Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][CH:12]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:23])[CH2:18]3)[CH2:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: COc1ccc(C2=CCC(=O)CC2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C2=CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
4-(6-Methoxy-pyridin-3-yl)-cyclohex-3-enone (as prepared in Step C, 1.02 g, 5.02 mmol) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide HCl salt (as prepared in the previous step, 2.54 g, 7.53 mmol) in DCM (15 mL) was treated with TEA (2.80 mL, 20 mmol) for 10 min followed by NaBH(OAc)3 (Aldrich, 3.20 g, 15 mmol) for another 4 hours at room temperature. The reaction was quenched with saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted 3 times with chloroform/IPA “cocktail” (˜3:1, v/v). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as white solids.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(#N)C>[OH:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][N:21]2[CH2:20][CH2:19][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:23][CH2:22]2)[O:4][CH:5]=1
Reactant: O=c1cc(CBr)occ1O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(=O)c(O)co2)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
2-(Bromomethyl)-5-hydroxy-4H-pyran-4-one (8.9 g, 43.4 mmol), tert-butyloxycarbonylpiperazine (8.5 g, 45.6 mmol), triethylamine (7 mL, 49.9 mmol) and acetonitrile (200 mL) were charged in a 500 ml round-bottomed flask equipped with a magnetic stirrer. The reaction mixture was stirred for 2 h at 90° C. Acetonitrile was evaporated and EtOAc (50 mL) was added. The precipitate of (C2H5)3N, HCl was filtered off and ethyl acetate was evaporated at 40° C. to dryness. The crude compound was purified by column chromatography (deactivated SiO2:CH2Cl2:triethylamine 98:2 to CH2Cl2:MeOH 95:5, purification: CH2Cl2:MeOH 99.5:0:5 to 96:4) to give after evaporation tert-butyl 4-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)piperazine-1-carboxylate 24 (10.5 g, 78% yield) as a white powder.
Reaction SMILES: C(O[C:4](=O)[NH:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1Br)C.C(N(CC)CC)C.[CH3:25][Si:26]([C:29]#C)([CH3:28])[CH3:27].O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCOCC>[F:13][C:12]([F:15])([F:14])[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:5][C:4]#[C:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:11]=1
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)Nc1cc(C(F)(F)F)ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#CNc1cccc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
Following the procedure described in J. Org. Chem. 1997, 62, 6507, combine N-(2-bromo-5-trifluoromethylphenyl)carbamic acid ethyl ester (34.33 g, 110 mmol), triethylamine (300 mL), dichlorobis (triphenylphosphine)palladium(II) (5.4 g, 7.7 mmol), and copper (I) iodide (1.47 g, 7.7 mmol). Evacuate the dark solution and fill with N2 twice and then quickly add (trimethylsilyl)acetylene (16.21 g, 165 mmol, 23.32 mL) with vigorous stirring. Heat to 80° C. When TLC indicates absence of the starting material, add water and Et2O and filter through celite and evaporate the filtrate in vacuo to give a residue. Dilute residue with water and extract with Et2O, combine the organic layers and remove the evaporate to give a dark brown oil. Absorb the oil onto silica gel and load onto a short column of silica gel equilibrated with 100% hexanes. Wash with 100% hexanes (2 L) and elute the product with 1% EtOAc in hexanes. Pool fractions containing the product and remove in vacuo the solvent to give 5-trifluoromethyl-2-trimethylsilanylethynyl phenylamine as a red/brown oil; MS (IS): m/z 330 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])([O:15][CH3:16])=[O:14]>C(#N)C>[CH3:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([NH:1][C:27]([NH:26][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:25])=[O:24])=[O:28])[N:11]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1nc(N)nc2ccccc12
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c2ccccc2n1
Reaction time: 16 h
Yield: 41.3 %

Procedure:
To 20 ml dry acetonitrile was added 1.0 g of 2-amino-4-methylquinazoline followed by 3.1 g of 2-carbomethoxybenzenesulfonyl isocyanate. The slurry was refluxed for 2 hours and allowed to stand at ambient temperature for 16 hours. The light yellow solid was filtered, washed with acetonitrile and dried to yield 1.04 g of methyl 2-[[(4-methylquinazolin-2-yl)aminocarbonyl]aminosulfonyl]benzoate, m.p. 182°-183°. The product showed characteristic absorption bands in the infrared spectrum at 1730 and 1700 cm-1 and at 2.9, 3.9 and 7.5-8.4 ppms in the nuclear magnetic resonance spectrum (60 MHz), indicating the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.B1([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(Br)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 90 %

