Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:34]([O:35][CH3:36])=[CH:33][C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:32])[CH2:14][CH2:15][NH:16][CH2:17][CH:18]3[CH2:25][C:24]4[C:19]3=[CH:20][CH:21]=[C:22]([O:26][CH2:27][C:28]([NH:30][CH3:31])=[O:29])[CH:23]=4)[CH2:11][CH2:12][C:6]=2[CH:5]=1.C=O.[C:39]([BH3-])#N.[Na+]>C(#N)C>[ClH:1].[CH3:36][O:35][C:34]1[C:4]([O:3][CH3:2])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([C:13](=[O:32])[CH2:14][CH2:15][N:16]([CH2:17][CH:18]3[CH2:25][C:24]4[C:19]3=[CH:20][CH:21]=[C:22]([O:26][CH2:27][C:28]([NH:30][CH3:31])=[O:29])[CH:23]=4)[CH3:39])[CH2:9][CH2:8][C:7]=2[CH:33]=1
Reactant: CNC(=O)COc1ccc2c(c1)CC2CNCCC(=O)N1CCc2cc(OC)c(OC)cc2CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: CNC(=O)COc1ccc2c(c1)CC2CN(C)CCC(=O)N1CCc2cc(OC)c(OC)cc2CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
At ambient temperature, to 0.83 g (1.72 mmol) of the compound obtained in Step C of Example 84, dissolved in 32 mL of acetonitrile, there are added, all at once, 1.4 mL (17.2 mmol) of 37% aqueous formaldehyde solution and then 0.22 g (3.44 mmol) of sodium cyanoborohydride. After stirring for 45 minutes at ambient temperature, concentration is carried out and the residue is taken up in 30 mL of water; the aqueous phase is extracted twice with 30 mL of dichloromethane; the organic phases are combined, washed with 30 mL of water and dried over magnesium sulphate. After concentration, the residue is chromatographed over silica (eluant: dichloromethane/ethanol/ammonia 95/5/0.5) to yield the desired compound in the form of the base.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:13][CH:14]([NH2:16])[CH3:15]>>[CH:14]([NH:16][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH2:2][CH2:3]2)=[O:12])([CH3:15])[CH3:13]
Reactant: O=C(O)c1ccc2c(c1)CCN2
Reactant: CC(C)N
Product: CC(C)NC(=O)c1ccc2c(c1)CCN2

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-10 using indoline-5-carboxylic acid and propan-2-amine (0.315 g, 31%); MS: 205 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([OH:16])[C:8]([F:15])([F:14])[C:9](OCC)=[O:10].O.[NH2:18][NH2:19].O>CCO>[F:14][C:8]([F:15])([CH:7]([OH:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9]([NH:18][NH2:19])=[O:10]
Reactant: NN
Reactant: CCOC(=O)C(F)(F)C(O)c1ccccn1
Solvent: O
Solvent: CCO
Product: NNC(=O)C(F)(F)C(O)c1ccccn1
Reaction time: 16 h

Procedure:
To stirring solution of 0.96 g (4.1 mmol) of ethyl 3-(2-pyridyl)-3-hydroxy-2,2-difluoropropanoate, prepared as described by Hallinan and Fried, Tetrahedron Lett., 25, 2301 (1984), in 8 mL of EtOH was added 0.41 g (8.2 mmol) of hydrazine hydrate. After 16 hours, a yellow precipitate had formed. To the reaction was added H2O. The precipitate was filtered and washed with a minimum of H2O. The yield of product was 0.44 g (49%) after drying in a steam cabinet. Analysis calculated for C8H9N3O2F2 (M.W. 217.18): C, 44.24; H, 4.18; N, 19.35. Found: C, 44.07; H, 4.16; N, 19.05.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[C:8]3[NH:16][N:15]=[N:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][CH2:27][CH2:28][O:29][CH:30]([CH3:32])[CH3:31])[N:20]=1>>[CH:30]([O:29][CH2:28][CH2:27][O:26][CH2:25][C:21]1[N:20]=[C:19]([CH2:18][N:14]2[C:9]3[N:10]=[C:11]([NH2:13])[N:12]=[C:7]([C:5]4[O:6][C:2]([CH3:1])=[CH:3][CH:4]=4)[C:8]=3[N:16]=[N:15]2)[CH:24]=[CH:23][CH:22]=1)([CH3:32])[CH3:31]
Reactant: Cc1ccc(-c2nc(N)nc3nn[nH]c23)o1
Reactant: CC(C)OCCOCc1cccc(CBr)n1
Product: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cccc(COCCOC(C)C)n2)o1

