Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[S:21]1[C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=[N:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:26]([C:25]3[S:21][N:22]=[CH:23][CH:24]=3)=[O:27])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1ccns1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccns1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-isothiazolecarboxylic acid as starting materials, MS (LC/MS): 414.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][C@@H:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])[N:10]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>C(OCC)(=O)C.[C].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][C@@H:11]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:10]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)/C=C/[C@@H]1CC[C@H](c2ccc(F)c(F)c2)N1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CC[C@@H]1CC[C@H](c2ccc(F)c(F)c2)N1C(=O)OC(C)(C)C
Yield: 94.2 %

Procedure:
Palladium-carbon (containing 50% water, 124 mg) was added to a solution of tert-butyl (E)-(2R,5S)-2-(3,4-difluorophenyl)-5-(2-methoxycarbonylvinyl)pyrrolidine-1-carboxylate (0.95 g) in ethyl acetate (30 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for six hours. Palladium-carbon in the reaction solution was removed by filtration through celite, and the filtrate was concentrated under reduced pressure to obtain 0.90 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C1C=NC2N(O)N=NC=2C=1.[F:36][C:37]1[CH:38]=[C:39]([NH:44][C:45]2[CH:50]=[N:49][CH:48]=[CH:47][N:46]=2)[C:40]([NH2:43])=[CH:41][CH:42]=1>C(Cl)Cl.CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:11](=[O:13])[NH:43][C:40]1[CH:41]=[CH:42][C:37]([F:36])=[CH:38][C:39]=1[NH:44][C:45]1[CH:50]=[N:49][CH:48]=[CH:47][N:46]=1)[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(F)cc1Nc1cnccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1cnccn1
Reaction time: 3 h
Yield: 48.7 %

Procedure:
N-(tert-Butoxycarbonyl)-L-alanine (150 mg, 0.78 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (165 mg, 0.86 mmol) and HOAt (106 mg, 0.78 mmol) were added to 4-fluoro-N2-pyrazin-2-yl-benzene-1,2-diamine (160 mg, 0.78 mmol) in DCM (10.0 ml) and DMF (1.00 ml) at 0° C. The reaction was stirred for 3 h then poured into water and the aqueous layer extracted with DCM (×3). The combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. The product was purified by chromatography (SiO2, 0-10% methanol/DCM) to yield the title compound (144 mg, 0.38 mmol, 50%). LCMS: RT 3.02 min [M+H]+ 376.2. 1H NMR (CDCl3, 400 MHz): δ 8.36 (1H, s), 8.12 (1H, dd, J2.8, 1.5 Hz), 8.03 (1H, br s), 8.02 (1H, d, J=2.7 Hz), 7.92 (1H, br s), 7.62 (1H, br s), 7.28 (1H, m), 6.77 (1H, td, J 8.4, 2.9 Hz), 4.97 (1H, br s), 4.20 (1H, m), 1.49 (3H, d, J 7.2 Hz), 1.45 (9H, s).
Reaction SMILES: [C:1](=[O:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1)([O-:12])=[O:11]>[C-]#[C-].[Cu+2].Cl[Cu].[Cu]>[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:1]([OH:3])=[O:2])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: C#Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C=O
Agent: Cl[Cu]
Agent: [Cu+2]
Agent: [Cu]
Product: O=C(O)C#Cc1ccc([N+](=O)[O-])cc1
Yield: 70 %

