Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12](OCC)=[O:13])=[CH:5]2.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][OH:13])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: Cn1c(CO)cc2cc(Br)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a solution of ethyl 5-bromo-1-methyl-1H-indole-2-carboxylate (ca. 9.0 g) in CH2Cl2 (80 mL) was added DIBAL-H (1.0M in hexanes, 70.0 mL, 2.2 eq) at −78° C. over 15 min. The reaction was monitored by LC-MS. After stirring for 1 h at −78° C., the reaction was quenched with 1N HCl (20 mL) at −78° C. then allowed to warm to room temperature and stirred for additional 30 min to break aluminum emulsion. The biphasic mixture was extracted by ether/EtOAc (1:1, 3×50 mL). The combined organic layers were dried over Na2SO4 then concentrated to give (5-bromo-1-methyl-1H-indol-2-yl)methanol (ca. 7.8 g, quant.) which was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[NH:7][CH:6]=1.[N-:15]=[N+:16]=[N-:17].[Na+].O>CN(C)C=O>[N:15]([CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[NH:7][CH:6]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1ccc2[nH]cc(CCCBr)c2c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCCc1c[nH]c2ccc(F)cc12
Yield: 91 %

Procedure:
A solution of 3-(3-bromopropyl)-5-flouro-1H-indole (0.95 g, 3 mmol) and sodium azide (0.59 g, 9 mmol) in anhydrous dimethyl formamide is stirred at 60° C. for 18 h, poured into water and extracted with methylene chloride. The extracts are combined, washed with water, dried over Na2SO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, EtOAc/hexane: 3/7) to afford the title product as a clear oil, 0.98 g (91% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[C:5]([O:8][C:9]1[C:10]([Cl:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13])(=[O:7])[CH3:6].[C-]#N.[Na+].O>CN(C)C=O>[C:5]([O:8][C:9]1[C:10]([Cl:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]([CH2:3][CH2:2][C:1]#[N:4])=[O:13])(=[O:7])[CH3:6]
Reactant: CC(=O)Oc1cccc(C=O)c1Cl
Reactant: C=CC#N
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1cccc(C(=O)CCC#N)c1Cl
Temperature: 35 °C
Reaction time: 4 h

Procedure:
A solution of redistilled acrylonitrile (20 g, 0.375 mole) in dimethylformamide (100 ml) was added dropwise to a stirred solution of 3-acetoxy-2-chlorobenzaldehyde (99.2 g, 0.5 mole) and sodium cyanide (12.25 g, 0.25 mole) in dimethylformamide (250 ml) at 35° C during 30 minutes. The mixture was stirred at 35° C for 4 hours, then poured into twice its own volume of water and the mixture was extracted with chloroform. The washed and dried extract was evaporated to give 3-(3-acetoxy-2-chlorobenzoyl)propionitrile.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([SH:9])[N:3]=1.[C:10]([CH2:14][C:15](OC)=[O:16])(=O)[CH2:11][CH3:12]>O>[CH2:11]([C:10]1[C:7]2[C:6](=[O:8])[NH:5][C:4](=[S:9])[NH:3][C:2]=2[O:1][C:15](=[O:16])[CH:14]=1)[CH3:12]
Reactant: Oc1cc(O)nc(S)n1
Reactant: CCC(=O)CC(=O)OC
Solvent: O
Product: CCc1cc(=O)oc2[nH]c(=S)[nH]c(=O)c12
Yield: 37.3 %

Procedure:
A mixture of 4,6-dihydroxy-2-mercapto-pyrimidine (20.0 g, 138.7 mmol) and methyl propionylacetate (21.8 mL, 173.4 mmol) was heated at 165° C. until the ester was completely reacted. The reaction mixture was cooled down and poured into water (75 mL) and then filtered through a sintered funnel. The solid residue was washed with water (2×20 mL) and dried under vacuum to yield 5-ethyl-2-thioxo-2,3-dihydro-1h-pyrano[2,3-d]pyrimidine-4,7-dione (11.6 g, 37%).
Reaction SMILES: [C:1]([Cl:4])([Cl:3])=[CH2:2].[C:5]([O:8][CH:9]=C)(=[O:7])[CH3:6].C=C.[O-]P(OP([O-])([O-])=O)(=O)[O-]>>[C:1]([Cl:4])([Cl:3])=[CH2:2].[C:5]([O:8][CH3:9])(=[O:7])[CH:6]=[CH2:1]
Reactant: C=COC(C)=O
Agent: C=C
Agent: O=P([O-])([O-])OP(=O)([O-])[O-]
Solvent: C=C(Cl)Cl
Product: C=CC(=O)OC

