Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[CH2:5]([O:7][C:8](=[O:14])[CH2:9][C:10]([CH2:12]Cl)=O)[CH3:6].C(=O)([O-])O.[Na+].Cl>C(O)(=O)C>[CH3:2][C:1]1[O:3][C:9]([C:8]([O:7][CH2:5][CH3:6])=[O:14])=[C:10]([CH3:12])[N:4]=1
Reactant: CC(N)=O
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1oc(C)nc1C
Reaction time: 10 h

Procedure:
800 mmol of acetoamide and 400 mmol of ethylchloroaceto acetate were dissolved into 146 g of anhydrous acetic acid. Reaction was carried out for 10 hours at 130° C. The reacted liquid was alkalized with saturated sodium hydrogen carbonate and then the product was extracted into an organic phase using ethyl acetate. The organic phase was dried under sodium sulfate and then the solvent was evaporated out, obtaining a black liquid. To this black liquid 6N hydrochloric acid aqueous solution was added to make it alkaline. Then the product was extracted into organic phase using ethyl acetate. The thus obtained solid substance was dissolved in hexane. Insoluble matter was eliminated and solvent was evaporated out, obtaining ethyl 2,4-dimethyl-1,3-oxazole-5-carboxylate, an yellowish white solid (yield: 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([CH2:8][N:9]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[N:10]2)[CH:7]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:6]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)[CH:7]=1
Reactant: O=[N+]([O-])c1cnn(Cc2cc(Cl)ccc2OCc2ccccc2)c1
Solvent: CCO
Product: Nc1cnn(Cc2cc(Cl)ccc2OCc2ccccc2)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of 1-({5-chloro-2-[(phenylmethyl)oxy]phenyl}methyl)-4-nitro-1H-pyrazole (for a preparation see intermediate 8; 476 mg, 1.39 mmol) in ethanol (15 ml) was added stannous chloride (hydrated) (1.59 g, 7.03 mmol) and the reaction stirred at 85° C. overnight, under nitrogen. The reaction mixture was applied to a 20 g SCX-2 cartridge (pre-washed with MeOH) and the cartridge washed with methanol (6 column volumes). The product was eluted with 10% NH3 (aqueous) in MeOH (4 column volumes). The combined basic fractions were concentrated in vacuo. The residue was loaded in dichloromethane and purified on silica (50 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound (191 mg) as a red gum; LCMS (System 1): MH+=314, tRET=2.69 min.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][CH:16]=[C:11]2[C:10]([C:17]2[O:18][C:19]([CH:22]=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.C(O)(=O)C>C(O)CC>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][CH:16]=[C:11]2[C:10]([C:17]2[O:18][C:19]([CH2:22][OH:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2nn(Cc3ccccc3)c3ncncc23)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCO
Solvent: O
Product: OCc1ccc(-c2nn(Cc3ccccc3)c3ncncc23)o1
Reaction time: 0.25 h

