Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])=[O:16])=[CH:10][CH:9]=1)[NH2:6].[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:28]=1[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])=[O:16])=[CH:12][CH:13]=1)[NH:6][C:29]([C:28]1[C:32]([CH3:36])=[CH:33][CH:34]=[CH:35][C:27]=1[Cl:26])=[O:30]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1c(C)cccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 105.9 %

Procedure:
To a solution of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester hydrochloride salt (272.5 mmol, 110 g) and 2-chloro-6-methyl benzoic acid (276 mmol, 47.15 g) in DMF (600 mL) were added HBTU (276 mmol, 105 g) and diisopropylethylamine (1.24 mol, 119 mL) at room temperature. The clear solution was stirred 48 h at room temperature at which time TLC analysis of the reaction mixture indicated the absence of the starting material. The reaction mixture was poured slowly into 5 L of water which contained some ice to lower the temperature. The white precipitated solid was allowed settle and the solid was collected by filtration. The solid cake was washed with water (1 L) and hexane (1 L) and air dried to obtain 150 g of a crude product. This solid product was dissolved in hot acetonitrile (1 L) and cooled in the refrigerator. The solid was collected by filtration and washed with hexane (500 mL) and air dried to obtain 101.1 g. The mother liquor was concentrated and the residue was purified by silica gel column chromatography eluting with dichloromethane and ethyl acetate (15:1) to obtain another 17.07 g (total=118.17 g, 83%). mp 244-245° C. 1H NMR, DMSO-d6 (400 MHz) δ10.66 (s, 1H), 8.83 (d, 1H, J=19 Hz), 7.47-7.6 (m, 5H), 7.15-7.29 (m, 5H), 4.58-4.68 (m, 1H), 3.65 (s, 3H), 3.12 (dd, 1H, J=17, 13 Hz), 2.87 (dd, 1H, J=17, 11 Hz), 2.09 (s, 3H). HR MS: Obs. mass. 518.0652. Calcd. mass, 518.0641.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH:12][C:13](=[NH:22])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[CH:5]=1.[O-]Cl.[Na+].C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:22]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)[NH:12][C:6]=2[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)=[O:23]
Reactant: COC(=O)c1ccc(OC)c(NC(=N)c2ccc(F)c(Cl)c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Product: COC(=O)c1ccc(OC)c2[nH]c(-c3ccc(F)c(Cl)c3)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 29.4 %

Procedure:
3-[(3-chloro-4-fluoro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester (3.24 g, 9.62 mmol) was dissolved in 50% methanol and 5% NaOCl (18 ml, 11.90 mmol) was added dropwise thereto at room temperature. After 5 min, Na2CO3 (2.04 g, 19.25 mmol) was added dropwise thereto and refluxed for 5 min. The resulting solution was cooled to room temperature, extracted with ethyl acetate, and the extract was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (0.95 g, 2.83 mmol) in a yield of 30%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:25])(=[O:24])[N:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].O[Li].O>O1CCOCC1.O>[C:20]([N:18]([CH3:19])[S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1)(=[O:25])=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc(-c2ccc(S(=O)(=O)N(C)C(C)(C)C)cc2)cc1
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CN(C(C)(C)C)S(=O)(=O)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Procedure T′: A 15 mL dioxane/H2O (2:1) mixture of 4′-(tert-butyl-methyl-sulfamoyl)-biphenyl-4-carboxylic acid methyl ester (318 mg, 0.88 mmol) and LiOH—H2O (46 mg, 1.1 mmol) is stirred at room temperature overnight. The reaction mixture is concentrated, is diluted with EtOAc, shaken with 1 N HCl, and the layers are separated. The 1 N HCl layer is extracted with EtOAc and the combined organic layers are washed with brine, then dried over Na2SO4 and evaporated to give the intermediate 4′-(tert-butyl-methyl-sulfamoyl)-biphenyl-4-carboxylic acid (270 mg, 88% yield). MS (ES−) 346.1 (M−H)−
Reaction SMILES: [CH2:1]([CH:4]1[NH:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([NH2:16])[CH2:6][CH2:5]1)[CH2:2][CH3:3].C([C@@H]1N[C@@H](C2C=CC=CC=2)[C@@H](N)CC1)CC.C([C@H]1N[C@H](C2C=CC=CC=2)[C@H](N)CC1)CC.[CH3:49][O:50][C:51]1[CH:60]=[C:59]2[C:54]([N:55]([CH3:63])[C:56](=[O:62])[CH:57]3[CH2:61][CH:58]32)=[CH:53][C:52]=1[CH:64]=O>>[CH3:49][O:50][C:51]1[CH:60]=[C:59]2[C:54]([N:55]([CH3:63])[C:56](=[O:62])[CH:57]3[CH2:61][CH:58]32)=[CH:53][C:52]=1[CH2:64][NH:16][CH:7]1[CH2:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[NH:9][CH:8]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCC1CCC(N)C(c2ccccc2)N1
Reactant: COc1cc2c(cc1C=O)N(C)C(=O)C1CC21
Agent: CCC[C@@H]1CC[C@@H](N)[C@@H](c2ccccc2)N1
Agent: CCC[C@H]1CC[C@H](N)[C@H](c2ccccc2)N1
Product: CCCC1CCC(NCc2cc3c(cc2OC)C2CC2C(=O)N3C)C(c2ccccc2)N1

