Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([Mg]Br)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16].Cl>CCOCC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH:15]([OH:16])[C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[Cl:12])[CH3:2]
Reactant: O=Cc1ccccc1Cl
Reactant: CCOc1cccc([Mg]Br)c1
Agent: Cl
Solvent: CCOCC
Product: CCOc1cccc(C(O)c2ccccc2Cl)c1
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To an ether solution of 3-ethoxyphenylmagnesium bromide [prepared from 3-ethoxybromobenzene (6 g, 30 m mol), magnesium (0.8 g, 33 m mol) and ether (30 ml)], an ether solution (30 ml) of 2-chlorobenzaldehyde (2.8 g, 20 m mol) was added dropwise with stirring and under cooling with ice. After 30 minutes, 1 N hydrochloric acid (50 ml) was added thereto. The ether layer was separated and the aqueous layer was extracted with ether (20 ml). After the combined ether layer was washed with a saturated aqueous solution of sodium chloride (15 ml) and dried, the solvent was distilled off under reduced pressure. The resulting residue was subjected to chromatography on silica gel (60 g) using hexane-ethyl acetate (5:1). The resulting fraction containing the desired compound was distilled to obtain the desired compound (3.4 g, 64%) as a colorless oily material (178-179° C./1 mmHg).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO.C(Cl)Cl.N>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3nccs3)CC2)c1[N+](=O)[O-]
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(-c2nc3c(N4CCN(Cc5nccs5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 85 °C
Yield: 25.2 %

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-(thiazol-2-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.072 g, 0.18 mmol) and EtOH (2 mL), p-anisaldehyde (0.079 g, 0.20 mmol) in EtOH (2 mL) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.54 mL, 0.54 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a off-white solid (0.022 g, 25%); 1H-NMR (500 Mz, DMSO-d6): δ 2.75 (m, 4H, piperazine N(CH2)2), 3.65-3.73 (m, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OMe), 3.95 (s, 2H, NCH2), 7.11 (d, J=9.0 Hz, 2H, ArH, C6H4—OMe), 7.69 (d, J=3.5 Hz, 1H, thiazole 5-H), 7.75 (d, J=3.0 Hz, 1H, thiazole 4-H), 8.14 (d, J=9.0 Hz, 2H, ArH, C6H4—OMe), 8.21 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.36 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 4.10 min—485/487 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 485.0759, calculated for C21H22BrN6OS (M+H)+: 485.0748.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]=2)=[C:13]([C:15]2[CH2:19][C:18]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:17][N:16]=2)[CH:14]=1)C1C=CC=CC=1>[Pd].C1COCC1>[C:31]([O:30][C:28](=[O:29])[CH2:27][C:18]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:17][N:16]=[C:15]([C:13]2[CH:14]=[C:9]([OH:8])[CH:10]=[CH:11][C:12]=2[CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:19]1)([CH3:33])([CH3:34])[CH3:32]
Reactant: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(OCc3ccccc3)ccc2C2=CCCCC2)=NO1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(O)ccc2C2CCCCC2)=NO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
A mixture of tert-butyl 3-(5-(benzyloxy)-2-(cyclohex-1-en-1-yl)phenyl)-5-(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (118 mg), 10% Pd/C (containing about 55% water, 15 mg), and THF (2 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (54.1 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].N1C=CC=CC=1.O>ClCCl>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(NS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-amino-1-Boc-piperidine (300 mg, 1.50 mmol) in dichloromethane (2.0 mL) was added a solution of methanesulfonyl chloride (348 μL, 4.49 mmol) in dichloromethane (1 mL) followed by a solution of pyridine (485 μL, 5.99 mmol) in dichloromethane (1 mL), and the reaction stirred at rt for 16 h. Water (10 mL) was added, the mixture separated and the organic layer washed with 1M HCl (10 mL), sodium bicarbonate solution (10 mL) then brine (2×10 mL). The solution was dried (MgSO4) and solvent removed in vacuo. The crude material was purified by chromatography using dichloromethane/methanol (95:5) as the eluent to give the title compound as an off-white powder. δH (CD3OD): 4.46–4.40 (1H, m), 4.09–3.97 (2H, m), 3.53–3.40 (1H, m), 3.0 (3H, s), 2.93–2.81 (2H, m), 2.01–1.93 (2H, m), 1.50–1.37 (2H, m).
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH:8]=[CH2:9])([OH:7])[CH2:5][CH2:4][NH:3]1.[F:10][C:11]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].C(=O)([O-])[O-].[Li+].[Li+]>>[F:10][C:11]1[CH:18]=[C:17]([N:3]2[CH2:4][CH2:5][C@@:6]([OH:7])([CH:8]=[CH2:9])[C@@H:2]2[CH3:1])[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: N#Cc1ccc(F)cc1F
Reactant: C=C[C@]1(O)CCN[C@H]1C
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C=C[C@]1(O)CCN(c2ccc(C#N)c(F)c2)[C@H]1C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3R)-2-methyl-3-vinylpyrrolidin-3-ol (554 mg), 2,4-difluorobenzonitrile (300 mg) and lithium carbonate (350 mg), the title compound was obtained as a colorless solid (yield: 177 mg, yield: 50%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].Cl.[CH2:18](N=C=NCCCN(C)C)[CH3:19].C(O)C>C(OCC)C.CN(C)C1C=CN=CC=1>[CH2:18]([O:15][C:14](=[O:16])[CH2:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)[CH3:19]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CC(=O)O)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 40 h
Yield: 95 %

