Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[S:6][C:7]=1[CH2:8]Cl.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH2:26])(=[O:25])=[O:24])([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]1[CH2:2][C:3]2[CH:4]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[S:6][C:7]=2[CH2:8]1)(=[O:24])=[O:25])([O-:16])=[O:15]
Reactant: COC(=O)c1cc(CCl)c(CCl)s1
Reactant: NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc2c(s1)CN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of methyl 4,5-bis(chloromethyl)thiophene-2-carboxylate (4.106 g, 17.17 mmol) and 2-nitrobenzenesulfonamide (3.825 g, 18.92 mmol) in acetone (40 mL) was added 2.5 M of potassium carbonate in water (20 mL, 50 mmol). The resulting biphasic mixture was stirred at room temperature for 1 hour then further heated at 45° C. overnight resulting in formation of precipitate. The reaction mixture was cooled to room temperature and the precipitate was collected by vacuum filtration. The solid obtained was washed with water followed by cold methanol and dried under vacuum to afford an off white solid (3.352 g, 53%). LCMS (FA) ES+ 369; 1H NMR (400 MHz, DMSO) δ 8.02 (ddd, J=7.8, 4.9, 1.4 Hz, 2H), 7.90 (td, J=7.7, 1.5 Hz, 1H), 7.84 (td, J=7.7, 1.4 Hz, 1H), 7.63 (s, 1H), 4.79 (t, J=2.9 Hz, 2H), 4.60 (t, J=2.9 Hz, 2H), 3.80 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=O.II.[CH2:13]([SH:16])[CH2:14][SH:15]>O1CCCC1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2([CH3:1])[S:16][CH2:13][CH2:14][S:15]2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: SCCS
Agent: II
Solvent: C1CCOC1
Product: CC1(c2ccc(Cl)cc2)SCCS1
Temperature: 25 °C
Yield: 48.1 %

Procedure:
A mixture of 4-chloroacetophenone (1.3 mL, 10 mmol), iodine (250 mg, 1 mmol), 1,2-ethanedithiol (0.85 mL, 10 mmol) in dry tetrahydrofuran (20 mL) was heated at reflux under an atmosphere of nitrogen for 16 h. The mixture was allowed to cool to room temperature and concentrated in vacuo and the residue taken up in ether (20 mL). The organic solution was washed with water (2×10 mL) and brine (1×10 mL), then dried (Na2SO4) and evaporated under reduced pressure. Flash column chromatography of the residue, eluting with 37% aqueous ammonia:ether:hexane (0.02:1:6) afforded 2-(4-chlorophenyl)-2-methyl-1,3-dithiolane (24) as a colourless oil (1.11 g, 48%). 1H nmr (300 MHz, CDCl3) 2.13 (s, 3H, CH3), 3.31-3.53 (m, 4H, SCH2CH2S), 7.27 (d, J=8.7 Hz, 2H, 2×ArH), 7.69 (d, J=8.7 Hz, 2H, 2×ArH).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[C:4]([C:5]([OH:7])=[O:6])=[C:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+:20]>CO>[CH3:1][N:2]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[C:4]([C:5]([O-:7])=[O:6])=[C:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+:20]
Reactant: Cc1cc(=O)c(C(=O)O)c(-c2ccccc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(=O)c(C(=O)[O-])c(-c2ccccc2)n1C

Procedure:
1.69 g of 1,6-dimethyl-2-phenyl-4-oxonicotinic acid is suspended in approximately 50 ml of methanol. NaOH pellets (0.305 g) are added with stirring. After both the acid and the sodium hydroxide dissolve the solution is evaporated to dryness in vacuo. Sodium 1, 6-dimethyl-2-phenyl-4-oxonicotinate is then isolated as a glossy, somewhat hydroscopic solid. Yield=1.6 g.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=O)[CH:18]=[CH:19][NH:20]2)=[CH:15][C:14]=1[C:24]([O:26][CH3:27])=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O>[CH2:5]([O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([Cl:3])=[CH:18][CH:19]=[N:20]2)=[CH:15][C:14]=1[C:24]([O:26][CH3:27])=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(Cl)ccnc2cc1OCc1ccccc1