Procedure:
In general, terminal aromatic alkynes with an electron withdrawing group are deactivated and often inert to many transformations. With an electron withdrawing group on the phenyl ring, the nucleophilicity of C1 carbon of alkynes is reduced dramatically. The carboxylation of 4-nitro-1-ethynylbenzene was unsatisfactory with a very low yield of the corresponding acid (0-8%) under standard conditions. Low yields (around 2%) were also observed as the reaction temperature was adjusted to 0° C. and 50° C. which may be due to the low reaction rate at low temperature and the low stability of reaction intermediate at high temperature. The key step for this transformation is thought to be CO2 insertion into a copper acetylide intermediate. Increasing the nucleophilicity of the carbanionic intermediate may increase the yield of carboxylic acid product. It is well known that N-heterocyclic carbenes (NHC) can activate CO2 in various catalytic transformations. With that in mind, a new NHC—Cu co-catalyst was designed using poly-N-heterocyclic carbene (PNHC) as both ligand and catalyst. PHNC has a three dimensional network structure with carbene units located and fixed in the backbone of the network. Poly(NHC)0.5(NHC—Cu)0.5 (P1) catalyst was prepared by the reaction of 1 equivalent of CuCl with 2 equivalent of PHNC. In the structure of this catalyst, only half of the carbene species were coordinated with copper with the remainder being free carbenes. The initial experiment was conducted by using 5 mol % of P1 with Cs2CO3 as base for the carboxylation of 4-nitro-1-ethynylbenzene with CO2 at ambient conditions. Remarkably, 4-nitro-phenylpropiolic acid was produced in 70% yield after acid workup. Good yields were also achieved for terminal aromatic alkynes with other electron withdrawing groups in 36 to 48 hrs (Table 6).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]=[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[Cl:27])=[C:4]([F:30])[CH:3]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[C:39](=[O:47])[C:40]([C:44](O)=[O:45])=[CH:41][NH:42][CH:43]=2)=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:27][C:8]1[C:9]([N:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:10][CH:11]=[CH:12][C:7]=1[O:6][C:5]1[CH:28]=[CH:29][C:2]([NH:1][C:44]([C:40]2[C:39](=[O:47])[C:38]([C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)=[CH:43][NH:42][CH:41]=2)=[O:45])=[CH:3][C:4]=1[F:30]
Reactant: Nc1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1
Reactant: O=C(O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene) pyridin-2-amine (836 mg, 2.0 mmol) and 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (490 mg, 2.0 mmol) in DMF (10 mL) at room temperature were added HATU (913 mg, 2.4 mmol) and DIPEA (1.05 ml, 6.0 mmol). The reaction mixture was stirred at room temperature for 3 h prior to being quenched by the addition of cold water (50 mL). The solid that formed was collected by filtration, and washed with water and ether. The solid was dissolved in DCM and purified by flash column chromatography (SiO2, DCM to 10% MeOH in DCM) to give the desired product (987 mg, 78%) as a light yellow solid. MS (ESI) m/z 633 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[O:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[BH4-].[Na+].Cl>C(O)C.O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CCCCCl)Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC(CCCCCl)Cc1ccccc1
Temperature: -5 °C
Reaction time: 2.5 h
Yield: 93 %

Procedure:
13.1 g of 6-chloro-1-phenyl-hexan-2-one in 75 ml of ethanol is loaded into a 250 ml three-necked flask. The reaction medium is cooled down to -5° C. and a solution of sodium borohydride (2.18 g) in 15 ml of water is added over 5 minutes. Agitation is carried out for 2.5 hours at -5° C., the temperature is allowed to rise to 20° C. over 1 hour, followed by cooling down to -5° C. 110 ml of 0.14 M hydrochloric acid is then added. Agitation is carried out for 10 minutes, followed by extraction 3 times with 80 ml of methylene chloride, drying over magnesium sulphate, filtering and concentration. In this way, 12.3 g of expected product is obtained.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][O:23][CH3:24])[CH2:18][CH2:17]2)=[O:14])=[N:9][CH:8]=1)C.[OH-].[Na+].Cl>CO>[CH:25]1([N:15]([C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][O:23][CH3:24])[CH2:20][CH2:21]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][N:9]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](COC)CC2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
{2-[3-Cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester was dissolved in methanol (10 mL) and 1N sodium hydroxide (5 mL) was added. Stirred at room temperature for 3 h then acidified with 1N hydrochloric acid. The white precipitate was filtered and dried to give the title compound (97 mg).
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[C:7]([CH3:22])[C:6](=[O:23])[CH2:5][CH2:4]2.[C:24]([O:27]C(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([OH:27])(=[O:26])[CH3:25].[OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[C:7]([CH3:22])[C:6](=[O:23])[CH2:5][CH2:4]2
Reactant: CC(=O)OC(C)=O
Agent: CC1=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(CO)CCC1=O
Solvent: c1ccncc1
Product: CC(=O)O

