Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([O:15][C:16]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=[O:17])[CH3:14].Cl[CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[NH4+]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH2:13]([O:15][C:16]([C:18]1([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:20][CH2:19]1)=[O:17])[CH3:14]
Reactant: ClCOCc1ccccc1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C1(COCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (15% solution in n-hexane; 9.5 mL, 0.022 mol) is added to a stirred solution of diisopropyl amine (3.1 mL, 0.022 mol) in tetrahydrofuran (15 mL) at −70° C. under an atmosphere of nitrogen and stirred for 30 minutes. A solution of piperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester (3 g, 0.012 mol) in tetrahydrofuran (10 mL) is introduced at −70° C. Hexamethyl phosphoramide (4.8 mL) is added and reaction mixture is allowed to stir till the temperature reaches at −45° C. Reaction mixture again cooled to −70° C., benzyl chloromethyl ether (5 mL, 0.035 mol) is added and stirred for 1 hour. Saturated aqueous solution of ammonium chloride (30 mL) is added slowly into the reaction mixture at −30° C. and stirred for 10 minutes. It is extracted with ethyl acetate (2×20 mL). Combined organic layer is dried over sodium sulfate. Removal of solvent under reduced pressure gives a viscous liquid which is purified by column chromatography (silica gel 230-400, toluene:ethyl acetate, 23:2 to furnish 4-benzyloxymethylpiperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester.
Reaction SMILES: C(O[C:4]1[N:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17](OC)[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)C.[CH3:21][N:22](C)C1N=CC(C2SC3C=C(O)C=CC=3N=2)=CN=1.C([O-])(O)=O.[Na+]>>[S:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[C:7]1[CH:6]=[CH:5][C:4]([NH:22][CH3:21])=[N:9][CH:8]=1
Reactant: CN(C)c1ncc(-c2nc3ccc(O)cc3s2)cn1
Reactant: CCOc1ccc(-c2nc3ccc(OC)cc3s2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Product: CNc1ccc(-c2nc3ccccc3s2)cn1

Procedure:
2-(6-Ethoxypyridin-3-yl)-6-methoxy-1,3-benzothiazole (23 mg, 80 μmol) was reacted according to the procedure used for the preparation of 2-[2-(dimethylamino)pyrimidin-5-yl]-1,3-benzothiazol-6-ol, with the following exceptions: The reaction mixture was allowed to reach rt on. sat. aq. NaHCO3 was added and the mixture was extracted with EtOAc. The organic phase was dried and concentrated under reduced pressure. Preparative HPLC of the residue gave the title compound (4 mg). 1H NMR (CHLOROFORM-d: CD3OD) δ 8.69 (d, 1H) 8.20 (dd, 1H) 7.79 (d, 1H) 7.29 (d, 1H) 6.99 (dd, 1H) 6.86 (d, 1H) 4.39 (q, 2H) 1.41 (t, 3H); MS m/z (M+H) 273.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].C=O.[NH2:8][CH2:9]C(O)=O.[P:13]([O-:18])([O:16]C)[O:14]C.Cl>CO>[P:13]([CH2:9][NH:8][CH2:2][C:1]([OH:4])=[O:3])([OH:18])([OH:16])=[O:14]
Reactant: NCC(=O)O
Reactant: CC(=O)[O-]
Reactant: COP([O-])OC
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: CO
Product: O=C(O)CNCP(=O)(O)O
Reaction time: 1 h

