Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[C:5]([C:14](O)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[NH2:25][CH2:26][CH2:27][NH:28]C(OC(C)(C)C)=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl>C(Cl)Cl.O.O1CCOCC1>[NH2:25][CH2:26][CH2:27][NH:28][C:14]([C:5]1[S:6][C:7]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[C:3]([C:1]#[N:2])[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])=[O:15]
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: N#Cc1c(N2CCOCC2)sc(C(=O)NCCN)c1-c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a solution of 4-cyano-3-(2,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxylic acid (3.10 g, 8.2 mmol) and N-(2-aminoethyl)(tert-butoxy)carboxamide (1.98 gr, 12.3 mmol) in methylene chloride (60 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.15 gr, 16.4 mmol) and 1-hydroxybenzotriazole (2.22 gr, 16.4 mmol) at room temperature. The solution was allowed to stir overnight. The reaction was diluted with methylene chloride and water. The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to give the intermediate boc-protected product as a yellow solid. The material was dissolved in dioxane (4 mL) and a solution 4N HCl in dioxane (9 mL) was added. The solution was stirred at room temperature for 30 minutes. The solvents were evaporated and the residue was dried under vacuum overnight. The product was converted to the free base by suspension in methylene chloride followed by addition of sodium carbonate solution. The layers were separated and the aqueous layer was extracted twice with methylene chloride. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the product as a free base (2.55 gr, 67%). LCMS: (FA) ES+ 463. 1H NMR (400 MHz, d1-chloroform) δ: 7.59-7.55 (m, 1H), 7.43-7.30 (m, 2H), 3.90-3.82 (m, 4H), 3.64-3.57 (m, 4H), 3.53-2.85 (m, 4H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(O[C:17]1(O[Si](C)(C)C)[CH2:19][CH2:18]1)C.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:17]1([NH:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC2CC2)C1

Procedure:
To a solution of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (400 mg, 2.15 mmol), (1-ethoxycyclopropoxy)trimethylsilane (1500 mg, 8.60 mmol) in methanol (30 mL) was added sodium cyanoborohydride (569 mg, 8.60 mmol) and acetic acid (0.2 mL). The mixture was stirred at reflux for 10 h. The volatiles were removed under reduced pressure. The residue was treated with water (20 mL) and extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine (3×10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound. MS (m/z): 227 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][O:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([O:22][CH2:23][CH:24]=O)[CH2:17]1.[BH4-].[Na+].C[OH:29]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][O:15][C@H:16]1[CH2:21][CH2:20][CH2:19][CH:18]([O:22][C@@H:23]([OH:29])[CH3:24])[CH2:17]1
Reactant: Cc1cccc(-c2nc(CO[C@H]3CCC[C@@H](OCC=O)C3)c(C)o2)c1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cccc(-c2nc(CO[C@H]3CCCC(O[C@H](C)O)C3)c(C)o2)c1
Reaction time: 1.5 h

Procedure:
2.3 g of 4-((1R,3S)-3-(allyloxycyclohexyloxymethyl)-5-methyl-2-m-tolyloxazole are dissolved in 65 ml of methyl tert-butyl ether and, at 0° C., 65 ml of water, 4.4 g of sodium metaperiodate and 3.3 ml of a 2.5% strength solution of osmium tetroxide in tert-butanol are added. After 20 min, the mixture is slowly warmed to 40° C. After 2 h, a further 700 mg of sodium metaperiodate were added and the mixture was stirred at 45° C. for 2 h. 140 ml of sat. sodium thiosulfate solution were added and the mixture was extracted with methyl tert-butyl ether. The combined organic phases are dried over sodium sulfate and the solvent is removed under reduced pressure. This gives 2-((1R,3S)-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]acetaldehyde as a colorless oil. C20H25NO4 (343.43), MS (ESI): 344 (M+H+). 2-((1R,3S)-[3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]acetaldehyde is, as a crude product, taken up in 60 ml of dry methanol, and 300 mg of sodium borohydride are added. After 1.5 h, the mixture is quenched with 3 ml of acetone and concentrated. The residue is taken up in 50 ml of ethyl acetate/50 ml of sat. sodium bicarbonate solution, and the org. phase is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is then purified by flash chromatography on silica gel (n-heptane/ethyl acetate=1:3). This gives 1.6 g of 2-((1R,3S)-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethanol as a colorless oil. C20H27NO4 (345.44), MS (ESI): 346 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.C(O[O:15][C:16]([CH3:19])(C)C)(C)(C)C.[C]=O.[CH2:22]([OH:24])C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:22]([O:15][CH2:16][CH3:19])=[O:24])=[CH:5][CH:4]=1
Reactant: COc1ccc(C)cc1
Reactant: CCO
Reactant: CC(C)(C)OOC(C)(C)C
Agent: [C]=O
Product: CCOC(=O)Cc1ccc(OC)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 84.6 %

