Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)=[CH:2]1.[C:21]([O:25][C:26]([N:28]1[CH2:37][C:36]([CH3:39])([CH3:38])[C:35]2[C:30](=[CH:31][C:32]([NH2:40])=[CH:33][CH:34]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:21]([O:25][C:26]([N:28]1[CH2:37][C:36]([CH3:39])([CH3:38])[C:35]2[C:30](=[CH:31][C:32]([NH:40][C:14](=[O:16])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[NH:11][CH2:10][C:3]3[C:4]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:1][CH:2]=3)=[CH:33][CH:34]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(O)c1ccccc1NCc1c[nH]c2ncccc12
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C(C)(C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3NCc3c[nH]c4ncccc34)ccc2C(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-[(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amino]-benzoic acid (Step A, 516 mg, 2.0 mmol), 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (552 mg, 2.0 mmol), TBTU (0.706 g, 2.2 mmol), and DIEA (0.7 mL) in 30 mL of CH2Cl2 was stirred at RT for 2 h, then diluted with more CH2Cl2. The organic layer was washed with water, brine, dried with MgSO4, filtered, and condensed. The residue was purified by flash column chromatography (0 to 30% of EtOAc in CH2Cl2), to obtain the titled compound as oil. MS (ES+): 526 (M+H)+. Calc'd for C31H35N5O3-525.27.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=[O:15])[CH2:3]1>[Pd].CO>[NH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH2:5][C:4](=[O:15])[CH2:3][N:2]2[CH3:1]
Reactant: CN1CC(=O)Cc2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CN1CC(=O)Cc2c(N)cccc21
Reaction time: 3 h