Procedure:
Argon is bubbled for 10 minutes into a mixture of 4.64 g (20.0 mmol) of the product prepared in step 4.1, 6.25 g (20.2 mmol) of 3,6-dihydro-2H-pyridine-1-N-Boc-4-boronic acid pinacol ester (Frontier Scientific) and 8.29 g (60.0 mmol) of potassium carbonate in 125 mL of anhydrous DMF. 0.98 g (1.2 mmol) of PdCl2dppf.CH2Cl2 is added and the mixture is heated under argon at 90°C. for 3 hours. The resulting mixture is diluted with ethyl acetate and washed twice with water and once with saturated aqueous NaCl. The organic phase is dried over Na2SO4, filtered and concentrated under vacuum. The crude solid obtained is purified by chromatography on a column of silica, eluting with a cyclohexane/ethyl acetate gradient (75/25 to 70/30). 6.02 g of a pale yellow solid are obtained, and are triturated in cyclohexane and then drained by suction and dried in an oven. 5.89 g of the expected product are finally recovered in the form of a white solid. Yield=88%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[C:11]([C:19]([N:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:22]2[CH2:27][C@@H:26]([CH:28]=[O:29])[CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:23]2)=[O:20])[N:10]=[N:9]1.S([CH2:51][N+:52]#[C-:53])(C1C=CC(C)=CC=1)(=O)=O.C[O-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[C:11]([C:19]([N:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:22]2[CH2:27][C@@H:26]([C:28]3[O:29][CH:53]=[N:52][CH:51]=3)[CH2:25][N:24]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:23]2)=[O:20])[N:10]=[N:9]1
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C=O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](c3cnco3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-formylpiperidine-1-carboxylate (235 mg) and tosylmethyl isocyanide (125 mg) were dissolved in methanol (4 ml), sodium methoxide (28% methanol solution, 325 mg) was added and the mixture was heated under reflux with stirring for 2 hr. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-100:0) was concentrated under reduced pressure to give the object product (98.5 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([O:19][CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[O:18])=[N:6][CH:7]=1.[F:34][C:35]([F:40])([F:39])[C:36]([O-:38])=[O:37]>>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([O:19][CH:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)=[O:18])=[N:6][CH:7]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(OC(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Product: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCNCC1
Product: O=C(O)C(F)(F)F
Yield: 99 %

Procedure:
Using a similar procedure to that described in Example 9-B, N-(5-chloropyridin-2-yl)-2-[(1-tert-butoxycarbonylpiperidin-4-yloxycarbonyl)amino]benzamide (1.90 g, 4.00 mmol) yielded 1.95 g (99%) of the titled compound as a trifluoroacetate salt.
Reaction SMILES: [CH2:1]([C:8]([CH2:10][CH3:11])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]([CH2:15]Cl)=[CH2:14]>>[CH3:14][C:13]([CH2:15][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8](=[O:9])[CH2:10][CH3:11])=[CH2:12]
Reactant: CCC(=O)Cc1ccccc1
Reactant: C=C(C)CCl
Product: C=C(C)CC(C(=O)CC)c1ccccc1

Procedure:
If ethyl benzyl ketone is reacted with β-methallyl chloride according to the foregoing details, then there is obtained 2-methyl-4-phenyl-hept-1-en-5-one of boiling point 93° C./3 mmHg; nD20 =1.5094.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]([CH3:15])([CH3:14])[C:12]#[CH:13])=[CH:7][C:4]=1[CH:5]=O.[NH2:16][C@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:18]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(OC(N1CCC[C@H](NCC2C=C(C(C#N)C)C=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:26]([O:25][C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@H:17]([NH:16][CH2:5][C:4]2[CH:7]=[C:8]([C:11]([CH3:15])([CH3:14])[C:12]#[CH:13])[CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[C@@H:18]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: C#CC(C)(C)c1ccc(OC)c(C=O)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Agent: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: C#CC(C)(C)c1ccc(OC)c(CN[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)c1

