Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][NH:5]1)([OH:3])=[O:2].S(Cl)([Cl:12])=O.[CH:14](OC(C)C)(C)C>CO>[ClH:12].[CH3:14][O:2][C:1]([C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][NH:5]1)=[O:3]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: CC(C)OC(C)C
Reactant: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Product: Cl
Reaction time: 1 h

Procedure:
In an atmosphere of nitrogen, (2S,4R)-2-carboxy-4-hydroxypyrrolidine (100 g, 0.763 mol) was suspended in methanol (400 ml) and the suspension was cooled to 5°-10° C. Then, thionyl chloride (99.8 g, 0.839 mol) was added dropwise thereto under 20° C. After completion of the dropwise addition, the reaction mixture was warmed to 60°-62° C. and stirred at this temperature for 1 hour. The reaction mixture was then cooled to 25°-30° C. for crystallization. To the mixture was added diisopropyl ether (180 ml) dropwise. After completion of the dropwise addition, the mixture was cooled to 0°-5° C. and stirred for 1 hour. The resulting crystal was collected by filtration and washed with diisopropyl ether (200 ml) twice. The washed crystal was dried in vacuo overnight to provide (2S,4R)-2-methoxycarbonyl-4-hydroxypyrrolidine hydrochloride (134.8 g).
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[C:16](=[O:17])[N:15]([C@H:18]([C:27](=[O:38])[NH:28][C:29]3[S:30][CH:31]=[C:32]([C:34](=[O:37])[CH2:35][CH3:36])[N:33]=3)[C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[C:14](=[O:39])[NH:13]2)=[CH:8][CH:7]=1.O.[OH-].[Li+]>O1CCCC1>[O:39]=[C:14]1[NH:13][CH:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:40])=[O:2])=[CH:7][CH:8]=2)[C:16](=[O:17])[N:15]1[C@H:18]([C:27](=[O:38])[NH:28][C:29]1[S:30][CH:31]=[C:32]([C:34](=[O:37])[CH2:35][CH3:36])[N:33]=1)[C@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20]
Reactant: CCC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc(OCC(=O)OC)cc3)C2=O)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)NC(c3ccc(OCC(=O)O)cc3)C2=O)n1

Procedure:
Prepared by hydrolysis of (4-{(R)-2,5-dioxo-1-[(1S,2S)-2-phenyl-1-(4-propionyl-thiazol-2-ylcarbamoyl)-propyl]-imidazolidin-4-yl}-phenoxy)-acetic acid methyl ester (prepared as described in example 21) with lithium hydroxide monohydrate in aqueous tetrahydrofuran. Under the conditions employed for the hydrolysis of the methyl ester racemization occurred at the 4-position of the imidazolidinedione ring.
Reaction SMILES: C1(C2(C(O)=[O:13])CCCC2)C=CC=CC=1.[F:15][C:16]([F:34])([F:33])[C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[CH2:20][N:21]1[CH2:25][C@H:24]2[C@@H:26]([NH2:29])[CH2:27][CH2:28][C@H:23]2[CH2:22]1.[CH2:35](N1C[C@H]2C(N)CC[C@H]2C1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[F:34][C:16]([F:33])([F:15])[C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[CH2:20][N:21]1[CH2:25][C@H:24]2[C@@H:26]([NH:29][C:35]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[O:13])[CH2:27][CH2:28][C@H:23]2[CH2:22]1
Reactant: N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Product: O=C(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)C1CCCCC1

