Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Pd].C1COCC1.CO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1
Reactant: O=C(Nc1cc([N+](=O)[O-])ccc1F)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(F)c(NC(=O)c2ccccc2)c1
Yield: 91 %

Procedure:
A mixture of N-(2-fluoro-5-nitro-phenyl)-benzamide (4.86 g, 18.7 mmol) and 10% Pd/C (486 mg) in a 1:1 mixture of THF-MeOH (80 ml) was hydrogenated at 23° C. After 2.5 h the reaction mixture was filtered through celite and concentrated to give N-(5-Amino-2-fluoro-phenyl)-benzamide (3.92 g, 91%). MS (ESI+) [M+H]/z Calc'd 231, found 231.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][CH3:12])[C:5]([CH:6]=O)=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][C:24](OC)=[O:25])[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]2[C:5]([CH:6]=[C:23]([C:17]3[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=[C:15]([O:14][CH3:13])[CH:16]=3)[C:24](=[O:25])[N:11]2[CH3:12])=[CH:4][N:3]=1
Reactant: COC(=O)Cc1cc(OC)cc(OC)c1
Reactant: CNc1c(C=O)cnc(Cl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(-c2cc3cnc(Cl)c(C)c3n(C)c2=O)c1
Temperature: 105 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A mixture of 6-chloro-5-methyl-4-(methylamino)nicotinaldehyde (3.11 g, 16.8 mmol), methyl 2-(3,5-dimethoxyphenyl)acetate (4.25 g, 20.2 mmol) and potassium carbonate (2.8 g, 20.3 mmol) in N,N-dimethylformamide (100 mL) was stirred at 105° C. overnight. LCMS monitored the reaction was completed. The reaction mixture was cooled to RT and quenched by water. The precipitate was filtered and dried to get the title compound (5.5 g, crude) as a yellow solid. MS (ES+) C18H17ClN2O3 requires: 344, 346. found: 345, 347 [M+H]+.
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl-].[NH4+:5].O.N.[CH:8]([C:10]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11]1)=O>O.C(O)C>[NH2:5][CH:8]([C:10]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11]1)[C:1]#[N:2]
Reactant: CCOC(=O)C1(C=O)CC1
Reactant: [NH4+]
Reactant: [C-]#N
Agent: N
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(C(N)C#N)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
An eggplant type flask was charged with 3.49 g of potassium cyanide and 3.74 g of ammonium chloride, and the contents were dissolved in 20 ml of water. After adding 40 ml of concentrated ammonia water to the solution, 5.01 g of ethyl 1-formylcyclopropane-1-carboxylate dissolved in 30 ml of ethanol was added thereto dropwise at room temperature, and the reaction solution was stirred for 2 hours at 50° C. After confirming completion of the reaction, the reaction solution was mixed with ice water and extracted with ethyl acetate. Next, the resulting organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and, after removing insoluble matter by filtration, concentrated under a reduced pressure. Thereafter, the resulting residue was subjected to a silica gel column chromatography (ethyl acetate) to obtain 5.44 g (97%) of the title compound in the form of colorless oil.
Reaction SMILES: [CH2:1]([NH:4][S:5]([CH3:8])(=[O:7])=[O:6])[C:2]#[CH:3].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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.[Cu]I>[F:9][C:10]1[C:11]([C:3]#[C:2][CH2:1][NH:4][S:5]([CH3:8])(=[O:7])=[O:6])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCNS(C)(=O)=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCNS(C)(=O)=O)c21