Procedure:
0.6 g (1.97 mmol) of 1-benzyl-3-(5-formyl-2-furyl)pyrazolo[3,4-d]pyrimidine (Rf=0.65, SiO2, ethyl acetate) is treated with 60 mg of NaBH4 with good stirring in 20 ml of 1-propanol at room temperature. After 15 min, 50 ml of water and 2.5 ml of glacial acetic acid are added. After partially concentrating in a rotary evaporator, the mixture is extracted with ethyl acetate, and the extract is dried and concentrated in a rotary evaporator after addition of toluene. After chromatography on SiO2, 74.8 mg (12.4% of theory) of product are obtained (m.p. 165° C., Rf=0.43, SiO2, ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:11](=[O:13])[CH3:12])=[C:5]([CH3:10])[CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N)c(C)c1
Solvent: ClCCl
Product: COc1ccc(NC(C)=O)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
To a solution of 4-methoxy-2-methylaniline (120 g, 0.88 mol) in DCM (400 mL) is added acetic acid anhydride (120 mL, 1.2 mol) dropwise. The reaction mixture is stirred at room temperature (RT) for 3 hours. After petroleum ether (PE) (1.6 L) is added, the slurry is stirred for another one hour. The precipitate is collected by filtration and is washed with PE to give the product as a pink solid (130 g, 82% yield). MS (m/z): 180.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=O)[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:27]=1.S(C)C.CO.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([CH2:19][N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:27]=1
Reactant: O=C(C1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21)N1CCOCC1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Fc1cccc2c1cc1n2C(CN2CCOCC2)Oc2ccc(Cl)nc2-1
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of (2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)(morpholino)methanone (60 mg, 0.16 mmol) in THF (2 mL) was added to BH3.SMe2 (1 mL, 1 mmol) at 0° C. After being stirred for overnight, MeOH and water was added, the mixture was extracted with EtOAc (10 mL*3). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether:EtOAc=2:1) to provide 2-chloro-11-fluoro-6-(morpholinomethyl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (50 mg, yield: 86.2%). 1H-NMR (CDCl3, 400 MHz) δ 7.28˜7.34 (m, 1H), 7.22˜7.26 (m, 1H), 7.13˜7.22 (m, 2H), 7.09 (d, J=8.4, 1H), 6.79˜6.86 (m, 1H), 6.43 (t, J=4.8 Hz, 1H), 3.45˜3.53 (m, 2H), 3.34˜3.43 (m, 2H), 2.80˜2.88 (m, 1H), 2.63˜2.70 (m, 1H), 2.30˜2.39 (m, 2H), 2.21˜2.29 (m, 2H). MS (M+H)+: 374.
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:37])[NH:7][C:8]1[N:9]=[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[CH:18]=3)=[N:12][N:11]2[CH:36]=1)(=O)C.[OH-].[Na+].Cl>CO>[C:6]([NH:7][C:8]1[N:9]=[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=4)[CH:20]=[CH:21][CH:22]=3)=[N:12][N:11]2[CH:36]=1)(=[O:37])[CH2:5][OH:4]
Reactant: CC(=O)OCC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(CO)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
A mixture of 2-oxo-2-{[6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]amino}ethyl acetate (250 mg, 0.486 mmol), 1N aqueous sodium hydroxide solution (3 mL) and methanol (5 mL) was stirred at room temperature for 3 hr. The reaction mixture was neutralized by the addition of 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with ethanol to give the title compound (185 mg, 81%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(N(CC)CC)C.[CH:42]1([CH2:45][C:46]#[C:47][Si](C)(C)C)[CH2:44][CH2:43]1>CCOC(C)=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.C1COCC1>[CH:42]1([CH2:45][C:46]#[C:47][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[CH:5]3)[CH2:44][CH2:43]1
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Reactant: C[Si](C)(C)C#CCC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C(#Cc1ccc2c(cnn2C2CCCCO2)c1)CC1CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
To a mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (4.0 g, 14.3 mmol; Intermediate 1), Pd(PPh3)2Cl2 (1.0 g, 1.43 mmol), CuI (271 mg, 1.43 mmol), TBAF (11.2 g, 42.8 mmol), triethylamine (20 mL), and THF (20 mL), was added (3-cyclopropylprop-1-yn-1-yl)trimethylsilane (7.9 g, 42.8 mmol) under N2 atmosphere. The resulting mixture was stirred at 80° C. for 16 hours under N2 atmosphere. Upon completion, the reaction mixture was diluted with EtOAc and filtered. The filtrate was washed with water (3×10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜10% EtOAc in petroleum ether) affording the title compound as yellow solid (3.4 g). 1H NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H), 7.84 (s, 1H), 7.69 (d, 1H), 7.39 (dd, 1H), 5.83 (dd, 1H), 3.89-3.86 (m, 1H), 3.77-3.70 (m, 1H), 2.49 (d, 2H), 2.43-2.34 (m, 1H), 2.05-1.94 (m, 2H), 1.79-1.71 (m, 1H), 1.60-1.55 (m, 2H), 1.06-0.96 (m, 1H), 0.52-0.46 (m, 2H), 0.30-0.25 (m, 2H); LCMS: 281 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[C:22](O)=[O:23]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cc(Cl)cc(Cl)c4)cc23)CC1
Yield: 85.3 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 17.2 mg (0.09 mMol) 3,5-dichlorobenzoic acid, 10.3 mg of the title compound were recovered.
Reaction SMILES: C([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH2:10][CH2:11][CH3:12])(OC(C)(C)C)=O.[NH2:16][C@H:17]([C:22]([NH2:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C@H:9]([C:13]([OH:15])=[O:14])[CH2:10][CH2:11][CH3:12].[NH2:16][C@H:17]([C:22]([NH2:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)C[C@H](N)C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](N)C(=O)O

