Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:17])[C@H:4]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[CH:5]([CH3:7])[CH3:6].[O-:18][C:19]#[N:20].[K+]>C(O)(=O)C>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:8]2[C@H:4]([CH:5]([CH3:6])[CH3:7])[C:3](=[O:17])[NH:20][C:19]2=[O:18])=[CH:15][CH:14]=1
Reactant: N#C[O-]
Reactant: COC(=O)[C@H](NCc1ccc(Cl)cc1)C(C)C
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)[C@@H]1C(=O)NC(=O)N1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.3 %

Procedure:
To a solution of 1.68 g (6.59 mmoles) of (R)-2-(4-chloro-benzylamino)-3-methyl-butyric acid methyl ester in 20 ml of acetic acid, 0.64 g (7.91 mmoles) of potassium cyanate is added at ambient temperature under N2 atmosphere. The mixture is stirred for 15 hours at ambient temperature and heated for 3 hours at 100° C., and then the reaction mixture is concentrated under reduced pressure. The mixture is extracted with AcOEt, and the combined extracts are washed with sat. NaHCO3 and brine, dried over MgSO4 and then concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 1.57 g of desired (R)-1-(4-chloro-benzyl)-5-isopropyl-imidazolidine-2,4-dione in 77% yield.
Reaction SMILES: [CH2:1]([CH:3]([CH2:11][CH2:12][C@H:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([OH:19])[CH2:14]1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH3:2].[H-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24].C(OC)(C)(C)C>CN(C)C=O>[CH2:24]([O:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][C@H:13]([CH2:12][CH2:11][CH:3]([CH2:1][CH3:2])[C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5])[CH2:14]1)[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: CCC(CC[C@H]1CCC[C@@H](O)C1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: C=CCO[C@@H]1CCC[C@H](CCC(CC)C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.19 g of tert-butyl 2-ethyl-4-(cis-3-hydroxycyclohexyl)butyrate are dissolved in 50 ml of dimethylformamide, and 210 mg g of sodium hydride (60% strength in paraffin oil) are added. The suspension is stirred at room temperature for 15 minutes, and 1.6 ml of allyl bromide are then added. After one hour, a further 320 mg of sodium hydride are added. After 12 hours of stirring at room temperature, another 320 mg of sodium hydride and then 1.6 ml of allyl bromide are metered in. Stirring at room temperature is continued for a further 12 hours. After addition of 200 ml of methyl tert-butyl ether, the mixture is washed three times with in each case 100 ml of water and the organic phase is separated off and dried over magnesium sulfate. The solvent is removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=60:1=>30:1. This gives 770 mg of tert-butyl 4-(cis-3-allyloxycyclohexyl)-2-ethylbutyrate as an oil. C19H34O3 (310.48), Rf(n-heptane:ethyl acetate=5:1)=0.48.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:46][CH2:47][C:48]1[C:49]([OH:56])=[N:50][C:51]([CH3:55])=[CH:52][C:53]=1[CH3:54]>ClCCl>[OH:56][C:49]1[C:48]([CH2:47][NH:46][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([CH:3]3[CH2:4][CH2:5][O:1][CH2:2]3)=[CH:14][CH:13]=2)=[C:53]([CH3:54])[CH:52]=[C:51]([CH3:55])[N:50]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: O=C(O)c1ccc(C2CCOC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C3CCOC3)cc2)c(O)n1