Procedure:
To a hot solution of 500 ml. methanol, 98 g. potassium acetate and 30 g. of formaldehyde 37.5 g. of glycine and 55 g. of dimethyl phosphite are added. The mixture is stirred for one hour at the boiling temperature. The mixture is cooled and under cooling 167 ml. conc. hydrochloric acid are added. The solution is stirred for 15 minutes at 5° C. and the precipitated salt is filtered off. One may further proceed as disclosed in Example 1. 54-55 g. of N-phosphonomethyl glycine are obtained. The quality of the product is as given in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([O:24][CH3:25])=[N:10][CH:11]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.BrCC1C=C(C2C=CC=C(Cl)C=2)[C:31]([O:34]C)=[N:32]C=1.[N+](C1C=CC(B(O)O)=CC=1)([O-])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:31]([NH2:32])=[O:34])=[CH:17][CH:16]=3)[CH:11]=[N:10][C:9]=2[O:24][CH3:25])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncc(CBr)cc1-c1cccc(Cl)c1
Reactant: COc1ncc(Cc2ccc([N+](=O)[O-])cc2)cc1-c1cccc(Cl)c1
Agent: O=[N+]([O-])c1ccc(B(O)O)cc1
Product: COc1ncc(Cc2ccc(NC(N)=O)cc2)cc1-c1cccc(Cl)c1

Procedure:
3-(3-Chlorophenyl)-2-methoxy-5-(4-nitrobenzyl)pyridine. The title compound was prepared in a manner analogous to Example 1, from Intermediate 2 and 4-nitrophenyl boronic acid to afford a tan solid. [M+H]=355.07.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[C:15](Cl)(=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1>>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:8]=2[C:9]=1[C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCCCc1cc2cc(Cl)ccc2o1
Product: CCCCc1oc2ccc(Cl)cc2c1C(=O)c1ccc(OC)cc1

Procedure:
2-n-Butyl-5-chlorobenzofuran (9.5 g., 0.046 mol.) was acylated with 8 g. (0.047 mol.) of p-anisoyl chloride as described in the procedure of Example 1 to give 2-n-butyl-5-chloro-3-(4-methoxybenzoyl)benzofuran. Demethylation gives 2-n-butyl-5-chloro-3-(4-hydroxybenzoyl)benzofuran.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:18])[CH3:17])[CH3:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.I[CH:24]([CH3:26])[CH3:25]>>[CH:24]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:18])[CH3:17])[CH3:14])=[CH:9][CH:8]=2)=[CH:21][CH:22]=1)([CH3:26])[CH3:25]
Reactant: CC(=O)N[C@@H](C)COc1ccc(Oc2ccc(O)cc2)cc1
Reactant: CC(C)I
Product: CC(=O)N[C@@H](C)COc1ccc(Oc2ccc(OC(C)C)cc2)cc1

Procedure:
N—{(S)-2-[4-(4-Hydroxyphenoxy)phenoxy]-1-methylethyl}acetamide (139 mg, 0.46 mmol) was reacted with 2-iodopropane in analogy to example 10b. Yield: 51 mg (32%), M+H+: 344.23.
Reaction SMILES: [CH:1]([N:4]1[C:18]2[C:19]3[C:6]([CH2:7][C@@H:8]4[C@@H:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:12][CH:11]([C:20]([OH:22])=O)[CH2:10][N:9]4[CH3:23])=[CH:5]1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:36][C@@H:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[OH:42].O>CN(C)C=O>[OH:42][CH:38]1[CH2:39][CH2:40][CH2:41][CH:37]1[NH:36][C:20]([C@H:11]1[CH2:12][C@H:13]2[C@H:8]([CH2:7][C:6]3[C:19]4[C:18](=[CH:17][CH:16]=[CH:15][C:14]2=4)[N:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=3)[N:9]([CH3:23])[CH2:10]1)=[O:22]
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: CC(C)n1cc2c3c(cccc31)[C@H]1CC(C(=O)O)CN(C)[C@@H]1C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@H](C(=O)NC3CCCC3O)CN(C)[C@H]1C2
Reaction time: 4 h

