Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[C:14]3[C:9]([CH2:10][CH2:11][CH2:12][CH:13]3O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:17]1[CH:21]=[C:20]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[N:19]=[CH:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC)=O)=NC(OC)=O>C1COCC1>[CH:25]([O:24][C:22]([C:20]1[N:19]([CH:13]2[C:14]3[C:9](=[CH:8][CH:7]=[C:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:15]=3)[CH2:10][CH2:11][CH2:12]2)[CH:18]=[N:17][CH:21]=1)=[O:23])([CH3:27])[CH3:26]
Reactant: OC1CCCc2ccc(N3CCCC3)cc21
Reactant: CC(C)OC(=O)c1c[nH]cn1
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1cncn1C1CCCc2ccc(N3CCCC3)cc21
Reaction time: 0.17 h

Procedure:
To a suspension of 7-pyrrolidin-1-yl-3,4-dihydro-2H-naphthalen-1-ol (0.300 g, 1.382 mmol), and isopropyl 4-imidazolecarboxylate (0.149 g, 0.967 mmol), which can be prepared as described in Example 1, in THF (10 mL) at 0° C. is added triphenylphosphine (0.293 g, 1.382 mmol) and dimethyl azodicarboxylate (40% wt. in toluene, 0.505 g, 1.382 mmol). After 10 minutes, the cooling bath is removed and the mixture is stirred for another 30 minutes. Water is added and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The resulting residue is purified by silica gel chromatography (elution with hexanes-ethyl acetate mixtures) to give 3-(7-pyrrolidin-1-yl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 354.2 (M+H)+; 1H NMR (400 MHz, MeOD) δ ppm 1.40 (d, J=6.3 Hz, 3 H), 1.41 (d, J=6.3 Hz, 3 H), 1.66-1.75 (m, 1 H), 1.79-1.87 (m, 1 H), 1.98-2.01 (m, 4 H), 2.13-2.25 (m, 2 H), 2.77 (ddd, J=16.7, 8.8, 5.3 Hz, 1 H), 2.88 (dt, J=16.7, 5.6 Hz, 1H), 3.12-3.24 (m, 4 H), 5.27 (sept, J=6.3 Hz, 1 H), 6.14 (d, J=2.5 Hz, 1 H), 6.24 (t, J=5.1 Hz, 1 H), 6.62 (dd, J=8.6, 2.5 Hz, 1 H), 7.08 (d, J=8.6 Hz, 1 H), 7.31 (s, 1 H), 7.73 (d, J=1.3 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]([O:25]CC)=[O:24])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCOCC1.Cl>O1CCCC1.C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=3)=[CH:11][C:10]([C:23]([OH:25])=[O:24])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cc(C(=O)O)nn2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A mixture of ethyl 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxylate (4.4 g) and 4N sodium hydroxide (5.7 ml) in tetrahydrofuran (20 ml), ethanol (10 ml and dioxane 20 ml was stirred at ambient temperature overnight. Water (50 ml) was added, and the mixture was acidified with hydrochloric acid. The precipitates were filtered and washed with water to give colorless crystals of 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxylic acid (4.1 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([N+:16]([O-])=O)=[C:14]([F:19])[CH:13]=[C:12]([O:20][CH3:21])[C:11]=1[F:22].[O-]S(S([O-])=O)=O.[Na+].[Na+].O>CCO>[F:19][C:14]1[CH:13]=[C:12]([O:20][CH3:21])[C:11]([F:22])=[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[C:15]=1[NH2:16]
Reactant: COc1cc(F)c([N+](=O)[O-])c(Nc2ccc(I)cc2F)c1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(F)c(N)c(Nc2ccc(I)cc2F)c1F
Temperature: 70 °C
Yield: 87.7 %