Procedure:
Using Method C above, N-(Prop-2-ynyl)-methanesulfonamide (80 mg, 0.62 mmol) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P)4Pd (24 mg, 0.02 mmol) and a catalylic amount of CuI in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (Z)-N-[3-[5-Fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-2,3-dihydro-1H-indol-4-yl]-prop-2-ynyl]-methanesulfonamide was obtained after HPLC purification with 40% EtOAc in hexanes and precipitation out of THF with excess of pentane. (Yield 48 mg, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C@H:15]2[CH2:19][CH:20]=[CH:21][CH2:22][C@@H:14]12>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[C:13]([CH:14]1[CH:15]([C:16]([OH:18])=[O:17])[CH2:19][CH:20]=[CH:21][CH2:22]1)=[O:23]
Reactant: COc1ccc([Mg]Br)cc1OC
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CC=CCC2C(=O)O)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
A solution of 3,4-dimethoxyphenylmagnesium bromide (59 mmol, 0.29 M) in THF was added dropwise to an ice-cooled solution of cis-1,2,3,6-tetrahydrophthalic anhydride in THF (120 mL) over a 1 h period. After the addition was complete, the resulting mixture was stirred for another 30 min at 0° C. The reaction mixture was allowed to warn to room temperature overnight. The reaction was quenched with sat. NH4Cl(aq) and then the pH was adjusted to 2 with concentrated HCl(aq) and extracted with diethyl ether. The combined organic extracts were washed with water and subsequently extracted with 1 M NaOH(aq). The combined aqueous extracts were neutralized with conc. HCl(aq) and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered through paper, and concentrated under reduced pressure to give an oil. The oil was dissolved in CH2Cl2 and filtered through silica to remove any dicarboxylic acid formed during the reaction work up. The product was recrystallized in diethyl ether to afford a white solid (1.62 g, 5.58 mmol, 10%).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[C:12]#[N:13].[OH2:14].O.O.C([O-])(=O)C.[Na+].Cl.[NH2:23]O>CO>[NH2:13][C:12]1[O:14][N:23]=[C:2]2[C:3]=1[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[N:7]2[CH3:8]
Reactant: Cn1c(Cl)c(C#N)c(=O)n(C)c1=O
Reactant: O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cn1c(=O)c2c(N)onc2n(C)c1=O
Yield: 87.2 %

Procedure:
1.4 g of 6-chloro-5-cyano-1,3-dimethyluracil was stirred together with a mixture of 150 ml of methanol, 6.0 g of sodium acetate trihydrate and 3.0 g of hydroxylamine hydrochloride at room temperature for 3 hours. Resulting precipitates were recovered by filtration and washed with 10 ml of water twice and then with 5 ml of methanol. The precipitates were recrystallized from dimethylformamide-water to give 1.2 g of light yellow prisms, melting point: 280°-284° C. (decomp.). Ultraviolet absorption spectrum: λmax H2O 266 nm (ε=8780)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[N:7]2.[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:38][CH3:39])=[C:24]([C:26]([CH3:37])([CH3:36])[CH2:27][C:28]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH:29]=O)[CH:25]=1>C(O)(=O)C.C1(C)C=CC=CC=1>[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:38][CH3:39])=[C:24]([C:26]([CH3:36])([CH3:37])[CH2:27][C:28]([C:31]([F:33])([F:34])[F:32])([OH:35])[CH:29]=[N:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([CH2:12][N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[N:7]3)[CH:25]=1
Reactant: Nc1cccc2nc(CN3CCOCC3)ccc12
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cccc2nc(CN3CCOCC3)ccc12)C(F)(F)F

Procedure:
Analogously to Example 37, 180 mg (0.74 mmol) of 5-amino-2-(morpholin-4-ylmethyl)quinoline is reacted with 274 mg (0.89 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal in 0.8 ml of concentrated acetic acid and 20 ml of toluene. After purification on silica gel with hexane-ethyl acetate (0-100%), 220 mg (56% of theory) of the product is obtained.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:9].[K+].C(Cl)(Cl)Cl.O>C(O)(C)(C)C>[C:1]([NH2:8])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: N#Cc1ccccc1
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(C)(C)O
Product: NC(=O)c1ccccc1

Procedure:
A sample of 3-[(2-dimethylamino)methyl]-1-hydroxycyclohexyl]-benzonitrile (Procedure A, 1.66 g, 6.4 mmol) as a mixture of diastereomers was dissolved in tert-butanol (20 mL), powdered potassium hydroxide (1.8 g, 32.1 mmol) was added, and the reaction was brought to reflux for 1 h. After cooling the reaction, chloroform (50 mL) and water (50 mL) were added. The organic layer was separated, dried (K2CO3), filtered, and concentrated to afford 3-[(2-dimethylamino)methyl]-1-hydroxycyclohexyl]-benzamide as a diastereomeric mixture (1.6 g, 93%). The mixture was purified on a reverse phase C-18 column with 0.5% ammonium acetate in water and acetonitrile as eluents. Compound 1, 3-[(1-RS,2-SR)-2-[(dimethylamino)methyl]-1-hydroxycyclohexyl]-benzamide, eluted first. Next to elute was Compound 2, 3-[(1-RR, 2-SS)-2-[(dimethylamino)methyl]-1-hydroxycyclohexyl]-benzamide.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1)=[O:2].[CH2:13](I)[CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([CH:11]=1)[C:8]([O:10][CH2:13][CH2:14][CH2:15][CH3:16])=[O:9])=[O:2]
Reactant: CCCCI
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1cc(C=O)ccc1O
Yield: 30 %