Procedure:
A mixture of 1-methyl-5-nitro-1,4-dihydroquinolin-3(2H)-one and catalytic amount of palladium on carbon in methanol is stirred under hydrogen for 3 hours. The resulting mixture is filtered through a pad of celite, and the filtrate is concentrated under reduced pressure to afford 5-amino-1-methyl-1,4-dihydroquinolin-3(2H)-one
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]=2[C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[CH:24]=3)[CH:19]=2)O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([CH2:6][CH2:7][C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]=2[C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[CH:24]=3)[CH:19]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2cc(-c3oc4ccccc4c3C(O)CC3CCCC3)ccc2c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2cc(-c3oc4ccccc4c3CCC3CCCC3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-cyclopentyl-1-[2-(6-methoxy-2-naphthyl)-1-benzofuran-3-yl]-1-ethanol (1.84 g, 4.77 mmol) in methylene chloride (50 mL) cooled in an ice bath was added triethylsilane (1.5 mL, 9.5 mmol). Trifluoroacetic acid (3.7 mL, 48 mmol) was then added drop-wise. The reaction mixture was stirred at room temperature for 1 hour, then concentrated. The residue was partitioned in ethyl acetate and sodium bicarbonate solution. The organic phase was washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by flash chromatography (Biotage apparatus) using 100% hexane as an eluant afforded 3-(2-cyclopentylethyl)-2-(6-methoxy-2-naphthyl)-1-benzofuran as a light beige wax (1.05 g). 1HNMR (200 MHz, DMSO-d6): δ8.25 (s, 1H), 7.95 (d, 2H, J=7.7 Hz), 7.85 (d, 1H. J=7.7 Hz), 7.55-7.75 (m, 2H), 7.2-7.4 (m, 4H), 3.9 (s, 3H), 2.95-3.05 (m, 2H), 1.4-2.0 (br m, 9H), and 1.1-1.3 ppm (br m, 2H).
Reaction SMILES: Br[C:2]1[S:6][C:5](/[C:7](/[CH3:24])=[CH:8]/[CH2:9][CH2:10][C:11]([CH2:22][CH3:23])([CH2:20][CH3:21])[O:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][CH:3]=1.C([Li])CCC.[BH4-].[Na+].[Cl-].[NH4+].C1C[O:37][CH2:36]C1>CN(C=O)C>[CH2:20]([C:11]([O:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])([CH2:22][CH3:23])[CH2:10][CH2:9]/[CH:8]=[C:7](/[C:5]1[S:6][C:2]([CH2:36][OH:37])=[CH:3][CH:4]=1)\[CH3:24])[CH3:21]
Reactant: C1CCOC1
Reactant: CCC(CC)(CC/C=C(\C)c1ccc(Br)s1)O[Si](CC)(CC)CC
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: CCC(CC)(CC/C=C(\C)c1ccc(CO)s1)O[Si](CC)(CC)CC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
2.8 g (6.5 mmol) of [(E)-5-(5-bromo-2-thienyl)-1,1-diethylhex-4-enyloxy]triethylsilane are dissolved in 50 mL of anhydrous THF and the mixture is then cooled to −78° C. 2.9 mL (7.1 mmol) of 2.5 M butyllithium solution are then added, after which the reaction medium is stirred for 15 minutes. 0.55 mL of anhydrous DMF is then added, after which the reaction medium is warmed to room temperature and stirred for 1 h. After treatment with saturated ammonium chloride solution and then extraction with ethyl acetate, the organic phases are combined, dried and concentrated under reduced pressure. The residue containing the desired 5-((E)-5-ethyl-1-methyl-5-triethylsilanyloxyhept-1-enyl)thiophene-2-carbaldehyde is then dissolved in 50 mL of anhydrous methanol, after which 150 mg (3.9 mmol) of sodium borohydride are added in two portions. After stirring for 10 minutes, the medium is treated with ammonium chloride solution and extracted with ethyl ether. The organic phases are combined, dried and concentrated under reduced pressure. After purification by chromatography on a column of silica, a yellow oil is obtained (m=1.76 g; Y=71%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Si:36]([O:43][C:44]1[C:45]([F:54])=[C:46]([CH:49]=[C:50]([CH2:52][CH3:53])[CH:51]=1)[CH:47]=[O:48])([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>C1COCC1>[Si:36]([O:43][C:44]1[C:45]([F:54])=[C:46]([CH:47]([C:9]2[N:10]([C:12]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[OH:48])[CH:49]=[C:50]([CH2:52][CH3:53])[CH:51]=1)([C:39]([CH3:40])([CH3:42])[CH3:41])([CH3:38])[CH3:37]
Reactant: c1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(O)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a solution of 4-phenyl-1-trityl-1H-imidazole (8.1) (1.37 g, 3.54 mmol) in 20 mL THF at 0° C., was added BuLi (1.6 M in hexanes, 2.66 mL, 4.25 mmol). The mixture was stirred at 0° C. for 30 min, then a solution of 3-(tert-butyldimethylsilyloxy)-5-ethyl-2-fluorobenzaldehyde (188.3) (1.00 g, 3.54 mmol) in 3 mL THF was added dropwise. The mixture was stirred at 0° C. for 5 min, was removed from the cooling bath and stirred 45 min, then was quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) to afford 1.75 g of Intermediate 448.1 as a white foam. LCMS (2 min gradient) RT=2.22 min, 669.28 (M+H)+.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl.[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36]Cl.O>CN(C)C=O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:36][CH2:35][CH2:34][N:33]([CH3:38])[CH3:32])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Reactant: CN(C)CCCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(=O)c1cnc2c(OCCCN(C)C)cccc2c1Nc1ccccc1C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.20 g, 10 mmol) and potassium t-butoxide (3.05 g, 25 mmol) were dissolved in dimethyl formamide (30 ml), warmed to 80° and 3-dimethylaminopropyl chloride hydrochloride (1.90 g, 12 mmol) added. The mixture was stirred for 1 hour at 80° then a further portion of potassium t-butoxide (2.44 g, 20 mmol) and 3-dimethylaminopropyl chloride hydrochloride (1.58 g, 10 mmol) added. After a further 2 hours at 80° the mixture was poured into water, extracted with ether and the ether extracts dried and evaporated. Chromatography (silica gel, 5% methanolic ammmonia in dichloromethane) and recrystallisation from ethyl acetate gave 3-butyryl-4-(2-methylphenylamino)-8-(3-dimethylaminopropoxy)quinoline (1.80 g, 88%), m.p. 109°-110°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=1>[I-].[K+]>[CH3:36][C:34]([C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][CH2:24][N:13]2[CH2:12][CH2:11][CH:10]([C:8]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[OH:9])[CH2:15][CH2:14]2)=[CH:33][CH:32]=1)([CH3:35])[CH3:37]
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CC(C)(C)c1ccc(OCCCCl)cc1
Agent: [I-]
Agent: [K+]
Product: CC(C)(C)c1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Yield: 41 %