Procedure:
The title compound was prepared by substituting cyclohexanecarboxylic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.74 (d, J=6.1, 1H), 7.71 (s, 1H), 7.62 (d, J=7.7, 1H), 7.57 (d, J=9.2, 1H), 7.47 (t, J=7.7, 1H), 4.48-4.41 (m, 1H), 3.53 (d, J=13.2, 1H), 3.47 (d, J=13.2, 1H), 2.84 (ddd, J=2.8, 7.9, 10.3, 1H), 2.75 (dd, J=2.8, 9.5, 1H), 2.51-2.43 (m, 1H), 2.37 (dd, J=2.8, 9.1, 1H), 2.34-2.29 (m, 1H), 2.27-2.19 (m, 2H), 1.94-1.83 (m, 2H), 1.80 (d, J=12.9, 1H), 1.73-1.60 (m, 6H), 1.57-1.51 (m, 1H), 1.35-1.27 (m, 1H), 1.22-1.10 (m, 3H); MS (ESI+) m/z 395 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][N:20]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCNC3)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCN(S(C)(=O)=O)C3)cc1
Reaction time: 1 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-ethylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0499 g, 0.122 mmol) in dry N,N-Dimethylformamide (0.60 mL, 7.7 mmol) was added N,N-Diisopropylethylamine (0.0636 mL, 0.365 mmol) followed by Methanesulfonyl chloride (0.01410 mL, 0.1822 mmol). The reaction mixture was stirred for 1 hour then submitted for purification. 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 8.16 (d, J=8.7, 2H), 7.48 (d, J=8.8, 2H), 6.18 (t, J=5.5, 1H), 4.32 (dd, J=36.6, 17.0, 2H), 4.01 (s, 1H), 3.85 (d, J=10.7, 1H), 3.79 (d, J=11.4, 1H), 3.68 (dd, J=20.5, 8.8, 2H), 3.59-3.49 (m, 2H), 3.43 (t, J=11.0, 1H), 3.26-3.17 (m, 1H), 3.16-3.06 (m, 2H), 3.02 (s, 3H), 2.94-2.81 (m, 1H), 2.77-2.63 (m, 1H), 1.88-1.69 (m, 2H), 1.06 (t, J=7.2, 3H), 0.83 (t, J=7.4, 3H). LC/MS-m/z+489.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][S:6][C:7]1[S:11][C:10]([NH2:12])=[N:9][CH:8]=1)[CH3:2].[CH:14]1([NH:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([CH2:26][CH3:27])[CH2:22][CH2:21]2)[CH2:18][CH2:17][CH2:16][CH2:15]1.C1C[O:31][CH2:30]C1>CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:30]([N:19]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[C@H:20]2[CH2:21][CH2:22][C@H:23]([CH2:26][CH3:27])[CH2:24][CH2:25]2)=[O:31])=[N:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: CC[C@H]1CC[C@H](NC2CCCC2)CC1
Reactant: C1CCOC1
Agent: CN(C)c1ccncc1
Product: CCOC(=O)CSc1cnc(NC(=O)N(C2CCCC2)[C@H]2CC[C@H](CC)CC2)s1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
An equimolar mixture of 1,1-carbonyldiimidazole, (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester and DMAP (5 mol %) in THF was heated for 5 h at 50-60° C. and then cooled to room temperature. Then cyclopentyl-(trans-4-ethyl-cyclohexyl)-amine (1 equivalent; see Step 2) was added and the reaction is stirred overnight at room temperature. The reaction mixture was quenched with water. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo. The crude product was dissolved in MeCN and purified (HPLC method 1) to give {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester. This material was dissolved in MeOH and treated with 15 equivalents of 1N NaOH over night at room temperature. MeOH was removed by evaporation. Addition of 1N HCl to pH<1 caused precipitation. The precipitate was isolated by filtration, washed with water and dried to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=[O:23])C=1Cl>C1COCC1.O>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[CH2:8][CH2:9][CH2:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2c3c([nH]c2c1)CCCC3
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCCc2[nH]c3cc(Br)ccc3c21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
A solution 7-bromo-2,3,4,9-tetrahydro-1H-carbazole (2.87 g, 11.5 mmol) in THF (103 mL) and H2O (11.5 mL) was cooled to 0° C. and treated with a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.23 g, 23.1 mmol) in THF (46 mL) at such a rate that the reaction mixture did not exceed 4° C. The resulting solution was allowed to stir for an additional 45 min at 0° C. The solution was concentrated to dryness under reduced pressure. The resulting solids were suspended in EtOAc (100 mL) and saturated NaHCO3 solution (300 mL). The solids were collected by filtration and washed with additional saturated NaHCO3 solution (400 mL) followed by H2O (150 mL). The solid was dried to provide the title compound (2.46 g, 81%) as a light pink solid: 1H NMR (500 MHz, DMSO-d6) δ 11.97 (s, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.27 (dd, J=8.5, 2.0 Hz, 1H), 2.95 (t, J=6.0 Hz, 2H), 2.42 (t, J=6.0 Hz, 2H), 2.14-2.09 (m, 2H); ESI MS m/z 263 [M+H]+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH2:16][C@H:17]([OH:30])[CH2:18][O:19][C:20]1[C:28]2[NH:27][C:26](=[O:29])[NH:25][C:24]=2[CH:23]=[CH:22][CH:21]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:52]=[CH:53][C:54]=1[O:55][CH3:56])[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]2)=[CH:41][CH:40]=1)=[O:37].C(O)(=O)C>CN(C)C=O>[OH:30][C@H:17]([CH2:18][O:19][C:20]1[C:28]2[NH:27][C:26](=[O:29])[NH:25][C:24]=2[CH:23]=[CH:22][CH:21]=1)[CH2:16][NH:15][CH:48]1[CH2:47][CH2:46][N:45]([C:42]2[CH:43]=[CH:44][C:39]([NH:38][C:36](=[O:37])[C:35]3[CH:52]=[CH:53][C:54]([O:55][CH3:56])=[C:33]([O:32][CH3:31])[CH:34]=3)=[CH:40][CH:41]=2)[CH2:50][CH2:49]1
Reactant: COc1ccc(C(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1OC
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)cc1OC
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (0.044 g, 2.1 mmol) was added to a solution of 4-((2S)-3-amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one (U.S. Pat. No. 5,786,356) (0.23 g, 1.05 mmol), 3,4-dimethoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzamide (which was obtained in Example 369) (0.41 g, 1.16 mmol), and acetic acid (0.07 mL, 1.16 mmol) in anhydrous dimethylforamide (8 mL). The reaction was stirred for 2 hours. The reaction was quenched with 50% water/saturated aqueous NaHCO3 (20 mL). The solids were captured on a filter and washed with ethyl acetate, diethyl ether, and hexanes to afford 0.31 g of the desired product as a brown solid; 1H NMR (300 MHz, DMSO-d6) δ 1.32 (m, 2H), 1.89 (m, 2H), 2.54 (m, 1H), 2.65 (m, 2H), 2.84(m, 2H), 3.56 (m, 2H), 3.83(s, 3H), 3.84 (s, 3H), 3.95 (m, 2H), 4.02 (s, 1H), 5.06(brs, 1H), 6.52 (d, 1H, J=7.1), 6.51(d, 1H, J=8.1 Hz), 6.88 (m, 2H), 7.08 (d, 1H, J=8.7 Hz), 7.58 (m, 5H), 8.87 (s, 1 H), 10.59 (brs, 1 H), 10.72 (brs, 1 H); MS (ES) m/z: 561.2 (MH+).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][S:10][C:9]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:16][C:15]=3[N:26]([CH3:36])[S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)(=[O:29])=[O:28])=[N:8]1)(=O)=O.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:25][O:24][CH2:23][CH2:22][O:21][C:17]1[CH:18]=[C:19]2[C:14](=[C:15]([N:26]([CH3:36])[S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)(=[O:29])=[O:28])[CH:16]=1)[NH:13][C:12]([C:9]1[S:10][CH2:11][C@@H:7]([CH2:6][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:8]=1)=[CH:20]2
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=N[C@H](COS(C)(=O)=O)CS3)cc2c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=N[C@H](CN4CCOCC4)CS3)cc2c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 2 %