Procedure:
This compound was prepared from Compound 22 and Compound 17 in the same manner of Compound 18.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][OH:12].Cl.C(N(C(C)C)CC)(C)C>C(O)C>[N:5]1[C:4]2[S:8][CH:9]=[CH:10][C:3]=2[C:2]([NH:11][OH:12])=[N:7][CH:6]=1
Reactant: NO
Reactant: Clc1ncnc2sccc12
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: ONc1ncnc2sccc12
Reaction time: 6 h

Procedure:
4-chlorothieno[2,3-d]pyrimidine (340 mg, 1.99 mmol), hydroxylamine-hydrogen chloride (550 mg, 7.91 mmol), and diisopropylethylamine (1 ml) in absolute ethanol (5 ml) was placed into a preheated oil bath at 75° C. After stirring for 6 h, the solution was concentrated under reduced pressure.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8]([NH:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:32])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)=[CH:16][CH:15]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH2:33]([OH:37])[CH2:34][C:35]#[CH:36]>N1CCCCC1.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu]I>[OH:37][CH2:33][CH2:34][C:35]#[C:36][C:2]1[S:10][C:9]2[C:8]([NH:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:32])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)=[CH:16][CH:15]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: C#CCCO
Reactant: O=C(Nc1ccc(CCNc2ncnc3cc(Br)sc23)cc1)c1cccc(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: N#Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C(Nc1ccc(CCNc2ncnc3cc(C#CCCO)sc23)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a nitrogen purged solution of compound 20.2 (0.79 mmol), 3-butyn-1-ol (2.5 equivalents), Pd(PhCN)2Cl2 (0.2 equivalent) in piperidine was added CuI (0.5 equivalent) followed by stirring at room temperature for 3 hours. The reaction mixture was then subjected to an aqueous work-up and purified by flash column chromatography on silica gel to provide N-(4-{2-[6-(4-hydroxy-but-1-ynyl)-thieno[3,2-d]pyrimidin-4-ylamino]-ethyl}-phenyl)-3-trifluoromethyl-benzamide (compound 23.1).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:20]1[C:25]2[CH:26]=[CH:27][C:28]([CH:30]=O)=[CH:29][C:24]=2[O:23][CH2:22][CH2:21]1>>[O:20]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:29][C:24]=2[O:23][CH2:22][CH2:21]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc2c(c1)OCCO2
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc5c(c4)OCCO5)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH:1]([C:5]1[C:6](O)=[C:7]([CH:10]=[C:11]([CH:13]=[CH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[O:16])[CH:12]=1)C=O)([CH2:3][CH3:4])[CH3:2].C(C1C(O)=C(C=C(/C=C/C(=O)C2C=CC(C)=CC=2)C=1)C=O)(CC)C.[C:49]([O:56][CH3:57])(=[O:55])[CH2:50][C:51]([O:53][CH3:54])=[O:52].CN1CCOCC1>CO>[CH:1]([C:5]1[CH:12]=[C:11]([CH:13]=[CH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[O:16])[CH:10]=[C:7]2[C:54]=1[O:53][C:51](=[O:52])[C:50]([C:49]([O:56][CH3:57])=[O:55])=[CH:6]2)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1cc(C=CC(=O)c2ccc(Cl)cc2)cc(C=O)c1O
Reactant: COC(=O)CC(=O)OC
Agent: CCC(C)c1cc(/C=C/C(=O)c2ccc(C)cc2)cc(C=O)c1O
Solvent: CN1CCOCC1
Solvent: CO
Product: CCC(C)c1cc(C=CC(=O)c2ccc(Cl)cc2)cc2cc(C(=O)OC)c(=O)oc12