Procedure:
Examples 1-8 are repeated with the following exceptions. Instead of using the PVdC set forth in Table I, a pellet having the following composition is employed: the pellet contains about 96.5 weight percent of a vinylidene chloride interpolymer; about 1.5 weight percent ethylene vinyl acetate; about 1.2 weight percent tetrasodiuum pyrophosphate; and about 0.8 weight percent of epoxidized soybean oil. The vinylidene chloride interpolymer comprises from about 99.8 weight percent of a vinylidene chloride copolymer formed from a monomer mixture comprising 94 weight percent vinylidene chloride and about 6 weight percent methyl acrylate; and about 0.2 weight percent of epoxidized soybean oil. The vinylidene chloride copolymer has a major melting point of 165° C. and a weight average molecular weight of 90,000.
Reaction SMILES: [NH:1]([C:37](OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:38])[C@H:2]([C:10]([NH:12][C@H:13]([C:34]([OH:36])=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[C:24]1[C:32](=[O:33])[CH2:31][C:28]([CH3:30])([CH3:29])[CH2:27][C:25]1=[O:26])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1CCCC[CH2:55]1.N[C@H](C(N[C@H](C(O)=O)CCCCNC(=C1C(=O)CC(C)(C)CC1=O)CC(C)C)=O)CC1C=CC=CC=1.C(OC(=O)C)(=O)C>CN(C=O)C>[NH:1]([C:37]([CH3:55])=[O:38])[C@H:2]([C:10]([NH:12][C@H:13]([C:34]([OH:36])=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[C:24]1[C:25](=[O:26])[CH2:27][C:28]([CH3:29])([CH3:30])[CH2:31][C:32]1=[O:33])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C1CCNCC1
Reactant: CC(C)CC(NCCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)=C1C(=O)CC(C)(C)CC1=O
Agent: CC(C)CC(NCCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O)=C1C(=O)CC(C)(C)CC1=O
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCCNC(CC(C)C)=C1C(=O)CC(C)(C)CC1=O)C(=O)O

Procedure:
To the deprotected Lys-resin sample was added Fmoc-Phe (8.8 mg, 33.2 μmol) in DCM/DMF and 1,3-diisopropylcarbodiimide (DIC) (3 μL, 20 μmol). The coupling reaction was continued for 2 h and ninhydrin tests gave negative amino group readings. The Fmoc-Phe-Lys(ivDde) on resin was then treated with photogenerated piperidine as described above. Upon completion of the reaction, the resin was washed with DCM/DMF. Capping of the NH2-Phe-Lys(ivDde)-resin was carried out for 1 h with acetic anhydride (470 μL, 5 mmol) and TEA (700 μL, 5 μmmol) in 1.5 mL DMF to give Ac-Phe-Lys(ivDde)-resin.
Reaction SMILES: [CH2:1]([C:3]1[S:42][C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]4[NH:40][C:39](=[O:41])[O:38][N:37]=4)=[CH:26][CH:25]=3)[C:8](=[O:22])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=O)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Cl.[NH2:44][O:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].N1C=CC=CC=1.Cl>O.C(Cl)(Cl)Cl.C(O)C>[CH2:1]([C:3]1[S:42][C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]4[NH:40][C:39](=[O:41])[O:38][N:37]=4)=[CH:26][CH:25]=3)[C:8](=[O:22])[N:9]([CH2:12][C:13](=[N:44][O:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(F)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Reactant: CCOC(=O)CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)CON=C(Cn1c(=O)c2cc(CC)sc2n(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c1=O)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 6-ethyl-3-[2-(4-fluorophenyl)-2-oxoethyl]-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 (0.2 g), ethyl (aminooxy)acetate hydrochloride (0.045 g), pyridine (10 mL) and ethanol (10 mL) was stirred at 100° C. for 16 hr. To the reaction mixture were added chloroform and water, and the mixture was adjusted to pH 4 with 1N hydrochloric acid. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a stereoisomer mixture (0.059 g, 25%).
Reaction SMILES: C([N:8]([CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH2:30])=[O:29])=[CH:23][CH:22]=1)[CH2:9][CH:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C1C=CC=CC=1.CCOCC.[ClH:36]>CC(O)C.C(O)(=O)C.[Pd].C(OCC)(=O)C>[ClH:36].[OH:17][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][NH:8][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH2:30])=[O:29])=[CH:23][CH:22]=1
Reactant: NC(=O)Cc1ccc(OCCN(Cc2ccccc2)CC(O)c2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: CCOCC
Product: NC(=O)Cc1ccc(OCCNCC(O)c2ccccc2)cc1