Procedure:
By a procedure similar to the previous examples 9 and 9A: prepared through the reaction of 6-propyl-2-phenyl-piperidin-3-ylamine [or (2S,3S,6S)-6-propyl-2-phenyl-piperidin-3-ylamine or (2R,3R,6R)-6-propyl-2-phenyl-piperidin-3-ylamine] with 6-Methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde [or (1S,1aR)-6-Methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde or (1R,1aS)-6-Methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde].
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12].Br[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C@H:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:22][CH2:21]2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[C@H:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:22][CH2:21]3)=[C:3]([CH2:10][CH2:11][CH3:12])[CH:4]=1)#[N:7]
Reactant: CCCc1cc(C#N)ccc1O
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCBr)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(C#N)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Temperature: 40 °C
Reaction time: 16 h
Yield: 65.8 %

Procedure:
To a mixture of 4-hydroxy-3-propylbenzonitrile (Example 29, 0.5 g, 3.1 mmol), ethyl [(1S)-5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 45, 1.1 g, 3.1 mmol) and Cs2CO3 (1.2 g, 3.7 mmol) in DMF (10 mL) was added water (6 drops). The reaction mixture was stirred at 40° C. for 16 h and then concentrated under reduced pressure. The residue was taken up in water and extracted with EtOAc (2×). The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/Hexane (v/v)=1:20) gave 0.86 g (66%) of the title compound as a light yellow oil. LC-MS: RT=4.12 min; (M+H)+ 422.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1/[CH:10]=[CH:11]/[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][N:13]=1)([O-])=O.[Sn].Cl.[OH-].[Na+]>C(O)C>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](/[CH:11]=[CH:10]/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])=[N:13]1
Reactant: O=[N+]([O-])c1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 40 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
(E)-3-[2-(2-nitrophenyl)vinyl]-1H-indazole (4 g, 15.08 mmol) obtained in Example 1 was dissolved in ethanol (68 mL), and the solution was added with tin (3.85 g, 32.40 mmol) and concentrated hydrochloric acid (34 mL, 400 mmol) under ice-cooling, followed by stirring at 40° C. for 3 hours. To the reaction mixture, 6 mol/L aqueous sodium hydroxide solution was added to neutralize the mixture under ice-cooling. Then the mixture was filtered. The filtrate was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. The residue was triturated in ethyl acetate to obtain Compound 2 (2.98 g, 84%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12]/[CH:13]=[N:14]/[NH:15]C(OCC)=O.[S:21](Cl)(Cl)=O>>[S:21]1[C:12]([N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])=[CH:13][N:14]=[N:15]1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)N/N=C/CN1C(=O)c2ccccc2C1=O
Product: O=C1c2ccccc2C(=O)N1c1cnns1
Reaction time: 24 h
Yield: 59.9 %

