Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1.[N-:19]=[N+:20]=[N-:21].[Na+].O>CN(C)C=O>[N:19]([CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1)=[N+:20]=[N-:21]
Reactant: O=C1c2ccccc2C(=O)c2cc(CCl)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1ccc2c(c1)C(=O)c1ccccc1C2=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
10 g (0.039 mole) of 2-chloromethylanthraquinone [prepared according to G. Izoret, Ann. Chim., 7, 180 (1962)] are dissolved in 50 ml of N,N-dimethylformamide (DMF), and 2.53 g (0.039 mole) of sodium azide are added, with stirring. After 1 hour, the temperature is increased to 50° C. and the mixture is stirred at this temperature for 10 hours. 250 ml of water are added and the precipitate is filtered off. 9.5 g (92.3% of theory) of 2-azidomethyl-anthraquinone are obtained;
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:3](=[O:10])[NH:2]1.O.O.[NH2:14]N>CCO>[C:1]1([OH:11])[N:14]=[N:2][C:3]([OH:10])=[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=12
Reactant: NN
Reactant: O=C1NC(=O)c2cnccc21
Solvent: O
Solvent: CCO
Product: Oc1nnc(O)c2cnccc12
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To 2H-pyrrolo[3,4-c]pyridine-1,3-dione 1 (25.01 g, 169 mmol) dissolved in EtOH (250 mL) and H2O (250 mL) was added hydrazine hydrate (23 ml, 464 mmol). The solution was warmed to reflux and stirred for 1 h. After cooling to 40° C., the solution was brought to pH 4 with 5 N HCl whereupon precipitation of a light yellow solid occurred. After cooling to room temperature, the precipitate was filtered, washed with water, air dried for 2 h, and dried under high vacuum for 24 h at 40° C. to provide a quantitative yield of pyrido[3,4-d]pyridazine-1,4-diol 2. 1H NMR (d6-DMSO) δ 11.67 (bs, 2H), 9.33 (s, 1H), 9.02 (d, J=5.5 Hz, 1H), 7.89 (d, J=5.5 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][CH2:15][C:16]2=O)=[CH:12][CH:11]=1)[CH3:8].[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:7]([O:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][CH2:15][CH:16]2[N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:12][CH:11]=1)[CH3:8]
Reactant: CCOc1ccc2c(c1)C(=O)CC2
Reactant: C1CNCCN1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Product: CCOc1ccc2c(c1)C(N1CCNCC1)CC2

Procedure:
Piperazine (19.8 g, 0.23 mol), 6-ethoxyindan-1-one (4.00 g, 23 mmol), titanium(IV) isopropoxide (15.3 ml, 46 mmol) and sodium borohydride (2.7 g, 71 mmol) were reacted by Method A to give the product which was converted to the fumurate salt (beige solid, 5.7 g, 68.5%, mp: 142°-147° C.). Calcd for C15H22N2O.C4H4O4 : C, 62.97%; H, 7.23%; N, 7.73%. Found: C. 62.88%; H, 7.22%; N, 7.48%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8](C)[CH2:7][C:6]12[CH2:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16]1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][C:6]12[CH2:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16]1
Reactant: COc1cc2c(cc1OC)C1(Cc3ccccc3O1)CN(C)C2
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)N1Cc2cc(OC)c(OC)cc2C2(Cc3ccccc3O2)C1
Yield: 61 %