Procedure:
After adding thionyl chloride (70 ml) and a catalytic amount of dimethylformamide to methyl 7-(benzyloxy)-4-oxo-1,4-dihydro-6-quinolinecarboxylate (7.19 g, 23.2 mmol), the mixture was heated to reflux for 3 hours while stirring. The reaction solution was concentrated under reduced pressure, a 2N sodium hydroxide solution was gradually added for neutralization, extraction was performed with ethyl acetate, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, diethyl ether was added for crystallization, and the crystals were filtered out and blow-dried to obtain the title compound (4.067 g, 12.4 mmol) as light brown crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[S:21][C:20]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[O:23])=[C:19]([CH3:33])[CH:18]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[S:21][C:20]([C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[O:23])=[C:19]([CH3:33])[CH:18]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)sc1C(=O)NCc1cccc(F)c1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Product: Cc1cc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1cccc(F)c1
Yield: 45 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 4-(benzyloxy)pyridin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with 5-bromo-N-(3-fluorobenzyl)-3-methylthiophene-2-carboxamide in place of N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 45% yield: mp 140-141° C.; 1H NMR (300 MHz, CDCl3) δ 7.56 (d, J=7.8 Hz, 1H), 7.43-7.27 (m, 6H), 7.11 (d, J=7.8 Hz, 1H), 7.04 (d, J=9.6 Hz, 1H), 7.00-6.92 (m, 1H), 6.84 (s, 1H), 6.29 (t, J=5.7 Hz, 1H), 6.14 (dd, J=7.8, 2.7 Hz, 1H), 6.05 (d, J=2.7 Hz, 1H), 5.02 (s, 2H), 4.58 (d, J=5.7 Hz, 2H), 2.54 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.8, 164.6, 163.0, 163.0 (d, JC-F=246.6 Hz), 162.2, 161.3, 140.7 (d, JC-F=7.0 Hz), 139.9, 139.7, 134.7, 134.4, 130.2 (d, JC-F=8.2 Hz), 128.8, 128.7, 127.8, 126.7, 123.2 (d, JC-F=2.9 Hz), 121.9, 114.6 (d, JC-F=15.2 Hz), 114.3 (d, JC-F=14.4 Hz), 103.4, 98.1, 70.6, 43.3, 15.9; MS (ES+) m/z 449.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:19])[CH2:15][C:16](N)=[O:17])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:20][Mg]Br>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:19])[CH2:15][C:16](=[O:17])[CH3:20])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(CC(N)=O)c1ccc(C2CCCCC2)c(Cl)c1
Reactant: C[Mg]Br
Product: CC(=O)CC(C)c1ccc(C2CCCCC2)c(Cl)c1
Yield: 74 %

Procedure:
4-(3-Chloro-4-cyclohexyl-phenyl)-2-pentanone was prepared analogous to Example 61 from 3-(3-chloro-4-cyclohexyl-phenyl)-butyramide and methyl-magnesium bromide with a yield of 74% of theory. The colorless, highly viscous oil had a b.p. of 153°-156°C at 0.1 mm Hg.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1.CN(C)C1C=CC=CC=1.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31].Cl>O1CCCC1>[C:29]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:18][CH:19]=1)(=[O:32])[CH:30]=[CH2:31]
Reactant: O=C(O)C=Cc1ccc(OCCCCCCO)cc1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)c1ccccc1
Product: C=CC(=O)OCCCCCCOc1ccc(C=CC(=O)O)cc1
Reaction time: 4 h
Yield: 53.3 %

