Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].CO.[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13](F)=[CH:12][C:11]=1[F:20].O>C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([O:4][CH3:2])=[CH:12][C:11]=1[F:20]
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: COc1cc(F)c(Cl)cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 51.8 %

Procedure:
To a suspension of potassium tert-butoxide (15.07 g, 134.3 mmol) in toluene (100 mL), and the appropriate alcohol, in this case methanol (3.80 g, 118.7 mmol), was added at 0° C. and stirred for 15 minutes. A solution of the appropriate 1-substituted 2,4-difluoro-5-nitrobenzene, in this case 1-chloro-2,4-difluoro-5-nitrobenzene (20.0 g, 103.3 mmol), in toluene (50 mL) was added at 0° C. and stirred for 5 hours at room temperature. Water (1000 mL) was added and the mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with water (150 mL), brine (150 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by column chromatography on neutral silica gel using 5-10% EtOAc in hexane to give the title compound (11.0 g, 52%) as a solid.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:12]([N:17]([CH3:25])[C:18](=[O:24])[C@H:19]([CH:21]([CH3:23])[CH3:22])[NH2:20])[C@@H:13]([CH3:16])[CH2:14][CH3:15])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:26][N:27]1[CH2:34][CH2:33][CH2:32][C@@:28]1([CH3:35])[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:26][N:27]1[CH2:34][CH2:33][CH2:32][C@@:28]1([CH3:35])[C:29]([NH:20][C@H:19]([C:18]([N:17]([C@@H:12]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])[CH3:25])=[O:24])[CH:21]([CH3:23])[CH3:22])=[O:30]
Reactant: CN1CCC[C@@]1(C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCN1C)C(C)C
Yield: 89.6 %

Procedure:
According to the general procedure D, from #6 (4.3 g, 12 mmol, 1 eq.), #150 (2.15 g, 12 mmol, 1 eq.), dichloromethane (50 mL), HATU (5.46 g, 14 mmol, 1.2 eq.), and diisopropylethylamine (8.17 mL) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 20 to 55% ethyl acetate in petroleum ether) to afford #202 (5.2 g, 89%) as a yellow oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[SH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH3:8][C:6]1[CH:7]=[C:2]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: OCCCCCCS
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Cc1cc(C)cc(SCCCCCCO)c1
Yield: 88.9 %

Procedure:
The general procedure in example 39 was followed. 5-Iodo-m-xylene (144 μL, 1.0 mmol), 6-mercaptohexanol (137 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 6-(3,5-dimethylphenyl)mercaptohexanol (212 mg, 92% yield) as colorless oil. Column chromatographic solvent (hexane/ethyl acetate=3/1). Rf=0.4 (hexane/ethyl acetate=2/1). 1H NMR (CDCl3, 300 MHz) δ 6.92 (s, 2 H), 6.78 (s, 1 H), 3.62 (q, 2 H, J=4.8 Hz), 2.90 (t, 2 H, J=7.2 Hz), 2.27 (s, 6 H), 1.30-1.68 (m, 9 H). 13C NMR (CDCl3, 75 MHz)δ 138.6, 136.5, 127.8, 126.7, 63.2, 33.8, 33.0, 29.5, 28.9, 25.7, 21.7. IR (neat, cm−1) 3320 (broad), 3060, 3022, 2972, 2847. MS (EI) m/z (relative intensity) 238 (40), 138 (100). Anal Cald for C14H22OS, Cald. C: 70.54, H: 9.30; Found C: 70.29, H: 9.33.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH3:26][CH:25]([NH:28]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1)[CH3:27]
Reactant: CC(C)N
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CC(C)N/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 54 %