Procedure:
Ethyl (2E)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethylidene]hydrazinecarboxylate (612 mg, 2.22 mmol) was slowly added to thionyl chloride (1.5 ml), and the mixture was stirred for 1 day. Crystals were collected by filtration and washed with ethyl acetate to give 308 mg (59.9%) of the desired product as a solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)[C:6]([C:19]([NH2:21])=[O:20])=[CH:5][N:4]=1.C(OO)(C)=[O:23]>C(C#N)(C)=O>[CH3:1][S:2]([C:3]1[N:8]=[C:7]([NH:9][C:10]2([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:11][CH2:12]2)[C:6]([C:19]([NH2:21])=[O:20])=[CH:5][N:4]=1)=[O:23]
Reactant: CSc1ncc(C(N)=O)c(NC2(c3ccccc3)CC2)n1
Reactant: CC(=O)OO
Agent: CC(=O)C#N
Product: CS(=O)c1ncc(C(N)=O)c(NC2(c3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 2-(methylthio)-4-(1-phenylcyclopropylamino)pyrimidine-5-carboxamide (636 mg) in AcCN (3 mL) was added AcOOH (39% in AcOH, 0.7 mL). The mixture was stirred at room temperature for 20 h, and the solids were collected by filtration and dried in vacuo to give 2-(methylsulfinyl)-4-(1-phenylcyclopropylamino) pyrimidine-5-carboxamide (530 mg). MS 317.2 (M+H).
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].[Cl:34]([O-:38])(=[O:37])(=[O:36])=[O:35].[Li+]>C(O)(=O)C>[Cl:34]([O-:38])(=[O:37])(=[O:36])=[O:35].[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S+:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCCC(=O)c1ccccc1)c1ccccc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(=O)O
Product: c1ccc(-c2cccc(-c3ccccc3)[s+]2)cc1
Yield: 24 %

Procedure:
The 1,5-diphenyl-1,5-pentanedione prepared in step 1 (10 mmol, 2.52 g) is mixed with phosphorus pentasulfide (15 mmol, 3.34 g), acetic acid (60 mL) and lithium perchlorate (60 mmol, 6.40 g) in a 100 mL two-necked round-bottomed flask, and then refluxed for 3 hours. The solution then becomes orange and a white precipitate forms. The precipitate is removed by filtration on a sinter funnel and then washed with hot acetic acid. The solution is concentrated on a rotary evaporator and recrystallized by addition of ether (500 mL). The precipitate obtained is filtered off on a sinter funnel and then dried on a rotary evaporator. The product obtained is a yellow solid in a mass of 850 mg. The reaction yield is 24%.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:21])[CH2:4][CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.[Cl:22]C1C=CN=C2NC=C(C(C3C=CC=CC=3)C3C(=O)OC(C)(C)OC3=O)C=12>>[Cl:22][C:13]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:8][CH:7]=[C:6]([CH:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:4][C:3]([NH:2][CH3:1])=[O:21])[C:14]=12
Reactant: CC1(C)OC(=O)C(C(c2ccccc2)c2c[nH]c3nccc(Cl)c23)C(=O)O1
Reactant: CNC(=O)CC(c1ccccc1)c1c[nH]c2ncccc12
Product: CNC(=O)CC(c1ccccc1)c1c[nH]c2nccc(Cl)c12
Yield: 73 %

Procedure:
3-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-3-phenyl-propionamide was prepared (73% yield) following the procedure described for preparation of N-methyl-3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionamide in Example 1, using 5-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione.
Reaction SMILES: [C:1]([CH2:4][S:5][C:6](=[N:13][OH:14])[C:7]([N+:10]([O-:12])=[O:11])([CH3:9])[CH3:8])(=[O:3])[NH2:2].[CH3:15][N:16]=[C:17]=[O:18]>C(N(CC)CC)C.C(#N)C>[CH3:15][NH:16][C:17]([O:14][N:13]=[C:6]([S:5][CH2:4][C:1](=[O:3])[NH2:2])[C:7]([N+:10]([O-:12])=[O:11])([CH3:9])[CH3:8])=[O:18]
Reactant: CN=C=O
Reactant: CC(C)(C(=NO)SCC(N)=O)[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNC(=O)ON=C(SCC(N)=O)C(C)(C)[N+](=O)[O-]
Yield: 71.5 %