Procedure:
p-Methoxy toluene (1.83 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 82 mg ethyl p-methoxyphenylacetate was obtained by column chromatography, in a yield of 85%. 1HNMR (400 MHz, CDCl3) δ 1.23 (t, J=6.8 Hz, 3H), 3.54 (s, 2H), 3.79 (s, 3H), 4.11 (q, J=6.8 Hz, 2H), 6.84-6.88 (m, 2H), 7.18-7.22 (m, 2H); 13CNMR (100 MHz, CDCl3) δ 14.2, 40.5, 55.3, 60.8, 113.9, 126.3, 130.3, 158.7, 171.9; HRMS (ESI) calcd. for C11H14NaO3 [M+Na]: 217.0835. found: 217.0838. The ethyl p-methoxyphenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 64 mg product p-methoxyphenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 91%.
Reaction SMILES: C1C(=O)N([O:8][C:9]([O:11][N:12]2[C:17](=[O:18])[CH2:16][CH2:15][C:13]2=[O:14])=[O:10])C(=O)C1.[CH2:19](N(CC)CC)[CH3:20].[CH3:26][CH2:27][O:28][C:29]([CH3:31])=[O:30]>C(#N)C>[O:28]1[C@H:29]2[O:30][CH2:19][CH2:20][C@H:31]2[C@H:26]([O:8][C:9](=[O:10])[O:11][N:12]2[C:13](=[O:14])[CH2:15][CH2:16][C:17]2=[O:18])[CH2:27]1
Reactant: CCOC(C)=O
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CCN(CC)CC
Solvent: CC#N
Product: O=C(O[C@@H]1CO[C@H]2OCC[C@H]21)ON1C(=O)CCC1=O

Procedure:
Compound 13 (2 g, 15.3 mmol), N,N′-disuccinimidyl carbonate (4.76 g, 18.5 mmol), and triethylamine (Et3N) (4.12 g, 40.8 mmol) in acetonitrile (CH3CN) (50 mL) were stirred for 24 hours. The reaction mixture then was diluted with EtOAc (100 ml), washed several times with brine, then dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide crude compound 15, which was purified by column chromatography to obtain the active carbonate 15. Yield (3.1 g, 75%), m.p 128-130° C. 1H NMR (CDCl3, 200 MHz): δ 5.74 (d, 1H, J=5.1 Hz), 5.26 (m, 1H), 4 (m, 4H), 3.1 (m, 1H), 2.84 (s, 4H), 1.88-2.2 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[CH:22])=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[Br:24][C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=1.C(N(CC)CC)C>CN(C=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.[Cu]I>[CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[C:22][C:28]2[CH:29]=[CH:30][C:25]([Br:24])=[CH:26][CH:27]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: C#Cc1cnc(C2CCCN2C(=O)C(NC(=O)OC)C(C)C)[nH]1
Reactant: Brc1ccc(Br)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#Cc2ccc(Br)cc2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 1.17 h
Yield: 50.7 %

Procedure:
{1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (57 mg, 0.179 mmol), 1,4-dibromobenzene (211 mg, 0.895 mmol), Pd(PPh3)4 (10 mg, 0.00895 mmol), CuI (3 mg, 0.0179 mmol) and triethylamine (0.249 mL, 1.79 mmol) were suspended in DMF (2 mL) and the mixture was degassed for 10 min with nitrogen. The reaction mixture was stirred at 80° C. for 70 min then diluted with 20 mL ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried with magnesium sulfate and concentrated. The crude residue was purified by silica column chromatography (0% to 5% MeOH/DCM) to afford (1-{2-[5-(4-Bromo-phenyl ethynyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (43 mg, 51%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12].S(=O)(=O)(O)O.[I:22](O)(=O)(=O)=O.II>C(O)(=O)C.O>[I:22][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH:2]([NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH2:3]2
Reactant: CC(C)S(=O)(=O)NC1Cc2ccccc2C1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)S(=O)(=O)NC1Cc2ccc(I)cc2C1
Yield: 483.7 %