Procedure:
Prepared as in Example 1 from 2-benzoyl-benzo[b]thiophen-3-ol, phosphorus(V) chloride and an aqueous 38.5% isopropylamine solution with a yield of 54% of theory. M.P. 112°-113° C. (ethyl acetate/petroleum ether 1:1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[S:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:33]=[O:34].O>C1(C)C=CC=CC=1>[F:25][C:19]1[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=1[CH:9]([S:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[C:5]1[C:6]([CH3:8])=[CH:7][C:2]([CH:33]=[O:34])=[N:3][CH:4]=1
Reactant: Cc1ccc(SC(c2cnc(Br)cc2C)c2cc(F)ccc2F)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(SC(c2cnc(C=O)cc2C)c2cc(F)ccc2F)cc1
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
A solution of 2-bromo-5-[(2,5-difluorophenyl)[(4-methylphenyl)thio]methyl]-4-methylpyridine (2.5 g, 6.0 mmol) in toluene (60 ml) was cooled to −78° C., and in an argon atmosphere, n-butyllithium (1.54 M hexane solution, 4.6 ml, 7.1 mmol) was added thereto. After stirring for 10 minutes at the same temperature, the mixture was allowed to warm to −40° C. and stirred for 30 minutes. The mixture was cooled again to −78° C., and then N,N-dimethylformamide (720 μl, 7.1 mmol) was added. After stirring for 30 minutes at the same temperature, water was added, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, subsequently dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel column chromatography. The fraction obtained from an elution with hexane:ethyl acetate=95:5 was concentrated under reduced pressure to obtain the title compound (900 mg, 2.4 mmol, 41%) as a pale yellow oily substance.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[C:12]([CH:14]([OH:17])C#N)[CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[C-]#N.[C-]#N.[Na+]>>[O:7]([C:8]1[CH:13]=[C:12]([CH:11]=[CH:10][CH:9]=1)[CH:14]=[O:17])[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Agent: [C-]#N
Agent: [Na+]
Product: O=Cc1cccc(Oc2ccccc2)c1

Procedure:
As has been indicated above, m-phenoxybenzyl chloride, alone or in admixture with m-phenoxybenzal chloride, may be converted to m-phenoxybenzaldehyde by a Sommelet reaction, using hexamine (or ammonia and formaldehyde) and an aqueous organic acid. If the Sommelet reaction is carried out in the presence of other compounds such as unreacted m-phenoxytoluene, the crude m-phenoxybenzaldehyde is isolated by extraction with a suitable solvent such as diisopropyl ether and it may then be purified by preparing the corresponding bisulphite compound, washing it with solvent and subsequently regenerating the pure aldehyde by treatment with an acid or base. Alternatively, the bisulphite compound may be isolated and dried to obtain a pure material which can be converted directly to m-phenoxybenzaldehyde cyanohydrin by reaction with a cyanide such as sodium cyanide, thereby avoiding the additional stage of isolating the purified m-phenoxybenzaldehyde.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH:8]([CH3:33])[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:32])[NH:17][CH:18]1[CH2:22][C:21](=[O:23])[O:20][CH:19]1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.[NH2:51][C:52]1[CH:60]=[CH:59][C:55](C(O)=O)=[CH:54][C:53]=1[Cl:61].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:25]([O:24][CH:19]1[CH:18]([NH:17][C:16]([CH:12]2[CH2:13][CH2:14][CH2:15][N:11]2[C:9](=[O:10])[CH:8]([NH:7][C:6](=[O:5])[C:55]2[CH:59]=[CH:60][C:52]([NH2:51])=[C:53]([Cl:61])[CH:54]=2)[CH3:33])=[O:32])[CH2:22][C:21](=[O:23])[O:20]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Reactant: Nc1ccc(C(=O)O)cc1Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1.899 g (3.99 mmol) sample of 75 in CH2Cl2 (20 ml) was treated with anhydrous TFA (5 ml) then stirred at room temperature under N2 for 1 hour and evaporated to dryness. The residue was repeatedly concentrated from CH2Cl2 (3×) then dried under vacuum. The resulting residue was dissolved in CH2Cl2 (20 ml), cooled to 0° C., then treated with DIEA (5.6 ml, 8 eq, 32.1 mmol), 4-amino-3-chloro-benzoic acid (0.910 g, 5.3 mmol), HOBT (0.824 g, 6.1 mmol), and EDC (1.197 g, 6.23 mmol). The resulting mixture was warmed to room temperature and stirred for 18 hours. The solvent was removed in vacuo and the residue dissolved in EtOAc then washed with distilled water (3×), 0.5N NaHSO4 (2×), saturated NaHCO3 (2×) and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a residue that was purified by flash chromatography using CH2Cl2/MeOH (99/1 to 97/3%). The title compound was obtained as a white solid (1.221 g, 58% yield). 1H-NMR (500 MHz, CD3OD) δ 1.15 (d, 0.25H), 1.29-1.60 (m, 2.75H), 2.41-2.54 (m, 0.5H), 2.55-2.70 (m, 0.5H), 2.77 (dd, 0.5H), 3.03 (ddd, 0.5H), 3.59-3.75 (m, 1H), 3.75-3.98 (m, 1H), 4.26-5.01 (m, 5H), 5.41-5.57 (m, 1H), 5.60-5.76 (m, 0.5H), 6.70-6.92 (m, 0.5H), 7.15-7.48 (m, 5H), 7.48-7.68 (m, 1H), 7.68-7.88 (m, 1H), 8.15-8.34 (m, 1H). Analytical HPLC (cyano column) (mixture of 2 diastereomers) 14.44, 14.89 min. LC-MS (ES+) m/e=529.3 (M+H).
Reaction SMILES: B.C1COCC1.[CH3:7][C:8]1[CH:9]=[C:10]([C:15]2[NH:16][C:17]3[C:22]([C:23]=2[CH2:24][CH2:25][NH:26][C:27](=O)[CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:21][C:20]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:19][CH:18]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=1.CO.CN(C)CCO>O1CCCC1>[CH3:14][C:12]1[CH:11]=[C:10]([C:15]2[NH:16][C:17]3[C:22]([C:23]=2[CH2:24][CH2:25][NH:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:21][C:20]([S:38]([CH3:41])(=[O:39])=[O:40])=[CH:19][CH:18]=3)[CH:9]=[C:8]([CH3:7])[CH:13]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(S(C)(=O)=O)cc3c2CCNC(=O)CCCc2ccncc2)c1
Agent: B
Agent: CN(C)CCO
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(S(C)(=O)=O)cc3c2CCNCCCCc2ccncc2)c1
Yield: 71 %

