Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]12[CH2:10][CH:9]1[CH2:8][NH:7][CH2:6]2)(=[O:3])[CH3:2].[CH2:11](N(CC)CC)[CH3:12].Cl[C:19]1[N:28]=[C:27]2[C:22]([C:23](=[O:40])[C:24]([C:37]([OH:39])=[O:38])=[CH:25][N:26]2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])=[CH:21][C:20]=1[F:41]>C(#N)C>[C:1]([NH:4][C:5]12[CH2:10][CH:9]1[CH2:8][N:7]([C:19]1[N:28]=[C:27]3[C:22]([C:23](=[O:40])[C:24]([C:37]([O:39][CH2:11][CH3:12])=[O:38])=[CH:25][N:26]3[C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[F:36])=[CH:21][C:20]=1[F:41])[CH2:6]2)(=[O:3])[CH3:2]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Reactant: CCN(CC)CC
Reactant: CC(=O)NC12CNCC1C2
Solvent: CC#N
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4CC4(NC(C)=O)C3)c(F)cc2c1=O
Yield: 100 %

Procedure:
A mixture of 1-acetylamino-3-azabicyclo[3.1.0]-hexane (60 mg, 0.28 mmol) and triethylamine (195 μl, 1.4 mmol) in acetonitrile (10 ml) was treated with the ethyl ester of 7-chloro-6-fluoro-1-{2,4-difluoro-phenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (95.6 mg, 0.25 mmol) and heated to 80° for 20 hours. The reaction mixture was concentrated in vacuo, diluted with chloroform and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: 189:10:1 chloroform: methanol: conc. ammonium hydroxide) to yield the title product as a yellow oil (120.8 mg, 0.25 mmol, 100% yield). 1H NMR (CDCl3) 8.35 (s, 1H), 8.01 (d, J=13 Hz, 1H), 7.36 (m, 1H), 7.04 (m, 2H), 6.11 (bs, 1H), 4.35 (q, J=7 Hz, 2H), 3.96 (vbs, 1H), 3.69 (vbs, 3H), 1.96 (s, 3H), 1.73 (m, 1H), 1.37 (t, J=7 Hz, 3H), 1.06 (m, 1H), 0.71 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8]CC(OCC)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH3:21])[CH:20]=CC=C[CH:16]=1.[O:22]1CCCC1.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:20][C:15]([OH:22])([CH3:16])[CH3:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Reactant: C1CCOC1
Reactant: Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(O)CNC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 33.7 %

Procedure:
Ethyl 2-(tert-butoxycarbonylamino)acetate (4.17 g, 20.52 mmol) was dissolved in tetrahydrofuran (60 ml). The solution was cooled to −78° C. A 22% solution of methyl magensium chloride in toluene/tetrahydrofuran (purchased from Chemmetallgesellschaft, 27.1 ml, 67.72 mmol) was added dropwise. The reaction mixture was stirred for 1.5 h at −78° C. and then warmed to room temperature. A 10% aqueous solution of ammonium chloride (200 ml) was added dropwise. The phases were separated. The aqueous phase was extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (200 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (110 g), using ethyl acetate/heptane (1:1) as eluent, to give 1.31 g of 2-hydroxy-2-methylpropylcarbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:9]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: Clc1cccc(C2CNc3ccccc32)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CC(c2cccc(Cl)c2)c2ccccc21
Reaction time: 1.5 h