Procedure:
The resulting 4-(6-hydroxyhexyloxy)cinnamic acid (6 g, 0.023 mole) and N,N-dimethylaniline (6.6 g, 0.054 mole) were dissolved in tetrahydrofuran (50 mL), and to this mixture was further added dropwise a solution prepared by dissolving acryloyl chloride (4.4 g, 0.049 mole) in tetrahydrofuran (20 mL). After this addition, the mixture was stirred for 4 hours. Then, the reaction solution was poured into 10% hydrochloric acid, and deposited crystal was filtrated off. The resulting coarse crystal was dissolved in ethyl acetate (100 mL), and an organic layer was washed with saturated saline solution and dried over magnesium sulfate. The organic solvent was distilled off under reduced pressure, and then the coarse crystal was re-crystallized (n-hexane-ethyl acetate) to obtain 4-(6-acryloyloxyhexyloxy)cinnamic acid (3.9 g, 54%) in the form of a colorless crystalline powder.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[C:21]2[C:20](=[O:22])[NH:19][CH:18]=[N:17][C:16]=2[N:15]([CH3:23])[C:14](=[O:24])[C:13]=1[CH3:25].Cl[CH2:27][C@H:28]1[CH2:32][O:31]C(C)(C)[O:29]1>CN(C=O)C>[OH:29][C@H:28]([CH2:32][OH:31])[CH2:27][N:19]1[C:20](=[O:22])[C:21]2[C:12]([NH:11][C:5]3[CH:6]=[CH:7][C:8]([I:10])=[CH:9][C:4]=3[F:3])=[C:13]([CH3:25])[C:14](=[O:24])[N:15]([CH3:23])[C:16]=2[N:17]=[CH:18]1
Reactant: CC1(C)OC[C@H](CCl)O1
Reactant: Cc1c(Nc2ccc(I)cc2F)c2c(=O)[nH]cnc2n(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Nc2ccc(I)cc2F)c2c(=O)n(C[C@H](O)CO)cnc2n(C)c1=O
Reaction time: 0.17 h
Yield: 25.1 %

Procedure:
Sodium hydride (67 mg, 3.5 mmol, 5 eq) was stirred in anhydrous DMF (500 μL) for 10 minutes. 5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (300 mg, 0.70 mmol, 1 eq, Example 12) in anhydrous DMF (300 μL) was added and the mixture stirred for 10 minutes. (R)-4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane (180 μL, 1.32 mmol, 5 eq) was added and the mixture subjected to microwave irradiation at 135° C. for 1 hour. The solvent was removed in vacuo. The residue was taken up in H2O (1 mL) and THF (1 mL). 1N HCl (1 mL) was added and the solution stirred at RT for 1 hour. After evaporation in vacuo the residue was purified by HPLC to give 88 mg (25%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.64 (s, 3H) 2.11 (s, 3H) 3.18 (d, J=5.31 Hz, 1H) 3.32-3.42 (m, 1H) 3.63-3.70 (m, 1H) 3.70-3.82 (m, 1H) 4.24-4.38 (m, 1H) 4.78 (t, J=5.56 Hz, 1H) 5.09 (d, J=5.56 Hz, 1H) 6.62 (t, J=8.72 Hz, 1H) 7.45 (dd, J=7.71, 2.15 Hz, 1H) 7.66 (dd, J=10.61, 2.02 Hz, 1H) 8.48 (s, 1H) 10.16 (s, 1H) [M+H] calc'd for C18H18FIN4O4, 501; found, 501.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH2:4]O.S(Cl)([Cl:14])=O.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][Cl:14]
Reactant: OCc1c(F)ccc(F)c1F
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(F)c(CCl)c1F

