Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:28])[C:14](=[O:27])[C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[C:3]1=[O:29].[CH:30]1([CH2:33][NH2:34])[CH2:32][CH2:31]1>>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([C:14]([N:13]([C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:5][CH2:6][CH:2]([NH:34][CH2:33][CH:30]5[CH2:32][CH2:31]5)[C:3]4=[O:29])=[CH:8][CH:9]=3)[CH3:28])=[O:27])=[CH:16][CH:17]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(Br)C2=O)cc1
Reactant: NCC1CC1
Product: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(NCC3CC3)C2=O)cc1

Procedure:
N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with cyclopropylmethylamine by method L. This resulted in the product with the molecular weight of 445.61 (C28H35N3O2); MS (ESI): 446 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][C@H:9]1[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:30]([N:32]=[C:33]=NCCCN(C)C)C.CNC.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CCCCCC.C(Cl)(Cl)Cl.O1CCCC1>[CH3:30][N:32]([CH3:33])[C:10]([C@@H:9]1[CH2:13][C:14]([F:17])([F:16])[CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:11]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)O
Agent: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
A 40 mL tetrahydrofuran solution of 4.00 g of the compound obtained in step 3-3 and 3.23 g of 1-hydroxybenzotriazole monohydrate was stirred for 30 minutes under ice cooling. 3.66 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was then added, and the reaction mixture was stirred for 30 minutes at the same temperature. 2.15 g of a 50% dimethylamine aqueous solution was added to the reaction solution, after which the reaction mixture was stirred for 1 hour at room temperature. 60 mL of chloroform and 50 mL of a 5% potassium carbonate aqueous solution were added to the reaction solution, liquid separation was performed, the aqueous layer was extracted with chloroform (50 mL×2), the combined organic layer was washed with 30 mL of saturated brine and then dried with magnesium sulfate, and the drying agent was filtered off, after which the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to column chromatography (silica gel 60, mobile phase: ethyl acetate/n-hexane=1/1 to 10/0; v/v) to obtain 4.02 g of the titled compound (colorless solid).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([CH2:8][CH3:9])[CH2:6][N:5](CC2C=CC=CC=2)[CH2:4][CH:3]1[CH2:17][CH3:18]>CO.[H][H].[Pd]>[NH2:1][CH:2]1[CH:7]([CH2:8][CH3:9])[CH2:6][NH:5][CH2:4][CH:3]1[CH2:17][CH3:18]
Reactant: [H][H]
Reactant: CCC1CN(Cc2ccccc2)CC(CC)C1N
Agent: [Pd]
Solvent: CO
Product: CCC1CNCC(CC)C1N

Procedure:
A mixture of 5% Pd on carbon (0.5 g) and 4-amino-1-benzyl-3,5-diethylpiperidine (3.4 g, 13.82 mmol) in methanol (25 ml) was stirred in hydrogen atmosphere (3 atm.) at 60° C. for 6 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-amino-3,5-diethylpiperidine as an oil. Yield 1.4 g (64.5%), C9H20N2, m/z 157 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8]([S:10][CH3:12])=[N:7][C:6]=2[CH:11]=1
Reactant: Sc1nc2cc(Cl)ccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1nc2cc(Cl)ccc2[nH]1
Reaction time: 0.83 h

