Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1[N:24]=[N:25][N:26]([CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:27]=1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:30]4[CH2:31][CH2:32][CH:28]([N:26]5[CH:27]=[C:23]([CH3:22])[N:24]=[N:25]5)[CH2:29]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1cn(C2CCNC2)nn1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cn(C2CCN(c3c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)nn1
Yield: 81.8 %

Procedure:
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (150 mg, 0.53 mmol) was reacted with 249 mg (1.33 mmol) of 3-(4-methyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride in the presence of 201 mg (1.33 mmol) of DBU in 15 ml of dry pyridine under nitrogen at 120° C. for 3 days. Small amounts of the solid present were removed by filtration, and the supernatant was concentrated under reduced pressure. Water and small amounts of acetonitrile were added to the residue and the grey solid was collected and dried to afford 180 mg (82%) of the desired product, m.p. 219°-220° C. 1H NMR (CDCl3) δ: 8.73 (s, 1H), 7.85 (dd, J=13.7Hz, 1.9HZ, 1H), 7.42 (s, 1H), 5.4-5.3 (m, 1H), 4.4-3.7 (m, 5H), 2.7-2.5 (m, 2H), 2.37 (s, 3H), 1.4-1.05 (m, 4H). Anal. calcd. for C20H19F2N5O3 : C, 57.83; H, 4.57; N, 16.86. Found: C, 57.81; H, 4.60; N, 16.31.
Reaction SMILES: CS(C)=O.[C:5](Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]([CH2:26][CH2:27][CH2:28]O)[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:11]([O:15][C:16]([N:18]([CH2:26][CH2:27][CH:28]=[CH2:5])[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: CCOC(=O)CCN(CCCO)C(=O)OC(C)(C)C
Reactant: O=C(Cl)C(=O)Cl
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=CCCN(CCC(=O)OCC)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 7.6 %

Procedure:
To a solution of dimethylsulfoxide (DMSO) (1.11 mL, 5.81 mmol) in dichloromethane (DCM)(15 mL) was added dropwise a solution of oxalyl chloride (1.01 mL, 11.62 mmol) in DCM (5 mL) at −78° C. To the mixture was added a solution of ethyl N-(tert-butoxycarbonyl)-3-(3-hydroxypropylamino)propionate (1.6 g, 5.81 mmol) in DCM (10 mL) after 30 minutes. The mixture was stirred for 30 minutes at −78° C., then triethylamine (5.91 mL) was added. After stirring for 30 minutes at room temperature, the mixture was quenched by a saturated aqueous NH4Cl solution, and extracted with DCM. The organic layer was washed with water and brine, dried over Na2SO4, and evaporated in vacuo. The residue was dissolved in THF (20 mL), then a Wittig reagent, which was prepared from methyltriphenylphosphonium bromide (2.49 g, 22.2 mmol) and 1N tert-BuOK THF solution (6.97 mL) in THF (10 mL), was added to the solution at 0° C. The mixture was stirred for an hour at room temperature, then quenched by a saturated aqueous NH4Cl solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of ethyl acetate and n-hexane (1:10) to give ethyl N-(tert-butoxycarbonyl)-3-(3-butenylamino)propionate (1.2 g, 0.44 mmol, 76.1%) as a colourless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][NH:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:7][CH2:6]2)#[N:2].[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[Cl:24][CH2:25][C:26]([N:13]([CH2:12][CH:8]1[C:9]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:27]
Reactant: CC(C)(C)OC(=O)NCCNCC1CCc2cc(C#N)ccc21
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(CC1CCc2cc(C#N)ccc21)C(=O)CCl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of tert-Butyl (2-{[(5-cyano-2,3-dihydro-1H-inden-1-yl)methyl]amino}ethyl)carbamate (184 mg, 0.58 mmol), chloro-acetyl chloride (85 mg, 0.76 mmol) and TEA (135 mg, 1.3 mmol) in 20 mL DCM was stirred at RT for 12 hours. The mixture was diluted with 50 mL DCM and then washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified via prep-TLC (EA/PE=1:1) to give the title compound. MS m/z: 392 [M+1]+.
Reaction SMILES: [O-:1][P:2]([O:5][P:6]([O-:9])([O-:8])=[O:7])(=[O:4])[O-:3].[Na+].[Na+].[Na+].[Na+].Cl.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>O>[OH:3][P:2]([O:5][P:6]([OH:9])([OH:8])=[O:7])(=[O:1])[OH:4].[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: O=P([O-])([O-])OP(=O)([O-])[O-]
Agent: C1CNCCN1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=P(O)(O)OP(=O)(O)O
Temperature: 10 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
In 300 g of water was dispersed 0.5 mol of sodium pyrophosphate. The dispersion was cooled to 10° C., and 1 mol of hydrochloric acid was added thereto. To the dispersion was added 0.5 mol of piperazine (purity: 97%) dissolved in 800 g of water at 20° C. or lower, whereupon a white solid precipitated. The reaction system was stirred at 10° C. for 3 hours. The white solid was collected by filtration and washed with water. To the filtrate was added 300 g of methanol, and the thus precipitated white solid was collected by filtration and washed with methanol and water. The combined white solid was dried to give 0.23 mol of piperazine pyrophosphate as a white powder.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:12]C(=O)C(C)(C)C)=[N:9][C:10]=1[CH3:11])[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:12])=[N:9][C:10]=1[CH3:11])[CH3:2]
Reactant: CCOCc1ccc(NC(=O)C(C)(C)C)nc1C
Agent: [Na+]
Agent: [OH-]
Product: CCOCc1ccc(N)nc1C