Procedure:
A mixture of 10 g (0.045 m) of 1-(carbamoylmethylthio)-2-nitro-2-methylpropionaldoxime, 150 ml. acetonitrile, 8.0 g (0.14 m) of methylisocyanate and three drops of triethylamine was allowed to stand at room temperature, with occasional shaking, for twenty hours. The acetonitrile and excess methyl isocyanate was removed from the product under reduced pressure. The solid residue was recrystallized from isopropanol and then dried at room temperature to give 9.0 g (72% yield) of 1-(carbamoylmethylthio)-2-nitro-2-methylpropionaldehyde O-(methylcarbamoyl)oxime; melting point=125-127° C. The nmr spectra confirmed the structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:41][C:42]1[CH:57]=[CH:56][C:45]([CH2:46][N:47]2[CH:52]=[C:51]([CH2:53][OH:54])[CH:50]=[CH:49][C:48]2=[O:55])=[CH:44][CH:43]=1>C1COCC1>[Cl:41][C:42]1[CH:43]=[CH:44][C:45]([CH2:46][N:47]2[CH:52]=[C:51]([CH2:53][O:54][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:50]=[CH:49][C:48]2=[O:55])=[CH:56][CH:57]=1
Reactant: O=c1ccc(CO)cn1Cc1ccc(Cl)cc1
Reactant: COc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(OCc2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
According to Scheme 16 Method B: 4-Methoxyphenol (1.5 eq, 0.68 mmol, 84.3 mg), PPh3 (2.0 eq, 0.91 mmol, 0.30 g) and DEAD (2 eq, 0.91 mmol, 0.16 g) were added to a solution of 1-(4-chlorobenzyl)-5-(hydroxymethyl)pyridin-2(1H)-one (1 eq, 0.45 mmol, 0.11 g) in THF (5 mL). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent, the reaction mixture was diluted with water. The organic layer washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2) using cyclohexane/AcOEt 80/20 to afford 1-(4-chlorobenzyl)-5-((4-methoxyphenoxy)methyl)pyridin-2(1H)-one (0.19 mmol, 0.07 g, 42%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:21]=[N:22][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[CH:24][CH:25]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:18][CH2:19][C:20]2[CH:21]=[N:22][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[CH:24][CH:25]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)nc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2CO)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a solution of ethyl 1-benzyl-3-[(6-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-pyridinyl)methoxy]-1H-pyrazole-4-carboxylate (1.00 g) in tetrahydrofuran (30 mL) was added lithium aluminum hydride (0.15 g) at 0° C. and the mixture was stirred at room temperature for 2 hrs. Sodium sulfate decahydrate (1.25 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated to give {1-benzyl-3-[(6-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-pyridinyl)methoxy]-1H-pyrazol-4-yl}methanol as colorless crystals (0.87 g, yield 95%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 94-95° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[F:8][CH2:9][C:10]([CH2:12][F:13])=O.C(OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[F:8][CH2:9][C:10]1([CH2:12][F:13])[O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2][O:1]1
Reactant: OCC(CO)CO
Reactant: O=C(CF)CF
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: COC(OC)OC
Solvent: O
Product: OCC1COC(CF)(CF)OC1
Temperature: 60 °C
Reaction time: 10 h
Yield: 42.4 %

Procedure:
A mixture of 2-(hydroxymethyl)-1,3-propanediol (2.2 g, 20.7 mmol), 1,3-difluoroacetone (3.89 g, 41.4 mmol), trimethyl orthoformate (3.44 ml, 20.7 mmol), and p-toluenesulfonic acid monohydrate (356 mg, 2.07 mmol) was stirred at 60° C. for 10 hours. After completion of the reaction, triethylamine (577 μl) was added to the reaction mixture, which was then concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to obtain the title compound (1.6 g, yield: 43.4%) as a light yellow oil.
Reaction SMILES: [CH2:1]([N:4]1[C@H:18]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19]=3[C:16]([CH2:17]2)=[CH:15][NH:14]4)=[CH:7][C@@H:6]([C:20]([OH:22])=O)[CH2:5]1)[CH2:2][CH3:3].[NH3:23]>C(O)CO>[CH2:1]([N:4]1[C@H:18]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19]=3[C:16]([CH2:17]2)=[CH:15][NH:14]4)=[CH:7][C@H:6]([C:20]([NH2:23])=[O:22])[CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCN1C[C@H](C(=O)O)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: N
Solvent: OCCO
Product: CCCN1C[C@@H](C(N)=O)C=C2c3cccc4[nH]cc(c34)C[C@H]21

