixture was then diluted with ice water (100 mL), extracted with EtOAc (3×50 mL) and the combined organic phases were washed with water (3×50 mL) and saturated brine solution (50 mL). The organic phase was dried (Na2SO4) and the solvent evaporated affording (1.1 g, 98%) of [1-(2-azidoethyl)-1H-benzimidazol-5-yl]-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)methanone. MS-ESI m/z 341 (M+1).