Procedure:
Following the procedure of Example 1, [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol and 4-(3-chloropropoxy)(1,1-dimethylethyl)benzene were reacted using potassium iodide catalyst to give white powder (recrystallizing from isopropyl alcohol) in 41% yield, m.p. 126°-127° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([CH2:15][CH2:16][CH:17]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:28][CH2:29][N:30]([CH2:17][CH2:16][CH2:15][C:9]2[CH:10]=[C:11]([CH2:12][CH2:13][CH3:14])[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:31][CH2:32]1
Reactant: CCCc1cc(CCC=O)nn1-c1ccccc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(C)cc3C)CC2)nn1-c1ccccc1

Procedure:
73 mg (49%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (80 mg, 0.330 mmol), 1-(2,4-dimethylphenyl)piperazine (63 mg, 0.330 mmol), DIPEA (0.090 mL, 0.495 mmol) and NaBH(OAc)3 (210 mg, 0.990 mmol).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC.O.[I-].[K+]>[I:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:7][CH:8]=1
Reactant: C1CCNCC1
Reactant: ClCCCOc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: Ic1ccc(OCCCN2CCCCC2)cc1
Temperature: 105 °C

Procedure:
A suspension of 4-(3-chloro-l-propoxy)iodobenzene (5 g), piperidine (2.2 mL), sodium carbonate (2.7 g), and potassium iodide (140 mg) in n-butanol (30 mL) was heated in a 105° C. bath for 18 h. The resulting mixture was allowed to cool to room temperature, diluted with water (50 mL), and extracted with methylene chloride (2×20 mL). The combined organic phases were dried (magnesium sulfate), and evaporated in vacuo. Kugelrohr distillation of the residue (5 mm Hg, 260° C.) gave the title compound as a white crystalline solid (4.8 g).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>C(O)C>[CH2:7]([O:6][C:4](=[O:5])[C:3]([N+:1]#[C-:2])=[CH:11][N:12]([CH3:14])[CH3:13])[CH3:8]
Reactant: COC(OC)N(C)C
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: CCO
Product: [C-]#[N+]C(=CN(C)C)C(=O)OCC

Procedure:
4-carboalkoxythiazoles are prepared essentially according to the procedure of Scholikopf, U., Porsch, P., Lau, H. Liebigs Ann. Chem. 1444 (1979). Thus, according to Method 55 and 56, reaction of ethyl isocyanoacetate with N,N-dimethylformamide dimethyl acetal in a suitable alcoholic solvent such as ethanol at room temperature gives the corresponding 3-dimethylamino-2-isocyano-acrylic acid ethyl ester. A solution of this compound in a suitable solvent such as tetrahydrofuran is treated with gaseous hydrogen sulfide in the presence of a suitable tertiary amine base such as triethylamine or diiso-propylethylamine or the like at room temperature to give the corresponding 4-carboethoxy-thiazole.
Reaction SMILES: [CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([O:29]C)=[O:28])=[O:19])=[CH:14][CH:13]=2)[C:9](=[O:31])[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1>[CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([OH:29])=[O:28])=[O:19])=[CH:14][CH:13]=2)[C:9](=[O:31])[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cccc(=O)n1Cc1ccc(C(=O)Nc2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCc1cccc(=O)n1Cc1ccc(C(=O)Nc2ccccc2C(=O)O)cc1
Reaction time: 48 h

Procedure:
A mixture of 404 mg of 6-butyl-1-[4-(2-methoxycarbonylanilinocarbonyl)benzyl]-1,2-dihydro-2-oxopyridine, 10 ml of 0.1N aqueous NaOH solution and 17 ml of THF is left to stand for 48 hours at 20°. The THF is evaporated off, the residue is acidified with HCl and extracted with methylene chloride and the extract is dried over Na2SO4 to give 6-butyl-1-[4-(2-carboxyanilinocarbonyl)benzyl]-1,2-dihydro-2-oxopyridine after evaporation.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]#[N:11])[C:7](Cl)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH:13]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14]1>CC#N>[C:1]([C:4]1[N:9]=[C:8]([C:10]#[N:11])[C:7]([N:13]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Cl)c(C#N)n1
Reactant: O[C@H]1CCNC1
Solvent: CC#N
Product: CC(=O)c1ccc(N2CC[C@H](O)C2)c(C#N)n1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 57.3 %