Procedure:
A solution of 3-sec-butyl-5-(3-(4-chlorophenyl)-3-oxoprop-1-enyl)-2-hydroxybenzaldehyde of formula III (0.5 g, 1.46 mmol), dimethyl malonate (0.19 g, 1.46 mmol) in methanol (30 mL) was treated with N-methyl morpholine (0.3 mL) and refluxed. Most of the excess solvent was evaporated under reduced pressure, and the residue was neutralized with acetic acid. To this residue water (25 mL) was added and extracted 3-fold with 25 mL of CHCl3. The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel (SiO2, 230-400 flash), eluting with a gradient of 20% ethyl acetate in hexane to 40% ethyl acetate in hexane. Concentration provides methyl 8-sec-butyl-6-(3-(4-chlorophenyl)-3-oxoprop-1-enyl)-2-oxo-2H-chromene-3-carboxylate (General Formula IV). (0.49 g, 80% yield). White solid, m. p. 145-146° C.; 1H NMR (CDCl3, 300 MHz); δ 8.59 (s, 1H), 7.99 (d, 2H, J=8.5 Hz), 7.84-7.75 (m, 3H), 7.58-7.47 (m, 3H), 4.0 (s, 3H), 3.45-3.36 (m, 1H), 1.78-1.69 (m, 2H), 1.32 (d, 3H, J=7.0 Hz), 0.89 (t, 3H, J=7.3 Hz): 13C NMR (CDCl3, 75 MHz); δ 188.6, 163.4, 156.1, 154.0, 149.1, 143.1, 139.5, 136.7, 136.2, 131.6, 131.4, 130.0, 129.0, 127.3, 122.3, 118.4, 118.2, 52.9, 33.5, 29.6, 20.4. 12.0; ESI-MS (m/z): 425 (M+H)+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1.[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>>[CH2:34]([NH:36][C:37]([N:30]1[CH2:31][CH2:32][CH:27]([N:12]2[C:13]3[C:22]4[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[C:17]=4[N:16]=[CH:15][C:14]=3[C:25](=[O:26])[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)[C:11]2=[O:33])[CH2:28][CH2:29]1)=[O:38])[CH3:35]
Reactant: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCNCC3)c12
Reactant: CCN=C=O
Agent: Cl
Product: CCNC(=O)N1CCC(n2c(=O)n(-c3cccc(Cl)c3)c(=O)c3cnc4c(OC)cccc4c32)CC1

Procedure:
4-[3-(3-Chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-piperidine-1-carboxylic acid ethylamide (40 mg) was prepared according to general procedure H from 3-(3-chloro-phenyl)-7-methoxy-1-piperidin-4-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (50 mg, 0.1 mmol) and ethyl isocyanate. LCMS: m/z 508 [M+1]+.
Reaction SMILES: [CH2:1]([P:3]([O-:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].[C:10](#[N:14])[C:11]([CH3:13])=[CH2:12]>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:12][CH:11]([C:10]#[N:14])[CH3:13])(=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCCCOP([O-])CC
Reactant: C=C(C)C#N
Solvent: Cc1ccccc1
Product: CCCCOP(=O)(CC)CC(C)C#N
Yield: 83.8 %

Procedure:
150 g (1 mol) of the butyl ethylphosphonite (produced as in Example 2) and 80 g (1.2 mol) of methacrylonitrile in 217 g of toluene are heated to about 100° C. While stirring, 124 g of a 10% strength solution of WakoV65 in toluene are metered in. The solvent is distilled off in vacuo to obtain 182 g (84% of theory) of butyl ethyl(2-cyano-2-methylethyl)phosphinate.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]1([CH:21]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:22]2[C@@H:27]([NH2:28])[CH:26]3[CH2:29][CH2:30][N:23]2[CH2:24][CH2:25]3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:37]([P:39]([C:43]1[CH:44]=[CH:45][C:46]([O:51][CH3:52])=[C:47]([CH:50]=1)[CH:48]=O)([CH2:41][CH3:42])=[O:40])[CH3:38].S(=O)(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)CCl>[C:31]1([CH:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:22]2[C@@H:27]([NH:28][CH2:48][C:47]3[CH:50]=[C:43]([P:39]([CH2:41][CH3:42])([CH2:37][CH3:38])=[O:40])[CH:44]=[CH:45][C:46]=3[O:51][CH3:52])[CH:26]3[CH2:29][CH2:30][N:23]2[CH2:24][CH2:25]3)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCP(=O)(CC)c1ccc(OC)c(C=O)c1
Reactant: N[C@H]1C2CCN(CC2)[C@H]1C(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCP(=O)(CC)c1ccc(OC)c(CN[C@H]2C3CCN(CC3)[C@H]2C(c2ccccc2)c2ccccc2)c1
Reaction time: 16 h