Procedure:
To a solution of 3-(3-chlorophenyl)indoline (3.88 g, 16.9 mmol) and DIEA (2.40 g, 18.6 mmol) in DCM (40 mL) was added dropwise methanesulfonyl chloride (2.13 g, 18.6 mmol) at about 0° C. The mixture was stirred for about 1.5 hours. The solution was diluted with DCM and washed with saturated NaHCO3 solution (2 times), 1N HCl aqueous solution (2 times) and brine (2 times) and dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluting with EtOAc/hexane 1:4. The title compound was obtained as an oil Yield: 4.40 g, 85%. Rf=0.41, silica, EtOAc/hexane 1:2. 1H NMR (300 MHz, CDCl3) δ: 7.52 (d, 1H), 7.24-7.34 (m, 3H), 7.20 (s, 1H), 7.02-7.14 (m, 3H), 4.59 (t, 1H), 4.38 (t, 1H), 3.87 (dd, 1H), 2.92 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([S:19][CH3:20])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:28]([F:33])([F:32])C([O-])=O.[Na+]>C(#N)C.C(Cl)(Cl)Cl>[F:32][CH:28]([F:33])[O:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([S:19][CH3:20])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: CSc1ncc(C#N)c(-c2cnc3c(O)cccn23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CSc1ncc(C#N)c(-c2cnc3c(OC(F)F)cccn23)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
20 mg of the 4-(8-hydroxyimidazo[1,2-a]pyridin-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile [158-1] was dissolved in 1 mL of acetonitrile, then 20 mg of potassium carbonate and 13 mg of sodium chlorodifluoroacetate were added, and stirred overnight at 90° C. After cooling the reaction mixture back to room temperature, diluted in 100 mL of chloroform, and washed with water and dried over anhydrous magnesium sulfate. The insolubles were filtered, then the filtrate was concentrated under reduced pressure and purified by preparative thin-layer chromatography, to obtain 15 mg of 4-[8-(difluoromethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(methylthio)pyrimidine-5-carbonitrile [161-1] as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=O)=[CH:15][CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([CH2:29]C#N)[CH:26]=[CH:27][CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4=[N:19][O:21][C:29]([C:25]5[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=5)=[C:17]4[CH:18]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(Cl)cc2)cc1
Reactant: N#CCc1cccc(F)c1
Product: Fc1cccc(-c2onc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cc23)c1

Procedure:
The title compound, light yellow solid (46 mg, 35%), MS (ISP) m/z=390.2 [(M+H)+], mp 184° C., was prepared in accordance with the general method of example 1 from 1-(4-chloro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate H) (100 mg, 353 μmol) and commercially available 2-(3-fluoro-phenyl)-acetonitrile.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]([C:17](=O)[CH2:18][CH3:19])[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([O-:3])=[O:2].[BH4-].[Na+].O.[NH3:24]>N.C(O)C.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[NH2:24][CH:17]([C:15]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([N+:1]([O-:3])=[O:2])[CH:16]=1)[CH2:18][CH3:19]
Reactant: N
Reactant: CCC(=O)c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC(N)c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reaction time: 6 h

Procedure:
Tert-butyl 2-nitro-4-propionylbenzoate (9.2 g) was suspended in 2N ammonia/ethanol solution (81 ml), then tetraisopropoxytitanium (18.7 ml) was added at room temperature and the mixture was stirred at that temperature for 6 hours. Next, sodium borohydride (1.8 g) was added to the mixture, and the resulting mixture was stirred at that temperature for 16 hours. Then 2.1N ammonia water (81 ml) and Celite (9g) were added to the reaction solution and the inspluble materials were filtered off and washed with water and ethyl acetate. The filtrate was concentrated in vacuo, then a 5N aqueous sodium hydroxide solution and ethyl acetate were added to the obtained residue. The separated organic layer was concentrated in vacuo, then the obtained residue was purified by silica gel column chromatography to obtain the title compound (7.6 g) as an oily substance.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:26]([O-])=O)=[C:6]([CH:25]=1)[C:7]([NH:9][C:10]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:11]=1)=[O:8].CC1C=C(N2C=CC(NC(C3C=C(N4CCCCC4)C=CC=3N[C:58]([C:60]3[CH:61]=[C:62]([CH:70]=[CH:71][CH:72]=3)[CH2:63][S:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68])=[O:59])=O)=N2)C=CC=1C.ClC1C=CC([N+]([O-])=O)=C(C=1)C(NC1C=C[N:84]([C:87]2[CH:92]=[CH:91][C:90]([CH3:93])=C(C)C=2)N=1)=O>>[N:84]1([C:2]2[CH:3]=[CH:4][C:5]([NH:26][C:58]([C:60]3[CH:61]=[C:62]([CH:70]=[CH:71][CH:72]=3)[CH2:63][S:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68])=[O:59])=[C:6]([C:7](=[O:8])[NH:9][C:10]3[CH:14]=[CH:13][N:12]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=4)[N:11]=3)[CH:25]=2)[CH2:87][CH2:92][CH2:91][CH2:90][CH2:93]1
Reactant: O=C(Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1ccc(-n2ccc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)n2)cc1C
Reactant: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3[N+](=O)[O-])n2)cc1C
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1