Procedure:
A solution of ((4R)-2-{5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-4-yl)methyl methanesulfonate (0.1 g), morpholine (0.032 mL) and potassium carbonate (0.050 g) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 18 hr, and the mixture was stirred at 50° C. for 6 hr. The same amount of morpholine (0.032 mL) and potassium carbonate (0.050 g) were added, and the mixture was stirred at 80° C. for 18 hr. The reaction mixture was concentrated, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate-methanol (4:1:0-0:10:1, volume ratio) to give the title compound (0.002 g, yield 2%) as a colorless amorphous solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C@@H:9]([CH2:21][CH2:22][CH3:23])[C@@H:10]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:11]([OH:13])=[O:12].[C:24](OC=O)(=[O:26])C.Cl>N1C=CC=CC=1>[CH:24]([N:8]([O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[C@@H:9]([CH2:21][CH2:22][CH3:23])[C@@H:10]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:11]([OH:13])=[O:12])=[O:26]
Reactant: CCC[C@H](NOC1CCCCO1)[C@@H](CC1CCCCC1)C(=O)O
Reactant: CC(=O)OC=O
Agent: Cl
Solvent: c1ccncc1
Product: CCC[C@@H]([C@@H](CC1CCCCC1)C(=O)O)N(C=O)OC1CCCCO1
Reaction time: 6 h
Yield: 99.9 %

Procedure:
(2R,3S)-3-(2-Tetrahydropyranyloxyamino)-2-(cyclohexylmethyl)hexanoic acid (2.00 g, 6.11 mmol) is dissolved in 15 mL of pyridine. Formic acetic anhydride (1.08 mL, 12.2 mmol) is added at 25° C. The reaction is stirred for an additional 6 h and then is poured into 50 mL of cold 1 M hydrochloric acid. The organics are extracted with two 250-mL portions of dichloromethane. The combined organic phases are then washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated in vacuo to afford (2R,3S)-3-(formyl-2-tetrahydropyranyloxyamino)-2-(cyclohexylmethyl)hexanoic acid (2.17 g, 100% yield). APCI-MS m/z 378 (M+Na)+, 354 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[C:19]([CH3:26])([CH3:25])[C:20](OCC)=[O:21].O>CS(C)=O>[CH3:25][C:19]1([CH3:26])[C:20](=[O:21])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:11]1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)Oc2cc([N+](=O)[O-])ccc2NC1=O
Temperature: 30 °C
Yield: 120.9 %