Procedure:
By allowing 3.1 g of the methyl ester of 9,10-didehydro-6-n-propyl-8β-ergoline carboxylic acid to stand in a solution of ammonia in ethylene glycol, a mixture of the isomeric amides is obtained; chromatographic separation of the reaction product yields 1.2 g of 9,10-didehydro-6-n-propyl-8α-ergoline carboxylic acid amide. [α]D25 =+297°; c=0.5 (pyridine).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-])=O)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C([O-])(=O)C.[NH4+].C(=O)([O-])O.[Na+]>CC(C)=O.[Cl-].[Ti+3].[Cl-].[Cl-]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH2:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Ti+3]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Yield: 51.6 %

Procedure:
5-Nitro-1H-indole-2-carboxylic acid ethyl ester (14.9 mmol) was suspended in acetone (50 ml) and added to a mixture of titanium(III) chloride (91 ml, >10% in 2M hydrochloric acid) and ammonium acetate (265 ml, 4M). The reaction was stirred for 2 h and neutralized with saturated sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (100 ml) and the organic layer dried (MgSO4). The solvent was removed in vacuo to give a light brown solid which was purified by silica chromatography to give the title compound as an off-white solid (1.57 g) m/z=205 in MS ES+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]([NH2:19])=[O:18].[Cl:20][C:21]1[CH:22]=[C:23]([CH2:29][C:30](OC)=O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:29][C:30]1[NH:19][C:17](=[O:18])[C:3]2[C:4]([CH3:16])=[N:5][N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[C:2]=2[N:1]=1
Reactant: CCCCCCC(CC)n1nc(C)c(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc(OC)c(Cl)c1
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CC)n1nc(C)c2c(=O)[nH]c(Cc3ccc(OC)c(Cl)c3)nc21
Yield: 46.4 %

Procedure:
13 mg (0.050 mmol) of 5-amino-3-methyl-1-(3-nonyl)-1H-pyrazole-4-carboxamide and 53 mg (0.248 mmol) of methyl 3-chloro-4-methoxyphenylacetate are refluxed for 6 hours in 0.5 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 10 mg (47%) of a solid, Rf=0.265 (dichloromethane/methanol=15:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[CH:10]1[C:27]([O-:29])=[O:28].COC1C=CC=CC=1C1C2C(=CC=CC=2)C(C2C=CC3OCOC=3C=2)=C1C(OCC)=O>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[CH:10]1[C:27]([OH:29])=[O:28]
Reactant: COc1ccccc1C1c2ccccc2C(c2ccc3c(c2)OCO3)C1C(=O)[O-]
Agent: [Pd]
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccccc1OC
Solvent: CCO
Product: COc1ccccc1C1c2ccccc2C(c2ccc3c(c2)OCO3)C1C(=O)O
Reaction time: 8 h
Yield: 100 %

Procedure:
Ethyl (1RS, 2RS, 3RS)-1-(2-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate. To a solution of ethyl (RS)-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (90 mg, 0.22 mmol) in EtOH (10 ml) was added 10% palladium on activated carbon (90 mg). The resulting suspension was shaken on a Parr hydrogenator at 60 psi H2 overnight, then was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford the title compound (90 mg, 100%), which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[CH:24]1([Mg]Cl)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)([OH:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: Cl[Mg]C1CCCCC1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1(O)C1CCCCC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 30.2 %

Procedure:
6-Methoxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (78 mg, 0.253 mmol) obtained in Example 1 was dissolved in THF, and 18%-cyclohexylmagnesium chloride (0.7 mL, 0.506 mmol) was added thereto, followed by stirring for 5 hrs at 0° C. The resulting mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 30 mg of the titled compound (yield: 30%).