Procedure:
This material was prepared in analogy to example 86 step B] from N-(5-ethoxymethyl-6-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.32 g) and 3M aqueous NaOH (2.62 mL) as a yellow oil (0.28 g) that was used directly in the next step.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][NH:3][C:2]=1/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9].CO>Cl.[Pd]>[NH:3]1[C:2]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:1][N:5]=[CH:4]1
Reactant: O=C(O)/C=C/c1cnc[nH]1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C(O)CCc1cnc[nH]1
Reaction time: 8 h

Procedure:
Urocanic acid (compound i, where R2 is H)(1.38 g, 10.0 mmol) was dissolved in 5% aqueous HCl (20 ml) plus MeOH (15 ml) containing 10% Pd on carbon (100 mg) and the mixture was shaken overnight under about 30 psi H2. The catalyst was removed by filtration through a 3 cm pad of diatomaceous earth and the filtrate was concentrated to a solid and dried overnight under vacuum. The crude material was used without further purification. Mass spec. 141.4 MH+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([OH:28])=O)=[CH:21][CH:20]=[CH:19]2.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[C:32]([NH2:37])[CH:31]=1>>[NH2:37][C:32]1[CH:31]=[C:30]([Cl:29])[CH:35]=[CH:34][C:33]=1[NH:36][C:26]([C:22]1[C:23]2[C:24](=[CH:25][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][CH:18]=2)[CH:19]=[CH:20][CH:21]=1)=[O:28]
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Reactant: Nc1ccc(Cl)cc1N
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)Nc5ccc(Cl)cc5N)cccc4c3)c2cc1OC
Yield: 85.6 %

Procedure:
The title compound (42.9 mg, 83% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4-chloro-o-phenylenediamine (17.1 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 4.01 (s, 6H, 2×OCH3), 5.31 (s, 2H, benzene-NH2), 6.65 (d, J=8.3 Hz, 1H, Ar—H), 6.86 (d, J=1.9 Hz, 1H, Ar—H), 7.41 (s, 1H, Ar—H), 7.58-7.67 (m, 4H, Ar—H), 7.89 (d, J=6.8 Hz, 1H, Ar—H), 8.01 (s, 1H, Ar—H), 8.09 (d, J=8.1 Hz, 1H, Ar—H), 8.37 (d, J=9.2 Hz, 1H, Ar—H), 8.55 (s, 1H, Ar—H), 9.84 (s, 1H, benzene-NH). LC-MS (m/z) 501 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][CH:5]([C:8]([O:10]C)=O)[C:4]1=O.[NH2:13][C:14]([NH2:16])=[S:15].[OH-].[K+].Cl>C(O)C.O>[SH:15][C:14]1[NH:16][C:8](=[O:10])[C:5]2[CH2:6][CH2:7][CH:3]([O:2][CH3:1])[C:4]=2[N:13]=1
Reactant: NC(N)=S
Reactant: COC(=O)C1CCC(OC)C1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC1CCc2c1nc(S)[nH]c2=O
Temperature: 25 °C
Yield: 41.4 %

Procedure:
3.44 g of methyl 3-methoxy-2-oxocyclopentane-1-carboxylate [prepared as described in step (b) above] and 1.52 g of thiourea were dissolved in 20 ml of ethanol. A solution of 1.4 g of potassium hydroxide in 10 ml of water was then added to the resulting solution, and the mixture was heated under reflux for 3 hours, after which it was cooled to room temperature. 4 ml of concentrated aqueous hydrochloric acid were added to the mixture, and the crystals which precipitated were collected by filtration, washed with water and dried, to give 1.64 g of the title compound, melting above 250° C.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][NH2:17]>C1C=CC=CC=1>[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][N:17]=[CH:7][C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CN(C)CCCN
Solvent: c1ccccc1
Product: CN(C)CCCN=Cc1ccc2c(c1)OCO2
Yield: 75.2 %