Procedure:
A preformed solution of 4-[2-(N-benzyl-N-(2-hydroxy-2-phenylethyl)amino)ethoxy]phenylacetamide in propan-2-ol and glacial acetic acid (see below) was hydrogenated in the presence of 10% w/w palladium on carbon (1.0 g) at about 20 bar and 60° C. for 12 hours. The mixture was cooled, filtered and the filtrate was evaporated under reduced pressure. The residual oil thus obtained was dissolved in ethyl acetate and treated with a solution of ether saturated with hydrogen chloride. The precipitated solid was crystallised from methanol to give 4-[2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetamide hydrochloride (6.8 g), m.p. 250°-251° C. (softens at about 248° C.); microanalysis: found C, 61.2; H, 6.5; N, 8.3; Cl, 10.3%; required for C18H23ClN2O3 : C, 61.6; H, 6.6; N, 8.0; Cl, 10.1%.
Reaction SMILES: [ClH:1].C[O:3][C:4]1[C:9]([C:10]2[C:15]([O:16]C)=[CH:14][CH:13]=[C:12]([C:18](=[NH:26])[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=2)=[CH:8][C:7]([C:27](=[NH:35])[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:6][CH:5]=1.Cl.N1C=CC=CC=1>O.Cl>[ClH:1].[OH:16][C:15]1[C:10]([C:9]2[C:4]([OH:3])=[CH:5][CH:6]=[C:7]([C:27](=[NH:35])[NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:8]=2)=[CH:11][C:12]([C:18](=[NH:26])[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(C(=N)Nc2ccccc2)cc1-c1cc(C(=N)Nc2ccccc2)ccc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: N=C(Nc1ccccc1)c1ccc(O)c(-c2cc(C(=N)Nc3ccccc3)ccc2O)c1
Temperature: 180 °C
Reaction time: 16 h
Yield: 38.2 %

Procedure:
A mixture of 2.5 g of 6,6'-dimethoxy-N,N"-diphenyl[1,1'-biphenyl]-3,3'-dicarboximidamide, monohydrochloride (see Example 1) and 25 g of dry pyridine hydrochloride is heated at 180° C for 75 minutes. The mixture is then cooled, diluted with 10 ml of water and acidified with 10 ml of concentrated hydrochloric acid. The mixture is further diluted with 100 ml of 10% hydrochloric acid and allowed to stand at 0° C for about 16 hours. The crystalline material so obtained is recrystallized from dilute HCl (10% hydrochloric acid and water until solution occurs at 100° C) to yield 900 mg of the title compound, melting point 306°-307° C.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([CH2:13][CH2:14][C:15](O)=[O:16])=O)=[CH:9][CH:8]=2)=[O:5])[CH2:3][CH2:2]1.O.[NH2:21][NH2:22]>C(O)C>[CH:1]1([C:4]([NH:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]3[CH2:13][CH2:14][C:15](=[O:16])[NH:21][N:22]=3)=[CH:9][CH:8]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(NC(=O)C2CC2)cc1
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(NC(=O)C3CC3)cc2)=NN1
Yield: 68.1 %