Procedure:
To a suspension of 6.24 g of 1-isopropyl-6-methylergoline-8-carboxylic acid in 120 ml of dimethylformamide under a nitrogen atmosphere were added 3.2 g of 1,1'-carbonyldiimidazole. After stirring for approximately four hours, a solution of 2.02 g of trans-2-aminocyclopentanol in 40 ml of dimethylformamide was added with stirring. After stirring at room temperature overnight, the mixture was added to water. The resulting precipitate was extracted three times into methylene chloride. The combined organic extracts were washed with a saturated sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo. The resulting solid was purified by preparative high pressure liquid chromatography over silica gel eluting with methylene chloride/methanol/ammonium hydroxide (100:10:1). The appropriate fractions containing the more mobile diastereomer were combined, concentrated to dryness, and crystallized from methanol to provide 1.15 g of the desired title isomer, m.p. 260°-263° C. NMR, MS.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12]([CH2:17][OH:18])=[CH:11]3)[CH:5]=[CH:6][CH:7]=1.[C:19](Cl)(=[O:21])[CH3:20]>>[C:19]([O:18][CH2:17][C:12]1[NH:13][C:14]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[CH:16][CH:15]=2)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: Cc1cccc(-c2ccc3[nH]c(CO)cc3c2)c1
Product: CC(=O)OCc1cc2cc(-c3cccc(C)c3)ccc2[nH]1

Procedure:
A mixture of (5-bromo-1H-indol-2-yl)methanol (9 g, 39.8 mmol), 3-methylbenzeneboronic acid (6.14 g, 43.78 mmol), potassium carbonate (13.75 g, 99.5 mmol), palladium(II) acetate (0.045 g) and tetrabutylammonium bromide (12.84 g, 39.8 mmol) in 10% dioxane in water (degassed, 0.38 L) was stirred at 70° C. The reaction was monitored by TLC. Additional 3-methylbenzeneboronic acid (5.6 g, 39.8 mmol) was added. After no 5-bromo-1-(4-tert-butylbenzyl)-1H-indole was detected by TLC, the reaction was cooled to room temperature and the solvent was decanted. The residual thick oil was stirred with hexane. The hexane was decanted and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed with water filtered and concentrated. The residue was purified by flash column chromatography using hexane/ethyl acetate (55:45) as an eluant to give [5-(3-Methylphenyl)-1H-indol-2-yl]methanol as a brown solid (6.0 g). Reaction of [5-(3-Methylphenyl)-1H-indol-2-yl]methanol with acetyl chloride according to the procedure described in step 4 of Example 1 afforded the title compound as an oil (3.94 g); Mass spectrum (ESI, [M−H]−) m/z 278. 1H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.46 (s, 1H), 7.42–7.36 (m, 3H), 7.30 (s, 1H), 7.10 (d, 1H, J=7.48 Hz), 6.50 (s, 1H), 2.37 (s, 3H), and 2.07 ppm (s, 3H).
Reaction SMILES: [N:1]1[C:6]2[C:7](=[O:11])O[C:9](=[O:10])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])#[C-].C1CCN2C(=NCCC2)CC1>CN(C=O)C.C1COCC1>[OH:11][C:7]1[C:6]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:9](=[O:10])[NH:12][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: O=C1OC(=O)c2ncccc21
Reactant: [C-]#[N+]CC(=O)OC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1[nH]c(=O)c2cccnc2c1O
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
This compound was prepared as described in M. Suzuki et.al., Synthetic Communications, 1978, pg. 461. To a solution of furo[3,4]pyridine-5,7-dione (130 g, 872 mmol) in anhydrous DMF (250 ml) was added 1 liter of dry THF and methyl isocyanoacetate (86.4 g, 872 mmol). This was stirred for 15 minutes at 40° C. under nitrogen, followed by dropwise addition of DBU (132.8 g, 130.4 ml, 872 mmol) which was dissolved in THF (300 ml). After one hour the solvent was removed under reduced pressure and the resultant crude 2-[4-(methoxycarbonyl)-1,3-oxazol-5-yl]nicotinic acid and regioisomeric 3-[4-(methoxycarbonyl)-1,3-oxazol-5-yl]pyridine-2-carboxylic acid products were taken up into MeOH (1 liter). Concentrated HCl (12 M, 291 ml) was then added dropwise while the solution stirred at 55° C. This was stirred for 0.5 hours at which time the crude solids were collected by vacuum filtration. The desired regioisomer was purified by successive recrystallizations in methanol. This provided pure yellow solids. TLC (silica, 90:10:3, dichloromethane, methanol, acetic acid), R f (desired regioisomer)=0.23, R f (undesired regioisomer)=0.62.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[F:9][C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([OH:16])[CH:15]=1.O>ClCCCl>[F:9][C:10]1[CH:15]=[C:14]([OH:16])[C:13]([O:17][CH3:18])=[CH:12][C:11]=1[C:5](=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: COc1ccc(F)cc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: COc1cc(C(C)=O)c(F)cc1O
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
To a suspension of AlCl3 (1.17 g; 8.79 mmol) in 1,2-dichloroethane (2 mL) was added acetyl chloride (0.55 g; 7.03 mmol). After 10 min stirring was added dropwise a solution of 5-fluoro-2-methoxyphenol (0.50 g; 3.52 mmol) in 1,2-dichloroethane (2 mL). The reaction mixture was stirred overnight at 40° C. The mixture was then poured on iced water and extracted with diethylether. The organic phases were combined, washed with brine, dried (Na2SO4) and concentrated to afford 582 mg (90%) of the title compound as an off-white solid.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5](=[O:25])[C:6]([F:24])([F:23])[C:7]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])([OH:14])[CH2:8][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl>O.C(OCC)(=O)C.O1CCCC1>[N:4]1([C:5]([C:6]([F:24])([F:23])[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])([OH:14])[CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[O:25])[CH2:3][CH2:2]1
Reactant: O=C(NCCO)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(N1CC1)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 38 %