Procedure:
A suspension of 2-fluoro-N-(2,5-difluoro-3-methoxy-6-nitrophenyl)-4-iodobenzeneamine (12.5 g, 29.5 mmol) in EtOH (200 mL) was heated at 70° C. to form a clear transparent solution and to this hot solution was added dropwise a freshly prepared solution of Na2S2O4 in water (15 g, 86 mmol, in 30 mL). The mixture was further heated for 1 h at 90° C. Upon cooling to room temperature the mixture was concentrated to remove ethanol under reduced pressure. The residue was diluted with ethyl acetate (25 mL), washed with water and brine, The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure to yield off white solid (10.2 g, 88%). The solid was used as was in the next reaction without purification.
Reaction SMILES: Cl[Sn](Cl)(Cl)Cl.ClC([O:9][CH3:10])Cl.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[CH3:19]>ClCCl>[CH3:11][C:12]1[C:13]([CH3:19])=[C:14]([CH3:18])[CH:15]=[CH:16][C:17]=1[CH:10]=[O:9]
Reactant: Cc1cccc(C)c1C
Reactant: COC(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(C=O)c(C)c1C
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of SnCl4 (39 g, 0.15 mol) in 50 mL of dichloromethane was added dropwise at -5° C. a solution of 15 g (0.13 mol) of dichloromethylmethylether. This solution was stirred at -5° C. for one hour before adding dropwise over 10 min a solution of 12 g (0.1 mol) of 1,2,3-trimethylbenzene. The mixture was stirred at 0° C. for 15 min before warming to room temperature where it was stirred an additional 1.5 hrs. After quenching onto 100 g of ice the organic layer was separated, washed with water, saturated aqueous sodium bicarbonate and water before drying over Na2SO4, filtering and evaporating to dryness in vacuo. The product was purified by distillation in vacuo. B.p. 120°-122° C. (11 mm). Lit. b.p. 121.5 (11 mm) Yield: 9.2 g (70%).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([OH:3])=O.S(Cl)(Cl)=O.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>C(OCC)(=O)C>[N:11]1([CH2:10][CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:4]([C:1]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:3])=[CH:5][CH:6]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(OCCn2ccnc2)cc1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(c1ccc(OCCn2ccnc2)cc1)N1CCOCC1

Procedure:
Successive treatment of 1-[2-(4-carboxyphenoxy)ethyl]imidazole (1.4 g) with thionyl chloride (1.4 g) and morpholine (10 ml) as described in Example 25 gave N-[4-(2-imidazol-1-yl)ethoxybenzoyl]morpholine, m.p. 109°-111° C. (from ethyl acetate). Found: C, 63.80; H, 6.40; N, 13.87. C16H19N3O3 requires: C, 63.77; H, 6.36; N, 13.94%.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH:13]([CH3:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH:13]([CH3:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(C)NS(=O)(=O)c1cccc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: CCOC(=O)CC(C)NS(=O)(=O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.8 %

Procedure:
A mixture of β-[[(3-methoxypheyl)sulfonyl]amino]-butanoic acid, ethyl ester (7.8 g, 25.7 mmol) and ethanethiol (8 g, 0.13 mol) in methylenechloride (200 ml) was cooled in ice-bath. Aluminum chloride (17.2 g, 0.13 mol) was added to above soultion. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with 3N HCl (200 ml). Organic layer was separated. Aqueous layer was extracted with methylene chloride (2×100 ml). Combined organic solution was concentrated and dried to give the title compound (7 g, 94%). The material was used for the next reaction without further purification. 1H NMR (300 MHz, CD3OD) □|□d, 3H, J=6.73 Hz), 1.23 (t, 3H, J=7.11 Hz), 2.31-2.49 (m, 2H), 3.66-3.74 (m, 1H), 4.01-4.16 (m, 2H), 7.00-7.04 (m, 1H), 7.27-7.41 (m, 3H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:22](=[O:24])[CH3:23])[CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:25]([O:27]C)=[O:26])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[OH-]>CO.O>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:22](=[O:24])[CH3:23])[CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:25]([OH:27])=[O:26])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)[C@@H]1C[C@H](N(C(C)=O)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)N(C1CCC(C)(C)CC1)[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
Methyl(2S,4S)-1-BOC-4-[acetyl(4,4-dimethylcyclohexyl)amino]pyrrolidine-2-carboxylate (0.98 g, 2.47 mmol) obtained in Step B, was dissolved in MeOH (8 mL) and water (1.6 mL). LiOH (0.18 g, 7.52 mmol) was added thereto at 0˜5° C. After the reaction mixture was stirred at room temperature for 3 hours and concentrated in vacuo, the obtained residue was diluted with water and the solution was extracted with EtOAc. The extracted organic solution was washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound (0.92 g, 97%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[Cl:23][C:24]1[CH:29]=[C:28]([N:30]=[C:31]=[O:32])[CH:27]=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]>>[Cl:23][C:24]1[CH:29]=[C:28]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:22])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:32])[CH:27]=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]
Reactant: O=C=Nc1ccc(C(F)(F)F)c(Cl)c1
Reactant: C[C@@H]1NCCN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(C(F)(F)F)c(Cl)c1
Yield: 83 %

