Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:15][CH:16]([NH2:18])[CH3:17]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:18][CH:16]([CH3:17])[CH3:15])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CC(C)N
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)NC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A solution of 4-bromobenzoic acid (4.00 g, 19.9 mmol, Aldrich: Cat. #108510) and thionyl chloride (10.0 mL, 137 mmol) was heated by microwave irradiation at 100° C. for 1 h, turning the heterogeneous solution to a homogeneous solution. The volatiles were removed in vacuo and the residue was azeotropically washed with dry acetonitrile several times (20 mL×4) to remove excess thionyl chloride. The residue was dissolved in anhydrous methylene chloride (40 mL) and cooled to 0° C. prior to the addition of 2-propanamine (8.0 mL, 94 mmol, 99.5% pure Aldrich [75-31-0]). After 1 hour, the reaction mixture was diluted with methylene chloride (20 mL) and quenched with H2O (5 mL). The layers were separated and the organic layer was washed with H2O (1×5 mL), saturated NaHCO3 (1×5 mL), H2O (1×5 mL), 1 N HCl (3×5 mL), H2O (1×5 mL), and brine (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford the desired product (4.50 g, 93% yield) which was used directly in the next step without further purification. LCMS (M+H)+: m/z=242/244.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=O)[CH3:6].P(Cl)(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1.Cl.[NH2:22][C:23]1[CH:24]=[C:25]([C:29]2[O:30][CH:31]=[CH:32][C:33]=2[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:26]=[CH:27][CH:28]=1>C(OCC)(=O)C>[CH3:6][C:5]1[N:22]([C:23]2[CH:24]=[C:25]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:26]=[CH:27][CH:28]=2)[CH2:2][CH2:3][N:4]=1
Reactant: CC(=O)NCCCl
Reactant: CCOC(=O)c1ccoc1-c1cccc(N)c1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccoc1-c1cccc(N2CCN=C2C)c1
Temperature: 2.5 °C
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
N-(2-chloroethyl)acetamide (1.21 g) in ethyl acetate (10 mL) was added over 10 min to a stirred suspension of phosphorus pentachloride (2.08 g) in ethyl acetate (2 ml) at 0° C. under nitrogen to give a clear pale straw solution. After 45 min. at 0° C. toluene (12 ml) was added, and ethyl 2-(3-aminophenyl)-3-furoate hydrochloride (1.78 g) was added in one portion into the above solution at 0-5° C. The mixture was stirred at 0-5° C. for 10 min. and then allowed to warm up to 20° C. After 2 h formation of the amidine was essentially complete (HPLC ethyl 2-(3-aminophenyl)-3-furoate hydrochloride <2% (220 nm, a/a). The mixture was cooled to 0-5° C., crushed ice (18 g) was added over 20 min. to destroy phosphorus oxychloride. Ammonium hydroxide (28%, 6.49 mL) was added at a rate that the internal temperature was kept below 25° C. (ca. 15 min). After 1 h at 20° C. additional ethyl acetate (12 ml) added to the above mixture, the organic layer was separated, washed with deionized water (2×12 ml), and concentrated under reduced pressure. The residue was dissolved in acetone (5 ml) and ethyl acetate (5 ml), and treated with oxalic acid (0.72 g) at 40° C. for 30 min. After aging at <20° C. for at least 12 h, the precipitate was collected by filtration, washed with acetone (2×0.5 vol), and dried in vacuo at 45-50° C. to yield 1.9 g (73%) of white solid.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]1C[O:15][CH2:14][CH2:13]1.[CH2:17]([C@@H:24]1[CH2:28][O:27][C:26](=[O:29])[NH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)(=O)CC>C(OCC)(=O)C>[CH2:17]([C@@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:14](=[O:15])[CH2:13][CH3:12])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: C1CCOC1
Agent: CCC(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 25 °C