Procedure:
In an oven-dried 2 L round bottom flask under nitrogen, ((3S)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-pyrrolidinyl)acetic acid (60 g, 262 mmol) dissolved in diethyl ether (600 mL) was treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (55.2 g, 288 mmol), 4-(dimethylamino)pyridine (3.20 g, 26.2 mmol), and ethanol (33.6 ml, 576 mmol) at room temperature and the mixture was stirred for 40 h. The reaction mixture began as a white suspension, but then became a pale yellow solution with gummy yellow material at the bottom of the flask after 1 h, which was difficult to stir. Another stir bar was added in order to get the mixture stirring; however, a vortex was not obtained so the reaction was stirred longer than overnight to ensure the reaction went to completion. The reaction mixture was diluted with ether (400 mL) and washed with 1M aqueous sodium hydrogen sulfate solution (800 mL) and saturated aqueous sodium bicarbonate solution (800 mL). The organic phase was isolated, dried over magnesium sulfate, and concentrated to dryness to give the title compound as a clear pale yellow liquid (64.1 g, 249 mmol, 95%). MS(ES)+ m/e 258.2 [M+H]+, 280.2 [M+Na]+.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27]3[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:11][C:3]=1[C:4]([O:6]CC(C)C)=[O:5].[OH-].[K+].S([O-])([O-])=O.[Na+].[Na+]>O>[OH:1][C:2]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]2[CH:18]=[CH:19][C:20]([S:23]([NH:26][C:27]3[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cccnc1NS(=O)(=O)c1ccc(C=Cc2ccc(O)c(C(=O)OCC(C)C)c2)cc1
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: Cc1cccnc1NS(=O)(=O)c1ccc(C=Cc2ccc(O)c(C(=O)O)c2)cc1
Temperature: 25 °C

Procedure:
The product from Example 12c (78 g) was added to a solution of potassium hydroxide (50 g, 0.78 mol) in water (600 mi) and the mixture was refluxed overnight. After addition of activated carbon (2 g) and sodium sulfite (0.5 g) the mixture was allowed to cool, with s&%g to room temperature and then filtered.
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)Br.O[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].[H-].[Na+].C(OC(C)C)(C)C>C(OCC)C.CN(C)C=O.O>[CH2:1]([O:7][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccco1
Reactant: O=Cc1cccc(O)c1
Agent: BrP(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CCOCC
Solvent: O
Product: O=Cc1cccc(OCc2ccco2)c1
Reaction time: 0.5 h