Procedure:
8.89 g of 6-chloro-2-mercaptobenzimidazole was dissolved in 150 ml of dimethylformamide, followed by the addition of 6.65 g of potassium carbonate and 6.15 g of methyl iodide under cooling with ice. The obtained mixture was stirred at that temperature for 50 minutes, followed by the addition of water. The resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated in a vacuum to give crude 6-chloro-2-methylthiobenzimidazole.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:14]([CH3:30])[C:15]([C@@H:17]1[CH2:21][C@@H:20]([OH:22])[CH2:19][N:18]1C(OC(C)(C)C)=O)=[O:16])[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13]>C(Cl)Cl>[CH2:8]([N:14]([CH3:30])[C:15]([C@@H:17]1[CH2:21][C@@H:20]([OH:22])[CH2:19][NH:18]1)=[O:16])[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13]
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid was added dropwise to a solution of compound 48 (1 g, 1 eq.) in DCM (10 mL). The reaction mixture was stirred for 3 hrs at room temperature, and then trifluoroacetic acid was removed under reduced pressure. The residue was co-evaporated with toluene to yield compound 49 as pale yellow oil in quantitative yield. MS (ESI+): m/z=227 (MH+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@H:5]([CH3:18])[CH2:4][CH2:3]1.[CH3:19]I.[H-].[Na+]>C1COCC1>[CH3:19][O:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@H:5]([CH3:18])[CH2:4][CH2:3]1
Reactant: CI
Reactant: C[C@@H]1CCC(O)CN1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CC[C@@H](C)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of benzyl (2R)-5-hydroxy-2-methylpiperidine-1-carboxylate (368 mg, 1.47 mmol) dissolved in THF (4.9 mL) at 0° C. was added methyl iodide (0.32 mL, 5.08 mmol) followed by sodium hydride (78 mg, 3.25 mmol). The mixture was stirred for 2 hours at room temperature. The reaction was quenched with ice, and diluted with diethyl ether. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford benzyl (2R)-5-methoxy-2-methylpiperidine-1-carboxylate. MS ESI calc'd. for C15H21NO3 [M+H]+ 264. found 264.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.Cl>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH:4]([O:7][S:14]([C:11]2[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=2)(=[O:16])=[O:15])[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCOCC1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of tetrahydo-4-pyranol (5.00 g; 48.9 mmol) in pyridine (30 mL) at 0-5° C. was added portionwise p-toluenesulfonyl chloride (13.9 g; 73.4 mmol). The mixture slowly warmed to room temperature, stirred overnight and poured onto 30 mL conc. HCl in ice. After stirring 15 minutes the solid was filtered and dried in vacuo. Trituration with t-butyl methyl ether provided 11.7 g of the desired product. 1H NMR (CDCl3) δ 7.82 (d, 2H), 7.35 (d, 2H), 4.70 (m, 1H), 3.88 (m, 2H), 3.47 (m, 2H), 2.46 (s, 3H), 1.86 (m, 2H), 1.76 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:14](C(OC)=O)C(OC)=O)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].Cl.[OH-].[Na+]>CCOC(C)=O>[CH3:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([F:12])([F:11])[F:13])=[CH:7][N:6]=1
Reactant: COC(=O)C(C(=O)OC)c1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 25.9 %

Procedure:
Dimethyl 2-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)malonate (320 mg, 0.993 mmol) was combined with aq HCl (3 M, 5 mL, 15.00 mmol) and the mixture was heated to reflux overnight. The reaction mixture was cooled to RT and poured into EtOAc. Aqueous NaOH (2 M, 10 mL, 20 mmol) was added and the organic layer was separated and washed with water and brine, dried (MgSO4) and concentrated in vacuo to provide 2-methyl-3-nitro-5-(trifluoromethyl)pyridine (53 mg, 9% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.19 (s, 1 H), 8.80 (s, 1 H), 2.82 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:22][CH:21]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: BrCc1ccc(Oc2ccccc2)cc1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(Oc2ccccc2)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-4-phenoxybenzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.82 min.; [M+H]+: 417.72 g/mol.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]3[C:48](=[CH:49][CH:50]=2)[C:29]2=[N:30][O:31][C:32]([C:33]4[CH:34]=[N:35][N:36]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:37]=4[C:38]([F:41])([F:40])[F:39])=[C:28]2[CH2:27][CH2:26]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:51][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.CN(C=O)C>C1COCC1>[C:1]1([C:7](=[N:14][C:15]([CH3:51])([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]3[C:48](=[CH:49][CH:50]=2)[C:29]2=[N:30][O:31][C:32]([C:33]4[CH:34]=[N:35][N:36]([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:37]=4[C:38]([F:40])([F:41])[F:39])=[C:28]2[CH2:27][CH2:26]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C(CCc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F)N=C(c1ccccc1)c1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)C(C)(CCc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F)N=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a stirred clear solution of ethyl 2-(diphenylmethyleneamino)-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (Preparation 50B, 150 mg, 0.222 mmol) in anhydrous THF (5 mL) was added a 1 M THF solution of lithium bis(trimethylsilyl)amide (333 μL, 0.333 mmol) dropwise at 0° C. under nitrogen. The reaction mixture was stirred at the same temperature for 30 min before iodomethane (50 μL, 0.800 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 1 hr. The reaction was not complete. Anhydrous DMF (2 mL) was added, followed by lithium bis(trimethylsilyl)amide (2 mL, 2 mmol) at 0° C. The reaction mixture was stirred at the same temperature for 30 min before iodomethane (0.2 mL) was added. The mixture was stirred at 0° C. for 1 hr and quenched using saturated aqueous ammonium chloride solution (5 mL), ethyl acetate (10 mL), and water (10 mL). The aqueous solution was separated and re-extracted with ethyl acetate (2×5 mL). The combined ethyl acetate extracts were dried over sodium sulfate and concentrated under reduced pressure. Flash chromatography purification using ISCO (4 g silica gel column, 10→100% ethyl acetate in hexanes) afforded ethyl 2-(diphenylmethyleneamino)-2-methyl-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (120 mg, 0.174 mmol, 78% yield) as a solid. LC/MS M+1=689.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[N:31]1>CO.N1CCCCC1>[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](/[CH:39]=[C:8]2\[O:9][C:5]3[C:4]([C:13]#[C:14][CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:31]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1C#CCCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1C#CCCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A solution of tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-ynyl]piperazine-1-carboxylate (0.0394 g, 0.0983 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0131 g, 0.0894 mmol) and piperidine (5 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}but-3-ynyl)piperazine-1-carboxylate (0.0315 g, 66%).
Reaction SMILES: S(Cl)(Cl)=O.S1C=CC=C1CC(O)=O.S1C=CC=C1CC(Cl)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1.[S:45]1[CH:49]=[CH:48][CH:47]=[C:46]1[CH2:50][C:51]([N:53]=[C:54]=[S:55])=[O:52]>C1(C)C=CC=CC=1.C(O)C>[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH:42][C:54]([NH:53][C:51](=[O:52])[CH2:50][C:46]2[S:45][CH:49]=[CH:48][CH:47]=2)=[S:55])=[CH:40][CH:39]=1
Reactant: O=C(Cc1cccs1)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)Cc1cccs1
Agent: O=C(O)Cc1cccs1
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4cccs4)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2-(2-thienyl)acetic acid (40 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2-(2-thienyl)ethanoyl isothiocyanate was prepared using the resultant 2-(2-thienyl)ethanoyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-(2-thienyl)ethanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (44 mg, yield 54%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH:6]1[C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].O1[CH2:27][CH2:26][CH2:25][CH2:24]1>CC1C=C(N=C=O)C=CC=1.C(#N)C>[C:10]([NH:9][C:7](=[O:8])[CH:6]1[CH2:14][CH2:15][CH:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:5]1[C:3](=[O:4])[CH2:2][NH:1][C:3]([NH:5][C:6]1[CH:14]=[CH:27][CH:26]=[C:25]([CH3:24])[CH:7]=1)=[O:4])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)NC(=O)C1CCC(c2ccccc2)N1C(=O)CN
Reactant: C1CCOC1
Agent: Cc1cccc(N=C=O)c1
Solvent: CC#N
Product: Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)NC(C)(C)C)CCC2c2ccccc2)c1