Procedure:
19-Hydroxy-4-methyl-4-androstene-3,17-dione is stirred under nitrogen with acetic anhydride and pyridine for about 16 hours. The yellow solution is poured onto water and the precipitate collected by suction filtration and washed well with water. Crystallization from acetone-hexane yields the desired 19-hydroxy-4-methyl-4-androstene-3,17-dione acetate.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([O:14][CH2:15][C@H:16]([NH:34][C:35](=[O:38])[CH2:36]Cl)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C=O)C>C(OCC)(=O)C>[CH2:7]([O:14][CH2:15][C@H:16]([NH:34][C:35](=[O:38])[CH2:36][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CCl)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: Cc1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nccn1CC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
2-Methylimidazole (64 mg, 0.786 mmol) was added to a flask charged with (S)-3-(benzyloxy)-2-(2-chloroacetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (150 mg, 0.393 mmol), prepared as in Example 15, and DMF (3 mL). The mixture was stirred at 40° C. for 30 minutes then diluted with ethyl acetate (20 mL). The dilution was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. Product was purified from the residue by reverse phase HPLC to provide Compound 160, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(2-methyl-1H-imidazol-1-yl)acetamido)propanamide (100.8 mg, 0.201 mmol, 51% yield) as an off-white solid. 1H-NMR (400 MHz, CDCl3): 8.38 (s, 1H), 7.38-7.21 (m, 7H), 7.05-6.89 (m, 7H), 6.45 (d, 1H), 4.66 (d, 1H), 4.61 (s, 2H), 4.55 (d, 1H), 3.91 (dd, 1H), 3.55 (t, 1H), 2.38 (s, 3H). MS (EI) for C28H27FN4O4. found 502.9 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:40]([C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[N:31]([CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:19]4[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:29][CH:28]=2)[C:32]([CH3:44])=[C:33]3[CH3:43])=[O:41])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N)c1cccc(Cl)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(Cl)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3-chlorophenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 537/538/539 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[N:18]3)[C:9]=1[CH:10]1[CH2:12][CH2:11]1)=[O:4].[OH-].[Na+]>O>[CH:10]1([C:9]2[N:8]([C:13]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:14]=3[CH:15]=[CH:16][CH:17]=[N:18]4)[N:7]=[CH:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:11][CH2:12]1
Reactant: COC(=O)c1cnn(-c2cccc3ncccc23)c1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cnn(-c2cccc3ncccc23)c1C1CC1

Procedure:
5-Cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid methyl ester is hydrolyzed with a base such as sodium hydroxide in water to form 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid, analogous to an acid of formula IX′.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.I([O-])(=O)(=O)=[O:19].[Na+]>CO.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:17])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:19]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)C=CC=CCSc1ccc(Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C=CC=CCS(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Yield: 76.4 %