Procedure:
Intermediate 1 (1.75 g, 7.32 mmol) was dissolved in glacial acetic acid (30 ml) and then treated with concentrated sulfuric acid (0.8 ml) followed by water (2.8 ml) with stirring. This mixture was then treated with periodic acid (0.23 eq., 0.38 g, 1.67 mmol) then iodine (0.43 eq., 800 mg, 3.15 mmol), and the whole mix was stirred at 60° C. for 3-4 h. The reaction mixture was allowed to cool and then partitioned between ethyl acetate and 10% aqueous sodium metabisulfite. The organic layer was separated and dried over sodium sulphate and evaporated in vacuo to give the title compound as a yellow oil (2.95 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C@:12]2([CH3:15])[CH2:14][O:13]2)=[O:11])=[CH:5][CH:4]=1.C1COCC1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([Mg]Br)=[CH:25][CH:24]=1>C(=O)=O.CC(C)=O>[OH:13][C@@:12]([CH3:15])([CH2:14][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)[C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:11]
Reactant: COc1ccc([Mg]Br)cc1
Reactant: COc1ccc(NC(=O)[C@]2(C)CO2)cc1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1ccc(C[C@](C)(O)C(=O)Nc2ccc(OC)cc2)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
To a 500 mL single-necked round-bottomed flask fitted with a stirring bar, rubber stopper and a nitrogen inlet was added (S)—N-(4-methoxyphenyl)-2-methyloxirane-2-carboxamide (1.00 g, 4.83 mmol) and anhydrous THF (50 mL). The solution was cooled to −78° C. in dry ice-acetone bath. 4-Methoxyphenylmagnesium bromide solution (14.50 mL of 0.5 M THF solution, 7.25 mmol) was added dropwise with stirring at −78° C. The resulted solution was stirred at −78° C. for 30 minutes and then at room temperature for 3 hours. The reaction was quenched by adding 20 mL of saturated NH4Cl solution at 0° C. EtOAc (3×30 mL) was added to extract the solution. The organic layers were separated, washed with brine (20 mL) and dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel, EtOAc/hexanes=1/1 v/v) to give a white solid product, (S)-2-hydroxy-N,3-bis(4-methoxyphenyl)-2-methylpropanamide (6c), 0.60 g, 39.5% yield.
Reaction SMILES: [C:1]([C:6]1(C(OCC)=O)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)([O:3]CC)=[O:2].[OH-].[Li+]>C(O)C>[C:1]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)([OH:3])=[O:2]
Reactant: CCOC(=O)C1(C(=O)OCC)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Dissolve 2,2-dicarboethoxy-indane (5.67 g, 21.7 mmol) in ethanol (150 mL). Add 1N lithium hydroxide (50 mL) and stir overnight at room temperature. Reflux for 1 hour and concentrate the solution in vacuo. Partition between ethyl acetate and 6N hydrochloric acid. Separate the organic phase and wash with brine. Dry (MgSO4) and evaporate the solvent in vacuo to give an off-white solid. Distill (120°-160° C. @0.2-0.5 mmHg) to give 2-carboxy-indan (2.5 g, 71%).
Reaction SMILES: C([Mg]Cl)(C)C.[Li+].[Cl-].[S:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[CH:13]([CH:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14]>C1COCC1>[OH:14][CH:13]([C:9]1[S:8][CH:12]=[CH:11][N:10]=1)[CH:15]1[CH2:16][CH2:17][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:20]1
Reactant: CCOC(=O)C1CCC(C=O)CC1
Reactant: c1cscn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(C(O)c2nccs2)CC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a 500 mL round bottom flask was added iPrMgCl-LiCl (1.3 M in THF, 99 mL, 129 mmol) and the solution cooled in an ice bath. Thiazole (9.7 mL, 135 mmol) was then introduced at such a rate that the internal temperature did not exceed 5° C. and then the thick slurry was stirred for 1 h. 100 mL of THF was introduced and the reaction mixture cooled to −50° C. at which point ethyl 4-formylcyclohexanecarboxylate (23 g) was added as a solution in THF (100 mL) via cannula. When complete the reaction mixture was permitted to warm slowly to 5° C. where it was stirred for 30 min then quenched by the addition of water and EtOAc. The layers were separated, the organic mixture dried with MgSO4, filtered and concentrated in vacuo to afford ethyl 4-[hydroxy(1,3-thiazol-2-yl)methyl]cyclohexanecarboxylate as a 3:2 mixture of trans:cis isomers both of which are racemic mixtures. This brown oil was used directly in the subsequent step without further manipulation.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7](O)=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].C[N:18]1CCOCC1.ClC(OCC(C)C)=O.N.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH2:18])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CN1CCOCC1
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred solution of N-Boc-L-Nle-OH (0.5 g, 2.2 mmol) in anhydrous THF (15 mL) under Ar at -23° C. was added 4-methylmorpholine followed by iso-butyl chloroformate (0.21 mL, 2.2 mmol). The reaction mixture was then treated with gaseous NH3 for 1 h. Stirring was continued at -23° C. for an additional 2 h. The mixture was warmed to R.T. and then poured onto 10% aqueous citric acid (20 mL). The mixture was extracted with EA (3×50 mL). The combined organics were washed with sat. NaHCO3 (3×25 mL), sat. NaCl (2×25 mL), dried (MgSO4), filtered and concentrated to afford N-Boc-L-Nle-NH2 as a white solid (0.48 g, 91%): 1H NMR (CDCl3, 300 MHz) δ 0.84-0.92 (m, 3H), 1.22-1.31 (m, 4H), 1.41 (s, 9H), 1.49-1.59 (m, 1H), 1.74-2.01 (m, 1H), 4.03-4.1 (m, 1H), 5.06 (d, 1H), 5.75 (s, 1H), 6.25 (s, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CC[N:13]=C=NCCCN(C)C.[CH2:22]([CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:22]([CH:29]1[CH2:34][CH2:33][N:32]([C:4]2[CH:3]=[C:2]([NH2:1])[CH:10]=[CH:9][C:5]=2[C:6]([NH2:13])=[O:8])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(N)cc1N1CCC(Cc2ccccc2)CC1
Reaction time: 20 h
Yield: 51.8 %