Procedure:
6-Acetyl-3-chloro-pyridine-2-carbonitrile (64) (1.80 g, 9.97 mmol) was dissolved in MeCN (19 mL). (S)-3-Pyrrolidinol (884 μL, 10.9 mmol) and TEA (4.16 mL, 29.8 mmol) were added and the mixture stirred at 100° C. in the microwave for 20 minutes. The solvent was evaporated in vacuo and the crude material dissolved in EtOAc (100 mL). The solution was washed with 1:1 saturated brine solution-H2O (100 mL), saturated brine solution (100 mL), then dried (MgSO4), filtered and the solvent evaporated in vacuo. The crude product was purified by flash chromatography (Biotage SP1, 50 g SNAP cartridge) eluting with 6:4 isohexane-EtOAc→8:2 EtOAc-isohexane to yield the title compound as a yellow solid (1.32 g, 64%); LCMS, Rt=2.04 min (MeOH-FA method), m/z 232 (MH+).
Reaction SMILES: [OH:1][CH:2]1[C:7](OC)([O:8]C)[CH2:6][CH2:5][N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3]1.FC(F)(F)C(O)=O>C1COCC1>[OH:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3]1
Reactant: CCOC(=O)N1CCC(OC)(OC)C(O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(=O)C(O)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 117.3 %

Procedure:
Ethyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate from Example 34A (5.00 g, 21.4 mmol) was dissolved in THF (50 mL), and trifluoroacetic acid (15.9 mL, 214 mmol) was added. The mixture was stirred for 3.5 h at rt. The solvent was then removed in vacuo. Twice, toluene was added and again removed in vacuo. The residue was dissolved in dichloromethane, dried over sodium sulfate, and the solvent was removed in vacuo to yield 4.70 g (95%) of an oil, which was used without further purification.
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[N:15]([CH2:21][CH2:22][CH2:23][O:24][CH3:25])[C:16](=[O:20])[CH:17]([CH3:19])[CH3:18]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:25][O:24][CH2:23][CH2:22][CH2:21][N:15]1[C:9]2[C:8](=[CH:13][CH:12]=[C:11]([CH3:14])[CH:10]=2)[C:17]([CH3:19])([CH3:18])[C:16]1=[O:20]
Reactant: COCCCN(C(=O)C(C)C)c1cc(C)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: COCCCN1C(=O)C(C)(C)c2ccc(C)cc21
Temperature: 50 °C
Reaction time: 22 h

Procedure:
The solution, prepared under argon, of 0.226 g of 1,3-bis(2,6-Di-L-propylphenyl)imidazolium chloride, 0.116 g of palladium(II) acetate and 1.497 g of sodium tert-butoxide in 90 ml of dioxane is admixed with stirring with the solution of 3.34 g of N-(2-bromo-5-methylphenyl)-N-(3-methoxypropyl)isobutyramide in 10 ml of dioxane and stirred at 50° C. over 22 hours. The reaction mixture is cooled, poured onto ice-water (250 ml) and extracted with tert-butyl methyl ether (2×250 ml). The organic phases are washed successively with water (2×250 ml) and brine (1×250 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.26 (1:1 EtOAc-heptane); Rt=16.60 (II).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[C:13]([O:27][CH3:28])=[C:14]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:15]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:17]=1.C([O-])(O)=O.[Na+].O>C1COCC1.C(Cl)Cl.C1CCCCC1>[C:5]1([O:4][C:2](=[O:3])[NH:11][C:12]2[CH:17]=[C:16]([C:18]([CH3:20])([CH3:21])[CH3:19])[CH:15]=[C:14]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:13]=2[O:27][CH3:28])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: O
Product: COc1c(NC(=O)Oc2ccccc2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 2 h
Yield: 97.2 %