Procedure:
5-Formylsalicylic acid (5.0 g, 30 mmol), n-butyl iodide (3.4 mL, 30 mmol), and potassium carbonate (4.2 g, 30 mmol) were stirred in DMF (40 mL) for 27 h at room temperature. After several EtOAc/H2O extractions, the mixture was dried (MgSO4), and concentrated. Chromatography on silica gel, eluting with 5% to 30% EtOAc in hexanes, followed by solvent removal gave a white solid (2.0 g). HR-MS: Calc'd 223.0970, Found 223.0968. Anal. Calc'd for C12H14O4 : C, 64.84; H, 6.36; Found: C, 64.82; H, 6.30.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[SH:18]>>[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:18][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[F:9]
Reactant: Fc1cc(Cl)ccc1I
Reactant: Fc1ccc(S)c(Br)c1
Product: Fc1ccc(Sc2ccc(Cl)cc2F)c(Br)c1

Procedure:
Prepared from 4-chloro-2-fluoro-1-iodo-benzene and 2-bromo-4-fluoro-benzenethiol.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH3:28])[C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH3:28])[C:25]([NH:9][CH2:8][C:7]3[CH:10]=[CH:11][C:4]([S:3][C:2]([F:12])([F:1])[F:13])=[CH:5][CH:6]=3)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1ccc(SC(F)(F)F)cc1
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(SC(F)(F)F)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-[(trifluoromethyl)thio]benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 391 (M+H)+; MS (ESI−) m/z 389 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.57 (d, J 7.1, 3H), 4.33 (d, J 6.1, 2H), 4.65 (q, J 7.1, 1H), 7.33 (d, J 8.1, 1H), 7.65 (m, 2H), 7.76 (m, 1H), 7.98 (m, 2H), 8.19 (d, J 7.1, 1H), 8.42 (d, J 7.8, 1H), 8.61 (br s, 1H), 8.62 (d, J 6.8, 1H), 8.73 (d, J 6.8, 1H), 8.96 (t, J 5.8, 1H), 9.86 (s, 1H); Anal. Calcd for C20H17F3N2OS+2.1HCl: C, 51.44; H, 4.12. Found: C, 51.35; H, 3.91.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)N(C2C=CC=CC=2)CN1CCO.[O:21]=[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)N(C)CN1CCO.[O:36]=[C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)[CH2:39][N:38]1[CH2:53][CH2:54][OH:55]>>[CH:2](=[O:1])[C:11]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1.[O:36]=[C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)[CH2:39][N:38]1[CH2:53][CH2:54][O:55][C:28]1[CH:27]=[CH:26][C:31]([CH:22]=[O:21])=[CH:30][CH:29]=1
Reactant: CN1CN(CCO)C(=O)c2ccccc21
Reactant: O=C1c2ccccc2N(c2ccccc2)CN1CCO
Reactant: O=C1c2ccccc2N(c2ccccn2)CN1CCO
Product: O=Cc1ccc(OCCN2CN(c3ccccn3)c3ccccc3C2=O)cc1
Product: O=Cc1ccccc1