Procedure:
To 10 ml of dried tetrahydrofuran were added 0.36 g of N-(2-hydroxyethyl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide, 0.39 g of triphenylphosphine and 0.26 g of diethyl azodicarboxylate. The resulting mixture was subjected to reaction at 20°-25° C. for 12 hours. The reaction mixture was introduced into a mixed solvent consisting of 20 ml of ethyl acetate and 10 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: toluene/ethyl acetate=10/1) to obtain 0.13 g of 1-aziridinylcarbonyl-2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propane.
Reaction SMILES: C([NH:8][C:9]1[C:10](=[CH:21][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:24]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(OC(C)(C)C)=O.Cl.C(OCC)(=O)C.CO.C([Cl:45])(=O)C>C(OCC)(=O)C>[ClH:45].[CH2:26]([O:25][C:22]1[CH:21]=[C:10]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[C:9]([NH2:8])=[CH:24][CH:23]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 86 %

Procedure:
N-Boc-5-benzyloxyanthranilic acid, benzyl ester (70 g, 161 mmol) was added to a 1.4 M HCl/ethyl acetate solution (prepared by the addition of methanol to acetyl chloride and subsequent dilution with ethyl acetate). The reaction mixture was stirred at room temperature for 21 hours. After cooling to 0° C., the reaction was gently stirred for an additional 2 hours. The crystalline product was filtered off and washed with 50 ml of cold ethyl acetate. Trace solvents were removed under high vacuum to yield 5-benzyloxyanthranilic acid, benzyl ester, hydrochloride (53.4 g, 86% yield).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]CC(C)C.O1[SiH2]O[SiH2]O[SiH2]O[SiH2]O[SiH2]1>>[CH3:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:19][CH2:3][CH2:2][CH2:1][OH:19]
Reactant: CC(C)CCCCCCCCCCCCCCCO
Agent: O1[SiH2]O[SiH2]O[SiH2]O[SiH2]O[SiH2]1
Product: CCCCCCCCCCCCCCOCCCO