Procedure:
Two grams of furfuryl alcohol was dissolved in 20 ml of anhydrous ethyl ether, and 3 ml of an anhydrous ethyl ether solution containing 2 g of phosphorus tribromide was added. The mixture was stirred for 30 minutes under ice cooling. The reaction mixture was washed with a 30% aqueous solution of sodium hydroxide, and dried over granular sodium hydroxide. The solution was then added to a previously prepared solution of 3-hydroxybenzaldehyde sodium salt (obtained by dissolving 2.44 g of 3-hydroxybenzaldehyde and 0.8 g of 60% oily sodium hydride in a mixture of 5 ml of anhydrous dimethylformamide and 10 ml of anhydrous ethyl ether), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added isopropyl ether and water. The organic layer was separated, washed with a 10% aqueous solution of sodium hydroxide, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was evaporated. The residue was purified by silica gel column chromatography (Wakogel C-200, 100 g; eluting solvent: hexane/ethyl acetate=3/1) to give 3-furfuryloxybenzaldehyde as a pale yellow oil.
Reaction SMILES: [C:1]1([P:7]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:9]2[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=2[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2P(C2C=CC=CC=2)(C2C=CC=CC=2)=O)=[O:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[SiH](Cl)Cl.[OH-].[Na+]>CCCCCC.C1(C)C=CC=CC=1>[C:1]1([P:7]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:9]2[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=2[CH:11]([OH:12])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1P(=O)(c1ccccc1)c1ccccc1)c1ccccc1P(=O)(c1ccccc1)c1ccccc1
Agent: Cl[SiH](Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: OC(c1ccccc1)c1ccccc1P(c1ccccc1)c1ccccc1
Yield: 36 %

Procedure:
Into 10 ml of toluene was dissolved 252 mg (0.36 mmol) of 2,2′-bis{diphenylphosphinyl}benzophenone, and further 2.0 ml (14.4 mmol) of triethylamine was added thereto. The resultant solution was cooled to 0° C. Thereto was added 360 μl (3.6 mmol) of trichlorosilane, and then the resultant solution was stirred for 30 minutes while the temperature thereof was kept at 0° C. Thereafter, the temperature thereof was slowly raised to a temperature at which the solution was allowed to be refluxed. The solution was then refluxed for 4 hours. The reaction mixture was cooled, and thereto was added dropwise 10 ml of 25% aqueous sodium hydroxide slowly. The aqueous phase was extracted with 10 ml of methylene chloride. The organic phases were combined, and the resultant was washed with 1N hydrochloric acid two times and then dried over magnesium sulfate. The resultant was concentrated under reduced pressure to distill off the solvent, and then purified by column chromatography on silica gel (ethyl acetate:hexane=1:6 to give 47.7 mg (yield: 20%) of the title compound in the form of a yellow solid.
Reaction SMILES: C(N1CCN2C=C(C(OCC)=O)C(O)=C2C1=O)C1C=CC=CC=1.[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][N:30]2[CH2:35][CH2:34][N:33]3[CH:36]=[C:37]([C:40]([O:42]CC)=[O:41])[C:38]([OH:39])=[C:32]3[C:31]2=[O:45])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:30]2[CH2:35][CH2:34][N:33]3[CH:36]=[C:37]([C:40]([OH:42])=[O:41])[C:38]([OH:39])=[C:32]3[C:31]2=[O:45])=[CH:46][CH:47]=1
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(F)cc1)CC2
Agent: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccccc1)CC2
Product: O=C(O)c1cn2c(c1O)C(=O)N(Cc1ccc(F)cc1)CC2

Procedure:
The title compound was prepared using a procedure similar to that described in Example 2, except that ethyl 2-benzyl-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo-[1,2-α]pyrazine-7-carboxylate was substituted wit ethyl 2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-α]pyrazine-7-carboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH2:22][CH:21]([NH2:25])[CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.C([O:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)(=O)C.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH2:22][CH:21]([NH:25][CH2:34][CH2:33][CH2:32][CH2:31][OH:30])[CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCCC(N)C4)n3)ccc21
Reactant: CC(=O)OCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCCC(NCCCCO)C4)n3)ccc21