Procedure:
By proceeding in a fashion similar to that described in Example 2, but starting from 1.9 g of (2RS,5SR)-1-(2-aminoacetyl)-5-phenyl-N-tert-butylprolinamide in solution in 20 cm3 of anhydrous tetrahydrofuran and 0.82 cm3 of 3-methylphenyl isocyanate, after recrystallistion in acetonitrile, 0.7 g of (2RS,5SR)-N-tert-butyl-1-[3-(3-methylphenyl)ureidoacetyl]-5-phenylprolinamide, melting at 169° C., is obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11]C)=O)[CH:6]=[CH:5][CH:4]=1.[CH3:13][NH:14][CH3:15]>>[OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([N:14]([CH3:15])[CH3:13])=[O:11])[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(CO)n1
Reactant: CNC
Product: CN(C)C(=O)c1cccc(CO)n1
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 103 %

Procedure:
Methyl 6-(hydroxymethyl)picolinate (0.598 mmol, 100 mg) was suspended in dimethylamine (2M in MeOH) (2.99 mmol, 1496 μl) and heated to 150° C. for 20 minutes in a microwave. Heating was repeated for a further 20 minutes then further dimethylamine (2M in MeOH) (2.99 mmol, 1496 μl) added and heating repeated again for 20 minutes. Solvent was evaporated under reduced pressure to yield 6-(hydroxymethyl)-N,N-dimethylpicolinamide (103% yield) as a clear oil. 1H NMR (CD3OD) δ: 7.95 (d, 1H), 7.82 (t, 1H), 7.50 (d, 1H), 4.75 (s, 2H), 2.73 (s, 6H).
Reaction SMILES: [CH:1](=[C:8]([C:12]([O-:14])=[O:13])C([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:15]#[N:16].[K+]>C(O)C.O>[C:15]([CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:8][C:12]([OH:14])=[O:13])#[N:16]
Reactant: O=C([O-])C(=Cc1ccccc1)C(=O)[O-]
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CC(CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of benzalmalonate (124 g., 0.5 mole) in ethanol (560 ml.) and water (240 ml.) was heated at reflux for 60 hours with potassium cyanide (45 g., 0.7 mole). The solution was cooled, concentrated to remove ethanol, and then acidified with concentrated hydrochloric acid. The product was extracted with dichloromethane, and the extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in ethyl acetate (500 ml.) and treated with dicyclohexylamine (82 ml.) to yield 118 g. (67%) of white crystals which were collected by filtration and washed sequentially with ethyl acetate and ether and dried. A suitable cation-exchange resin in the acid form, such as Dowex® 50x8-100 ion-exchange resin, (20 g.) was washed with acetone and suspended in methanol (130 ml.) with dicyclohexylammonium salt (15 g.). After stirring at ambient temperature for 1 hour, the cation exchange resin was removed by filtration and the filtrate was concentrated to yield 3-cyano-3-phenylpropionic acid as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH:9]([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[N:15]([CH3:18])[N:14]=[N:13]1.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.[Br:37]N1C(=O)CCC1=O.ClC1C=CC=CC=1>O>[Br:37][CH2:1][C:2]1[C:7]([O:8][CH:9]([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[N:15]([CH3:18])[N:14]=[N:13]1
Reactant: Cc1c(OC(F)F)cccc1-n1nnn(C)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: Clc1ccccc1
Solvent: O
Product: Cn1nnn(-c2cccc(OC(F)F)c2CBr)c1=O
Yield: 84.1 %