Procedure:
1.5% dialkoxy-polydimethylsiloxane (Abil wax 2440 from Goldschmidt, Hopewell, Va.); 1.5% isostearyl alcohol; 5.8% phenyltrimethicone; 26.2% cyclopentasiloxane; 18% siliconized polyamide; 1% fragrance.
Reaction SMILES: [CH:1]([N:4]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:5](=[O:24])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([CH3:3])[CH3:2].[C:33]1([NH:39][N:40]=[C:41]([C:45](Cl)=[O:46])[C:42](Cl)=[O:43])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH:1]([N:4]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:5](=[O:24])[CH2:6][N:7]1[C:42](=[O:43])[C:41](=[N:40][NH:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:45](=[O:46])[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]1=2)([CH3:3])[CH3:2]
Reactant: COc1ccc(CNc2ccccc2NCC(=O)N(c2ccc(OC)cc2)C(C)C)cc1
Reactant: O=C(Cl)C(=NNc1ccccc1)C(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)c(=NNc3ccccc3)c(=O)n(CC(=O)N(c3ccc(OC)cc3)C(C)C)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of N-isopropyl-2-[2-(4-methoxybenzylamino)-phenylamino]-N-(4-methoxy phenyl)-acetamide (3.25 g, 7.51 mmol) in THF (50 mL) cooled in an ice bath (<5° C.) was added 2-(phenyl-hydrazono) propandioyl dichloride (1.84 g, 7.51 mmol) in THF (50 mL) dropwise over 20 minutes. After complete addition, the solution was allowed to warm to room temperature and stirred overnight. The solvent was evaporated under reduced pressure and the resultant oil was dissolved in ethyl acetate (300 mL), washed with saturated sodium bicarbonate solution (100 mL) and brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (4.55 g, 7.51 mmol) as a yellow oil: 1H NMR (300 MHz, CDCl3): d 11.46 (s, 0.5H), 10.69 (s, 0.5H), 7.56-6.95 (m, 15H), 6.77-6.66 (m, 2H), 5.34 (m, 1H), 5.05 (m, 1H), 4.79 (m, 1H), 4.34-4.08 (m, 2H), 3.86 (s, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 1.11 (m, 6H); TLC (EtOAc/Hexanes(2:3)): Rf =0.30.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.O.O.O.[F:10][C:11]([F:19])([F:18])[C:12]([C:14]([F:17])([F:16])[F:15])=[O:13]>C(OCC)(=O)C>[NH2:1][C:2]1[S:3][C:4]([C:12]([OH:13])([C:14]([F:17])([F:16])[F:15])[C:11]([F:19])([F:18])[F:10])=[CH:5][N:6]=1
Reactant: Nc1nccs1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Temperature: 100 °C
Yield: 73.1 %

Procedure:
A catalytic amount of molecular sieves powder (4A) was added to a mixture of 2-aminothiazole 200 mg (2 mmol) and hexafluoroacetone trihydrate (880 mg, 4 mmol). The mixture was heated at 100° C. for 8 h. Ethyl acetate was added and the mixture was filtered. Organic solvents were evaporated under reduced pressure. The residue was recrystallized in THF and hexanes to afford the title product (389 mg) as a white solid. 1H NMR (DMSO-d6) δ7.12 (s, 1H), 7.45 (brs, 2H), 8.85 (s, 1H); ESIMS: m/z 267 (M+H).
Reaction SMILES: [CH:1]1([N:7]([CH3:36])[C:8]2[C:9]([CH3:35])=[C:10]([CH:24]=[C:25]([C:27]3[CH:28]=[N:29][C:30]([CH:33]=O)=[CH:31][CH:32]=3)[CH:26]=2)[C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:37][NH:38][CH3:39].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:1]1([N:7]([CH3:36])[C:8]2[C:9]([CH3:35])=[C:10]([CH:24]=[C:25]([C:27]3[CH:28]=[N:29][C:30]([CH2:33][N:38]([CH3:39])[CH3:37])=[CH:31][CH:32]=3)[CH:26]=2)[C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNC
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)nc3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
To a stirred solution of compound 3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(6-formylpyridin-3-yl)-2-methylbenzamide (1 equiv.) and dimethylamine (5 equiv.) in methanol (10 mL), acetic acid (2 equiv.) was added and reaction stirred at room temperature for 8 h. Then sodium cyanoborohydride (2.5 equiv.) was added at 0° C. and reaction stirred overnight at room temperature. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford the title compound (0.017 g, 11% yield). LCMS: 516.35 (M+1)+; HPLC: 90.32% (@254 nm) (Rt; 4.203; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate; 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.78 (s, 1H), 8.18 (t, 1H), 8.05 (d, 1H, J=6 Hz), 7.50 (d, 1H, J=8.4 Hz), 7.34 (s, 1H), 7.20 (s, 1H), 5.86 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.75 (bs, 2H), 2.75 (m, 1H), 2.65 (s, 3H), 2.34 (bs, 6H), 2.22 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.69-1.71 (m, 4H), 1.54-1.56 (m, 2H), 1.42-1.45 (m, 2H), 1.08-1.23 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].C(Cl)(=O)C([Cl:13])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([Cl:13])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCC(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCC(F)(F)F
Yield: 57 %