Procedure:
The preparation is carried out as described starting from 75 mg (0.20 mmol) of 1-[4(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-3-ylamine and 45 μl (0.31 mmol) of 4-bromobutyl acetate. The protecting group is cleaved off by means of a 1N NaOH solution in methanol. The product is in the form of the hydrochloride.
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([CH3:27])([CH3:26])[C:21]([O:23]CC)=[O:22])[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[OH-].[Na+]>C(O)=O.CCO.O>[C:6]([C:8]1([CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([CH3:26])([CH3:27])[C:21]([OH:23])=[O:22])[CH2:10][CH2:9]1)([OH:7])=[O:5]
Reactant: CCOC(=O)C(C)(C)CCCCC(=O)CCCCC1(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Solvent: CCO
Product: CC(C)(CCCCC(=O)CCCCC1(C(=O)O)CC1)C(=O)O
Yield: 79.8 %

Procedure:
A solution of ethyl 11-[1-(t-butoxycarbonyl)cyclopropyl]-2,2-dimethyl-7-oxoundecanoate (9.27 g, >90% pure by NMR, 21.0 mmol) in HCO2H (50 mL) was stirred for 1.5 h, evaporated in vacuo and coevaporated from toluene (10 mL). The remaining residue was dissolved in a mixture of EtOH and H2O (2:1, 100 mL) and NaOH (5.33 g, 132 mmol) was added. The resulting clear solution was warmed to 80° C. and after 5 h EtOH was evaporated in vacuo. The remaining solution was diluted with H2O to ˜100 mL, extracted with Et2O (3×100 mL), acidified to pH ˜1 with cone aqueous HCl (˜9 mL) and extracted with Et2O (3×100 mL). The latter organic layers were combined, dried (Na2SO4) and evaporated in vacuo. The remaining residue was purified by column chromatography (silica, heptane:EtOAc=2:1 (containing 1% (v/v) HOAc)) to give 11-(1-carboxycyclopropyl)-2,2-dimethyl-7-oxoundecanoic acid (5.83 g, >90% pure by 1H NMR, 80%) as a slightly yellow oil which turns solid when stored at −18° C. for several days. mp: 49-52° C. 1H NMR (CD3OD): δ=2.44 (t, J=7.2 Hz, 4H), 1.57-1.42 (m, 10H), 1.30-1.19 (m, 2H), 1.17-1.07 (m, 2H), 1.14 (s, 6H), 0.59 (dd, J=6.6, 3.9 Hz, 2H). 13C NMR (CD3OD): δ=213.5, 181.4, 178.9, 43.5, 43.4, 43.0, 41.7, 34.9, 28.5, 25.9 (3×), 25.5, 25.2, 24.3, 16.4 (2×). Anal. calcd for C17H28O5: C, 65.36; H, 9.03. found: C, 65.06; H, 9.02.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1C(=O)CCC1.CCOC(C)=O.O>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([O:18][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=2)[CH:20]=1
Reactant: Oc1cccnc1
Reactant: COc1cc(Br)ccc1C=O
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1cc(Oc2cccnc2)ccc1C=O
Yield: 62.4 %