Procedure:
A mixture of 6',7'-dimethoxy-2'-methylspiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (20.6 g), ethyl chloroformate (10.9 g) and potassium carbonate (20 g) in dry benzene (400 ml) is heated under reflux overnight. The reaction mixture is cooled and stirred with water (200 ml) for 15 minutes. The organic phase is washed with water, diluted hydrochloric acid, saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the solvent is removed to yield 14.9 g of product as an oil. An analytical sample is obtained by passing 2.0 g of the oil through a silical gel dry column using ethyl acetate as the eluent and chloroform as the extractor. Removal of the solvent yields 1.8 g of an oil which crystallizes in the cold over petroleum ether, yielding a solid, mp, 72°-76°. The solid is recrystallized from hexane to yield white crystals, mp 75°-76°.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH3:18].C(Cl)(=O)C([Cl:24])=O.[Cl-]>C(Cl)(Cl)Cl>[C:1]([Cl:24])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH3:18]
Reactant: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 10 g of α-linolenic acid in 100 ml of anhydrous chloroform was kept cooled with ice and 4.6 g of oxalic chloride was added dropwise thereto. The solution containing the chloride was stirred at room temperature for three hours. The resultant reaction solution was dried under a vacuum. The α-linolenic acid chloride consequently formed was dissolved in 100 ml of anhydrous chloroform. The solution consequently obtained was cooled to -50° C. and 2.2 g of paraformaldenyde was added thereto and subsequently 12.2 g of zinc chloride was added thereto. Thereafter, the resultant reaction solution was stirred at room temperature for three hours. It was subjected to alumina chromatography. From the methylene chloride eluate consequently separated, 4.1 g of α-linolenyl oxymethyl chloride was obtained. The physicochemical data obtained of this product were as shown below. They prove the identity of α-linolenyl oxymethyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].N1C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N+:32]([O-:34])=[O:33])=[C:27]([CH:31]=1)[C:28](Cl)=[O:29]>ClCCl>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N+:32]([O-:34])=[O:33])=[C:27]([CH:31]=1)[C:28]([NH:15][C:12]1[N:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)=[CH:14][N:13]=1)=[O:29]
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1ccc(-c2cnc(N)nc2)cc1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(Cl)ccc3[N+](=O)[O-])nc2)cc1C

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 5-(3,4-dimethylphenyl)pyrimidin-2-amine (1.41 g, 7.07 mmol, 1.00 equiv) in dichloromethane (90 mL), and pyridine (1.73 g, 3.00 equiv). This was followed by dropwise addition of a solution of 5-chloro-2-nitrobenzoyl chloride (1.60 g, 7.27 mmol, 1.00 equiv) in dichloromethane (30 mL) with stirring. The resulting solution was stirred overnight at 25° C. in an oil bath. The resulting solution was diluted with 60 mL of dichloromethane. The resulting mixture was washed with 1×30 mL of hydrogen chloride (aq) and 3×200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved in 100 mL of methanol, to this was added potassium carbonate (5.12 g). The mixture was stirred for 3 h at 30° C. The resulting mixture was concentrated under vacuum and dissolved in 100 mL of ethyl acetate. The resulting mixture was washed with 3×50 mL brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was washed with ethyl acetate:n-hexane (30 mL:30 mL). This resulted in 0.78 g (29%) of 5-chloro-N-(5-(3,4-dimethylphenyl)pyrimidin-2-yl)-2-nitrobenzamide as a off-white solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][C@H:28]1[NH:33][C@@H:32]([CH3:34])[CH2:31][N:30]([C:35]2[N:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=2)[CH2:29]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:33]2[C@H:32]([CH3:34])[CH2:31][N:30]([C:35]3[N:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]=3)[CH2:29][C@@H:28]2[CH3:27])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: C[C@@H]1CN(c2ncc3ccccc3n2)C[C@H](C)N1
Product: C[C@@H]1CN(c2ncc3ccccc3n2)C[C@H](C)N1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-quinazoline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(F)cc1)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 101.9 %