Procedure:
Reactions were carried out in the same manner as in the Preparation Example 3, except that 2-(4-oxo-1-phenyl-1,2,3,4-tetrahydroquinazolin-3-yl)ethanol was replaced by 2-(4-oxo-1-methyl-1,2,3,4-tetrahydroquinazolin-3-yl) ethanol or 2-[4-oxo-1-(2-pyridyl)-1,2,3,4-tetrahydroquinazolin-3-yl]ethanol, to produce 4-[2-(4-oxo-1-methyl-1,2,3,4)-tetrahydroquinazolin-3-yl)ethoxy]benzaldehyde (Compound 4L) and 4-[2-[4-oxo-1-(2-pyridyl)-1,2,3,4-tetrahydroquinazolin-3-yl]ethoxy]benzaldehyde (Compound 4M) , respectively.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][N:7]1[C:11]([S:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)=[C:10]([CH2:21][C:22]#[N:23])[N:9]=[C:8]1[CH3:24].CN(C)P(=O)(N(C)C)N(C)C.CI>CCCCCC>[CH3:6][N:7]1[C:11]([S:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)=[C:10]([CH:21]([CH3:1])[C:22]#[N:23])[N:9]=[C:8]1[CH3:24]
Reactant: [Li]CCCC
Reactant: Cc1cc(C)cc(Sc2c(CC#N)nc(C)n2C)c1
Solvent: CI
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1cc(C)cc(Sc2c(C(C)C#N)nc(C)n2C)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To this, 0.3 ml of 1.62 M hexane solution of n-butyllithium was added under a stream of nitrogen, and the mixture was stirred for 10 minutes. The mixture was cooled to -78° C., and 85 mg (0.31 mmol) of [1,2-dimethyl-5-(3,5-dimethylphenylthio)imidazol-4-yl]acetonitrile (42d) was added, and the mixture was stirred for 15 minutes. Then, 86 mg (0.48 mmol) of hexamethylphosphoric triamide and 68 mg (0.48 mmol) of methyl iodide were added dropwise, and the mixture was stirred at -78° C. for 30 minutes. The reaction mixture was poured into ice-water, extracted with diethyl ether, and the extract was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate) to give 51 mg of 2-[1,2-dimethyl-5-(3,5-dimethylphenylthio)-1H-imidazol-4-yl]propiononitrile (43a) as oil (yield 57%).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].N1C=CC=CC=1.[CH2:14]([OH:17])[CH2:15][OH:16]>C(Cl)Cl>[C:2](=[O:3])([O:4][CH:5]([CH3:7])[CH3:6])[O:16][CH2:15][CH2:14][OH:17]
Reactant: CC(C)OC(=O)Cl
Reactant: OCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(=O)OCCO
Temperature: 25 °C
Reaction time: 15 h
Yield: 42 %

Procedure:
To a stirred solution of isopropyl chloroformate (2 g, 0.016 mol.) in 10 mL of DCM at 0° C. under nitrogen atmosphere was added pyridine (3.8 mL, 0.048 mol) and then ethylene glycol (2.7 mL, 3 eq). The progress of the reaction was monitored by thin layer chromatography (TLC). After stirring for 15 hrs at room temperature. After removing the solvent under reduce pressure, the residue was purified by silica gel column chromatography to give 2-hydroxyethyl isopropyl carbonate as a colorless oil (0.5 g, 42% yield). 1HNMR (400 MHz, CDCl3): δ 1.22 (t, J=7.2 Hz, 3H); 2.94 (sbroad, 1H); 3.78 (t, J=4.4 Hz, 2H); 4.18 (t, J=4.4 Hz, 2H); 4.07 (q, J=7.2H, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[N:16]1([CH2:15][C@@H:11]2[CH2:12][CH2:13][CH2:14][N:10]2[C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:22][CH2:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:3][CH:4]=2)=[O:9])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: FC(F)(F)CCCBr
Reactant: O=C(c1ccc(O)cc1)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1ccc(OCCCC(F)(F)F)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure E except the reaction mixture is stirred at room temperature overnight starting from (4-hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 1-bromo-4,4,4-trifluorobutane. MS (ES+) 385.2.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](/[C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13]\[CH3:14].C(=O)(O)[O-].[Na+].[N+:32]([CH3:35])([O-:34])=[O:33]>>[CH:12](/[C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[CH:17]([CH2:35][N+:32]([O-:34])=[O:33])[CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13]\[CH3:14]
Reactant: C/C=C/c1ccccc1C=CC(=O)OC
Reactant: C[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Product: C/C=C/c1ccccc1C(CC(=O)OC)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
1,8-Diazabicyclo[5.4.0]-7-undecene (0.1 mL) was added to a solution (10 mL) of methyl 2-((E)-1-propenyl)cinnamate (102 mg, 0.50 mmol) in nitromethane, followed by-stirring at room temperature for 3 hours. Next, the reaction solution was added to a saturated aqueous solution of sodium bicarbonate under ice-cooling to neutralize the reaction solution, and the mixture was then extracted with diethyl ether. After the extract was washed with a saturated brine and then dried over sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developed with diethyl ether/hexane=1/4) to give methyl 3-[2-((E)-1-propenyl)phenyl]-4-nitrobutyrate (52 g, yield 40%).
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C>[CH3:3][C:4]([O:11][C:10](=[O:12])[C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1])([CH3:9])[CH3:5]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)[C@H](N)Cc1ccccc1
Temperature: 25 °C
Yield: 11.1 %