Procedure:
4-Bromo-2-methoxybenzaldehyde (1.00 g, 4.65 mmol), cesium carbonate (3.03 g, 9.30 mmol), 3-hydroxypyridine (0.884 g, 9.30 mmol), cuprous chloride (0.230 g, 2.325 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.214 g, 1.163 mmol) in NMP (11.6 mL) in a sealed microwave vial was heated to 120° C. overnight in an oil bath. The reaction vessel was allowed to cool before water was added to dilute the mixture; EtOAc was then added to extract the product. The organic phase was separated and washed with water (2×) and brine (1×) before being dried with Na2SO4 and evaporated to afford an oil. This material was chromatographed on silica 0-80% EtOAc in hexanes to yield 4-(pyridine-3-yloxy)-2-methoxybenzaldehyde (0.665 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([C:8]([OH:10])=O)[NH:5][C:6]=1[CH3:7].[NH2:13][C@@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][C@@H:15]1[O:25][CH2:26][CH3:27].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([C:8]([NH:13][C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][C@@H:15]2[O:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)N1CC[C@@H](N)[C@@H](OCC)C1
Reactant: Cc1[nH]c(C(=O)O)c(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)N1CC[C@@H](NC(=O)c2[nH]c(C)c(Cl)c2C#N)[C@@H](OCC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 16, 1.01 g, 5.55 mmol) and ethyl (3S,4R)-4-amino-3-ethoxypiperidine-1-carboxylate (Intermediate 24, 1.2 g, 5.55 mmol) in dichloromethane (480 mL) were added HOBt (850 mg, 5.55 mmol) and N-methyl morpholine (1.82 mL, 16.66 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (1.9 g, 9.99 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 2N hydrochloric acid (120 mL). The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL) and brine, dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. Purification by flash column chromatography (silica, 35% ethylacetate in pet ether) afforded ethyl (3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate 1.5 g (71%) as solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([NH:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:24])=[CH:21][N:22]=2)[CH:19]=1.[Li+].[OH-]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24])=[CH:21][N:22]=2)[CH:19]=1
Reactant: CCOC(=O)CNC(=O)c1cnc2ccc(N3CCC[C@H]3c3cc(F)ccc3F)cn12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNC(=O)c1cnc2ccc(N3CCC[C@H]3c3cc(F)ccc3F)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
To a stirred solution of (S)-ethyl 2-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxamido)acetate (Example-18; Isomer-II) (0.08 g, 0.18 mmol) in ethanol (10 mL) was added 1M LiOH solution at 20° C. then stirred for 1 h RT. After completion of reaction solvent was remove under reduced pressure then residue was dissolved in water and washed with diethylether and water layer was acidified with 2N HCl (pH˜2) and solid was filter to afford pure (S)-2-(6(2(2,5difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxamido)acetic acid (Isomer-II) (0.035 g, 47.29% Yield). MS (ESI): m/z 401.3 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 12.66-12.60 (1H, bs), 8.75-8.72 (2H, m), 8.27 (1H, s), 7.59-7.55 (1H, d J=12 Hz), 7.35-7.28 (1H, m), 7.16-7.10 (1H, m), 7.00-6.93 (2H, m), 5.00-4.98 (1H, d J=6 Hz), 3.93-3.91 (2H, d J=6 Hz), 3.79-3.74 (1H, m), 2.03-1.87 (3H, m) ppm.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=2[C:21]#[C:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:13]([O:15]CC)=[O:14])[CH2:3][CH2:2]1.CO>O>[CH3:24][C:23]([CH3:26])([CH3:25])[C:22]#[C:21][C:20]1[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#CC(C)(C)C)c(OCCN2CCOCC2)c1
Solvent: O
Solvent: CO
Product: CC(C)(C)C#Cc1ccc(C(=O)O)cc1OCCN1CCOCC1
Yield: 76.2 %

Procedure:
Ethyl 3-(2-morpholinoethoxy)-4-(3,3-dimethylbut-1-ynyl)benzoate (0.34 g, 0.95 mmol) and LIOH (68 mg, 2.84 mmol) were placed in a 3:1 mixture of methanol:water (30 mL) and heated at 60° C. for 3.5 h. The reaction was cooled and concentrated in vacuo to a volume of 20 mL. The mixture was placed in an ice-water bath and acidified to pH 5 with conc. HCl. A white solid precipitated which was filtered and washed thoroughly with water. The solid was dried in a vacuum oven to give the product (0.24 g, 70%) as a solid. m/z=330.1 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1B(O)O.Cl[C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+].O>CCOC(C)=O.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.CCO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: Cc1cccc(C)c1B(O)O
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: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2c(C)cccc2C)ncc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
A mixture of 2,6-dimethylphenylboronic acid (6.5 g, 43.5 mmol), 2-chloro-4-methyl-5-nitro-pyridine (5 g, 28.9 mmol), Pd(PPh3)4, (1.5 g, 1.5 mmol), Na2CO3 (4.6 g, 43.5 mm water (20 mL), and EtOH (5 mL) is heated in a sealed tube under nitrogen at 110° C. for 18 hours. The mixture is cooled to room temperature, diluted with EtOAc (150 mL), washed with saturated solution of Na2CO3 (50 mL 3×), water (50 mL) and brine (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (Hexane/EtOAc, 6:1) to afford 2-(2,6-dimethyl-phenyl)-4-methyl-5-nitro-pyridine as a colorless oil.