Procedure:
This compound was prepared from 5-chloro-2-nitro-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide 6c using the procedure described for the preparation of 3-(3-(2-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-ylcarbamoyl)-4-(piperidin-1-yl)phenylcarbamoyl)-benzylthio)propanoic acid 5 from 5-chloro-N-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-yl)-2-nitrobenzamide 4g. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.715(d, J=6.9 Hz, 1H), 8.390-8.397(m, 1H), 8.180(s, 1H), 8.057-8.077(m, 1H), 8.020(s, 2H), 7.894-7.914(m, 1H), 7.679-7.719(m, 2H), 7.591-7.642(m, 2H), 7.520-7.558(m, 1H), 7.147-7.154(m, 1H), 3.889(s, 2H), 3.614-3.640(m, 4H), 2.690-2.725(m, 2H), 2.563-2.598(m, 2H), 2.002-2.055(m, 4H), 1.804-1.818(m, 2H). MS (ES, m/z): 652 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)=[O:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH2:23]1COC[CH2:24]1.C([Mg]Br)#C.CC(C)=O.CCCCCC>C(OCC)C>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C:11]([C:5]2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)([OH:12])[C:23]#[CH:24])[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=1
Reactant: COc1cc(OC)cc(C(=O)c2cc(OC)cc(OC)c2)c1
Reactant: C1CCOC1
Agent: C#C[Mg]Br
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CC(C)=O
Product: C#CC(O)(c1cc(OC)cc(OC)c1)c1cc(OC)cc(OC)c1
Yield: 73 %