Procedure:
To a solution of 2-amino-5-nitrophenol (200 g) in dimethylsulfoxide (1000 mL) was added anhydrous potassium carbonate (269 g) under stirring at 30° C. or lower, then to the mixture was added ethyl 2-bromo-2-methylpropionate (278.4 g) at 30° C. or lower, and the mixture was stirred at 26° C. for 24 hours. To the reaction mixture was added water (2000 mL) at 40° C. or lower, and then stirred at room temperature for 3 hours. The reaction product was collected by filtration, and successively washed with dimethylsulfoxide/water (2:1, 800 mL) and water (3200 mL) to obtain the title compound (348.6 g) as a yellow solid (wet material) (yield: 121%, purity: 96%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3O[C:16](=O)[C:15]([C:19]#[N:20])=[C:14]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[CH:13]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[Na+].[CH2:29]1[CH2:33]O[CH2:31][CH2:30]1>>[N:21]1([C:14]2[CH:13]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[CH:2]4)=[CH:7][CH:8]=3)[C:5]3[C:4]4[C:30](=[CH:29][CH:33]=[CH:2][CH:3]=4)[CH2:31][C:16]=3[C:15]=2[C:19]#[N:20])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccc(-n3cccc3)cc2)oc1=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccc(-n3cccc3)cc2)c2c1Cc1ccccc1-2

Procedure:
A mixture of 6-(4-(1H-pyrrol-1-yl)phenyl)-2-oxo-4-(piperidin-1-yl)-2H-pyran-3-carbonitrile (345 mg), indanone-2 (132 mg) and NaH (47 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 224-226° C.; ESMS 416 (M++1); IR (KBr) 2211 cm−1 (CN); 1H NMR (200 MHz, CDCl3) δ 1.60-1.66 (m, 2H, CH2), 1.79-1.82 (m, 4H, 2CH2), 3.22-3.30 (m, 4H, 2CH2) δ 6.42 (t, J=2 Hz, 2H, CH), 6.82 (s, 1H, ArH), 6.93 (d, J=7.8 Hz, 1H, ArH), 7.07 (t, J=7.5 Hz, 1H, ArH), 7.17-7.24 (m; 4H, ArH & CH), 7.46-7.59 (m, 4H, ArH).
Reaction SMILES: [CH2:1](/[C:4](=[CH:7]\[CH2:8][C@H:9]1[CH2:13][CH:12]=[C:11]([CH3:14])[C:10]1([CH3:16])[CH3:15])/[CH:5]=[O:6])[CH2:2][CH3:3].NCCN.[OH-].[K+]>C(O)(C)C>[CH2:1](/[C:4](=[CH:7]\[CH2:8][C@H:9]1[CH2:13][CH:12]=[C:11]([CH3:14])[C:10]1([CH3:15])[CH3:16])/[CH2:5][OH:6])[CH2:2][CH3:3]
Reactant: CCC/C(C=O)=C\C[C@H]1CC=C(C)C1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: NCCN
Product: CCC/C(=C\C[C@H]1CC=C(C)C1(C)C)CO