Procedure:
To a solution of 4-fluorobenzenesulfonyl chloride (3.97 g, 20 mmol) in methylene chloride (40 ml), at 0° C., under nitrogen, with stirring, is added morpholine (4.4 mL, 50 mmol). The mixture is stirred at 0° C. for 15 min. and then warmed to room temperature for 18 hrs. The resulting suspension is filtered, and the filtrate is stirred with 10% potassium carbonate for 2 hrs. The methylene chloride is evaporated, and the aqueous suspension is filtered, and the precipitate is washed with water, and then dried in vacuo to give 5.0 g of a white solid; mp 106-107° C.; MS (APCI) m/z 246.1 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13]C)[C:9]([CH3:15])=[N:8][C:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([O:24]C)[CH:17]=1)=[CH:6]2.C(=O)=O.CC(C)=O.B(Br)(Br)Br>C(Cl)(Cl)Cl.ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[C:9]([CH3:15])=[N:8][C:7]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:24])[CH:17]=1)=[CH:6]2
Reactant: COc1ccc(-c2cc3cc(OC)c(OC)cc3c(C)n2)cc1OC
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1nc(-c2ccc(O)c(O)c2)cc2cc(O)c(O)cc12
Temperature: -50 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
Compound 12a (250 mg, 0.74 mmol) was dissolved in 5 mL dry chloroform and chilled to -50° C. using a mixture of dry ice and acetone. To this mixture was added dropwise 7.4 mL of a 1.0 M solution of boron tribromide in dichloromethane. The reaction mixture was allowed to come to room temperature over a period of 4 h. The precipitate was filtered and washed twice with 2 mL portions of ether. This crude product was recrystallized from ethanol to give 13 in 98% yield as white needles; mp >280° C. dec; IR (Nujol) 3326, 1602, 1531; 1H NMR (CD3OD) δ 3.08 (s, 3H), 6.98 (d, 1H, J=8.1), 7.19 (dd, 1H, J=8.1, 1.9), 7.24 (s, 1H), 7.37 (s, 1H), 7.61 (s, 1H), 7.94 (s, 1H); 13C NMR (CD3OD) δ 17.8, 109.6, 110.6, 116.1, 117.3, 119.6, 121.2, 122.8, 125.6, 138.4, 142.5, 147.7, 149.5, 152.0, 154.3, 158.3; HRMS calcd for C16H13NO4 : 283.0844; found 283.0839.
Reaction SMILES: [CH:1]1([CH:7]([N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C:22]2[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:34]I.O>CN(C)C=O.C(OCC)(=O)C>[CH3:34][O:9][C:8](=[O:10])[CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[N:11]1[C:15]2[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C:22]1[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)O)C2CCCCC2)c(OC)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C1CCCCC1)n1c(-c2ccc(OC)nc2OC)nc2cc(F)c(F)cc21

Procedure:
To a solution of 5.86 g (13.58 mmol) cyclohexyl-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetic acid in 60 ml N,N-dimethylformamide was added 652 mg (14.94 mmol) sodium hydride (55% dispersion in mineral oil) and 2.02 g (14.26 mmol) methyl iodide. The reaction mixture was poured on 300 ml water and 300 ml ethyl acetate and the phases were separated. The aqueous layer was extracted a second time with 300 ml ethyl acetate. The combined organic layers were washed twice with 300 ml water and once with 300 ml brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40). Light yellow solid (88%). MS (Turbo Spray) m/z=446.3 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18](=[O:20])[CH3:19])[CH2:13][CH2:12]1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:19][C:18](=[O:20])[CH2:17][N:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)CN1CCOCC1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C=CC(=O)CN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 71.9 %

Procedure:
Condensation 13.6 g (0.1 mole) of p-methoxybenzaldehyde is dissolved in 14.3 g (0.1 mole) of morpholinoacetone and this solution is added dropwise to 100 cm3 of a solution of 1 N sodium hydroxide cooled in an ice-containing water bath. The temperature is allowed to return to ambient temperature while stirring for 5 hours. The precipitate obtained is filtered and rinsed several times with water. 18.8 g of 1-(p-methoxyphenyl)-4-morpholino-1-buten-3-one is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:9]=[N:10][C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]([O:27][CH2:28][CH3:29])=[CH2:26])CCC>CN1C(=O)CCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:28]([O:27][C:25]([C:2]1[N:7]=[CH:6][C:5]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:9]=[N:10][C:4]=2[CH:3]=1)=[CH2:26])[CH3:29]
Reactant: COc1ccc(Cn2cnc3cc(Cl)ncc32)cc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: C=C(OCC)c1cc2ncn(Cc3ccc(OC)cc3)c2cn1
Temperature: 140 °C
Yield: 77.7 %