Procedure:
Interaction of 50 g of piperonal and 34 g of 3-dimethylaminopropylamine in 240 ml. of benzene following the procedure described in Example 1 yields 58.6 g of the product as an oil, boiling point 131°-136° C. at 0.2-0.3 mm. of Hg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([CH:23]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:24]([NH:26][C@H:27]2[C@H:34]3[C@H:30]([CH2:31][NH:32][CH2:33]3)[CH2:29][CH2:28]2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.OC1C2N=NNC=2C=CC=1.CN(C)CCCN=C=NCC>ClCCl>[CH:35]1([CH:23]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:24]([NH:26][C@H:27]2[C@H:34]3[C@H:30]([CH2:31][N:32]([C:14](=[O:16])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:33]3)[CH2:29][CH2:28]2)=[O:25])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(N[C@@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H]2CC[C@@H](NC(=O)C(C3CCCCC3)C3CCCCC3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N-(tert-Butoxycarbonyl)-D-leucine (72.7 mg, 0.314 mmol), 2,2-dicyclohexyl-N-[(3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide (95 mg, 0.286 mmol) from Example 74, and hydroxybenzotriazole (48.1 mg, 0.314 mmol) were combined in dichloromethane (10 mL). After 20 minutes, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.056 mL, 0.314 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water. The separated organic layer was reduced in volume, and the crude material was applied to a silica gel cartridge (Analogix®, Burlington, Wis., RS-12) and eluted first with 10% to 100% ethyl acetate/hexanes and then with 1-10% methanol (2 N ammonia)/dichloromethane to give tert-butyl(R)-1-((3aS,4R,6aR)-4-(2,2-dicyclohexylacetamido)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-methyl-1-oxopentan-2-ylcarbamate: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.26 (dd, J=7.2, 24.0, 1H), 7.91 (d, J=8.6, 1H), 4.48-4.36 (m, 1H), 4.12-3.96 (m, 1H), 3.87 (dd, J=7.4, 10.3, 1H), 3.70 (ddd, J=8.0, 14.4, 23.7, 1H), 3.40 (dd, J=5.7, 12.3, 1H), 2.77 (s, 1H), 2.58 (d, J=6.1, 1H), 2.08 (s, 1H), 2.01 (dd, J=5.6, 10.4, 2H), 1.96-1.55 (m, 17H), 1.54-1.50 (m, 9H), 1.49-1.37 (m, 2H), 1.19 (qdd, J=12.3, 22.3, 24.7, 11H), 1.00 (t, J=6.6, 3H), 0.88 (d, J=6.6, 1H).
Reaction SMILES: [C@@H:1]12[O:9][CH2:8][C@@H:6]([O:7]1)[CH:5]=[CH:4][C@@H:2]2[OH:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Cl:39])[CH:38]=1)[C:33](O)=[O:34].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Cl:39])[CH:38]=1)[C:33]([O:3][C@@H:2]1[CH:4]=[CH:5][C@H:6]2[CH2:8][O:9][C@@H:1]1[O:7]2)=[O:34]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: O[C@H]1C=C[C@H]2CO[C@@H]1O2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@@H]1C=C[C@H]2CO[C@@H]1O2)c1cc(Cl)cc(Cl)c1
Yield: 77.7 %

Procedure:
1.28 g (10.0 mmol) of 1,6-anhydro-3,4-dideoxy-β-D-threo-hex-3-enopyranose, 5.25 g (20.0 mmol) of triphenyl phosphine, and 3.80 g (20.0 mmol) of 3,5-dichlorobenzoic acid were added to 16 ml of dry THF, and a solution obtained by dissolving 3.48 g (20.0 mmol) of diethylazodicarboxylate in 16 ml of dry THF was gradually dropped in the above mixture in a nitrogen-sealed ice-water bath. The resultant solution was stirred at room temperature for 41 hours. The solvent was distilled from the reaction solution at a reduced pressure. Triphenyl phosphine oxide as a byproduct was eliminated from the residue using a silica gel column (eluent: chloroform). The solvent was distilled from the resultant eluate at a reduced pressure, and the residue was purified using a silica gel column (hexane:ethyl acetate=6:1) to obtain 2.34 g (yield: 77.7%) of 1,6-anhydro-2-O-(3,5-dichlorobenzoyl)-3,4-dideoxy-β-D-erythro-hex-3-enopyranose. This product was recrystallized from a solvent mixture of hexane, diethyl ether, and chloroform.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8]CC)=[O:7])[CH:3]=[N:2]1.[H-].[Na+].CS(O[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)(=O)=O.[OH-].[K+]>CN(C=O)C.O>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][CH:18]([N:2]2[CH:3]=[C:4]([C:6]([OH:8])=[O:7])[CH:5]=[N:1]2)[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)O)cn2)CC1
Temperature: 100 °C
Reaction time: 24 h
Yield: 40.6 %