Procedure:
To a solution of 6-(4-chlorophenylsulfanyl)-hexa-2,4-dienoic acid methyl ester (0.396 g, 1.47 mmol) in methanol (20 mL) was added dropwise at 0° C. a solution of sodium metaperiodate (0.37 g, 1.72 mmol) in distilled water (10 mL). The mixture was allowed to warm to 20° C., then heated at reflux for 5 hours. The solution was concentrated under reduced pressure to give an oil that was dissolved in ethyl acetate (20 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (10 mL), distilled water (10 mL), then with brine. The organic layer was then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an oil that was purified by flash chromatography (2:8 ethyl acetate:40-60° C. petroleum ether). The resulting powder was recrystallised from ethylacetate/40-60° C. petroleum ether to give the title compound (0.32 g, 77%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:11]=[C:10]([CH:12]=[O:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:5]=1[C:6]#[N:7])[CH3:2].CC(=CC)C.Cl([O-])=[O:23].[Na+].O.P([O-])(O)(O)=O.[Na+].Cl>O1CCOCC1.O1CCCC1.O.C(OCC)(=O)C>[C:6]([C:5]1[CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[C:10]([C:12]([OH:23])=[O:13])=[N:11][C:4]=1[O:3][CH2:1][CH3:2])#[N:7]
Reactant: CCOc1nc(C=O)c([N+](=O)[O-])cc1C#N
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCOc1nc(C(=O)O)c([N+](=O)[O-])cc1C#N
Yield: 24.5 %

Procedure:
To a stirred solution of the compound prepared in Example 446 (0.61 g) in dioxane (10 mL) at ambient temperature was added of a 2 mol/L solution of 2-methyl-2-butene in tetrahydrofuran (8.4 mL). To the resulting stirred solution was added a solution of sodium chlorite (80%, 1.37 g) and sodium dihydrogen phosphate monohydrate (1.37 g) in water (8 mL). The resulting mixture was vigorously stirred at ambient temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (15 mL), and after stirring for 10 minutes, the mixture was transferred to a separatory funnel. The aqueous layer was acidified with 6M hydrochloric acid to pH 1.5, and then extracted with chloroform (20 mL). The organic layer was dried over sodium sulfate and concentrated to provide the title compound (0.16 g) with the following physical data.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]2[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=2)[CH:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=2)[CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[C:30]([C:34]3[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=3)[CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: CCCCOc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: CCCCOc1ccc(N(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-butoxyphenyl)amino]piperidine (696 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH2:16][CH2:17][C:18](O)=[O:19])=[C:11]([CH3:21])[CH:10]=1>C1COCC1>[OH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH2:16][CH2:17][CH2:18][OH:19])=[C:11]([CH3:21])[CH:10]=1
Reactant: Cc1cc(CO)cc(C)c1CCC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CO)cc(C)c1CCCO
Yield: 98.7 %

Procedure:
To a suspension of LiAlH4 (219 mg, 5.76 mmol) in THF (35 mL), a solution of 3-(4-hydroxymethyl-2,6-dimethyl-phenyl)-propionic acid (1.0 g, 4.80 mmol, intermediate from Aldehyde 4) in THF (10 mL) is added dropwise. Upon complete addition the suspension is refluxed for 2 h. The suspension is diluted with THF (10 mL) and another portion of LiAlH4 (182 mg, 4.80 mmol) is added. The mixture is refluxed for further two hours, then cooled with an ice-bath. The reaction is carefully quenched by adding sat. aq. NH4Cl solution (2 mL) followed by 2 N aq. HCl until a clear solution forms. The mixture is diluted with water and extracted twice with EA. The combined organic extracts are dried over MgSO4, filtered and the solvent of the filtrate is evaporated to leave 3-(4-hydroxymethyl-2,6-dimethyl-phenyl)-propan-1-ol (920 mg) as a colourless crystalline solid; LC-MS: tR=0.70 min, [M+1−H2O]+=177.20.
Reaction SMILES: [F:1][C:2]([F:34])([C:12]([F:33])([F:32])[C:13]([F:31])([F:30])[C:14]([F:29])([F:28])[C:15]([F:27])([F:26])[C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:3][CH2:4][SiH:5]([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7].C([Br:38])C=C>C1C=CC=CC=1.Cl[Pd]Cl>[F:34][C:2]([F:1])([C:12]([F:32])([F:33])[C:13]([F:30])([F:31])[C:14]([F:28])([F:29])[C:15]([F:26])([F:27])[C:16]([F:24])([F:25])[C:17]([F:22])([F:23])[C:18]([F:19])([F:20])[F:21])[CH2:3][CH2:4][Si:5]([Br:38])([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)[SiH](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(C)C
Reactant: C=CCBr
Agent: Cl[Pd]Cl
Solvent: c1ccccc1
Product: CC(C)[Si](Br)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(C)C
Temperature: 60 °C
Yield: 99.6 %