Procedure:
A mixture of 6-chloro-3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridine (500 mg, 1.83 mmol), tributyl(1-ethoxyvinyl)stannane (866 mg, 2.40 mmol), Pd (PPh3)4 (243 mg, 0.27 mmol) in NMP (10 mL) was heated at 140° C. for 72 h. The reaction mixture was quenched with water and extracted with EtOAc (50 mL×3). The combined extracts were washed with water (100 mL) and brine (50 mL), dried (MgSO4) filtered and concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with 3% MeOH/DCM to afford 440 mg (78%) of 6-(1-ethoxyvinyl)-3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridine as a gray solid. MS (EST): m/z=310.3 [M+1]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[NH:13]C(=O)C(C)(C)C)=O.[H-].[Li+].[F:22][C:23]([F:32])([F:31])/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(OCC)(=O)C>CS(C)=O>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:8]=[C:3]2[C:4](=[CH:5][CH:6]=1)[NH:13][CH:24]([C:23]([F:31])([F:32])[F:22])[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:1]2
Reactant: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1C=O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C1=Cc2cc(C(F)(F)F)ccc2NC1C(F)(F)F
Temperature: 30 °C
Yield: 1.1 %

Procedure:
To a suspension of N-(2-formyl-4-(trifluoromethylphenyl)-2,2-dimethyl propanamide (Step 2) (921 mg, 3.7 mol) and lithium hydride (115 mg, 14.5 mmol) in dimethyl sulfoxide (10 mL) was added ethyl 4,4,4-trifluorocrotonate (2.83 g, 16.8 mmol) and the contents warmed to 30° C. for 4 hours. After the addition of ethyl acetate (50 mL), the reaction was washed with water (2×30 mL), saturated ammonium chloride solution (2×30 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford a yellow solid. The product was purified by flash chromatography (silica gel, eluant: ethyl acetate-hexanes, 1:9) to yield, upon concentration of the appropriate fractions, ethyl 6-trifluoromethyl-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as a yellow solid (65 mg, 5%): mp 138-139° C. 1H NMR (CDCl3 /300 MHz) 7.67 (s, 1H), 7.26 (s, 1H), 7.04 (d, 1H, J=6.6 Hz), 6.62 (m, 1H,), 5.14 (m, 1H), 4.60 (brs, 1H), 4.32 (m, 2H), 1.35 (t, 3H, J=7.0 Hz). ESHRMS m/z 338.0592 (M-H Calc'd 338.0616). Anal. Calc'd for C13H11F3NO2 : C, 49.57; H, 3.27; N, 4.13; Found: C, 49.23; H, 2.81; N, 3.93.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:19]=[CH:18][C:8]([CH2:9]P(=O)(OCC)OCC)=[CH:7][CH:6]=1)=[O:4].C1OCCOCCOCCOCCOC1.[H-].[Na+].O=[C:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH:9]=[C:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)=[CH:18][CH:19]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1ccc(C(=O)OC)cc1)OCC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
To a mixture of diethyl 4-(methoxycarbonyl)benzylphosphonate (20.5 g, 71.5 mmol), 15-crown-5 (1.4 ml, 7.1 mmol) and THF (120 ml) was added sodium hydride (60% in oil, 2.9 g, 71.5 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 h. A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (11.9 g, 59.6 mmol) in THF (45 ml) was added dropwise to the resulting mixture over period of 10 min at 0° C. The mixture was stirred at room temperature for 20 h. The resulting mixture was poured into ice-water (200 ml) and the whole was extracted with ethyl acetate (100 ml×2). The extracts were washed with 5% aqueous sodium bicarbonate (100 ml), saturated sodium chloride solution (100 ml) successively. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 200 g, ethyl acetate/hexane=1/10) followed by recrystallization from hexane to give tert-butyl 4-(4-methoxycarbonylbenzylidene)piperidine-1-carboxylate (6.9 g, 35%) as a colorless crystalline powder. A mixture of tert-butyl 4-(4-methoxycarbonylbenzylidene)piperidine-1-carboxylate (6 g, 18 mmol) in methanol (150 ml) was hydrogenated over 10% palladium carbon (50% wet, 1 g) for 5 h at room temperature. The catalyst was, removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 90 g, ethyl acetate/hexane=1/10) to obtain the title compound (6.1 g, 100%) as pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:18][CH2:19][N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CCC)C(=O)CC1C=CC(OCC2C=CC=CC=2)=C(N)C=1)CC>>[NH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:18][CH2:19][N:20]([CH2:21][CH2:22][CH3:23])[CH2:24][CH2:25][CH3:26])=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCN(CCC)CCc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: CCCN(CCC)C(=O)Cc1ccc(OCc2ccccc2)c(N)c1
Product: CCCN(CCC)CCc1ccc(N)c(OCc2ccccc2)c1
Yield: 70.1 %