Procedure:
A mixture of ethyl 1H-pyrazole-4-carboxylate (700 mg, 5 mmol) and NaH 60% (6 mmol) was stirred under nitrogen at 0° C. for 1 hour in dry DMF (15 mL). tert-Butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (1.53 gr, 5.5 mmol) dissolved in 4 mL of dry DMF was added and the resulting solution was heated at 100° C. overnight. Reaction mixture was quenched with water and extracted (×3) with ethyl acetate. Collected organic phases were dried over Na2SO4, filtered and evaporated to dryness. Residue was dissolved in MeOH (20 mL) and water (5 mL) and KOH (1.12 gr, 20 mmol) was added. The resulting solution was stirred at room temperature 24 hours, then solvents removed under reduced pressure. The residue was taken-up with AcOEt and KHSO4 5% solution. Aqueous phase was extracted with EtOAc several times. Collected organic phases were dried with Na2SO4, filtered and evaporated to dryness affording 600 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]#[CH:12])=[CH:5][C:4]=1[O:13][CH3:14].[Li]CCCC.CON(C)[C:23]([C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:24].[NH4+].[Cl-]>C1COCC1>[CH3:14][O:13][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[O:9][CH2:10][C:11]#[C:12][C:23]([C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:24]
Reactant: C#CCOc1ccc(OC)c(OC)c1
Reactant: CON(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(OCC#CC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a THF (50 mL) solution of 1,2-dimethoxy-4-(prop-2-yn-yloxy)benzene (2.118 g), n-BuLi (4.0 mL, 2.64 N hexane solution) was added dropwise at −78° C. and the resulting mixture was stirred at the same temperature for 30 minutes; the reaction mixture was then added dropwise to a solution of (S)-t-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (2.578 g) in THF (100 mL) at −78° C. and, after stirring at the same temperature for an hour, temperature was raised to room temperature over an hour. The reaction mixture was added to a saturated aqueous solution of NH4Cl (300 mL) to separate the organic layer, which was washed with a saturated aqueous solution of NH4Cl (100 mL), dried (Na2SO4), filtered and concentrated to give a crude product, which was further purified by neutral silica gel chromatography (AcOEt/hexane) to give the titled compound (2.479 g, pale brown oil.)
Reaction SMILES: N1C2CCCC(=O)C=2C=C1.C(OCC)(=O)CC(C)=O.P([O-])(O)(O)=O.[Na+].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:40][C:41]1[NH:42][C:43]2[C:44](=[O:55])[CH2:45][CH2:46][CH2:47][C:48]=2[C:49]=1[C:50]([O:52]CC)=[O:51]>>[CH3:40][C:41]1[NH:42][C:43]2[C:44](=[O:55])[CH2:45][CH2:46][CH2:47][C:48]=2[C:49]=1[C:50]([OH:52])=[O:51]
Reactant: CCOC(=O)c1c(C)[nH]c2c1CCCC2=O
Agent: O=C1CCCc2[nH]ccc21
Agent: O=P([O-])(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOC(=O)CC(C)=O
Product: Cc1[nH]c2c(c1C(=O)O)CCCC2=O