Procedure:
Sodium triacetoxyborohydride (202 mg, 0.95 mmol) was added to a solution of (2S,3S)-2-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-amine (150 mg, 0.51 mmol) and 5-diethylphosphoryl-2-methoxybenzaldehyde (150 mg, 0.55 mmol) dissolved in methylene chloride (5 ml) at rt, and the resulting solution was stirred for 16 h. Ethylene chloride and 1N sodium bisulfate were added to the reaction mixture. After 5 min the organic layer was washed with aq. sodium bicarbonate solution and brine. The extracts were dried over magnesium sulfate, and concentrated by evaporation. The residual oil was purified by following process: (1) silica-gel chromatography (4-14% methanol-methylene chloride), (2) Merck Lobar Li Chroprep NH2 (25-70%), (3) crystallization from diisopropyl ether. The title compound was obtained in a pure form (11 mg). IR (CH2Cl2) 1270 cm-1 1 H NMR δ: 7.66 (ddd, J=13, 8, 2 Hz, 1H), 7.39 (dd, J=13, 2 Hz, 1H), 7.31-7.03 (m, 10H), 6.75 (dd, J=8, 3.5 Hz, 1H), 4.47 (d, 12.2 Hz, 1H), 4.10 (m, 4H), 3.69-3.57 (m, 2H), 3.54 (s, 3H), 3.25-3.10 (m, 1H), 3.19 (d, J=13 Hz, 1H), 1H), 2.87 (dd Hz, 1H), 2.75 (m, 2H), 2.60 (m, 1H), 2.05 (m, 1H), 1.88 (m, 1H), 1.70-1.20 (m, 3H), 1.35 (t, J=7 Hz, 3H), 1.34 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(C)C)(C)C.[CH2:28]([O:30][CH:31]=[CH:32][C:33](Cl)=[O:34])[CH3:29]>C(N(CC)CC)C>[CH2:28]([O:30][CH:31]=[CH:32][C:33]([N:14]([CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:34])[CH3:29]
Reactant: CCOC=CC(=O)Cl
Reactant: c1ccc(CN2CCC(Nc3ccccc3)CC2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Product: CCOC=CC(=O)N(c1ccccc1)C1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Yield: 89.3 %

Procedure:
To a mixture of N-(1-benzyl-4-piperidinyl)aniline (0.9 g), diisopropyl ether (30 ml) and triethylamine (0.5 g) is added β-ethoxyacrylic acid chloride (0.7 g) in portions at 60° C. After refluxing for 1 hour, the reaction mixture is poured into ice-water and extracted with ethyl acetate. The extract is dried and concentrated and to the resulting residue is added n-hexane and the formed crystals are separated by filtration and recrystallized from n-hexane to give N-(β-ethoxyacryloyl)-N-(1-benzyl-4-piperidinyl)aniline (1.1 g) as white powders, m.p. 106°-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[CH:12]1[S:17][CH2:16][CH2:15][CH2:14][S:13]1.O1CCCC1>C(O)(=O)C.C(OCC)C.[Fe]>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[C:3]([CH:12]2[S:17][CH2:16][CH2:15][CH2:14][S:13]2)[CH:4]=1
Reactant: O=[N+]([O-])c1cc(C2SCCCS2)c(Cl)cc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1cc(C2SCCCS2)c(Cl)cc1F
Temperature: 50 °C
Yield: 75.2 %

Procedure:
To a stirred mixture of 20.0 g (0.0681 mole) of 2-(2-chloro-4-fluoro-5-nitrophenyl)-1,3-dithiane in 150 mL of acetic acid was added 75 mL of tetrahydrofuran. Iron powder (15.8 g, 0.269 mole) was added portionwise. Upon complete addition, the reaction mixture was heated to about 50° C. for approximately 30 minutes. The reaction mixture was cooled in an ice bath and was diluted with diethyl ether. The resultant mixture was filtered through a pad of Celite® filter aid. Water was added to the filtrate, and the organic phase was removed. An aqueous, sodium bicarbonate solution was added to the organic phase with vigorous stirring until the mixture was slightly basic. The aqueous phase was allowed to separate from the organic phase and was removed. The aqueous phase was extracted with diethyl ether, and the extracts were added to the organic phase. This organic solution was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure to yield 13.5 g of 2-(5-amino-2-chloro-4-fluorophenyl)-1,3-dithiane as a solid, m.p. 112°-115° C.