Procedure:
In a 100 mL flask, bis(3,5-dimethoxy-phenyl)methanone (compound B, 1.2 g, 3.9 mmol) was dissolved in 20 mL diethyl ether. Approximately 5 mL THF was added to help solvate the ketone followed by the slow addition of ethynylmagnesium bromide (0.5 M in THF, 12 mL). The reaction was monitored by TLC and upon consumption of starting material, 2N HCl was added to the flask. The mixture was extracted 3 times with ethyl acetate and the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give a yellow oil. Purification was achieved with column chromatography using a gradient of 30% to 50% acetone/hexane. The product was obtained as a pale yellow oil in 73% yield: Rf 0.14 (30:70 acetone/hexane); IR (cm−1): 3441, 3280, 2940, 2837, 1598, 1460, 1289, 1205, 1156, 1053, 834, 748, 689; 1H NMR (250 MHz, C6D6): δ 2.38 (s, 1H), 2.94 (br s, 1H), 3.27 (s, 12H), 6.42 (t, J=2.5 Hz, 2H), 3.99 (d, J=2.5 Hz, 4H); 13C NMR (63 MHz, C6D6): 54.8 (4C), 74.5, 75.3, 86.8, 100.1 (2C), 104.9 (4C), 147.6 (2C), 161.2 (4C).
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](OS(C1C(C)=CC=CC=1)(=O)=O)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3].[CH2:33]([N:35]([CH2:38]C)[CH2:36]C)[CH3:34].[CH3:40][N:41](C=O)C>C(OCC)(=O)C>[OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([N:41]([CH3:40])[CH2:34][CH2:33][N:35]([CH3:38])[CH3:36])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3]
Reactant: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(C)O)C2C1
Reactant: CN(C)C=O
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(O)C1C(=O)N2C(C(=O)OCc3ccccc3)=C(N(C)CCN(C)C)CC12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of benzyl 6-(1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (46 mg) N-methyl-N-(2-dimethylaminoethyl)amine (10.2 mg), and triethylamine (28 μl) in anhydrous DMF (0.5 ml) is stirred at room temperature for 4 hrs. The mixture is diluted with ethyl acetate (10 ml) washed with H2O (5×2 ml) and brine, dried with MgSO4, filtered and evaporated in vacuo to provide benzyl 6-(1-hydroxyethyl)-3-[N-methyl-N-(2-dimethylaminoethyl)amino]-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([NH:27][C:28]([NH:30][C:31]1[N:36]=[CH:35][C:34]([C:37]2[S:38][C:39]([C:42]([OH:44])=O)=[CH:40][N:41]=2)=[CH:33][CH:32]=1)=[O:29])[CH3:26].CCN(CC)CC.[C:52]([NH2:61])([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([CH3:54])[CH3:53]>CN(C=O)C.O>[CH2:25]([NH:27][C:28]([NH:30][C:31]1[N:36]=[CH:35][C:34]([C:37]2[S:38][C:39]([C:42]([NH:61][C:52]([CH3:54])([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH3:53])=[O:44])=[CH:40][N:41]=2)=[CH:33][CH:32]=1)=[O:29])[CH3:26]
Reactant: CCNC(=O)Nc1ccc(-c2ncc(C(=O)O)s2)cn1
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2ncc(C(=O)NC(C)(C)c3ccccc3)s2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (0.078 mg, 0.225 mmol) was added to a solution of 2-(6-{[(ethylamino)carbonyl]amino}pyridin-3-yl)-1,3-thiazole-5-carboxylic acid (Example 17, 60 mg, 0.205 mmol), Et3N (84 μL, 0.41 mmol) and cumylamine (28 mg, 0.205 mmol) in 3 mL DMF. After stirring at room temperature for two hours, the mixture was diluted with water and extracted with EtOAc. The product precipitated during the workup and it was collected by filtration, washed with water and EtOAc and dried (20 mg). MS (ESP): 410 (M+H+) for C21H23N5O2S.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][CH2:7]2)[N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:4][N:3]1[C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32]([O:34]C)=[O:33].O.[OH-].[Li+].Cl.O1CCOCC1>CO.O>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][C:15](=[O:22])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11]2)[N:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:4][N:3]1[C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32]([OH:34])=[O:33]
Reactant: COC(=O)c1cccc(N2CN(c3ccccc3)C3(CCN(CCCC(=O)c4ccccc4)CC3)C2=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc(N2CN(c3ccccc3)C3(CCN(CCCC(=O)c4ccccc4)CC3)C2=O)c1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-(4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate (0.08 g, 0.16 mmol) in methanol (3 mL) was added lithium hydroxide monohydrate (0.013 g, 0.32 mmol) in water (1 mL). After stirring at 55° C. for 18 h, the reaction mixture was concentrated in vacuo, isolated by preparatory TLC (10% methanol/dichloromethane/0.1% acetic acid) and lyophilized with 4M HCl/dioxane (0.5 mL) to obtain the title compound as a hydrochloride salt (0.011 g, 13%); 1H NMR (DMSO-d6): δ 2.07-2.16 (m, 4H), 2.91 (br, 2H), 3.21-3.24 (m, 4H), 3.56-3.62 (m, 4H), 5.25 (s, 2H), 6.90 (t, 1H, J=7.2 Hz), 7.24-7.34 (m, 4H), 7.53-7.68 (m, 4H), 7.81 (d, 1H, J=7.6 Hz), 7.92 (dd, 1H, J=8 and 1.6 Hz), 8.00 (d, 2H, J=8 Hz), 8.69 (s, 1H), 10.29 (br, 1H), 13.18 (br, 1H); MS for C30H31N3O4 m/z 498 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH:10]1[CH2:16][CH:15]2[N:17]([CH3:18])[CH:12]([CH2:13][CH2:14]2)[CH2:11]1)=O.O.[NH2:20][NH2:21]>C(O)C>[NH:20]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]([CH:10]2[CH2:16][CH:15]3[N:17]([CH3:18])[CH:12]([CH2:13][CH2:14]3)[CH2:11]2)=[N:21]1
Reactant: CN1C2CCC1CC(C(=O)c1ccccc1F)C2
Reactant: NN
Solvent: O
Solvent: CCO
Product: CN1C2CCC1CC(c1n[nH]c3ccccc13)C2
Temperature: 25 °C