Procedure:
1.57M n-butyllithium hexane solution (96 ml, 150 mmol) was slowly added dropwise to a THF (400 ml) solution of (R)-4-benzyl-2-oxazolidinone (25.36 g, 143 mmol) at −78° C. under stirring. Subsequently propionyl chloride (13.7 ml, 157 mmol) was added at once and the reaction solution was stirred at the same temperature for 30 minutes. After the reaction solution was warmed to room temperature for 30 minutes, it was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; heptane:ethyl acetate=5:1) to obtain the title compound (36.58 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:19][CH2:20][C@H:21]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:39]([O:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51]Br)=[CH:49][CH:48]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C)C=O>[CH2:39]([O:46][C:47]1[CH:48]=[CH:49][C:50]([CH2:51][C:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])([CH2:19][CH2:20][C@H:21]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:53][CH:54]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: BrCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(OCc2ccccc2)cc1)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 1.00 g di-tert-butyl (5S)-2-(benzyloxycarbonyl)-5-[(tert-butoxycarbonyl)-amino]hexanedioate (1.97 mmol) in NA-dimethyl formamide (20 mL) was added under argon atmosphere 71 mg of sodium hydride (60% in oil, 1.77 mmol). The resulting mixture was stirred at room temperature for 30 minutes. A solution of 546 mg 4-benzyloxybenzyl bromide (1.97 mmol; prepared according to Helv. Chim. Acta, 2002, 85, 3422) in N,N-dimethylformamide (10 mL) was added, and the mixture was stirred at 60° C. for one hour. After cooling to room temperature, the mixture was concentrated in vacuo and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel (2.5→20% ethyl acetate in hexane) to give 1.22 g of the title compound (88% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.CC(C)([O-])C.[K+].O>O1CCOCC1>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:4]1[CH:3]=[C:2]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[C:11]2[C:6]([N:5]=1)=[N:7][CH:8]=[CH:9][N:10]=2
Reactant: Nc1ccncc1
Reactant: Fc1ccccc1-c1cc(Cl)c2nccnc2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccccc1-c1cc(Nc2ccncc2)c2nccnc2n1
Reaction time: 0.08 h

Procedure:
A solution of 52.2 mg (0.20 mmol) 8-chloro-6-(2-fluoro-phenyl)-pyrido[2,3-b]pyrazine in 1 ml dioxane was heated to 80° C. under nitrogen. Then 20.7 mg (0.22 mmol) 4-aminopyridine and 47.3 mg (0.42 mmol) potassium-tert-butoxide were added and the mixture was stirred at the same temperature for 5 minutes. Water was added to the reaction mixture. The resulting precipitate was filtered off and washed with water. The filtrate was extracted several times with dichloromethane; the organic phase was dried over sodium sulphate and evaporated. The residue was combined with the filtrate and purified by preparative HPLC. The fractions containing product were evaporated and partitioned between sodium hydrogen carbonate solution and dichloromethane. The organic phase was dried over sodium sulphate and evaporated yielding [6-(2-fluoro-phenyl)-pyrido[2,3-b]pyrazin-8-yl]-pyridin-4-yl-amine as yellow crystals HPLC/MS (A): 1.37 min, [M+H] 318.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].Cl[CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(COC)OC>[CH3:22][C:20]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1c(C)nc2ccccn12
Yield: 61.6 %

Procedure:
To a stirred solution of 2-aminopyridine (15.0 g. 159.00 mmol) in dimethoxyethane (150 mL) was added NaHCO3 (14.72 g, 175 mmol) followed by ethyl 2-chloroacetoacetate (39.34 g, 239 mmol) at room temperature. After refluxing for 16 h the solvent was removed under reduced pressure. The residue was taken up in water (200 mL) and extracted with dichloromethane (2×200 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), and dried over anhydrous Na2SO4. Evaporation of solvents under reduced pressure afforded crude product which was further purified by column chromatography to give 20 g of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 1.44 (t, J=6.9 Hz, 3H), 2.72 (s, 3H), 4.43 (q, J=7.2 Hz, 2H), 6.98 (t, J=6.6 Hz, 1H), 7.38 (t, J=8.7 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 9.31 (d, J=6.9 Hz, 1H); ESI-MS (m/z) 205.13 (MH)+.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([CH2:10][N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([NH2:20])[C:14]=3[C:13]([CH3:21])=[N:12]2)[CH:7]=[CH:6][CH:5]=1)(C)C.[Br:22][C:23]1[CH:28]=[CH:27][N:26]2[C:29]([C:32](OC)=[O:33])=[CH:30][N:31]=[C:25]2[CH:24]=1.FC1C=CN2C(C(OCC)=O)=CN=C2C=1>>[Br:22][C:23]1[CH:28]=[CH:27][N:26]2[C:29]([C:32]([NH:20][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[C:13]([CH3:21])=[N:12][N:11]4[CH2:10][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([CH3:1])[N:9]=3)=[O:33])=[CH:30][N:31]=[C:25]2[CH:24]=1
Reactant: COC(=O)c1cnc2cc(Br)ccn12
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(N)c12
Agent: CCOC(=O)c1cnc2cc(F)ccn12
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(Br)ccn45)cccc32)n1
Yield: 62 %