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
To a solution of 4-(tetrahydrofuran-3-yl)benzoic acid (100 mg, 0.52 mmol) in dichloromethane (20 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (35 mg, 0.5 mmol), triethylamine (32 mg, 0.7 mmol). The mixture was stirred for 0.5 hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (27 mg, 0.4 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was washed with water (50 mL), the organic layer was concentrated. The residue was purified by preparative-HPLC to give Compound I-83 as a white solid (35 mg, 21%). LRMS (M+H+) m/z: calcd 326.16. found 326. 1H NMR (300 MHz, CD3OD): δ 7.75 (d, J=6 Hz, 2H), 7.36 (d, J=6 Hz, 2H), 6.10 (s, 1H), 4.48 (s, 2H), 4.06 (m, 2H), 4.03 (m, 1H), 3.88 (m, 1H), 3.70 (m, 1H), 2.37 (s, 3H), 2.35 (s, 3H), 2.00 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:25])[CH2:6][CH2:7][C:8]1[NH:9][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1.[CH3:26][Si:27]([CH2:30][CH2:31][O:32][CH2:33]Cl)([CH3:29])[CH3:28].O>CN(C=O)C>[CH3:3][O:4][C:5](=[O:25])[CH2:6][CH2:7][C:8]1[N:12]([CH2:33][O:32][CH2:31][CH2:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:9]=1
Reactant: COC(=O)CCc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1nc(-c2ccccc2)c(-c2ccccc2)n1COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
47 mg of sodium hydride were added portionwise to a solution of 300 mg of 3-(4,5-diphenyl-1H-imidazol-2-yl)-propionic acid methyl ester in 2 mL of anh. DMF at 0° C. The mixture was stirred for 1 h at 0° C. then 179 mg of SEM-Cl were added dropwise at 0° C. The reaction mixture was allowed to warm up to rt, stirred for 1 h then poured into water and extracted with Et2O. The organic phase was washed with water/brine, dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using heptane/EtOAc from 88/12 to 0/100 as eluant to yield 308 mg of 3-[4,5-diphenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-propionic acid methyl ester as a yellowish oil.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:18]([OH:28])=[CH:19][C:20]4[O:24][C:23](=[O:25])[N:22]([CH3:26])[C:21]=4[CH:27]=3)[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[C:18](=[CH:19][C:20]5[O:24][C:23](=[O:25])[N:22]([CH3:26])[C:21]=5[CH:27]=4)[O:28][CH2:36]3)[C:9]2=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cn1c(=O)oc2cc(O)c(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc21
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: Cn1c(=O)oc2cc3c(cc21)C1(CO3)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 5-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-1-methylspiro[furo[3,2-f][1,3]benzoxazole-7,3′-indole]-2,2′(1H,1′H)-dione was obtained (65%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ7.47-7.28 (m, 11H), 7.18-7.11 (m, 2H), 7.06-6.99 (m, 1H), 6.89 (s, 1H), 6.64 (d, J=7.9 Hz, 1H), 6.45 (s, 1H), 4.92 (d, J=9.4 Hz, 1H), 4.81 (d, J=9.4 Hz, 1H), 3.18 (s, 3H); MS (ES+) m/z 475.0 (M+1).
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=CC=1.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][CH:13]=1>>[C@@H:10]12[CH2:9][C@@H:5]1[CH2:6][N:8]([CH2:6][CH2:5][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:16][CH:17]=1)[CH2:2]2
Reactant: NC(=O)c1ccc(O)cc1
Reactant: CC(=O)Nc1ccc(O)cc1
Product: CC(=O)Nc1ccc(OCCCCN2C[C@H]3C[C@H]3C2)cc1