Procedure:
Boc-norvaline (2.0 g, 9.2 mmol) and leucinamide (1.53 g, 9.2 mmol) were dissolved in dry DMF (90 mL). The reaction was cooled to 0° C. and DCC (2.3 g, 11 mmol), HOBt (1.48 g, 11 mmol), and DEA (1.9 mL, 11 mmol) added. The mixture was stirred for 20 min at 0° C. and allowed to slowly warm to room temperature overnight (17 h). The mixture was concentrated to 1/3 its original volume, cooled, and filtered. The filtrate was concentrated, affording a yellow oil which was purified by column chromatography (SiO2, 1:1 hexanes/EtOAc→EtOAc) providing Boc-norvaline-leucinamide as white solid (selected signals 400 MHz, 1H NMR, CDCI3: δ 4.93 (m, 1 H), 4.45 (m, 1 H), 3.99 (m, 1 H), 1.81-1.71 (m, 2 H), 1.68-1.50 (m, 4 H), 1.41 (s, 9 H), 1.4-1.3 (m, 2 H), 0.9 (m, 9 H)). The Boc-protecting group was removed by treatment of Boc-norvaline-leucinamide (1.5 g, 4.6 mmol) with 50% TFA/DCM (60 mL) at room temperature (30 min). The reaction mixture was concentrated in vacuo and the peptide triturated with diethyl ether and dried in vacuo overnight providing norvaline-leucinamide as a foamy white solid (Electrospray MS M+H=230.1). Boc-valine (233 mg, 1.1 mmol) and norvaline-leucinamide (246 mg, 1.1 mmol) were dissolved in DMF (5 mL) and the solution cooled to 0° C. DCC (266 mg, 1.3 mmol), HOBt (174 mg, 1.3 mmol), and DIEA (224 μL, 1.3 mmol) were added and the reaction allowed to slowly warm to RT (overnight, 17 h). The reaction was filtered and the filtrate concentrated in vacuo affording a solid which was purified by column chromatography (SiO2, EtOAc). This provided the desired Boc-valine-norvaline-leucinamide as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](/[C:6](=[C:11](\[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)/[CH2:7][C:8](O)=[O:9])=[O:5])[CH3:2].B.CO.O>O1CCCC1>[Cl:28][C:25]1[CH:24]=[CH:23][C:22](/[C:11](/[C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=2)=[C:6](/[CH2:7][CH2:8][OH:9])\[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:27][CH:26]=1
Reactant: CCOC(=O)/C(CC(=O)O)=C(\c1ccc(Cl)cc1)c1ccc(S(C)(=O)=O)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOC(=O)/C(CCO)=C(\c1ccc(Cl)cc1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 350 g of (Z)-3-ethoxycarbonyl-4-(4-chloro phenyl)-4-(4-methanesulfonylphenyl)-3-butenoic acid, prepared in Example 63, in 1.5 l of tetrahydrofuran are added dropwise, and with good stirring, 120 ml of borane/dimethyl sulfide complex. At the end of the addition, the solution is stirred for 2.5 hours at room temperature. The borane in excess is hydrolyzed with 100 ml of methanol and 100 ml of water. After evaporation of the solvent under vacuum, the residue is crystallized in water, filtered and washed with water to give ethyl (Z)-3-(4-chlorophenyl)-3-(4-methanesulfonylphenyl)-2-(2-hydroxyethyl)-2-propenoate in the form of moist crystals which are used as such in the next step. By drying these crystals and recrystallizing them in propan-2-ol, ethyl (Z)-3-(4-chlorophenyl)-3-(4-methanesulfonylphenyl)-2-(2-hydroxyethyl)-2-propenoate is obtained in the form of crystals of HPLC purity 98.3% and of melting point 128° C.
Reaction SMILES: [C:1]1(=[O:11])[CH:9]2[CH:4]([CH:5]3[CH2:10][CH:8]2[CH2:7][CH2:6]3)[CH2:3][O:2]1.CO>C1(C)C=CC=CC=1.[Cl-].[Na+]>[OH:11][CH:1]1[CH:9]2[CH:4]([CH:5]3[CH2:10][CH:8]2[CH2:7][CH2:6]3)[CH2:3][O:2]1
Reactant: O=C1OCC2C3CCC(C3)C12
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: OC1OCC2C3CCC(C3)C12
Reaction time: 6 h
Yield: 97.6 %