Procedure:
Borane-THF ((1.0M soln in tetrahydrofuran, 27 mL) was added dropwise to a solution of N-[2-[2-(3,5-dimethylphenyl)-5-methanesulfonyl-1H-indol-3-yl]ethyl]-4-pyridin-4-yl-butyramide (1.45 g, 2.96 mmol) in dry tetrahydrofuran (20 mL), and the solution was heated at reflux for 2 hours. At this time, methanol was added to quench excess borane, and the resulting solution was evaporated to dryness. The residue was dissolved in tetrahydrofuran (20 mL), and N,N-dimethylethanolamine (8.9 mL, 88.86 mmol) was added. The solution was heated at reflux for 2.5 hr and then concentrated to dryness. The crude material was purified by flash chromatography on silica gel (methylene chloride:methanol, 95:5) to give the title compound (1.0 g, 71%). m/e=476 (M+H)
Reaction SMILES: [SH:1][C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.Cl.[N:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1>C(O)C>[N:15]1[CH:20]=[CH:19][C:18]([CH2:21][S:1][C:2]2[N:12]3[C:13]4[C:8]([CH2:9][CH2:10][CH2:11]3)=[CH:7][CH:6]=[CH:5][C:4]=4[N:3]=2)=[CH:17][CH:16]=1
Reactant: Sc1nc2cccc3c2n1CCC3
Reactant: ClCc1ccncc1
Agent: Cl
Solvent: CCO
Product: c1cc2c3c(c1)nc(SCc1ccncc1)n3CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
To a suspension of 5,6-dihydro-2-mercapto-4H-imidazo [4,5,1-ij]quinoline (1.9 g) in ethanol was added 4-picolyl chloride HCl (1.68 g) and the mixture was stirred at ambient temperature for 16 hours and at reflux for 2 hours. The solvent was removed by evaporation and the residue dissolved in water. The solution was washed with EtOAc and then basified (aqueous NaOH) and extracted with CHCl3. Following short column chromatography (SiO2 /CHCl3) the residue was crystallised from EtOAc to give the title compound (1.25 g, 44%). mp 105°-7° C. (Found: C,68.20; H,5.50; N,15.30. C16H15N3S requires C,68.30; H,5.40; N,14.90).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[CH:4]=[N:3][CH:2]=1.[I:10]N1C(=O)CCC1=O>C(#N)C>[I:10][C:9]1[C:5]2[CH:4]=[N:3][CH:2]=[N:1][C:6]=2[NH:7][CH:8]=1
Reactant: c1ncc2cc[nH]c2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Ic1c[nH]c2ncncc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
A mixture of 7H-pyrrolo[2,3-d]pyrimidine (Preparation 202, 28.0 g, 235 mmol) and N-iodosuccinimide (55.4 g, 246 mmol) in acetonitrile (470 mL) was stirred at room temperature for 16 hours. The solids were filtered, rinsed with acetonitrile (150 mL) and dried in vacuo. The solid was dissolved in 1.5 L of 1N aqueous sodium hydroxide solution and to it was added 2N aqueous hydrogen chloride solution until ˜pH 9. The resulting precipitate was filtered, rinsed with water (300 mL), and dried in vacuo for 16 hours at 70° C., ˜10 mbar, to afford the title compound in 81% yield, 46.84 g.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:15][CH3:16])[C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([O:15][CH3:16])[C:12]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([C:18]#[N:17])=[CH:20][CH:21]=2)=[O:14])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1ccc(NC(C)=O)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(NC(C)=O)cc1