Procedure:
2.0 g (7.7 millimoles) of 3-(p-cyclopropylcarbonylaminobenzoyl)-propionic acid, 0.45 g (9.0 millimoles) of hydrazine hydrate and 20 ml of ethanol are refluxed for 6 hours. The product is filtered off at 10° C. and recrystallized from dimethylformamide/water, giving 1.35 g (68% of theory) of 6-(p-cyclopropylcarbonylaminophenyl)-4,5-dihydro-3(2H)-pyridazinone, as colorless crystals, identical with the compound from Example 1.
Reaction SMILES: Cl([O-])=O.[Na+].[OH2:5].P([O-])(O)(O)=O.[Na+].[CH3:12][C:13]([O:16][C:17]([N:19]([C:27]1[NH:28][C:29]([CH:33]=[O:34])=[C:30]([Br:32])[N:31]=1)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:18])([CH3:15])[CH3:14].CC(=CC)C>O.C1COCC1.CC(O)(C)C>[CH3:26][C:23]([O:22][C:20]([N:19]([C:17]([O:16][C:13]([CH3:12])([CH3:14])[CH3:15])=[O:18])[C:27]1[NH:28][C:29]([C:33]([OH:5])=[O:34])=[C:30]([Br:32])[N:31]=1)=[O:21])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Br)c(C=O)[nH]1
Reactant: O
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Br)c(C(=O)O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
A solution of sodium chlorite (0.348 g, 3.84 mmol) and sodium dihydrogenphosphate monohydrate (0.318 g, 2.306 mmol) in water (4 mL) was added to a solution of bis(1,1-dimethylethyl)(4-bromo-5-formyl-1H-imidazol-2-yl)imidodicarbonate (0.150 g, 0.384 mmol), 2-methyl-2-butene (2M in THF) (2.402 mL, 4.80 mmol), t-BuOH (2 mL) and THF (6 mL). The mixture was stirred at RT overnight and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated. The residue was triturated with ether to give the desired product (0.047 g, 30%) as a white solid. ES MS: m/z 406 (M+1).
Reaction SMILES: COC([C:5]1([C:18]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[C:25]([F:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=O.[Li+].[Cl-].O.[Na+].[Cl-]>CS(C)=O>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][CH:5]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[C:25]([F:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1(c2ncnc3cc(F)c(F)cc23)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)c(F)cc23)CC1
Temperature: 150 °C
Reaction time: 7.5 h
Yield: 39.1 %

Procedure:
A mixture of 4-(6,7-Difluoro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (451 mg, 1.11 mmol), as prepared in the previous step, LiCl (89 mg, 2.12 mmol), water (60 μL, 3.3 mmol), and DMSO (430 μL) was stirred at 150° C. for 7.5 hrs with a reflux condenser. The reaction was then allowed to cool to rt, shaken with 1M NaCl (5 mL), and extracted with DCM (1×3 mL) and 9:1 DCM/MeOH (1×3 mL). The organic layers were combined, dried (Na2SO4), and concentrated. The residue was purified by silica flash chromatography (3:1 hex/EtOAc→2:1 eluent) to provide the title compound (151.8 mg, 39%). 1H-NMR (300 MHz, CDCl3) δ 9.22 (s, 1H), 7.90 (dd, 1H), 7.81 (dd, 1H), 4.33 (br m, 2H), 3.50 (tt, 1H), 2.96 (br t, 2H), 2.11-1.82 (m, 4H), 1.49 (s, 9H). LC/MS (ESI): calcd mass 349.2, found 368.3 (MH.H2O)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]1
Reactant: COC(=O)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 0 °C
Yield: 85.8 %