Procedure:
In analogy to the procedure described in Example 30, (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 13) and 2-chloro-4-isocyanato-1-trifluoromethyl-benzene (intermediate 16) gave the titled compound in 83% yield as white foam. MS: 531.20 (MH+, 1Cl).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([CH3:30])[CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:17]=[C:18]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:19]=[CH:20][CH:21]=1)([CH3:3])[CH3:2].[CH:31](OC1C=CC=CC=1NCCNCC1C=C(C(N2CCCCC2)=O)C=CC=1)(C)C>>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([CH3:30])[CH2:12][CH2:13][N:14]([CH2:15][C:16]1[CH:17]=[C:18]([C:22]([N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:23])[CH:19]=[CH:20][CH:21]=1)[CH3:31])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccccc1NCCNCc1cccc(C(=O)N2CCCCC2)c1
Reactant: CC(C)Oc1ccccc1N(C)CCNCc1cccc(C(=O)N2CCCCC2)c1
Product: CC(C)Oc1ccccc1N(C)CCN(C)Cc1cccc(C(=O)N2CCCCC2)c1

Procedure:
The title compound was prepared as in Example 27 substituting [3-({2-[(2-isopropoxy-phenyl)-methyl-amino]-ethylamino}-methyl)-phenyl]-piperidin-1-yl-methanone for (3-{[2-(2-isopropoxy-phenylamino)-ethylamino]-methyl}-phenyl)piperidin-1-yl-methanone. MS (ESI): mass calculated for C26H37N3O2, 323.29; m/z found, 324.5 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.71 (dd, J=5.9, 3.3 Hz, 1H), 7.53 (dd, J=5.9, 3.3 Hz, 1H), 7.30-7.33 (m, 2H), 6.93-6.82 (m, 4H), 4.59 (hept, J=6.1 Hz, 1H), 3.70 (br s, 2H), 3.52 (s, 2H), 3.31 (br s, 2H), 3.25 (t, J=7.3 Hz, 2H), 2.80 (s, 3H), 2.63 (t, J=7.3 Hz, 2H), 2.19 (s, 3H), 1.67 (br s, 6H), 1.35 (d, J=6.1 Hz, 6H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][C:13](=O)[CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([Cl:21])[CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc2c([nH]1)CCN(Cc1ccccc1)C2
Product: Clc1ccc2c(n1)CCN(Cc1ccccc1)C2
Temperature: 100 °C