Procedure:
(RS)-(4-Acetylamino-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-2-(4-acetylamino-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide. Off-white, amorphous solid. MS 338.3([M+H]+)
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][CH2:9][CH2:10][OH:11].[H-].[Na+].Br[C:20]1[N:28]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C:27]2[C:26](=[O:37])[N:25]([CH2:38][CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[C:24](=[O:47])[N:23]([CH3:48])[C:22]=2[N:21]=1.[Cl-].[NH4+]>C1COCC1>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][N:28]2[C:27]3[C:26](=[O:37])[N:25]([CH2:38][CH2:39][O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)[C:24](=[O:47])[N:23]([CH3:48])[C:22]=3[N:21]=[C:20]2[O:11][CH2:10][CH2:9][CH2:8][O:7][C:6]2[CH:12]=[CH:13][CH:14]=[C:4]([O:3][C:2]([F:15])([F:16])[F:1])[CH:5]=2)=[CH:35][CH:34]=1
Reactant: OCCCOc1cccc(OC(F)(F)F)c1
Reactant: Cn1c(=O)n(CCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCOC2CCCCO2)c(=O)c2c1nc(OCCCOc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(3-(trifluoromethoxy)phenoxy)propan-1-ol (95 mg, 0.4 mmol, intermediate 35) in THF (5 mL) was added sodium hydride (19 mg, 0.40 mmol) at 0° C. After stirred at 0° C. for 30 min, 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-purine-2,6(3H,7H)-dione (0.1 g, 0.20 mmol, intermediate 13) was added. The mixture was allowed to warm to room temperature and stirred for 16 h. Then the reaction was chilled to 0° C. and aqueous ammonium chloride solution (2 mL) was added. The mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated to give crude product which was used without purification. LCMS MH+-THP 569.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[CH2:10])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:19])C=1.O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[O:19][CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1ccc(Cl)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Clc1ccc(CC2CO2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-(4-chlorophenyl)prop-1-ene (9.0 g) in chloroform (100 ml) was added portionwise metachloroperbenzoic acid (12.2 g), and the solution was stirred for 5 h at room temperature. The mixture was poured into water, the water layer was separated and the organic layer washed successively with sodium bicaronate, sodium sulphite and water. After drying, evaporation of the solvent gave 1-(4-chlorophenyl)-2,3-epoxypropane as a pale yellow oil. (9.51 g). NMR in CDCl3 :
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.Cl[CH2:17][CH2:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21].[OH-].[Na+]>[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C(Cl)Cl.O>[C:1]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:2]=[CH:3][C:4]([CH:7]([CH2:17][CH2:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[C:8]#[N:9])=[CH:5][CH:6]=1
Reactant: N#CCc1ccc(-c2ccccc2)cc1
Reactant: CC(C)N(CCCl)C(C)C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)N(CCC(C#N)c1ccc(-c2ccccc2)cc1)C(C)C
Temperature: 25 °C

Procedure:
The mixture of 50 parts of α-(4-biphenylyl)acetonitrile, 45.8 parts of 2-chloro-N,N-diisopropylethylamine, 80 parts by volume of 50% sodium hydroxide, 250 parts by volume of methylene chloride and 1 part of benzyltrimethylammonium bromide is stirred at room temperature with slight cooling in an icy water bath for about 24 hours. The mixture is then poured into water and to this mixture additional quantity of methylene chloride is added. The organic layer is separated, washed with water, dried over anhydrous sodium sulfate and concentrated to afford α-(4-biphenylyl)-α-[2-(diisopropylamino)ethyl]acetonitrile, as a solid. This compound is identical to that of Example 1.
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][NH:4][CH2:5][CH:6]([OH:8])[CH3:7].[CH2:10]=O>>[OH:9][CH:2]([CH3:1])[CH2:3][N:4]1[CH2:5][CH:6]([CH3:7])[O:8][CH2:10]1
Reactant: CC(O)CNCC(C)O
Reactant: C=O
Product: CC(O)CN1COC(C)C1