Procedure:
The experimental procedure is the same as Steps 1 and 2 of Example 3, but replacing the 4-hydroxybenzamide in Step 1 by N-(4-hydroxyphenyl)acetamide.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@H:28]([CH3:33])[C:29]([O:31]C)=O)[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:33][C@@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[C:29](=[O:31])[N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: C1CCNC1
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)N1CCCC1
Yield: 60.5 %

Procedure:
Using the same procedure as in Example 26, methyl (2R)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.43 mmol) was reacted with pyrrolidine (0.36 ml, 4.3 mmol) to give the title compound as a solid (130 mg, 60%), except that the mixture was heated at 45° C. for 20 hours and purified by chromatography on silica gel (eluant: 3% methanol in DCM). NMR Spectrum 1.60 (d, 3H), 1.81 (m, 2H), 1.94 (m, 2H), 3.47-3.38 (m, 3H), 3.77 (m, 1H), 5.62 (q, 1H), 5.79 (s, 2H), 7.26 (d, 1H), 7.35 (d, 1H), 7.51 (s, 1H), 7.77-7.71 (m, 2H), 7.83 (m, 1H), 8.11 (s, 1H), 8.53 (m, 2H), 9.04 (s, 1H), 11.07 (br s, 1H); Mass spectrum MH+ 500.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][N:26]=[C:25]3[NH:29][CH:30]=[CH:31][C:24]=23)O1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[CH3:14][N:5]1[C:4]2[CH:3]=[C:2]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[NH:29][CH:30]=[CH:31][C:24]=34)[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]1([CH3:13])[CH3:12]
Reactant: CC1(C)OB(c2ccnc3[nH]ccc23)OC1(C)C
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CN1c2cc(-c3ccnc4[nH]ccc34)sc2C(=O)NC1(C)C
Yield: 30 %

Procedure:
A mixture of 6-bromo-1,2,2-trimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (138 mg, 0.50 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (183 mg, 0.75 mmol), cesium carbonate (489 mg, 1.50 mmol), 1,2-dimethoxyethane (5 mL) and water (1 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. This mixture was refluxed for 18 h. Then, the mixture was poured into saturated aqueous NaHCO3 (100 mL) and extracted with 2:1 EtOAc/THF (100 mL×3), and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. This residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc then to 90:10 EtOAc/MeOH). The obtained yellow solid was triturated with EtOAc/hexane, and the precipitate was collected by filtration to afford the title compound (46.9 mg, 30%) as a pale yellow solid:
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][C:5]([OH:7])=O)#[N:2].[OH-].[K+].C(Cl)(=O)C(Cl)=O.[CH:22]([NH:25][CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23]>C1C=CC=CC=1.C(OCC)C>[CH:22]([N:25]([CH:26]([CH3:28])[CH3:27])[C:5](=[O:7])[CH2:4][CH:3]([C:1]#[N:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:24])[CH3:23]
Reactant: CC(C)NC(C)C
Reactant: N#CC(CC(=O)O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(C)N(C(=O)CC(C#N)c1ccccc1)C(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
3-Cyano-3-phenylpropanoic acid (67.7 g, 0.389 mol) was dissolved in 2-PrOH. To the filtered acid solution was carefully added KOH (18.4 g, 0.33 mol) dissolved in 2-PrOH (200 mL), diethyl ether (100 mL) was added and the precipitate was filtered off. The dried acid salt (51.9 g, 0.24 mol) was suspended in benzene (400 mL) and oxalyl chloride was carefully added. The reaction mixture was stirred at 80° C. for 2 hours. The solvent was evaporated and the residue was co-evaporated twice with benzene. The brown oil was dissolved in benzene (200 mL) and cooled in an ice-bath. A solution of diisopropylamine (82 g, 0.81 mol) in benzene (200 mL) was added to the stirred reaction mixture during 45 min. The mixture was left to slowly warm up to room temperature overnight. The solvent was evaporated and the residue was taken up in diethyl ether and 1 M HCl. The organic phase was washed once with water, once with 1 M NaOH, again with water, dried (Na2SO4) and the solvent evaporated to afford the title compound as a dark brown oil, 41.7 g (41%): 1H NMR (CDCl3) δ1.07 (d, 3H), 1.17 (d, 3H), 1.36 (m, 6H), 2.77 (m, 1H), 2.97 (m, 1H), 3,51 (br, 1H), 3.81 (m, 1H), 4.50 (dd, 1H), 7.39 (m, 5H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26](=[O:30])[C:27]([OH:29])=[O:28])=[CH:18]1.[F:31][C:32]1[C:37](O)=[C:36]([F:39])[C:35]([F:40])=[C:34]([F:41])[C:33]=1[F:42].C(O)(=O)C>O1CCCC1>[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26](=[O:30])[C:27]([O:29][C:37]2[C:36]([F:39])=[C:35]([F:40])[C:34]([F:41])=[C:33]([F:42])[C:32]=2[F:31])=[O:28])=[CH:18]1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: Cn1cc(C(=O)C(=O)O)c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c2ccccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 21.9 %