Procedure:
To POCl3 (20 mL) is added 6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one (1.21 g, 5.04 mmol) and the mixture is heated at 100° C. for 6 hr. Solvent is removed and the thick oil is poured onto crashed ice (60 g). Upon stirring, solid Na2CO3 is added to the suspension until pH>7. EtOAc (60 ml) is added and the layers are separated. The aqueous layer is extracted with EtOAc (30 ml) and the combined extracts are dried and evaporated. The residue is purified by flash silica gel column eluting with hexane/EtOAc (4:1) to give the title compound as a light yellow solid. MS (M+1): 259.1.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:16])=[C:4]([CH3:15])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[C:7](=[O:12])[C:6]=2[C:13]=1[CH3:14].[C:17]1(O)C=CC=CC=1.COS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CC(C)=O>[CH3:17][O:1][C:2]1[C:3]([CH3:16])=[C:4]([CH3:15])[C:5]2[O:9][C:8]([CH3:10])([CH3:11])[C:7](=[O:12])[C:6]=2[C:13]=1[CH3:14]
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)C(C)(C)O2
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1c(C)c(C)c2c(c1C)C(=O)C(C)(C)O2
Yield: 98.6 %

Procedure:
A mixture of phenol 5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-one (7.16 g, 32.54 mmol), dimethylsulfate (6.16 g, 48.8 mmol) and potassium carbonate (13.5 g, 97.63 mmol) in acetone (160 mL) is refluxed under nitrogen for 3 days. After cooling, 3N sodium hydroxide (100 mL) is added and most of the acetone is evaporated under reduced pressure. The mixture is extracted with ethyl acetate (200 mL) and the organic layer is washed with 3N sodium hydroxide (2×100 mL), water, brine, dried (magnesium sulfate)and evaporated to dryness to give 7.52 g (99%) of 5-methoxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-one as a yellow solid which is used without purification for the next step. Rf=0.4 (heptane/ethyl acetate 90:10)
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Ca+2].[H-].[CH3:21]N(C)C=O>>[C:1]1([N:7]2[CH:21]=[C:10]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)[C:9](=[O:17])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C=O
Reactant: O=C(Cc1ccncc1)NNc1ccccc1
Agent: [Ca+2]
Agent: [H-]
Product: O=c1[nH]n(-c2ccccc2)cc1-c1ccncc1
Temperature: 170 °C
Reaction time: 8 h

Procedure:
N′-Phenyl-2-pyridin-4-ylacetohydrazide (460 mg, 2.02 mmol) and calcium hydride (141 mg, 3.34 mmol) were dissolved in dimethylformamide (8 mL) and heated at 170° C. After 8 h, the reaction cooled to ambient temperature and was filtered. The mixture was concentrated and redissolved in dichloromethane (50 mL). The precipitate was filtered and dried under high vacuum overnight to give the desired product. MS 238.04 (M+1)
Reaction SMILES: [F:1][C:2]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[CH:18][C:17]([CH3:27])=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([OH:14])[C:8]=1[CH3:15])=O>C1COCC1>[F:13][C:12]1[CH:11]=[CH:10][C:9]([OH:14])=[C:8]([CH3:15])[C:7]=1[NH:6][CH2:4][C:3]1[CH:16]=[C:17]([CH3:27])[CH:18]=[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[C:2]=1[F:1]
Reactant: Cc1cc(C(=O)Nc2c(F)ccc(O)c2C)c(F)c(-c2cccc(F)c2)c1
Solvent: C1CCOC1
Product: Cc1cc(CNc2c(F)ccc(O)c2C)c(F)c(-c2cccc(F)c2)c1
Temperature: 60 °C
Yield: 93.3 %

Procedure:
To a stirred solution of 2-fluoro-N-(6-fluoro-3-hydroxy-2-methyl-phenyl)-3-(3-fluorophenyl)-5-methyl-benzamide (200 mg, 0.54 mmol, 1.0 eq) in THF (5 mL) under nitrogen was added a solution of BH3 (1M in THF, 3.0 mL, 3.0 mmol, 5.6 eq) dropwise over 5 min. the mixture was heated at 60° C. overnight, then the reaction cooled to room temperature and quenched by addition of aqueous NH4Cl. The reaction was further diluted with water and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 100:1 to 25:1) to give the title compound as a colorless oil (180 mg, 93%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:10]1[CH2:15][CH2:14][C:13]2([C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:16]2)[CH2:12][CH2:11]1)(=O)[CH3:8]>O1CCCC1>[CH2:7]([N:10]1[CH2:15][CH2:14][C:13]2([C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:16]2)[CH2:12][CH2:11]1)[CH3:8]
Reactant: CC(=O)N1CCC2(CC1)OC(c1ccccc1)c1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN1CCC2(CC1)OC(c1ccccc1)c1ccccc12