Procedure:
A mixture of (2-fluorophenyl) (8-methyl-8-azabicyclo-[3.2.1]octan-3-yl) methanone (24.6 g), hydrazine hydrate (14.4 ml), and ethanol (250 ml) was heated to reflux for four hours. The reaction was cooled to room temperature and concentrated to an oil. This residue was dissolved in dimethylformamide (DMF) (250 ml). Potassium carbonate (28 g) was added to the mixture which was subsequently heated at reflux for 2 days. The reaction mixture was cooled and filtered and the DMF was removed in vacuo. residue was dissolved in ethanol and 5.2 g of 3-(1H-indazol-3-yl)-8-methyl-8-azabicyclo[3.2.1]octane precipitated from solution, as a powder, m.p. 191°-192° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.C(O)(=O)[CH2:20][C:21]([OH:23])=[O:22].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:20][C:21]([OH:23])=[O:22]
Reactant: O=C(O)CC(=O)O
Reactant: COc1c(C=O)cccc1Oc1ccccc1C
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1c(C=CC(=O)O)cccc1Oc1ccccc1C
Yield: 53.3 %

Procedure:
2-Methoxy-3-(o-tolyloxy)benzaldehyde (28 g), malonic acid (24 g), pyridine (200 ml) and piperidine (2 ml) were treated in a similar manner to that of Example 4-(4), and the resultant crude product was crystallized with a mixture of benzene and n-hexane to give 3-[2-methoxy-3-(o-tolyloxy)phenyl]acrylic acid (17.5 g). mp 143°-146° C.
Reaction SMILES: [ClH:1].CC1(C)CC(C2C=CC=C([C:19]([F:22])([F:21])[F:20])C=2)C2C(=CC(OCCNC)=CC=2)O1.Cl.[CH3:30][C:31]1([CH3:53])[CH2:40][CH:39]([C:41]2[CH:46]=[CH:45][C:44](F)=[CH:43][CH:42]=2)[C:38]2[C:33](=[CH:34][C:35]([O:48][CH2:49][CH2:50][NH:51][CH3:52])=[CH:36][CH:37]=2)[O:32]1.Cl.CC1(C)CC(C2C=CC=CC=2)C2C(=CC(OCCNC)=CC=2)O1.Cl.CC1(C)CC(C2C=CC=C(F)C=2)C2C(=CC(OCCN(C)C)=CC=2)O1>>[ClH:1].[CH3:30][C:31]1([CH3:53])[CH2:40][CH:39]([C:41]2[CH:46]=[CH:45][C:44]([C:19]([F:22])([F:21])[F:20])=[CH:43][CH:42]=2)[C:38]2[C:33](=[CH:34][C:35]([O:48][CH2:49][CH2:50][NH:51][CH3:52])=[CH:36][CH:37]=2)[O:32]1
Reactant: CNCCOc1ccc2c(c1)OC(C)(C)CC2c1cccc(C(F)(F)F)c1
Reactant: CNCCOc1ccc2c(c1)OC(C)(C)CC2c1ccc(F)cc1
Agent: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2c1cccc(F)c1
Agent: CNCCOc1ccc2c(c1)OC(C)(C)CC2c1ccccc1
Agent: Cl
Product: CNCCOc1ccc2c(c1)OC(C)(C)CC2c1ccc(C(F)(F)F)cc1