Procedure:
To a stirred solution of 3,4-difluoro nitrobenzene (1b, 3.5 g, 22 mmol) and methyl 4-piperidine carboxylate (2, 3.15 g, 22 mmol) in DMF solvent and K2CO3 (7.6 g, 55 mmol) as base and heated at 80° C. for 10 h, after completion of the reaction, reaction is poured into ice water and extracted into ethyl acetate finally purification by column chromatography to afford pure compound methyl 1-(2-fluoro-4-nitrophenyl)-4-piperidine carboxylate (3b, 5.33 g, 86%). To a stirred solution of ester (3b, 5.0 g, 18 mmol) in ethanol, NH2NH2.H2O (2.25 g, 45 mmol) is added and refluxed for 12 h. After completion of the reaction ethanol is evaporated under vacuum and water is added and extracted into ethyl acetate finally purification by column chromatography to afford pure compound 1-(2-fluoro-4-nitro phenyl)-4-piperidinecarbohydrazide (4b, 4.62 g, 91%). Addition N,N-dimethyl carbamyl chloride (1.29 g, 12 mmol) to hydrazide (4b, 3.38 g, 12 mmol) in pyridine at room temperature (27° C.) and followed by reflux at temperature 85° C. for 2.5 h. After completion of the reaction, the reaction mixture is cooled and filtered. The residue is recrystallized from water to get 5-[1-(2-fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5b, 1.47 g, 40%). Nitro compound (5b, 1.23 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-amino-2-fluorophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7e, 920 mg, 83%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl) carbodi imide)) (0.19 g, 1 mmol) and amine compound (7e, 0.28 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-3-fluoro-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8e, 333 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([F:8])=[N:6][CH:7]=1.[H][H]>C(O)C.[Ni]>[NH2:9][C:4]1[C:5]([F:8])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1F
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(Cl)cnc1F
Yield: 76.4 %

Procedure:
7.5 g (0.042 mol) of 5-chloro-2-fluoro-3-nitropyridine are dissolved in 80 ml of ethanol. This solution is hydrogenated with hydrogen, in the presence of 1 g of Raney nickel catalyst, under normal pressure and at a temperature in the range from 20° to 25° C. After a hydrogenation period of 20 hours, the catalyst is removed and the solvent is evaporated off. The residue is taken up in ethyl acetate and the resultant solution is filtered through a layer of silica gel. The solvent is evaporated off and the residue is triturated in hexane. The precipitate is subsequently filtered and dried, affording 4.7 g (76%) of 3-amino-5-chloro-2-fluoropyridine, m.p. 74° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[C:26]([F:28])[CH:27]=2)=[C:4]([NH:8][C:9](=O)[C@@H:10]([NH:12][C:13](=O)[O:14]C(C)(C)C)[CH3:11])[CH:5]=[CH:6][CH:7]=1.[CH3:29]C(O)=O>>[Br:1][C:2]1[C:3]2[N:21]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([F:28])[CH:27]=3)[C:9]([CH:10]([NH:12][C:13](=[O:14])[CH3:29])[CH3:11])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc(Br)c1Nc1cncc(F)c1
Product: CC(=O)NC(C)c1nc2cccc(Br)c2n1-c1cncc(F)c1
Reaction time: 120 h

Procedure:
A solution of (S)-tert-butyl 1-(3-bromo-2-(5-fluoropyridin-3-ylamino)phenylamino)-1-oxopropan-2-ylcarbamate (2.4253 g, 5.35 mmol) in AcOH (17.83 mL) was heated at 100° C. with stirring. After 5 days, the mixture was removed from the heat and poured into a biphase of DCM (100 mL) and satd. sodium bicarbonate solution (100 mL). The mixture was basified with 10N NaOH (10 mL). The organic layer was washed with water (100 mL×3) and brine (100 mL X1), dried over MgSO4, filtered, and concentrated in vacuo to provide N-(1-(7-bromo-1-(5-fluoropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethyl)acetamide as a dark brown solid: LC-MS (ESI) m/z 376.9 [M+H (79Br)]+ and 379 [M+H (81Br)]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[CH:4][CH:5]1[CH2:9][CH:8]([N:10]2[C:14]3[N:15]=[C:16]([S:29][CH2:30][CH2:31][CH3:32])[N:17]=[C:18]([NH:19][CH:20]4[CH2:22][CH:21]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:13]=3[N:12]=[N:11]2)[CH:7]([OH:33])[CH:6]1[OH:34]>O1CCCC1>[OH:1][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH:8]([N:10]2[C:14]3[N:15]=[C:16]([S:29][CH2:30][CH2:31][CH3:32])[N:17]=[C:18]([NH:19][CH:20]4[CH2:22][CH:21]4[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:13]=3[N:12]=[N:11]2)[CH:7]([OH:33])[CH:6]1[OH:34]
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C=CCO)C(O)C3O)c2n1
Solvent: C1CCOC1
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(CCCO)C(O)C3O)c2n1
Yield: 64.7 %