Procedure:
Prepared according to Example 1, Step A, substituting 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine for 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine and methyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate for ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate, to give the title compound (62%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].F[C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[C:14]#[N:15]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: Nc1ccccc1S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1N
Reaction time: 0.5 h

Procedure:
2-Aminothiophenol (6.26 g, 50 mmol) was added to a mixture of sodium hydride (2.0 g of 60% oil dispersion, 50 mmol) in DMF (100 ml) at 0° under nitrogen. After stirring for 30 minutes at 0°, 2-fluoro-5-nitrobenzonitrile (8.3 g, 50 mmol) in DMF (20 ml) was added and the mixture kept at room temperature overnight. The reaction mixture was evaporated and azeotroped with toluene, then the residue was partitioned between chloroform and water and the layers separated. Drying (sodium sulphate) and evaporation of the organic layer gave a residue which was separated from chloroform as bright yellow crystals (10.1 g, Rf 0.52 in 1:1 ethyl acetate/hexane).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[CH2:22]([NH:29][OH:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:29]([OH:30])[C:16]([C:14]1[CH:15]=[C:10]2[CH:9]=[CH:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=3)[C:11]2=[CH:12][N:13]=1)=[O:18])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1cc2ccn(Cc3ccc(F)cc3)c2cn1
Reactant: ONCc1ccccc1
Agent: Cl
Product: O=C(c1cc2ccn(Cc3ccc(F)cc3)c2cn1)N(O)Cc1ccccc1

Procedure:
The title compound was prepared by coupling of 1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid with N-benzyl hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (DMSO-d6) δ; 8.92 (s, 1H), 8.11 (s, 1H), 7.91 (d, 1H, J=2.8 Hz), 7.26–7.38 (m, 7H), 7.16 (d, 2H, J=8.5 Hz), 6.72 (d, 1H, J=2.8 Hz), 5,58 (s, 2H), 4.97 (s, 2H). LCMS (API-ES, M+H+): 376.1, HRMS calcd for C22H19FN3O2 (M+H) 376.1461. found 376.1448. Anal. (C22H18FN3O2) C, H, N. HPLC: 100% purity.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[O:7][CH:8]=[CH:9][N:10]=1.[N+:11]([CH:14]=[C:15](SC)[S:16][CH3:17])([O-:13])=[O:12]>>[N+:11]([CH:14]=[C:15]([S:16][CH3:17])[NH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[O:7][CH:8]=[CH:9][N:10]=1)([O-:13])=[O:12]
Reactant: NCCCSc1ncco1
Reactant: CSC(=C[N+](=O)[O-])SC
Product: CSC(=C[N+](=O)[O-])NCCCSc1ncco1
Yield: 63 %