Procedure:
4-Aminobenzoic acid (1.61 g, 10 mM) was reacted with EDAC (1.92 g, 10 mM) in 40 mL dry DMF for 15 minutes. 4-Benzylpiperidine (1.75 g, 10 mM) was added followed by DMAP (20 mg, catalyst ) and the reaction mixture was stirred for 20 h. The mixture was poured into water and extracted with methylene chloride (3×100 mL). The combined extract was washed with dilute hydrochloric acid, saturated sodium bicarbonate and water and dried over MgSO4. After evaporation of the solvent, the residue was chromatographed with methylene chloride-methanol (0 to 2% methanol, gradient) to yield 1.60 g (50%) of the title compound after recrystallization from ether-Hexane. 1H NMR (CDCl3): δ 7.40-7.10 (m, 7 H), 6.70 (d, 2 H), 3.95-3.90 (broad m, 2 H), 2.85-2.75 (broad m, 2 H), 2.6 (d, 2 H), 1.85-1.80 (m, 1 H), 2.75-2.65 (broad m, 2 H), 1.15-1.05 (broad m, 2 H). MS (ESI) m/e 294 (M+).
Reaction SMILES: [NH:1]=[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:9]2[C:4](=[CH:5][C:6]([O:22][CH3:23])=[CH:7][CH:8]=2)[S:3]1.SC1C=C(OC)C=CC=1C(C1C=CC=C(OC)C=1)=O.C(#N)C[C:45]#[N:46].N1CCCCC1>C(O)C>[NH:1]=[C:2]1[C:11]([C:45]#[N:46])([C:12]#[N:13])[CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:9]2[C:4](=[CH:5][C:6]([O:22][CH3:23])=[CH:7][CH:8]=2)[S:3]1
Reactant: COc1cccc(-c2c(C#N)c(=N)sc3cc(OC)ccc23)c1
Reactant: N#CCC#N
Agent: COc1cccc(C(=O)c2ccc(OC)cc2S)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cccc(C2c3ccc(OC)cc3SC(=N)C2(C#N)C#N)c1
Yield: 75 %

Procedure:
2-Imino-3-cyano-7-methoxy-4-(3-methoxy-phenyl)-2H-thiochromene: To a mixture of (2-mercapto-4-methoxyphenyl)-(3′-methoxyphenyl)-methanone (35 mg, 0.13 mmol) and malononitrile (8.5 mg, 0.13 mmol) in approximately 200 μL of dry ethanol was added piperidine (7.0 μL, 0.06 mmol) at approximately 0° C. The resultant mixture was stirred at approximately 0° C. for approximately 2.5 h. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, EtOAc:hexanes, 1:4) to yield 31 mg (75%) of 2-imino-3-cyano-7-methoxy-4-(3′-methoxy-phenyl)-2H-thiochromene-3-carbonitrile as an orange waxy oil. 1H NMR (CDCl3): 9.31 (brs, 1H), 7.42-7.46 (m, 1H), 7.03-7.11 (m, 2H), 6.91 (d, J=7.8 Hz, 1H), 6.85-6.86 (m, 1H), 6.80 (bs, 1H), 6.68 (dd, J=9.1, 2.6 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][NH:19][C:18](=[O:21])[CH2:17][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26]>C1COCC1>[C:29]([O:28][C:24](=[O:27])[CH2:25][CH2:26][N:19]1[C:18](=[O:21])[CH2:17][O:16][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)[CH2:20]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: O=C1COC(c2ccc(OCc3ccccc3)cc2)CN1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCN1CC(c2ccc(OCc3ccccc3)cc2)OCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a mixture of 6-(4-benzyloxy-phenyl)-morpholin-3-one (13.40 g; 47.3 mmol) and powdered NaOH (3.78 g; 94.6 mmol) in THF (250 mL) was added tert-butyl acrylate (13.7 mL; 94.6 mmol). The resulting mixture was stirred at RT for 2 hours and subsequently concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O) to afford 3-[2-(4-benzyloxy-phenyl)-5-oxo-morpholin-4-yl]-propionic acid tert-butyl ester (14.20 g).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6].[CH3:16]O>>[OH:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[C:5]([CH2:7][CH2:8][C:9]([O:11][CH3:16])=[O:10])=[O:6]
Reactant: O=C(O)CCC(=O)c1ccccc1O
Reactant: CO
Agent: Cl
Product: COC(=O)CCC(=O)c1ccccc1O
Temperature: 0 °C
Yield: 98 %