Procedure:
To a solution of 2,3,6-trifluorobenzyl alcohol (41 g) in dichloromethane (100 ml) is added dropwise a solution of thionyl chloride (50 ml) in dichloromethane (80 ml) under ice cooling with stirring, and the mixture is stirred at room temperature overnight. To the mixture is added triethylamine (10 ml), and the solvent is distilled off under reduced pressure to give 2,3,6-trifluorobenzyl chloride (28.6 g), as colorless oil, b.p. 63;L ° C. (13 mmHg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([Br:15])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:20]>C1COCC1>[C:1]([O:5][C:6](=[O:16])[N:7]([C:8]1[C:13]([CH3:14])=[CH:12][C:11]([Br:15])=[CH:10][N:9]=1)[CH3:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: Cc1cc(Br)cnc1NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Br)cnc1N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (5-bromo-3-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (409 mg) in THF (20 mL) was added sodium hydride (68 mg) and the reaction was stirred at room temperature for 20 min. Then, iodomethane (0.11 mL) was added and the reaction was stirred at room temperature for 16 h. The reaction was quenched with water (30 mL) and extracted into ethylacetate (2×20 mL). The organic layers were washed with brine (2×40 mL), dried (MgSO4) and reduced in vacuo to give (5-bromo-3-methyl-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[C:4](OCC)[C:3]=1[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cu](C#N)[C:32]#[N:33].N.C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([C:32]#[N:33])[CH:29]=1
Reactant: CCOc1nn(-c2cc(C(=O)NC3CC3)ccc2C)c(N)c1C(=O)c1ccccc1
Reactant: N#C[Cu]C#N
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C#N)c2)c1N
Temperature: 80 °C
Yield: 51 %

Procedure:
To a stirred solution of iodide 4 (7.4 g, 0.015 mol, 1.0 equiv) in N,N-dimethyl formamide (25 ml) under N2 was added copper cyanide. The resultant suspension was refluxed for 1 hour. The reaction was monitored by TLC and checked for the completion. Heating was discontinued and the reaction mixture was cooled down to 80° C. Ice water (15 ml), 25% aqueous ammonia (15 ml), and ethyl acetate (50 ml) were added to quench the reaction. The mixture was filtered to remove the solids. From the filtrate organic layer was separated. The organic layer was washed with water, saturated brine and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure and the crude material dried at 60° C. under high vacuum then purified by column with ethyl acetate as eluent to provide the product (3 g, 51%) as an off white solid. HPLC (Waters X-Terra 5 micron C18 column 4.6 mm×250 mm, 1.0 mL/min, mobile phase: 0.1% TEA in H2O/acetonitrile 70/30, 30 min elution) tR 23.70 min, 99.4% purity; 1H NMR (400 MHz, CDCl3) δ8.10 (t, J=2.9 Hz, 1H), 8.06 (t, J=2.7 Hz, 1H), 8.04 (m, 1H), 7.85 (t, J=2.5 Hz, 1H), 7.83 (m, 1H), 7.81 (d, J=1.8 Hz, 1H), 7.95 (d, J=1.6 Hz, 1H), 7.37 (s, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 6.41 (s, 1H), 5.94 (s, 2H), 2.88 (m, 1H), 2.24 (s, 3H), 0.86 (dd, J=6.9, 6.1 Hz, 2H) 0.61 (m, 2H) ppm; 13C NMR (400 MHz, CDCl3) δ186.6, 167.2, 151.5, 141.3, 140.7, 140.3, 135.1, 134.5, 134.0, 132.2, 131.8, 129.5, 128.7, 126.2, 118.1, 113.0, 103.7, 30.9, 23.2, 17.7, 6.8 ppm.