Procedure:
In one more aspect, the present invention relates to pyrrolo[b]cyclohexanone, the intermediate of Formula (II), which is synthesized by the route outlined below: 6-amino-5-oxohexanoic acid hydrochloride(S1) and ethyl acetoacetate were refluxed in a.q. sodium dihydrogen phosphate to generate substituted pyrrole(S2). Then the compound S2 was solved in polyphosphoric acid (PPA), P2O5 used as dehydrant, reacted to generate ethyl 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylate (S3) at 70° C. 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) is obtained by the hydrolysis of (S3) in 1 mol/L a.q. LiOH. Finally, S4 is reacted with H—R6 at room temperature for 24 hours in DMF to give pyrrolo[b]cyclohexanone of Formula (II) by using a condensation reagent.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[S:18]1[CH2:22][CH:21]([C:23]([NH2:25])=[O:24])[NH:20][CH2:19]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:20]3[CH:21]([C:23]([NH2:25])=[O:24])[CH2:22][S:18][CH2:19]3)=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: NC(=O)C1CSCN1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: NC(=O)C1CSCN1C(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 47 b, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 100 mg, 429 μmol) and 4-thiazolidinecarboxamide (CAN 103749-87-7, 62.3 mg, 472 μmol) as starting materials and isolated (114 mg, 77%) as white solid; LC-MS (UV peak area, ESI) 100%, 348.1377 [MH+].
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:15][C:14]2[C:16]([O:21][CH3:22])=[CH:17][CH:18]=[C:19]([CH3:20])[C:13]=2[C@H:12]([CH2:23][Br:24])[O:11]1)C1C=CC=CC=1.[H][H]>[Pt].CO.C(OCC)(=O)C>[Br:24][CH2:23][C@H:12]1[C:13]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([O:21][CH3:22])[C:14]=2[CH2:15][C@@H:10]([CH2:9][OH:8])[O:11]1
Reactant: COc1ccc(C)c2c1C[C@@H](COCc1ccccc1)O[C@H]2CBr
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C)c2c1C[C@@H](CO)O[C@H]2CBr
Reaction time: 8 h

Procedure:
5% Platinum on carbon (1.0 g) is added to a solution of [1R,3S] 3-benzyloxymethyl-1-bromomethyl-3,4-dihydro-5-methoxy-8-methyl-1H-2-benzopyran (3.42 g, 8.7 mmol), from Step 2, in 150 mL of methanol and 5 mL of ethyl acetate. The reaction mixture is sealed under 4 atmospheres of hydrogen and shaken overnight. The reaction mixture is filtered to remove the catalyst and concentrated. The residue is purified by column chromatography on silica gel to give the title compound.
Reaction SMILES: O[CH2:2][C:3]1([CH3:10])[CH2:7][N:6]([CH3:8])[C:5](=[O:9])[NH:4]1.N1C=CC=CC=1.S(Cl)([Cl:19])=O>ClCCCl>[Cl:19][CH2:2][C:3]1([CH3:10])[CH2:7][N:6]([CH3:8])[C:5](=[O:9])[NH:4]1
Reactant: CN1CC(C)(CO)NC1=O
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CN1CC(C)(CCl)NC1=O
Yield: 24.3 %

Procedure:
A solution of 4-(hydroxymethyl)-1,4-dimethylimidazolidin-2-one (3.3 g, 22.7 mmol), anhydrous pyridine (8.25 ml, 102 mmol), and thionyl chloride (8.26 ml, 114 mmol) in 46 ml of 1,2-dichloroethane was heated at reflux temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, diluted with dichloromethane, and filtered to remove solids. The organic layer was washed with once 2 N HCl, which was back-extracted three times with dichloromethane, and the combined organic fractions were dried over sodium sulfate and concentrated to 2.2 g of yellow oil. The crude product was purified by column chromatorgraphy, eluting from silica gel with a gradient of 0-10% methanol in dichloromethane to give 897 mg of desired product as a white solid (25% yield). 1H NMR (400 MHz, CDCl3) δ 1.42 (s, 3H), 2.79 (s, 3H), 3.17-3.20 (d, J=9.2 Hz, 1H), 3.36-3.39 (d, J=9.2 Hz, 1H), 3.50 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 24.2, 30.3, 51.5, 55.0, 57.0, 160.6. LRMS (ESI/APCI): 163 [M+H]+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].I[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH:25]1([CH2:24][CH:19]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([O:10][CH3:9])[CH:12]=2)[C:20]([OH:22])=[O:21])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: ICC1CCCC1
Reactant: COc1ccc(CC(=O)O)cc1OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COc1ccc(C(CC2CCCC2)C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (58.5 mL of a 0.91M stock solution, 53.2 mmol) cooled to −78° C. was treated with (3,4-dimethoxy-phenyl)-acetic acid (4.97 g, 25.3 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (25.3 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min and at 25° C. for 15 min. At this time, the reaction was cooled to 0° C. and was treated with a solution of iodomethylcyclopentane (5.87 g, 27.8 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The reaction mixture was stirred at 0° C. for 30 min. The reaction was then warmed to 25° C. and was stirred at 25° C. for 18 h. The reaction mixture was then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (10 mL). The resulting mixture was concentrated in vacuo. The residue was diluted with water (100 mL) and acidified to pH=1 with a 1N aqueous hydrochloric acid solution. This solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dimethoxy-phenyl)-propionic acid (4.5 g, 63.8%) as a yellow solid: mp 111-112° C.; EI-HRMS m/e calcd for C16H22O4 (M+) 278.1518 found 278.1517.