Procedure:
Hydrogen chloride was bubbled into a gently boiling solution of the known 3-(2-hydroxybenzoyl)propionic acid (10 g, 0.05 mole) in dry methanol (20 ml) until esterification was complete. The solution was poured into ice-water and the ester extracted into dichloromethane. The organic solution was washed with water and evaporated to give methyl 3-(2-hydroxybenzoyl)-propionate (10.55 g. 98%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[NH:10][C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]I>CN(C=O)C>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[N:10]([CH3:24])[C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Brc1ccc2[nH]c(-c3ccccc3)c(Cc3ccccc3)c2c1
Solvent: CN(C)C=O
Product: Cn1c(-c2ccccc2)c(Cc2ccccc2)c2cc(Br)ccc21

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 3-benzyl-5-bromo-2-phenyl-1H-indole (1.811 g, 5 mmol) was reacted with k-t-butoxide (0.589 g, 5.25 mmol) and methyl iodide (0.745 g, 5.25 mmol) in DMF (20 ml) to give the product (1.537 g, 4.085 mmol, 82%) as a white solid, mp 141-145° C. 1H DMSO-d6) δ 3.56 (s, 3H), 3.93 (s, 2H), 7.02 (d, J=6.8 Hz, 2H), 7.07 (t, J=7.3 Hz, 1H), 7.15 (t, J=7.2 Hz, 2H), 7.23 (dd, J=2.0, 8.7 Hz, 1H), 7.40-7.52 (m, 7H); [ESI(+)], m/z 377/379 (M+H)+.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17]>CCOC(C)=O>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(CN)OC
Solvent: CCOC(C)=O
Product: COC(CNC(=O)n1ccnc1)OC
Reaction time: 0.25 h
Yield: 69.5 %

Procedure:
A mixture of 1,1′-carbonylbis[1H-imidazole] (2 mol) in EtOAc (800 ml) was stirred and cooled on an ice-bath, resulting in a suspension. 2,2-dimethoxyethanamine (2 mol) was added dropwise while the temperature was kept below 25 ° C. The resulting reaction mixture was stirred for 2 hours at RT, then for 30 minutes while cooling on an ice-bath. The precipitate was filtered off, stirred in EtOAc (400 ml) during 15 minutes, and on an ice-bath during 15 minutes. The precipitate was filtered off, washed with DIPE (2×50 ml), and dried, yielding 277 g (70%) of N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (interm. 5).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1Cl.[C:11]([O-])([O-])=[O:12].[K+].[K+]>CO>[Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1[O:12][CH3:11]
Reactant: O=C([O-])[O-]
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Agent: [K+]
Solvent: CO
Product: COc1cnn(C)c(=O)c1Cl
Reaction time: 1 h
Yield: 93.8 %

Procedure:
10 g (55.8 mmoles) of intermediate 3a are placed in the presence of 115 g (837 mmoles) K2CO3 in 725 mL MeOH. The reaction medium is agitated for 1 h under reflux then filtered through celite. The filtrate is concentrated to dryness and the residue solubilized in CH2Cl2 and washed with water. After drying over Na2SO4, the organic phases are evaporated and the residue obtained is purified by silica gel flash chromatography (CH2Cl2—AcOEt, gradient 100:0 to 60:40 over 45 min). 9.14 g of intermediate 4b are thus obtained in the form of a white solid (yield 94%). TLC silica gel 60 F 254 Merck, CH2Cl2—AcOEt: 50:50, Rf=0.36.