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[CH2:32]([C:34]1[C:35]([NH:51][C@H:52]2[CH2:56][O:55][CH2:54][C@H:53]2[OH:57])=[N:36][C:37]([CH2:49][CH3:50])=[C:38]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[CH3:48])[N:39]=1)[CH3:33]>>[CH2:2]([O:57][C@H:53]1[CH2:54][O:55][CH2:56][C@H:52]1[NH:51][C:35]1[C:34]([CH2:32][CH3:33])=[N:39][C:38]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[CH3:48])=[C:37]([CH2:49][CH3:50])[N:36]=1)[CH3:3]
Reactant: CCc1nc(-c2ccc(OC)cc2C)c(CC)nc1N[C@H]1COC[C@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1COC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting of cis-(+/−)-4-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}tetrahydrofuran-3-ol and making non-critical variations provided the title compound as a light yellow solid. IR (liq.) 2972, 2935, 2874, 1609, 1564, 1481, 1395, 1294, 1243, 1204, 1160, 1123, 1077, 1069, 1058 cm−1; OAMS supporting ions at: ESI+ 386.2; MS (EI) m/z 385 (M+); HRMS (FAB) calcd for C22H31N3O3+H1 386.2443, found 386.2457. Anal. Calcd for C22H31N3O3: C, 68.54; H, 8.11; N, 10.90. Found: C, 68.22; H, 8.05; N, 10.76.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.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:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:15]=2)=[C:53]([CH3:54])[CH:52]=[C:51]([CH3:55])[N:50]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
4-Phenoxybenzoic acid (214 mg, 1.0 mmol), 1-hydroxybenzotriazole (203 mg, 1.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (290 mg, 1.5 mmol) and triethylamine (0.7 mL, 5 mmol) were dissolved in dichloromethane (15 mL). The mixture was stirred at room temperature for 0.5 hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (190 mg, 1.0 mmol) was added to the solution. The mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was concentrated and the residue was purified by column chromatography (silica gel, dichloromethane/methane=40:1) to give the product as a white solid (120 mg, 34%). LRMS (M+H+) m/z: calcd 348.15. found 348. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.28 (m, 1H), 7.86 (s, 1H), 7.83 (s, 1H), 7.40 (t, J=7.2 Hz, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.06 (s, 1H), 7.03 (s, 1H), 6.98 (s, 1H), 6.95 (s, 1H), 5.84 (s, 1H), 4.27 (d, J=7.5 Hz, J=3.6, 2H), 2.15 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12]([C@@H:16]([C@H:18]([C:20]([O:22][CH3:23])=[O:21])[OH:19])O)([O:14][CH3:15])=[O:13]>CO>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:2]2[O:19][C@@H:18]([C:20]([O:22][CH3:23])=[O:21])[C@H:16]([C:12]([O:14][CH3:15])=[O:13])[O:1]2)[CH:11]=[CH:10][C:8]=1[OH:9]
Reactant: COc1cc(C=O)ccc1O
Reactant: COC(=O)[C@H](O)[C@@H](O)C(=O)OC
Solvent: CO
Product: COC(=O)[C@@H]1OC(c2ccc(O)c(OC)c2)O[C@H]1C(=O)OC