Procedure:
10.9 g of N-[2-(3-benzyloxy-4-nitrophenyl)ethyl]-N,N-dipropylamine is hydrogenated analogously to the production of 2-(3-amino-4-benzyloxyphenyl)acetic acid dipropylamide and the product chromatographed on silica gel with methylene chloride/acetone (1:1), thus obtaining 7.0 g of N-[2-(4-amino-3-benzyloxyphenyl)ethyl]-N,N-dipropylamine as an oil.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Mg+2].[Cl-].[Na].C(N(CC)CC)C.[CH:31](=[O:40])/[CH:32]=[CH:33]/[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl[Si](C)(C)C>C(OCC)(=O)C>[CH2:16]([C@@H:15]([C@@H:31]([OH:40])/[CH:32]=[CH:33]/[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([N:9]1[C@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:19])[CH:17]=[CH2:18]
Reactant: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: O=C/C=C/c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CC[C@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)[C@@H](O)/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 79.4 %

Procedure:
A mixture of (R)-4-benzyl-3-pent-4-enoyloxazolidin-2-one (50 g, 193 mmol), magnesium chloride (18.3 g, 193 mmol), sodium hexafluorostibate(V) (14.9 g, 58 mmol), triethylamine (80 mL, 579 mmol), (trans)-cinnamaldehyde (30.6 g, 232 mmol) and chlorotrimethylsilane (37.2 mL, 290 mmol) in ethyl acetate (500 mL) was stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate and filtered to remove solids. The filtrate was concentrated to small volume, and then diluted with methanol (500 mL) and a small amount of ethyl acetate. After treatment with trifluoroacetic acid (3 mL), the resulting solution was stirred at room temperature for 1 h, and then concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:10) to afford the title compound (60 g, 80%) as a yellow semi-solid. MS (ES+) C24H25NO4 requires: 391, found: 374 [M+H−H2O]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:23]([O-:25])=[O:24])[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Na+].[CH3:27]N(C)P(=O)(N(C)C)N(C)C.IC>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:23]([O:25][CH3:27])=[O:24])[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: Cc1ccc(NC2(C(=O)[O-])CCN(CCc3ccccc3)CC2)cc1
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC(=O)C1(Nc2ccc(C)cc2)CCN(CCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 19 parts of sodium 4-[N-(4-methylphenyl)amino]-1-(2-phenylethyl)-4-piperidinecarboxylate and 200 parts of hexamethylphosphoric triamide is heated to 80° C for a while. After cooling, 12.3 parts of iodomethane are added dropwise at a temperature below 15° C. Upon completion, stirring is continued for 24 hours at room temperature. The reaction mixture is poured onto 600 parts of water and the product is extracted with trichloromethane. The extract is washed twice with water, dried, filtered and evaporated. The oily residue is poured onto 200 parts of water while stirring. The supernatant aqueous phase is decanted and the residual oil is dissolved in trichloromethane. The solution is washed with water, dried, filtered and evaporated. The residue is purified twice by column-chromatography over silica gel using a mixture of trichloromethane and 7% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is suspended in 2,2'-oxybispropane. The product is filtered off and dried, yielding methyl 4-(4-methylphenylamino)- 1-(2-phenylethyl)-4-piperidinecarboxylate; mp. 94.5° C.