Procedure:
30.4 g (0.2 mole) of hexahydro-4,7-methano-iso-benzofuran-1(3H)-one are introduced into 800 ml of absolute toluene, under an inert gas, and 84.8 ml (0.3 mole) of sodium bis-(2-methoxy-ethoxy)-dihydridoaluminate (70% strength solution in toluene), diluted with 200 ml of absolute toluene, are allowed to run in at -70° to -78° C. The mixture is stirred at -70° to -78° C. for 6 hours. Thereafter, 580 ml of 50% strength aqueous methanol are added dropwise at -70° C. and the mixture is subsequently stirred at 20° C. for 15 minutes and diluted with 400 ml of saturated aqueous sodium chloride solution. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution and dried over sodium sulphate and the solvent is evaporated off in vacuo. 30.1 g (98% yield) of 1-hydroxyoctahydro-4,7-methano-iso-benzofuran are obtained in this manner.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]([C:14]([NH2:16])=[O:15])[CH2:3][CH2:2]1.CCOCCOCCO>[Pd]>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([C:14]([NH2:16])=[O:15])=[CH:3][CH:2]=1
Reactant: NC(=O)C1CCCc2[nH]c3ccccc3c21
Agent: [Pd]
Solvent: CCOCCOCCO
Product: NC(=O)c1cccc2[nH]c3ccccc3c12

Procedure:
A 1,2,3,4-tetrahydrocarbazole-4-carboxamide or 4-carboxhydrazide (13) is dehydrogenated by refluxing in a solvent such as carbitol in the presence of Pd/C to produce the carbazole-4-carboxamide. Alternately, treatment of (13) with DDQ in an appropriate solvent such as dioxane yields carbozole (14).
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].ClC(OC[C:27]1[CH:32]=[CH:31]C=[CH:29][CH:28]=1)=O>>[C:17]([C:9]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:11][N:6]([C:1]([O:3][CH2:4][C:5]2[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=2)=[O:2])[CH2:7][CH2:8]1)([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)N1CCC(C(=O)OCC)(C(=O)OCC)CC1
Product: CCOC(=O)C1(C(=O)OCC)CCN(C(=O)OCc2ccccc2)CC1

Procedure:
In a manner analogous to that described by S. Huybrechts and G. J. Hoornaert, Synthetic Communications, 11 (1), 17-23 (1981) for the preparation of 1,4,4-tricarbethoxypiperidine but using benzyl chloroformate in place of ethyl chloroformate there was obtained benzyl 4,4-dicarbethoxypiperidine-1-carboxylate in the form of an oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:8]([C:14]([O:16][CH2:17][CH2:18][N:19]2C(=O)C3=CC=CC=C3C2=O)=[O:15])=[C:9]([CH3:13])[NH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].O.NN>C(O)C>[CH2:1]([NH:3][C:4]([C:6]1[CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:8]([C:14]([O:16][CH2:17][CH2:18][NH2:19])=[O:15])=[C:9]([CH3:13])[NH:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCNC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2C(=O)c3ccccc3C2=O)C1c1ccccc1OCc1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCNC(=O)C1=C(C)NC(C)=C(C(=O)OCCN)C1c1ccccc1OCc1ccccc1

Procedure:
A solution of 11.0 g (18.97 mmol) of N-ethyl 4-(2-benzyloxyphenyl)-1,4-dihydro-2,6-dimethyl-3-(2-phthalimido-ethoxycarbonyl)-pyridine-5-carboxamide (Example 28) and 95.0 mmol of hydrazine hydrate are heated under reflux in 100 ml of ethanol for 2 h. The solution is then cooled and the residue is filtered. The latter is subsequently washed with methylene chloride and the filtrate is concentrated in vacuo. The concentrated residue is then washed once with a 2 N solution of potassium hydroxide and then 3 times with water. The product is purified on a silica gel column using methylene chloride/methanol mixtures.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:15][CH2:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: Nc1ccncc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ccncc1
Temperature: 0 °C

Procedure:
A suspension of 4-aminopyridine (0.96 g) in dry dichloromethane (10 mL) under nitrogen was cooled to 0° C. in an ice bath. Triethylamine (1.56 mL) was added, followed by the slow addition of chloroacetyl chloride (0.89 mL). The ice bath was removed and the reaction mixture allowed to reach room temperature. The reaction mixture was diluted with water (20 mL) and dichloromethane (25 mL). The solid was filtered off, washed with pentane and dried to give the title compound as a brown solid (0.87 g). The layers of the filtrate were separated and the organic layer was washed with water, dried and the solvent was evaporated to give a dark brown glass. Trituration with pentane gave another batch of the title compound (0.91 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]#[CH:24].C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:24][C:23]#[CH:22])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: C#CCn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Temperature: 25 °C