Procedure:
In a fashion similar to that described for Example 3, vanillin and dimethyl L-tartrate were condensed to provide (4R,5R)-2-(3-methoxy-4-hydroxy-phenyl)-4,5-dicarbomethoxy-1,3-dioxolane, mp 88°-90° C., [α]D25 -35.1° (c, 0.1, methanol). 1H-NMR (CDCl3) δ7.20 (1H, d, J=1.8 Hz), 7.06 (1H, dd, J=1.8 Hz and 8.2 Hz), 6.19 (1H, d, J=8.2 Hz), 6.08 (1H,s), 5.82 (1H, s), 4.96 (1H, d, J=3.8 Hz), 4.85 (1H, d, J=3.8 Hz), 3.91 (3H,s), 3.87 (3H,s), 3.84 (3H,s). IR (film) 3450, 1750, 1600, 1510, 1460, 1430 cm-1. Ms m/e (% abundance) 313(2), 312(12), 253(40), 168(84), 151(100), 124(22), 109(14), 59(18).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.CC(C)([O-])C.[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>CS(C)=O>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[N:9]([CH2:24][CH2:25][CH2:26][Cl:27])[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: ClCCCBr
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCCl)C=C2
Temperature: 0 °C

Procedure:
First 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (131.5 g, 0.6 mol) is suspended in dimethylsulfoxide (900 ml) and mixed with potassium tert.butoxide (80.8 g, 0.72 mol) with stirring. After 10 minutes the solution obtained is added dropwise to 1-bromo-3-chloropropane (77 ml, 0.72 mol) in dimethylsulfoxide (300 ml), while cooling with ice water. After an hour the mixture is poured onto ice water. After a short time the greasy precipitate begins to crystallize. The precipitate is suction filtered, dissolved in acetone, precipitated again water water, suction filtered and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)[Cl:31]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][Cl:31]
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1ccc(Cl)c(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClCc1ccc(Cl)c(Br)c1
Reaction time: 18 h
Yield: 88.6 %

Procedure:
To a solution of 3-bromo-4-chlorobenzyl alcohol (9.6 g, 43 mmol) in CH2Cl2 (100 mL) was added Ph3P (17.1 g, 1.5 mmol) and CCl4 (6.3 mL, 65 mmol). After 18 h, the solution was washed with brine (3×100 mL) and passed through a short silica gel column to afford the product as colorless oil (9.14 g, 88%). 1H NMR (400 MHz, CDCl3): 7.65 (d, J=2.1 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.27 (dd, J=8.3, 2.1 Hz, 1H), 4.51 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][C:7](=[N:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)[CH3:3].[BH4-].[Na+]>CO>[CH3:3][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)[CH3:1]
Reactant: CC(C)N1CCC(=Nc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)N1CCC(Nc2ccccc2)CC1
Reaction time: 8 h

Procedure:
To a stirred and warmed (30°-40° C.) solution of 72 parts of N-[1-(1-methylethyl)-4-piperidinylidene]-benzenamine in 480 parts of methanol are added potionwise 20 parts of sodium borohydride. Upon completion, stirring is continued overnight at at room temperature. The reaction mixture is evaporated and the residue is dissolved in water. The solution is extracted with 4-methyl-2-pentanone. The extract is washed with water and acidified with a diluted hydrochloric acid solution. The aqueous acid phase is alkalized with a diluted sodium hydroxide solution till pH 9 and the product is extracted with 4-methyl-2-pentanone. The extract is washed with water, dried, filtered and evapoarated. The residue is distilled (bp. 135-140° C. at 0.2 mm. pressure) and the distillate is crystallized from petroleumether, yielding 21 parts of 1-(1-methylethyl)-N-phenyl-4-piperidinamine; mp. 69.3° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CC(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: C1COCCN1
Solvent: CC(C)O
Product: O=C(O)CCc1oc(N2CCOCC2)nc1-c1ccc(Cl)cc1
Yield: 98 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43 g), morpholine (2.2 ml) and 2-propanol (20 ml) was stirred under reflux for 4 hours. The reaction mixture was concentrated, and water was added to the residue. The pH was then adjusted 3 with 2 N hydrochloric acid. The crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-morpholino-5-oxazolepropionic acid (1.64 g, 98%). This was recrystallized from ethanol to give colorless needles. mp 180-181° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:14]=2[CH3:22])[S:11][CH:12]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(O)(=O)C.C(OCC)(=O)C>[CH3:22][C:14]1[CH:15]=[CH:16][C:17]([NH:19][C:23](=[O:25])[CH3:24])=[CH:18][C:13]=1[C:10]1[S:11][CH:12]=[C:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:9]=1
Reactant: Cc1ccncc1-c1csc(-c2cc([N+](=O)[O-])ccc2C)n1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C)c(-c2nc(-c3cnccc3C)cs2)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
4-Methyl-3-[2-(2-methyl-5-nitrophenyl)-1,3-thiazol-4-yl]pyridine (100 mg) and reduced iron (180 mg) were suspended in acetic acid (2 ml)-acetic anhydride (0.04 ml) and the mixture was stirred at 70° C. for 4 hrs. The reaction mixture was diluted with ethyl acetate and the insoluble material was filtered off. The organic layer was neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was separated and concentrated by drying. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1–0:1) for purification. Recrystallization from ethyl acetate gave the title compound (43 mg) as colorless powder crystals.