Procedure:
133 g of diisopropanol amine and 33 g of paraformaldehyde are reacted as described under (a).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([NH:1][CH2:2][CH2:3][NH:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])(=[O:22])=[O:21]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
In a 1000 ml reaction flask, 36.9 g of tert-butyl 2-aminoethylaminoformate and 200 ml of dichloromethane were added. The mixture was stirred by an electromagnetic stirrer, cooled with ice-bath, added with 96 ml of triethylamine, slowly added dropwise with 35.9 g of methylsulfonyl chloride in 200 ml of dichloromethane. The temperature of the mixture was naturally warmed to room temperature and the mixture was conducted overnight. The mixture was added dropwise with ice-water to quench reaction, the organic layer was separated, and the water layer was extracted with dichloromethane. The organic layers were combined, washed sequentially with 5 mol/L dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtrated, and distilled under a reduced pressure to remove the solvent to obtain 28.6 g of brown yellow solid, yield 52.1%.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([NH2:27])=O)[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:18][CH:19]1[CH2:20][CH2:21][CH:22]([C:25]#[N:27])[CH2:23][CH2:24]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OC1CCC(C(N)=O)CC1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](OC1CCC(C#N)CC1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6.42 g of 4-((tert-butyl(diphenyl)silyl)oxy)cyclohexanecarboxamide and 2.39 ml of dimethylsulfoxide in 90 ml of methylene chloride was added a solution of 2.06 ml of oxalyl chloride in 10 ml of methylene chloride at −78° C., followed by stirring the reaction mixture at −78° C. for 15 minutes. To the reaction mixture was added 7.05 ml of triethylamine at −78° C., followed by stirring the reaction mixture at −78° C. for 30 minutes and then stirring at room temperature for 1.5 hours. The reaction mixture was washed with water and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The obtained residue was purified by a silica gel column chromatography (eluent: hexane to hexane/ethyl acetate=4/1) to give the title compound as a pale yellow oil.
Reaction SMILES: C([BH3-])#N.[Na+].[NH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][CH2:6]1.C(O[C:20]1(O[Si](C)(C)C)[CH2:22][CH2:21]1)C.C(O)(=O)C>C1COCC1.CO>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][CH:8]1[CH2:9][CH2:10][N:5]([CH:20]2[CH2:22][CH2:21]2)[CH2:6][CH2:7]1)[CH3:16]
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CCOC(=O)CC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)CC1CCN(C2CC2)CC1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
Sodium cyanoborohydride (2.2 g) was added to a mixture of ethyl 4-piperidine acetate (2.0 g), (1-ethoxycyclopropoxy)trimethylsilane (6.1 g), acetic acid (6.7 mL), a molecular sieve 3A (2.0 g), MeOH (20 mL), and THF (20 mL) at room temperature, and the mixture was stirred at 65° C. for 6 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. After EtOAc was added to the residue, the mixture was stirred, and the insoluble material was separated by filtration. After water was added to the filtrate, potassium carbonate was added to alkalify the mixture. Extraction was performed on the mixture using EtOAc, and the extract was washed with a saturated aqueous NaHCO3 solution and saturated brine. The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3:MeOH=100:0 to 95:5), whereby ethyl(1-cyclopropylpiperidin-4-yl)acetate (2.1 g) was obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13](OCC)=[O:14])=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cncn1-c1ccc(Br)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cncn1-c1ccc(Br)cc1
Temperature: -20 °C

Procedure:
To a solution of 3-(4-bromophenyl)-3H-imidazole-4-carboxylic acid ethyl ester (4) (590 mg, 2.0 mmol) in dry THF was added lithium aluminium hydride (2.4 mL, 2.4 mmol, 1.0M in THF) dropwise at −40° C. under nitrogen, and the resulting mixture slowly warmed to −20° C. over 1 h. The reaction mixture was then quenched with saturated aqueous ammonium chloride solution (3 mL) at −20° C. and diluted with ethyl acetate (40 mL). The suspension was filtered and the filtrate was washed with brine (20 mL), dried over anhydrous sodium sulphate and concentrated in vacuo to afford [3-(4-bromophenyl)-3H-imidazol-4-yl]-methanol (5). MS (ES+): m/z 253/255 (1/1) [MH+]. 1H NMR (CDCl3, 400 MHz): δ=2.25 (br s, 1H), 4.56 (s, 2H), 7.14 (s, 1H), 7.40 (d, J=8.8 Hz, 2H), 7.63 (s, 1H), 7.64 (d, J=8.8 Hz, 2H).