Procedure:
Hydrochloric acid (90 ml) was added to potassium thiocyanate in ethanol (1.8 1.) with stirring. Following filtration from inorganic material, glycollaldehyde (35.9 g) was added and the resulting solution was heated under reflux for 24 hours. Concentration, followed by cooling afforded a white solid, which following recrystallisation from ethanol afforded oxazole-2-thiol (30 g), m.p. 143°-144°. (ii) 3-Bromopropylphthalimide (13.4g) was added to a stirred solution of sodium ethoxide (from 1.15 g sodium) and oxazole-2-thiol (5.1 g) in ethanol (100 ml). The resultant solution was heated under reflux for 2.5 hour and concentrated under reduced pressure. The residue was triturated with water (100 ml) to afford 2-(3-phthalimidopropylthio)oxazole (14 g), m.p. 101°. Recrystallisation from ethanol gave the pure oxazole, m.p. 102°-103°. (iii) Hydrazine hydride (5.3 g) was added carefully to a solution of 2-(3-phthalimidopropylthio)oxazole (10 g) in ethanol (173 ml) with stirring. The solution was then heated under reflux for 25 minutes. After cooling, and filtration from phthalhydrazide, the filtrate was concentrated under reduced pressure and the residue was re-evaporated with ethanol to yield crude 2-(3-aminopropylthio)oxazole. (iv) By the procedure of Example 8(i), 2-(3-aminopropylthio)oxazole (2.1 g) is reacted with 1-nitro-2,2-bis-methylthioethylene (2.0 g) to give 1-nitro-2-methylthio-2-[3-(2-oxazolylthio)propylamino]ethylene (2.1 g) which, on reaction with methylamine by the procedure of Example 8(ii) gives the title product (1.8 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([NH:16][C@H:17]4[CH2:22][CH2:21][C@H:20]([N:23]([CH3:24])[CH3:25])[CH2:19][CH2:18]4)[C:6]([S:12]([CH3:15])(=[O:13])=[O:14])=[CH:7][N:8]=3)[N:3]=2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43]
Reactant: CN(C)[C@H]1CC[C@H](Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)[C@H]1CC[C@H](Nc2c(S(C)(=O)=O)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)nc23)CC1

Procedure:
Following general procedure II, trans-N1-(6-chloro-3-(methylsulfonyl)-1,5-naphthyridin-4-yl)-N4,N4-dimethylcyclohexane-1,4-diamine (28 mg, 0.073 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.15 mmol) followed by formation of the dihydrochloride salt to afford the desired product (30 mg, 72%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 8.92 (s, 1H), 8.51 (d, J=9.0 Hz, 1H), 8.37 (d, J=8.9 Hz, 1H), 8.02 (t, J=1.7 Hz, 1H), 7.92 (dd, J=11.5, 2.2 Hz, 1H), 5.64 (br s, 1H), 3.52-3.42 (m, 1H), 3.39 (s, 3H), 2.91 (s, 6H), 2.65-2.55 (m, 2H), 2.33-2.26 (m, 2H), 1.88-1.72 (m, 4H); ESI MS m/z 493 [M+H]+; HPLC 98.3% (AUC), tR=9.62 min.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1.I[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:17]([OH:19])=[O:18])=[CH:14][CH:15]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (78.0 mL of a 0.91M stock solution, 70.98 mmol) cooled to −78° C. was treated with (4-chloro-phenyl)-acetic acid (5.76 g, 33.8 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (84 mL, 3:1). The resulting solution was stirred at −78° C. for 1 h. Iodomethylcyclopentane (7.45 g, 35.49 mmol) was then added in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). This solution was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (20 mL). The excess solvent was removed in vacuo. The residue was acidified to pH=1 with a 1N aqueous hydrochloric acid solution. The mixture was then poured into water (150 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid (6.76 g, 79.1%) as a yellow solid: mp 82-84° C.: EI-HRMS m/e calcd for C14H17ClO2 (M+) 252.0917, found 252.0906.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[O:20][C:19](=[O:21])[NH:18][N:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:22](Br)[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:22]([N:18]1[N:17]=[C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[O:20][C:19]1=[O:21])[CH3:23]
Reactant: O=c1[nH]nc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)o1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1nc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)oc1=O
Temperature: 0 °C
Yield: 91.9 %