Procedure:
In a 100 ml stainless steel autoclave were charged 6.60 g (0.03 mol) of (E)-(R)-2-propyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)-2-buten-1-al synthesized from (1S)-α-pinene having an optical purity of 97% e.e. in a conventional manner, 28.7 mg (0.03 mmol) of RuCl2 (PPh3)3, 2.4 ml of a 0.1M 1,2-diaminoethane (0.24 mmol) solution in isopropyl alcohol, and 15 ml of a 0.1M potassium hydroxide (1.5 mmol) solution in isopropyl alcohol in a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 hours under a hydrogen pressure of 50 atm.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([O:31]C)=[O:30])[CH:25]=[CH:26][CH:27]=2)[O:17][N:16]=1.[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([OH:31])=[O:30])[CH:25]=[CH:26][CH:27]=2)[O:17][N:16]=1
Reactant: COC(=O)Cc1cccc(OCc2cc(OCc3nc(-c4ccccc4)oc3C)no2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1cc(COc2cccc(CC(=O)O)c2)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 2-[3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethoxy]phenyl]acetate (604 mg) was dissolved in methanol-tetrahydrofuran (1:1, 12 mL) and a 1N aqueous sodium hydroxide solution (3 mL) was added. The mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, 1N hydrochloric acid (3 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals of 2-[3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethloxy]phenyl]acetic acid. Recrystallization from ethanol-hexane gave colorless needle crystals (522 mg, 89%). melting point: 128-129° C.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].CCCCCC.[CH3:12][O:13][C:14]1[N:19]=CC(C=O)=[CH:16][N:15]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.O>[CH3:12][O:13][C:14]1[N:15]=[CH:16][C:2]([CH:3]=[CH2:4])=[CH:1][N:19]=1
Reactant: [Li]CCCC
Reactant: COc1ncc(C=O)cn1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: C=Cc1cnc(OC)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (24.8 g, 69.4 mmol) in THF (150 mL) at −78° C. under an atmosphere of nitrogen was added 2.5 M of n-butyllithium in hexane (28 mL, 70 mmol) during a period of 12 mins. The reaction was warmed to room temperature to yield a deep red ylide solution. To the ylide solution, cooled in ice, was introduced 2-methoxypyrimidine-5-carbaldehyde (8 g, 65.6 mmol) in THF (50 mL). The reaction was allowed to reach room temperature and stirred for 3 hours. The result suspension was heated to 60° C. over 30 minutes and then heated at 60° C. for 1 hour. After cooling, the reaction mixture was diluted with water (400 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography (EtOAc/hexane 0-30%) to yield title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:14](O)=[O:15])=O)=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>C(O)C>[NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:14](=[O:15])[NH:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: Nc1ccc(C(=O)C2=C(C(=O)O)CCCC2)cc1
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2n[nH]c(=O)c3c2CCCC3)cc1

Procedure:
10.3 g of 2-(4-amino-benzoyl)-cyclohex-1-enecarboxylic acid (42 mmol) were dissolved in 45 mL ethanol, 2.7 g (54 mmol) hydrazine hydrate was added and the mixture was heated under reflux for 30 hours. Precipitation of the product already started several hours after heating. After cooling in the refrigerator overnight the precipitated product was filtered and washed with cold ethanol.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]1[N:12]([CH3:31])[C:13](=[O:30])[C:14]([O:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:15]([C:17]([O:19][CH3:20])=[O:18])[N:16]=1.N1C=CC=CC=1.Cl.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45](Cl)=[O:46]>ClCCl.CN(C1C=CN=CC=1)C>[C:22]([O:21][C:14]1[C:13](=[O:30])[N:12]([CH3:31])[C:11]([CH:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]2[C:45]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=2)=[O:46])=[N:16][C:15]=1[C:17]([O:19][CH3:20])=[O:18])(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1nc(C2CCc3ccccc3N2)n(C)c(=O)c1OC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccccn1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1nc(C2CCc3ccccc3N2C(=O)c2ccccn2)n(C)c(=O)c1OC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
The residue of Step 1 was dissolved in dichloromethane. Pyridine, picolinoyl chloride hydrochloride and a catalytic amount of DMAP were added. A further addition of the reactants was made after two hours. After evaporation of the solvent, the residue was diluted with EtOAc, the organic phase washed with water, dried (Na2SO4) and evaporated to afford the title product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[NH:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([O-:14])=[O:13]
Reactant: NCCC(=O)O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 97.2 %

Procedure:
60 g (0.27 mol) of 2-chloro-1-nitro-5-trifluoromethylbenzene, 50 g (0.56 mol) of β-alanine and 41 g (0.3 mol) of potassium carbonate were refluxed in a mixture of 300 ml of dimethylformamide and 50 ml of water for 6 h. The mixture was then poured into ice-water, the aqueous phase was acidified with hydrochloric acid, and the precipitate was filtered off with suction to yield 73 g (99%) of the product.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[C:13][Si](C)(C)C)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:18])[CH:3]=1>CN(C=O)C.[Cu]I>[Cl:18][C:4]1[CH:3]=[C:2]2[C:11]([CH:12]=[CH:13][NH:1]2)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)c(N)cc1Cl
Agent: [Cu]I
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc[nH]c2cc1Cl
Temperature: 110 °C

Procedure:
A mixture of compound 70p (0.532 mmol, 150 mg) and CuI (0.32 mmol, 60 mg) in DMF (1.5 mL) was heated at 110° C. for 5 h and them cooled to room temperature. The reaction was quenched with water and extracted with EtOAc. The organic layer was concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 70q.