Procedure:
A solution of the product of Example 53, step (c) (0.2 g) and triisopropylbenzenesulphonylhydrazide (0.3 g) in tetrahydrofuran (10 ml) was heated at 70° C. for 4 hours. The mixture was then purified (SiO2, ethyl acetate as eluant) to afford the title compound (0.13 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[N:12]1([CH2:18][CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:12]1([CH2:18][CH2:19][NH:20][C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: NCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(NCCN2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 48 h
Yield: 20.9 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (1.3 g, 7.0 mmol), 2-(4-morpholinyl)-ethylamine (2.8 g, 20 mmol), and K2CO3 (3.0 g, 22 mmol) in DMF (20 mL) was stirred at 110° C. for 48 h. The reaction mixture was cooled to room temperature, poured into water (200 mL) and extracted with dichloromethane (CH2Cl2) (250 mL). The combined organic extracts were washed with water (200 mL) and brine (200 mL), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (silica gel, 4×15 cm, eluted with 90:10 EtOAc/MeOH) to yield the product as an orange solid (0.39 g, 20%).
Reaction SMILES: CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)C(C)C)(C)C.[C:31]([O:35][C:36]([N:38]1[CH2:42][C@@H:41]([C:43](=[O:53])[NH:44][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]#[N:52])[CH:46]=2)[C@H:40]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([C:60](O)=[O:61])[CH:55]=2)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].[CH3:63][N:64]1[CH2:69][CH2:68][C:67]2[N:70]=[C:71]([NH2:73])[S:72][C:66]=2[CH2:65]1>CC(N(C)C)=O.O>[C:31]([O:35][C:36]([N:38]1[CH2:39][C@@H:40]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([C:60](=[O:61])[NH:73][C:71]3[S:72][C:66]4[CH2:65][N:64]([CH3:63])[CH2:69][CH2:68][C:67]=4[N:70]=3)[CH:55]=2)[C@H:41]([C:43](=[O:53])[NH:44][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]#[N:52])[CH:46]=2)[CH2:42]1)=[O:37])([CH3:33])([CH3:34])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)Nc2cccc(C#N)c2)[C@H](c2cccc(C(=O)O)c2)C1
Reactant: CN1CCc2nc(N)sc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN1CCc2nc(NC(=O)c3cccc([C@@H]4CN(C(=O)OC(C)(C)C)C[C@H]4C(=O)Nc4cccc(C#N)c4)c3)sc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
Add N-(-3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.10 g, 0.52 mmol), followed by hydroxybenzotriazole (0.07 g, 0.52 mmol) and N,N-diisopropylethyl amine (0.18 mL, 1.00 mmol) to a solution of trans-3-(3-carboxy-phenyl)-4-(3-cyano-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.17 g, 0.39 mmol) in dimethylacetamide (5 mL). Stir the mixture at room temperature for 1 h then add 5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamine (0.08 g, 0.50 mmol) and heat the mixture to 50° C. with stifling overnight. Cool the reaction to room temperature and dilute with water causing a solid to precipitate from solution. Collect the formed solid by filtration, wash with water and dry on the filter pad to provide 0.23 g (quant.) of trans-3-(3-cyano-phenylcarbamoyl)-4-[3-(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylcarbamoyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a powder.