Procedure:
1110 mg (3.61 mmol) of the compound from Example 5A were dissolved in 30 ml of acetonitrile, and 451 mg (3.79 mmol) of 3-bromo-1-propyne and 2.35 g (7.22 mmol) of cesium carbonate were added. The mixture was heated under reflux for 1 h. For work-up, the reaction mixture was allowed to cool to RT, and about 30 ml of water were added. The mixture was extracted twice with in each case 30 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1, then 3:1). This gave 203 mg (16% of theory) of the title compound.
Reaction SMILES: [C:1]([C:3](=[CH:9][NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1)[C:4](OCC)=[O:5])#[N:2].[NH:18]1C(C2C(=O)N3C=CC=CC3=NC=2)=N[N:20]=[N:19]1>>[CH3:17][C:15]1[CH:14]=[CH:13][N:12]2[C:4](=[O:5])[C:3]([C:1]3[NH:2][N:20]=[N:19][N:18]=3)=[CH:9][N:10]=[C:11]2[CH:16]=1
Reactant: CCOC(=O)C(C#N)=CNc1cc(C)ccn1
Reactant: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Product: Cc1ccn2c(=O)c(-c3nnn[nH]3)cnc2c1
Yield: 16 %

Procedure:
The title compound (16% yield, m.p. 307° with decomposition) was prepared from ethyl 2-cyano-3-(4-methyl-2-pyridylamino)acrylate in a manner similar to that described for the preparation of 3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]-pyrimidin-4-one in Example 2.
Reaction SMILES: COC[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21].Cl>CO>[NH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4]
Reactant: COCOCCCCCCCCCCCCCCCCN
Agent: Cl
Solvent: CO
Product: NCCCCCCCCCCCCCCCCO

Procedure:
To a suspension of 0.65 g of 16-methoxymethoxyhexadecylamine in 40 ml of methanol was added 1 ml of conc. hydrochloric acid and the mixture was heated under reflux for one hour. The reaction solution was distilled under reduced pressure. The residue was diluted with a 1N aqueous solution of sodium hydroxide, extracted with chloroform, dried over anhydrous sodium sulfate and distilled under reduced pressure to afford the title compound as a colorless crystal.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[N:6]([CH3:10])[CH2:5]1.[N:11]1([C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[CH3:10][N:6]1[CH2:5][CH:4]([CH2:3][CH2:2][N:14]2[CH2:13][CH2:12][N:11]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH2:23])=[O:22])=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)[O:8][C:7]1=[O:9]
Reactant: NC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CN1CC(CCCl)OC1=O
Product: CN1CC(CCN2CCN(c3ccc(C(N)=O)cc3)CC2)OC1=O

Procedure:
Following the procedure of Example 2, the title compound is prepared from 5-(2-chloroethyl)-3-methyl-2-oxazolidinone and 4-(1-piperazinyl)benzamide.
Reaction SMILES: CCN(C(C)C)C(C)C.C(OC(=O)[CH:14]([C:20]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:22](F)[C:21]=1[F:29])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.CS(C)=O.[Cl:35][C:36]1[CH:37]=[C:38]([C:42]([F:46])([F:45])[CH2:43][NH2:44])[CH:39]=[CH:40][CH:41]=1>C([O-])(O)=O.[Na+]>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:20]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:22]([NH:44][CH2:43][C:42]([C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([Cl:35])[CH:37]=2)([F:45])[F:46])[C:21]=1[F:29])[CH3:19]
Reactant: NCC(F)(F)c1cccc(Cl)c1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(C#N)ccc(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1c(C#N)ccc(NCC(F)(F)c2cccc(Cl)c2)c1F
Temperature: 110 °C
Reaction time: 69 h
Yield: 64.1 %

Procedure:
To a solution of DIPEA (1.38 mL, 7.9 mmol), 2-(6-cyano-2,3-difluorophenyl)malonic acid diethyl ester (1.35 g, 6.00 mmol), as prepared in the preceding step, and DMSO (1.7 mL) was added 2-(3-chlorophenyl)-2,2-difluoroethylamine (1.44 g, 7.51 mmol), as prepared in Example 2d. The reaction was stirred under argon at 110° C. for 69 h and then allowed to cool to room temperature. The mixture was diluted with saturated NaHCO3 (15 mL) and extracted with ether (2×15 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica gel (3:1 hexane/EtOAc) to afford the title compound (1.525 g, 64%) as a tan crystalline solid. 1H NMR (300 MHz, CDCl3) δ 7.51-7.41 (m, 2H), 7.40-7.36 (m, 2H), 7.30 (dd, J=8.6 Hz, 1.3 Hz, 1H), 6.63 (t, J=8.2 Hz, 1H), 4.67 (br, 1H), 4.20 (q, J=7.0 Hz, 2H), 3.84 (d, J=2.0 Hz, 2H), 3.81 (dt, J=13.3 Hz, 6.9 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H). LC/MS (ESI) calcd for C21H20ClF3N3O2 (MH+.MeCN) 438.1. found 438.2.