Procedure:
Phenyl chloroformate (0.5 mL, 3.99 mmol) was added to a stirred solution of N-(3-amino-5-(tert-butyl)-2-methoxyphenyl)methanesulfonamide (see, for example, Cirillo, P. F. et al., WO 2002/083628, 24 Oct. 2002; 1 g, 3.67 mmol) and NaHCO3 (620 mg, 7.38 mmol) in THF (10 mL) and DCM (10 mL). The mixture was stirred for 2 h then water (20 mL) was added. The organic layer was separated, dried (MgSO4), filtered and evaporated to furnish a brown foam, which was stirred in cyclohexane (20 mL) to afford the sub-title compound (1.4 g) as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[N:12]O)C(=O)[NH:8]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C1CCN2C(=NCCC2)CC1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:8][C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[C:6]#[N:12]
Reactant: O=C1Nc2cc(Br)ccc2C1=NO
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: N#Cc1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a cold solution of oxime (10) (8 g, 33.33 mmol) in CH2Cl2 (200 mL) at 0° C. was added 2,6-lutidine (4.5 mL, 38.7 mmol), followed by the dropwise addition of triflouromethanesulfonic anhydride (5.6 mL, 33.33 mmol). The cooling bath was removed, and the mixture was heated to reflux for 3 h. The reaction mixture was cooled to room temperature, and DBU (9.9 mL, 66.66 mmol) was added dropwise while maintaining the internal temperature of the reaction below 30° C. The mixture was further stirred at room temperature for 1 h and poured with vigorous stirring into excess dilute NaHCO3. This mixture was then stirred for several minutes, and the organic layer was separated. The aqueous layer was re-extracted with CH2Cl2 (100 mL×2). The combined extracts were dried with MgSO4 and concentrated to leave a dark brown solid, which was passed through a short silica column, eluting with CH2Cl2 (100%). The resulting fraction was dried under vacuum, triturated with CH2Cl2/hexanes, and the solid formed was filtered and dried under vacuum to afford 5.36 g (82%) of 11 as a light yellow solid. IR (KBr) νmax. cm−1: 3436, 3310 (NH2), 3032 (Ar—H), 2920 (Alph-H), 2246 (CN), 1610, 1512, 1418 (C═C). 1H NMR (500 MHz, CDCl3) δ=4.47 (br. s, 2H, NH2); 6.88 (dd, 1H, J=2.8, 8.2 Hz, H-5); 6.94 (br. s, 1H, H-3); 7.24 (d, 1H, J=8.2 Hz, H-6); 13C NMR (125.7 MHz, CDCl3) δ=95.17 (C-1), 117.16 (CN), 118.15 (C-3), 121.60 (C-5), 129.03 (C-4), 133.60 (C-6), 150.47 (C-2). Calculated (%) for C7H5BrN2 (195.96); C: 42.67, H: 2.56, N: 14.22. found (%); C: 42.60, H: 2.61, N: 14.17.
Reaction SMILES: C([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30](OC)=[CH:31][CH:32]=[C:33](C)[C:7]=2[N:6]=1)CCC>C(Cl)Cl.C(O)C>[N:9]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=[CH:5]1
Reactant: CCCCc1nc2c(C)ccc(OC)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(Cn2cnc3ccccc32)cc1

Procedure:
tert.butyl 4'-[(2-n-butyl-7-methoxy-4-methyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.50 (Silica gel: methylene chloride/ethanol=19:1)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]2=[O:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.O.[ClH:26].[H][H]>[C].[Pd].CO>[ClH:26].[O:24]=[C:15]1[N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16]1
Reactant: O=C1Oc2ccccc2CN1C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1Oc2ccccc2CN1C1CCNCC1

Procedure:
In this reference example, 16.0 g of 1-benzyl-4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl)-piperidine and 4.0 g of 10% palladium carbon are added to a mixture of 150 ml of water, 50 ml of 1 N hydrochloric acid and 300 ml of methanol. While the resultant mixture is stirred, hydrogen gas is passed therethrough overnight. Then, the reaction mixture is filtered and the filtrate is concentrated. The white crystals as a residue are mixed with methanol and separated by filtration to obtain 11.4 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:10]([C:11]3[CH:18]=[CH:17][C:14]([CH3:15])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Nc1cc(Br)cnc1N
Product: Cc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 4-methylbenzaldehyde using the method described in Example 1.