Procedure:
1.13 g (5.5 mol) of dicyclohexylcarbodiimide were added to a solution, cooled in ice, of 1 g (5 mmol) of 1-methylindole-3glyoxylic acid and 1.01 g (5 mmol) of pentafluorophenol in 50 ml of dry tetrahydrofuran. After stirring for 4 hours under a nitrogen atmosphere at 0° C., the mixture was allowed to warm to room temperature and left to stand for 60 hours. Then, 3 ml of glacial acetic acid were added and the mixture obtained was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane for the elution to give 404 mg (22%) of pentafluorophenyl 1-methylindole-3-glyoxylate in the form of a pale yellow solid of melting point 168°-9° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Si:9]([O:16][C@H:17]([CH2:23][C:24](=[O:32])[CH2:25]P(OC)(OC)=O)[CH2:18][C:19]([O:21][CH3:22])=[O:20])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(O)(C)C>[Si:9]([O:16][C@H:17]([CH2:23][C:24](=[O:32])/[CH:25]=[CH:1]/[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:18][C:19]([O:21][CH3:22])=[O:20])([C:12]([CH3:14])([CH3:13])[CH3:15])([CH3:11])[CH3:10]
Reactant: COC(=O)C[C@@H](CC(=O)CP(=O)(OC)OC)O[Si](C)(C)C(C)(C)C
Reactant: O=Cc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COC(=O)C[C@@H](CC(=O)/C=C/c1cccnc1)O[Si](C)(C)C(C)(C)C
Temperature: 22 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
In 5 mL of isopropanol (water content: 10,000 ppm) were dissolved 140 mg (1.3 mmol.) of nicotinaldehyde (pyridin-3-aldehyde) and 500 mg (1.3 mmol.) of methyl (R)-3-[(tert-butyldimethylsilyl)oxy]-6-(dimethoxyphosphinyl)-5-oxohexanoate (optical purity: 99% ee) to give an alcoholic solution. To the alcoholic solution was added 181 mg (1.3 mmol) of potassium carbonate, and the mixture was stirred for 3 hours at room temperature (22° C.). To the resulting reaction mixture was added 20 mL of ethyl acetate, and the mixture was stirred and washed with 10 mL of water. The washing was repeated twice. The organic phase was separated, dried over anhydrous magnesium sulfate, and filtered to give a filtrate. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent:hexane/ethyl acetate=1/1, volume ratio) to give 469 mg (yield: 99%) of methyl (3R,6E)-3-[(tert-butyldimethylsilyl)oxy]-5-oxo-7-(pyridin-3-yl)-6-heptenoate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1C=O.[C:8](O)(=O)[CH2:9][C:10]([OH:12])=[O:11].N1CCCCC1>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:9](=[CH2:8])[C:10]([OH:12])=[O:11]
Reactant: O=Cc1cccs1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: C=C(C(=O)O)c1cccs1

Procedure:
2-thienyl acrylic acid was prepared by reaction of 2-thiophene carboxaldehyde with malonic acid. A solution of 2-thiophene carboxaldehyde (25.7 g.), malonic acid (41.6 g.), pyridine (100 ml.), and piperidine (2 ml.) was refluxed for 31/2 hours. 2-thienyl acrylic acid was recovered from the reaction mixture in a manner parallel to that described in Example 41.
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[CH2:3][C:4]#[N:5].[N+:7]([CH3:10])([O-:9])=[O:8].C1CCN2C(=NCCC2)CC1>ClCCl>[CH3:1][C:2]([CH3:6])([CH2:10][N+:7]([O-:9])=[O:8])[CH2:3][C:4]#[N:5]
Reactant: C[N+](=O)[O-]
Reactant: C=C(C)CC#N
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(CC#N)C[N+](=O)[O-]
Temperature: 103 °C
Yield: 93.6 %