Procedure:
5-[1-(4-Nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5a, 1.16 g, 4 mmol) on reacting with C2H5Br (0.53 g, 4.8 mmol) in DMF in the presence of base K2CO3 (1.38 g, 10 mmol) at room temperature (27° C.) for 10 h, after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography to afford pure compound 3-ethyl-5-[1-(4-nitro phenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (6b, 1.17 g, 92%). Nitro compound (6b, 1.27 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-aminophenyl)-4-piperidyl]-3-ethyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7c, 1.02 g, 89%). 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 (7c, 0.29g, 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 N2-4-[4-(4-ethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperi dino]phenyl-5-nitro-2-furamide (8c, 367 mg, 86%).
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:17]=[C:16]([F:18])[C:15]([N+:19]([O-])=O)=[CH:14][C:5]=1[C:6]([O:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7]>C(O)C.[Fe]>[NH2:19][C:15]1[C:16]([F:18])=[CH:17][C:4]([Cl:3])=[C:5]([CH:14]=1)[C:6]([O:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7]
Reactant: O=C(OC1CCCC1)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(C(=O)OC2CCCC2)c(Cl)cc1F
Temperature: 75 °C
Reaction time: 2 h

Procedure:
71 g of iron powder are placed in 190 ml of ethanol, 50 ml of water and 5 ml of 32% hydrochloric acid while stirring and the whole is heated to 75° C. (internal temperature). A warm solution of 100 g of cyclopentyl 2-chloro-4-fluoro-5-nitrobenzoate in 50 ml of ethanol is added dropwise to this mixture. The reaction mixture is stirred at 70°-75° C. (internal temperature) for a further 2 hours, cooled, after cooling suction filtered over Celite and the residue on the suction filter is rinsed with 500 ml of water followed by 200 ml of ethyl acetate. The filtrate is brought to a PH value of 8 with saturated potassium bicarbonate solution and the resulting brown precipitate is filtered off over Celite. The filtrate is extracted twice with 400 ml of ethyl acetate each time. the combined organic phases are washed twice with 200 ml of saturated sodium chloride solution each time, dried over anhydrous magnesium sulphate and concentrated. Then, the residue is purified by chromatography on a silica gel column using ethyl acetate/n-hexane (1:4) as the eluent and crystallized from diisopropyl ether/n-hexane. In this manner there is obtained cyclopentyl 5-amino-2-chloro-4-fluorobenzoate, m.p. 61°-62° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([F:21])[CH:9]=2)=[CH:6][C:5](Br)=[CH:4][N:3]=1.[S:23]1[CH2:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH2:25][CH2:24]1>C([O-])([O-])=O.[Na+].[Na+].C(O)CCC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([F:21])[CH:9]=2)=[CH:6][C:5]([C:26]2[CH2:27][CH2:28][S:23][CH2:24][CH:25]=2)=[CH:4][N:3]=1
Reactant: CC1(C)OB(C2=CCSCC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc(Br)cnc2N)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2cc(C3=CCSCC3)cnc2N)cc1F
Temperature: 130 °C
Yield: 95 %

Procedure:
A degassed mixture of tert-butyl 4-(2-amino-5-bromopyridin-3-yl)-2-fluorobenzoate (400 mg, 1.09 mmol), 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (296 mg, 1.31 mmol), Pd(PPh3)4 (126 mg, 0.109 mmol) in 2.0 M Na2CO3 aqueous solution (1.63 mL) and n-butanol (5 mL) was microwave heated to 130° C. for 15 min. The reaction was diluted with ethyl acetate (20 mL), and then washed with water (10 mL) and brine (10 mL). The organics were dried over sodium sulfate, filtered, concentrated, and then purified by flash chromatography (10-60% ethyl acetate/heptane eluent) to provide tert-butyl 4-(2-amino-5-(3,6-dihydro-2H-thiopyran-4-yl)pyridin-3-yl)-2-fluorobenzoate (400 mg, 95% yield). LCMS (m/z): 387.1 (MH+), 0.87 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.83-7.76 (m, 2H), 7.68 (d, J=1.96 Hz, 1H), 7.37-7.34 (m, 1H), 7.33-7.29 (m, 2H), 7.28-7.24 (m, 2H), 7.24-7.18 (m, 1H), 5.10 (t, J=5.87 Hz, 1H), 3.83-3.69 (m, 2H), 2.81-2.70 (m, 2H), 2.63-2.49 (m, 3H), 2.08 (dd, J=2.74, 13.30 Hz, 2H), 1.72 (dq, J=2.93, 12.59 Hz, 2H).