Procedure:
A strictly analogous procedure led to the production of 2,2-dimethyl-7-methylaminoethyloxy-4-(3-trifluoromethylphenyl)chroman hydrochloride, m.p. 182°-184° C, to 2,2-dimethyl-7-methylaminoethyloxy-4-(4-fluorophenyl)chroman hydrochloride, m.p. 222°-224° C, to 2,2-dimethyl-7-methylaminoethyloxy-4-phenylchroman hydrochloride, m.p. 191°-193° C, and to 2,2-dimethyl-7-dimethylaminoethoxy-4-(3-fluorophenyl)chroman hydrochloride, m.p. 168°-171.5° C.
Reaction SMILES: C([OH:4])(C)C.[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.C1CCN2C(=NCCC2)CC1.[CH:28]1([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH:42](Br)[CH3:43])[CH2:36][CH2:35]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CO.C(Cl)(Cl)Cl>[CH:28]1([N:34]2[CH2:39][CH2:38][N:37]([C:40]([CH2:41][CH2:42][CH2:43][O:5][C:6]3[CH:7]=[C:8]4[C:13](=[CH:14][CH:15]=3)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]4)=[O:4])[CH2:36][CH2:35]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: CC(Br)CCN1CCN(C2CCCCC2)CC1
Reactant: CC(C)O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCc2cc(OCCCC(=O)N3CCN(C4CCCCC4)CC3)ccc2N1

Procedure:
Into 100 ml of isopropanol were added 1.6 g of 6-hydroxy-3,4-dihydrocarbostyril and 1.8 ml of DBU. The mixture was refluxed under stirring and 4.2 g of 4-cyclohexyl-1-γ-bromobutylpiperazine was added thereto. After the addition operation, the reaction mixture was further refluxed under stirring for 8 hours, then concentrated. The residue thus obtained was extracted with chloroform and the chloroform layer was washed with 1N-NaOH aqueous solution and water, then dried with anhydrous sodium sulfate. The drying agent was removed by filtration and the mother liquor was concentrated. The residue thus obtained was treated by a silica-gel column chromatography [the solvent used was a mixture of chloroform:methanol=20:1 (vol/vol)]. 2.8 Grams of 6-[3-(4-cyclohexyl-1-piperazinylcarbonyl)propoxy]-3,4-dihydrocarbostyril was obtained as in the form of colorless needle-like substance. Melting point: 133°-134° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:13](=O)[CH2:14][CH3:15]>>[CH:13]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[CH:14][CH3:15]
Reactant: CCC=O
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC=CN1CCOCC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
A reaction flask was charged with morpholine (938 g, 10.8 mol) and potassium carbonate (K2CO3) (800 g, 5.8 mol) and heated to 40° C. with stirring. Propionaldehyde (500 g, 8.6 mol) was added dropwise while the temperature was kept under 60° C. with a water bath. After the completion of the addition, the reaction mixture was aged for two hours and filtered. The obtained filtrate was further distilled to provide 4-propenyl-morpholine (850 g, 6.7 mol).
Reaction SMILES: C(O[C:4](=O)[C:5](=[CH:11][O:12][CH2:13][CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.Cl.[NH:17]([CH2:19][C:20]([O:22][CH2:23][C:24]1C=CC=CC=1)=[O:21])[NH2:18].C(N(CC)CC)C.C(#N)C>C(O)C.C(=O)([O-])O.[Na+]>[CH2:13]([O:12][C:11]1[N:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=[CH:4][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:14]
Reactant: NNCC(=O)OCc1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC#N
Product: CCOC(=O)Cn1ncc(C(=O)OCC)c1OCC
Temperature: 80 °C
Reaction time: 5 h
Yield: 14 %

Procedure:
To a solution of diethyl(ethoxymethylidene)propanedioate (3.52 g, 16.3 mmol) in ethanol (35 mL) were added benzyl hydrazinoacetate hydrochloride (3.20 g, 14.8 mmol), triethylamine (2.20 ml, 16.3 mmol) and acetonitrile (15 mL), and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was diluted with diluted aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give ethyl [5-ethoxy-4-(ethoxycarbonyl)-1H-pyrazol-1-yl]acetate (0.56 g, 14%) wherein benzyl ester was converted to ethyl ester. To a solution of the present compound (0.56 g, 2.07 mmol) in tetrahydrofuran (10 mL) was added 1N aqueous sodium hydroxide solution (2.07 mL, 2.07 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was extracted with water, and washed with ether. The aqueous layer was neutralized with 1N hydrochloric acid (2 mL), and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (401 mg, 80%) as colorless crystals.