Procedure:
In a one liter glass reactor equipped with a thermometer, a cooling apparatus and a stirrer, 3-methyl-3-butenenitrile (37.0 g, 0.456 mol) and nitromethane (557.0 g, 9.125 mol) were charged. Then, 1,8-diazabicyclo[5.4.0]-7-undecene (13.9 g, 0.091 mol) was dropwise added over a period of 5 minutes at room temperature while stirring. After the dropwise addition, the mixture was heated and refluxed at 103° C. for 13.5 hours. After cooling the mixture to room temperature, unreacted nitromethane was evaporated off under reduced pressure. To the residue, dichloromethane (300 g) and 5% sulfuric acid (300 g) were added and stirred. Thereafter, the mixture was phase separated to obtain a dichloromethane layer. To the aqueous layer, dichloromethane (300 g) was added and the mixture was phase separated to obtain a dichloromethane layer. Two dichloromethane layers were combined and washed with water (300 g). After drying the dichloromethane solution over anhydrous sodium sulfate, dichloromethane was evaporated off under reduced pressure to obtain brown crystal 3,3-dimethyl-4-nitrobutanenitrile (60.7 g), a purity of which was 92.0%. Its yield was 86.1% based on 3-methyl-3-butenenitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].Br[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: COc1ccc(CCBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 5.6 %

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.22 g, 0.001 mol) was dissolved in N-methyl 2-pyrolidone (3.0 mL). Powdered potassium hydroxide (0.224 g, 0.004 mol) was added and heated at 100 deg C. for 3 h. 1-(2-Bromo-ethyl)-4-methoxy-benzene (0.214 g, 0.001 mol) was added at the same temperature and stir for 6 h. at RT. Reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (4% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as light yellow oil (0.02 g, 6% yield). 8-Chloro-5-[2-(4-methoxy-phenyl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.020 g, 0.0564 mol) was dissolved in THF (1.0 mL), A solution of oxalic acid dihydrate (0.007 g, 0.0564 mol) in 1.5 mL THF was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as white solid (0.01 g, 40% yield).
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[C:32]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:33]=4)=[CH:22][CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[C:32]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:33]=4)=[CH:22][CH:21]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cncc(-c4ccccc4)c3)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3cncc(-c4ccccc4)c3)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
After a mixture of ethyl 3-[3-phenyl-1-[4-(5-phenyl-3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (980 mg), 1N aqueous sodium hydroxide solution (4 ml), tetrahydrofuran (10 ml) and ethanol (10 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (4 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-phenyl-1-[4-(5-phenyl-3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (760 mg, yield: 82%). This was recrystallized from acetone-hexane. Melting point: 161–162° C.
Reaction SMILES: I[C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C1(C)C=CC=CC=1>[C:15]1([C:2]2[C:7]3[O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: Ic1cccc2c1oc1ccccc12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2cccc3c2oc2ccccc23)cc1
Temperature: 25 °C

Procedure:
4-iododibenzo[b,d]furan (4 g, 13.60 mmol), phenylboronic acid (1.99 g, 16.32 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (0.447 g, 1.08 mmol), Pd2(dba)2 (0.250 g, 0.272 mmol), K3PO4 (10.1 g, 47.6 mmol), 150 mL toluene and 15 mL water were charged in a 250 mL flask. The reaction mixture was degassed by bubbling N2 for 30 minutes and then heated to reflux under N2 overnight. The reaction was cooled to room temperature and the crude product was purified by silica gel column to yield 3.3 g (99%), which was confirmed by GC-MS.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1OCCOCC1CC1
Reactant: CC(C)(C)N
Product: CC(C)(C)NCC(O)COc1ccc(OCCOCC2CC2)cc1
Yield: 74 %

Procedure:
Following the procedure of Example I, 1-{4-[2-(cyclopropylmethoxy)-ethoxy]-phenoxy}-2,3-epoxy-propane is prepared and then treated with t-butylamine. 7.6 g (yield=74%) of crude 1{4-[2-(cyclopropylmethoxy)-ethoxy]phenoxy}-3-t-butylamino-propan-2-ol are thus obtained, and this material is converted to the fumarate by mixing stoichiometric amounts of the base and of the acid in solution in isopropanol. The neutral fumarate which has precipitated is filtered off and recrystallised from ethanol (yield=80%), M.p.=158°-160° C.