Procedure:
Method 5 General Experimental: 4,4,4-Trifluorobutyric acid (70.0 mmol, 10.0 g) in CH2Cl2 (190 ml) was treated with oxalyl chloride (140 mmol, 12.3 ml) and DMF (1 drop), then heated to reflux for 1 h. Solvent and excess oxalyl chloride were removed from the volatile product by simple distillation of the reaction mixture at atmospheric pressure to provide crude 4,4,4-trifluorobutyric acid chloride (6.4 g). 1H NMR (CDCl3) δ3.20 (2H, t, J=7.2), 2.65-2.45 (2H, m).
Reaction SMILES: [CH3:1][C:2]([CH3:14])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:13])=[CH:7]/[CH:8]=[CH:9]/[C:10]([CH3:12])=[O:11]>[Pd]>[CH3:14][CH:2]([CH2:3][CH2:4][CH2:5][CH:6]([CH2:7][CH2:8][CH2:9][C:10]([CH3:12])=[O:11])[CH3:13])[CH3:1]
Reactant: CC(=O)/C=C/C=C(\C)CCC=C(C)C
Agent: [Pd]
Product: CC(=O)CCCC(C)CCCC(C)C
Reaction time: 250 h

Procedure:
The hydrogenation of pseudoionone was carried out in a 243-ml fix-bed reactor with heating/cooling jacket with thermoelements placed in the centre of the reactor and on the reactor wall. Pressure-control valves were provided at the entrance end the exit site of the reactor. The reactor was charged with 162 ml (73 g) of catalyst (0.5% (wt./wt.) Pd on SiO2) and 81 ml of carrier material with 1 part by volume catalyst and 2 parts by volume of carrier in the bottom third of the reactor (entrance site), 2 parts by volume of catalyst and 1 part by volume of carrier in the middle third of the reactor, and catalyst alone at the top third of the reactor (exit site). The reactor was first flushed with nitrogen. The temperature at the entrance site of the reactor was adjusted to 80° C. and substrate, pseudoionone at a rate of 0.6 kg per hour, and hydrogen at a rate of 900 NL (norm liter) per hour were fed from separate storage tanks via a static mixer to the entrance site of the reactor. The hydrogenation was carried out in an up-flow mode. The mass flow was 8.3 kg of feed per hour per kg of catalyst and the pressure was set to 150 bar. The gradient of the maximum temperature in the reactor was 210° C.→170° C. and the temperature at the reactor outlet was adjusted to 80° C. The reaction product was released over a pressure valve into a separator where excess hydrogen was separated from the liquid hydrogenation product, hexahydropseudoionone. The reaction was allowed to proceed for 250 h, with yields of hexahydropseudoionone varying from 94 to 96% over that period (as determined by GC).