Procedure:
To a solution of D-phenylalanine (5.5 g, 33 mmol) in 430 mL of t-butyl acetate was added concentrated perchloric acid (2 mL, 33 mmol). After stirring at room temperature, the reaction mixture was filtered and the filter cake washed with copious diethyl ether. The filter cake was suspended in diethyl ether and washed with two portions of 5% citric acid. The acid washes were combined, neutralized with solid NaHCO3 and extracted with two portions of diethyl ether. The combined organic extracts were washed with brine, dried with magnesium sulfate and concentrated to give the title compound (404 mg) as a pale yellow liquid and the structure verified by NMR.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=O)[CH:9]=[CH:8]2.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc2cccc(C(F)(F)F)c2[nH]1
Product: FC(F)(F)c1cccc2ccc(Cl)nc12
Reaction time: 0.25 h
Yield: 33 %

Procedure:
8-Trifluoromethyl-1H-quinolin-2-one (8.35 g, 39.2 mmol) was taken in a 25 mL RB POCl3 (10 mL) was added, and then refluxed for 1 h. The excess POCl3 was distilled off and ice was added to the reaction mixture. This was stirred for 15 min, the precipitate was filtered off and then dried under vacuum to afford the title compound (3 g, yield: 33%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:13]=[N:12][C:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[N:10][C:9]=2[N:19]([CH2:21][CH3:22])[CH:20]=1)=[O:5])C.[OH-].[Na+].CCN1C2C(=NC=C(N3CCCC3)N=2)C(=O)C(C(O)=O)=C1>O>[N:14]1([C:11]2[N:12]=[CH:13][C:8]3[C:7](=[O:23])[C:6]([C:4]([OH:5])=[O:3])=[CH:20][N:19]([CH2:21][CH3:22])[C:9]=3[N:10]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)c1cn(CC)c2nc(N3CCCC3)ncc2c1=O
Agent: CCn1cc(C(=O)O)c(=O)c2ncc(N3CCCC3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCCC3)nc21

Procedure:
Saponification of this ester (5.5 g) under reflux in an alkaline solution (NaOH: 0.8 g / water: 40 cm3) gives, after acidification, the corresponding acid (pyromidic acid, melting point 322° C), which is identical to the product described in the literature.
Reaction SMILES: [OH:1][N:2]1[C:7](=[O:8])[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)=[C:5]([CH2:24][CH2:25][CH3:26])[N:4]=[C:3]1[CH3:27].[C:28]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:33]=CC=C[CH:29]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:61]([O:64][CH2:65][CH3:66])(=O)[CH3:62]>O1CCCC1.O>[CH3:62][C@@H:61]1[CH2:33][CH:28]([O:1][N:2]2[C:7](=[O:8])[C:6]([CH2:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]4[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:14][CH:15]=3)=[C:5]([CH2:24][CH2:25][CH3:26])[N:4]=[C:3]2[CH3:27])[CH2:29][C@H:65]([CH3:66])[O:64]1
Reactant: CCOC(C)=O
Reactant: CCCc1nc(C)n(O)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nc(C)n(OC2C[C@@H](C)O[C@@H](C)C2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 4′-[(1-hydroxy-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.50 g), (2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-ol (0.54 g) and triphenylphosphine (1.1 g) in tetrahydrofuran (5 mL) was added diisopropyl azodicarboxylate (2.2 mL, 1.9 M toluene solution), and the mixture was stirred for 1 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.62 g, 95%).