Procedure:
In an oven-dried round-bottom flask equipped with a stir bar and cooled under N2, 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyldiisopropylsilane (9.97 g, 17.7 mmol) was dissolved in 15 mL anhydrous benzene (benzene dried by boiling off 10% by volume prior to use). To this was added allyl bromide (3.22 g, 26.6 mmol, 1.5 eq.) and PdCl2 (35 mg, 1 mol %). The solution was heated to 60° C. for 15 hr, then cooled, and concentrated via rotary evaporation. The resulting suspension was dissolved in pentane, filtered to remove residual catalyst, and then solvent was removed to yield (3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyldiisopropylsilyl)bromide (11.3 g) as a pale brown liquid. The bromide was treated under anhydrous conditions with 1.2 eq. (based on initial silane) of ethynylmagnesium bromide and heated to 40° C. for 6 hr. The reaction was quenched with water and dilute sulfuric acid, pentane was added, and the organic layer was separated. The organic layer was washed with water (6×50 mL), dried over MgSO4, filtered, and concentrated via rotary evaporation. Further purification via flash chromatography using hexane yielded pure (3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyldiisopropylsilyl)acetylene (9.0 g, 15 mmol, 87%) as a colorless liquid. Analysis of the product provided the following data: 1H-NMR (200 MHz, CDCl3) δ=2.4 (s, 1H), 2.2 (m, 2H), 1.0 (m, 14H), 0.8 (m, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]([C:8]1[CH:9]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:10]([C:16]([O:18][CH3:19])=[O:17])=[C:11]([CH3:15])[NH:12][C:13]=1[CH3:14])=[O:7].[F:29][C:30]1[CH:43]=[CH:42][C:33]([C:34]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[O:35])=[CH:32][CH:31]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(OCC)(=O)C>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:34]([CH:36]2[CH2:41][CH2:40][N:39]([CH2:2][CH2:3][CH2:4][O:5][C:6]([C:8]3[CH:9]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=4)[C:10]([C:16]([O:18][CH3:19])=[O:17])=[C:11]([CH3:15])[NH:12][C:13]=3[CH3:14])=[O:7])[CH2:38][CH2:37]2)=[O:35])=[CH:42][CH:43]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCl)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCN2CCC(C(=O)c3ccc(F)cc3)CC2)C1c1cccc([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
A mixture of 16.4 g of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl ester 3-chloropropyl ester and 16.6 g of 4-(p-fluorobenzoyl)-piperidine is kept for 1 hour under argon in a bath heated to 145°. After cooling, 100 ml of ethyl acetate and 50 ml of 2N hydrochloric acid are added and the mixture is stirred until the reaction mass has completely dissolved. The partly oily aqueous-acidic phase is adjusted to pH 10 with 50% potassium carbonate solution; methylene chloride is added and the whole is filtered with suction. The methylene chloride phase of the filtrate is separated off and concentrated by evaporation and the residue is dissolved in ethyl acetate; the solution is dried over sodium sulphate and filtered. Filtration is then carried out over 1 kg of silica gel Merck 9385 using a hexane/ethyl acetate/methanol mixture (4:2:0.5) as eluant. The 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl ester 3-[4-(p-fluorobenzoyl)-piperidino]-propyl ester obtained after working up is converted by means of ethereal hydrogen chloride solution into the hydrochloride which, after recrystallisation from isopropanol, melts at 198°-205° with the evolution of gas.