Procedure:
To a stirred suspension of 0.53 g. of lithium aluminum hydride in 50 ml. of tetrahydrofuran is added dropwise a solution of 2.20 g. of 1'-acetyl-1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine] (Example 80), in 50 ml. of tetrahydrofuran. The mixture is heated under reflux for 2 hours, cooled, quenched cautiously with water, and extracted with ether. The ether solution is dried over sodium sulfate and concentrated to a solid. Recrystallization from chloroform provides colorless crystals, m.p. 113°-115°.
Reaction SMILES: C1(C2C=CN=[N:6][C:5]=2[C:10]2N=CO[N:11]=2)CC1.[CH:15]1([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27]N=NC=3)[N:19]=2)[CH2:17]C1>>[CH:23]1([C:20]2[N:19]=[C:18]([C:15]3[CH:17]=[N:11][CH:10]=[CH:5][N:6]=3)[O:22][N:21]=2)[CH2:28][CH2:27]1
Reactant: c1cc(-c2noc(C3CC3)n2)cnn1
Reactant: c1cc(C2CC2)c(-c2ncon2)nn1
Product: c1cnc(-c2nc(C3CC3)no2)cn1

Procedure:
The cyclopropyl-1,2,4-oxadiazolylpyridazine according to claim 1: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-pyridazine.
Reaction SMILES: C[O-].[Na+].[C:4]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH2:31][C:32]#[C:33][CH3:34])[C:20]3[C:25](=[O:26])[N:24]([CH2:27][C:28]#[N:29])[N:23]=[CH:22][C:21]=3[N:30]=2)[CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].C(O)(=O)C.[C:39]([OH:48])(=O)[C:40]1[C:41](=[CH:43][CH:44]=[CH:45][CH:46]=1)[NH2:42]>CO>[C:4]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH2:31][C:32]#[C:33][CH3:34])[C:20]3[C:25](=[O:26])[N:24]([CH2:27][C:28]4[NH:29][C:39](=[O:48])[C:40]5[C:41](=[CH:43][CH:44]=[CH:45][CH:46]=5)[N:42]=4)[N:23]=[CH:22][C:21]=3[N:30]=2)[CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2cnn(CC#N)c(=O)c21
Reactant: Nc1ccccc1C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2cnn(Cc3nc4ccccc4c(=O)[nH]3)c(=O)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
40 mg sodium methoxide (95%) are added to a solution of 605 mg 2-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(2-butyn-1-yl)-5-cyanomethyl-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one in 9 ml of methanol. The mixture is stirred for one hour at ambient temperature and then neutralised with 41 μL glacial acetic acid. Then a solution of 195 mg anthranilic acid in 2 ml of methanol is added and the reaction mixture is heated to 70° C. After about two hours a white, voluminous precipitate is formed and the reaction mixture is cooled to ambient temperature. The precipitate formed is suction filtered, washed with cold methanol and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[O:16]C(C)C)[C:8](=[O:20])[C:7]=2[CH:6]=[C:5]([O:21]C(C)C)[CH:4]=1.B(Cl)(Cl)Cl>C(Cl)Cl>[OH:21][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[OH:16])[C:8](=[O:20])[C:7]=2[CH:6]=1
Reactant: COc1cc(OC(C)C)cc2c1-c1c(OC(C)C)cccc1C2=O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1cc(O)cc2c1-c1c(O)cccc1C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-methoxy-2,5-bis-(1-methylethoxy)-9H-fluoren-9-one (0.58 g, 1.8 mmol) in CH2Cl2 (15.0 mL) is added BCl3 (7.2 mL, 7.2 mmol) (1.0M) at 0° C. The green mixture is allowed to warm to ambient temperature and stirred for 2 hours under argon. The mixture is cooled to OC and quenched with H2O (20 mL). The precipitated red solid is removed by filtration and recrystallized from MeOH/H2O affording 0.331 g (76%) of the title compound as a red solid: mp 235-237° C. (lit., 238-240° C.); IR (KBr) 1697, 1614, 1597 cm-1 ; UV (EtOH) 1 max=265, 274 and 338 nm (e=32,576, 36,000 and 3,406 nm.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([CH3:13])[C:9]([NH:14]C(OCC)=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(O)(=O)C>[OH-].[Na+]>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]([CH3:13])[C:9]([NH2:14])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)NC1=NN(c2ccccc2)C(=O)C1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC1C(=O)N(c2ccccc2)N=C1N