Procedure:
To a mixture of 1-(2-methyl-3-difluoromethoxyphenyl)-4-methyl-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 2) 1.0 g, 1,1′-azobis(cyclohexane-1-carbonitrile) 0.19 g, N-bromosuccinimide 0.80 g and chlorobenzene 50 ml was stirred with heating under reflux for eight hours. After cooling the mixture, to the reaction solutions was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-(2-bromomethyl-3-difluoromethoxyphenyl)-4-methyl-1,4-dihydrotetrazole-5-one 1.1 g.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[N:11]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)[N:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2nc(Cn3ncc(N)n3)cs2)OCCO1
Product: CC(=O)c1nc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)cs1

Procedure:
Following general procedure A followed by B, starting from 2-[2-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-4-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][C@H:21]([O:23][CH3:24])[CH2:20][N:19]3[CH2:25][C:26]3[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=3)[O:29][CH2:30][C:31]([OH:33])=[O:32])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:37]([OH:46])(=[O:45])[C@@H:38]([C@H:40]([C:42]([OH:44])=[O:43])[OH:41])[OH:39].CCCCCC>CCO>[C:42]([CH:40]([CH:38]([C:37]([OH:46])=[O:45])[OH:39])[OH:41])([OH:44])=[O:43].[C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][C@H:21]([O:23][CH3:24])[CH2:20][N:19]3[CH2:25][C:26]3[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=3)[O:29][CH2:30][C:31]([OH:33])=[O:32])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CO[C@H]1C[C@H](c2nc(-c3ccccc3)c(-c3ccccc3)o2)N(Cc2cccc(OCC(=O)O)c2)C1
Solvent: CCO
Solvent: CCCCCC
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-{[(2R, 4S)-2-(4,5-diphenyloxazol-2-yl)-4-methoxypyrrolidin-1-yl]methyl}phenoxyacetic acid (100 mg) in EtOH (0.65 mL) was added a solution of L-(+)-tartaric acid (32 mg) in EtOH (1.3 mL) at room temperature. To the mixture was added n-hexane (3.9 mL), and the mixture was stirred at room temperature for 2 hours. The resulting precipitate was collected and dried under reduced pressure to give 3-{[(2R, 4S)-2-(4,5-diphenyloxazol-2-yl)-4-methoxypyrrolidin-1-yl]methyl}phenoxyacetic acid tartrate (a L-(+)-tartaric acid addition salt of 3-{[(2R, 4S)-2-(4,5-diphenyloxazol-2-yl)-4-methoxypyrrolidin 1-yl]methyl}phenoxyacetic acid) (102 mg).
Reaction SMILES: O=[C:2]1[C:11]([C:12]#[N:13])=[C:10]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:9]2[CH2:8][CH2:7][C:6]3[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=3[C:4]=2O1.[H-].[Na+]>C1COCC1>[N:14]1([C:10]2[C:9]3[CH2:8][CH2:7][C:6]4[C:20](=[CH:21][CH:22]=[CH:23][CH:5]=4)[C:4]=3[C:23]3[C:5]4[C:6]([CH2:20][C:2]=3[C:11]=2[C:12]#[N:13])=[CH:7][CH:8]=[CH:9][CH:4]=4)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: N#Cc1c(N2CCCCC2)c2c(oc1=O)-c1ccccc1CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c2c(c3c(c1N1CCCCC1)CCc1ccccc1-3)-c1ccccc1C2

Procedure:
A mixture of 2-oxo-4-(piperidin-1-yl)-5,6-dihydro-2H-benzo[h]chromene-3-carbonitrile (306 mg), indanone-2 (132 mg) and NaH (29 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 170-172° C.; IR (KBr) 2218 cm−1 (CN); MS (ESI) 377 (M++1); 1H NMR (200 MHz, CDCl3) δ 1.61-1.65 (m, 6H, 3CH2), 2.77-2.81 (m, 4H, 2CH2), 3.22-3.25 (m, 4H, 2CH2), 4.06 (s, 2H, 2CH2), 7.13-7.37 (m, 5H, ArH), 7.56 (d, J=7.21 Hz, 1H, ArH), 7.86-7.94 (m, 2H, ArH).