Procedure:
A solution of 261 g (1 mole) of 1-phenyl-3-carbethoxyamino-4-methyl-2-pyrazolin-5-one in 1600 ml of 2.5 N sodium hydroxide was refluxed for 30 min. The solution was cooled and neutralized by addition of 250 ml of concentrated hydrochlorid acid and 50 ml of glacial acetic acid. The precipitate was separated and dried. Yield: 160 g (84%). Melting point: 147° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]([CH:15]1[CH2:17][CH:16]1[CH2:18][CH2:19][C:20]#[C:21][CH2:22][OH:23])=[O:14].C(N(CC)CC)C.[Cl-].[Na+]>ClCCl>[CH3:11][O:12][C:13]([CH:15]1[CH2:17][CH:16]1[CH2:18][CH2:19][C:20]#[C:21][CH:22]=[O:23])=[O:14]
Reactant: COC(=O)C1CC1CCC#CCO
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)C1CC1CCC#CC=O
Temperature: -40 °C
Reaction time: 0.08 h
Yield: 97.1 %

Procedure:
Oxalyl chloride (0.40 g, 3.1 mmol) was dissolved in dichloromethane, and the solution was cooled to -40° C. A solution of dimethyl sulfoxide (0.52 g, 6.2 mmol) in dichloromethane (2 ml) was added thereto over a period of 5 minutes, and the mixture was stirred for 20 minutes. A solution of 2-(5-hydroxy-3-pentynyl)cyclopropanecarboxylic acid methyl ester (0.37 g, 2 mmol) in dichloromethane (5 ml) was added thereto, and the mixture was stirred for 30 minutes. Then, triethylamine (1.7 ml, 12 mmol) was added thereto. The temperature was raised to 0° C., and a saturated sodium chloride aqueous solution was added thereto. The product was extracted with dichloromethane, dried over anhydrous magnesium sulfate and then purified by silica gel column chromatography to obtain the above identified compound (0.35 g, yield: 96%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]2[C:7](O[C:10](=O)[C:3]=2[CH:2]=1)=O.N[C:13]1C=CC=CC=1>>[NH:1]1[C:2]2[C:4](=[CH:7][CH:13]=[CH:10][CH:3]=2)[CH:5]=[CH:6]1
Reactant: Nc1ccccc1
Reactant: O=C1OC(=O)c2cnccc21
Product: c1ccc2[nH]ccc2c1

Procedure:
In like fashion, reaction of 3,4-pyridinedicarboxylic anhydride (Formula Vb hereinbelow) with an aniline of Formula VI or an indole of Formula VII (Z-H hereinbelow) produces a mixture of 3-(Z-CO)-4-pyridinecarboxylic acid (Formula IIc) and 4-(Z-CO)-3-pyridinecarboxylic acid (Formula IId). The mixture is in turn reacted with a diarylamine of Formula III to produce an isomeric mixture of furo[3,4-c]pyridine-1(3H)-one (Formula Ic) and furo-[3,4-c]pyridine-3(1H)-one (Formula Id). ##STR22##