Procedure:
Prepared from 7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and 2-bromomethyl-6-(isopropyloxyethoxymethyl)pyridine by the alkylation method described in Example 36.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:8]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=2)(=[O:20])=[O:19])[N:7]([CH3:28])[N:6]=1.[H-].[Na+].[Cl:31][C:32]1[CH:33]=[N:34][C:35](S(C)(=O)=O)=[N:36][CH:37]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Cl:31][C:32]1[CH:33]=[N:34][C:35]([O:1][CH2:2][CH2:3][O:4][C:5]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:8]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=3)(=[O:19])=[O:20])[N:7]([CH3:28])[N:6]=2)=[N:36][CH:37]=1
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C)cn2)cc1
Reactant: CS(=O)(=O)c1ncc(Cl)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(OCCOc3ncc(Cl)cn3)nn(C)c2NS(=O)(=O)c2ccc(C)cn2)cc1
Reaction time: 0.33 h
Yield: 78.9 %

Procedure:
To N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-2-pyridine sulphonamide (Example 50) (100 mg) in dry tetrahydrofuran (5 ml) at room temperature was added sodium hydride (80% dispersion in oil, 20 mg) the mixture was stirred for 20 minutes. A solution of 5-chloro-2-methylsulphonylpyrimidine (72 mg) in dry tetrahydrofuran (2.5 ml) was then added and the mixture was stirred for a further 16 hours. The mixture was then treated with further sodium hydride (80% dispersion in oil, 20 mg) and after 15 minutes stirring further 5-chloro-2-methylsulphonylpyrimidine (84 mg) was also added. The mixture was stirred for 4 hours. The reaction was treated with citric acid (10% aq.) and extracted with ethyl acetate (50 ml). The organic fraction was washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with a solvent gradient of pentane:ethyl acetate (8:2 to 0:1) to yield the tile compound as a yellow solid (101 mg).
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[N:23][C:17]=4[NH:16][C:15]3=[O:24])[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[N:23][C:17]=3[NH:16][C:15]2=[O:24])[CH2:12][CH2:13]1
Reactant: O=C1Nc2ncccc2CN1C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1Nc2ncccc2CN1C1CCNCC1

Procedure:
A solution of 4.7 g (0.0146 mol) of 3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-pyrido[2,3-d]-pyrimidinone in 50 ml of methanol was hydrogenated at a temperature of 50° C. and in the presence of 2.0 g of 20% palladium/charcoal until the uptake of hydrogen ceased. After removal of the catalyst and solvent 3.3 g (97.3% of theory) of a colourless oil of Rf=0.35 (FM1) were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:14]2[C:6](=[CH:7][C:8]3[C:9](=O)[CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([CH3:17])([CH3:16])[CH2:4][CH2:3]1.[BH4-].[Na+].[CH3:21]CO.Cl>C(OCC)C>[CH3:1][C:2]1([CH3:18])[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][C:10]([CH3:21])=[CH:11][C:12]=3[CH:13]=2)[C:5]([CH3:17])([CH3:16])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)CCC3=O
Reactant: CCO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Product: CC1=Cc2cc3c(cc2C1)C(C)(C)CCC3(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
2,3,5,7-Tetrahydro-5,5,8,8-tetramethyl-1H-Benz(f)inden-1-one (14.89 g, 58.08 mmol) and NaBH4 (2.21 g, 58.5 mmol) were stirred in diethylether (200 mL) at 0° C. while EtOH (100 mL) was added slowly. This mixture was allowed to warm slowly to room temperature and then stirred at room temperature overnight. After the reaction period the mixture was poured onto crushed ice and made acidic with HCl. The organic layer was then separated and washed with 1 M HCl (1×100 mL). The volatiles were then removed from the organic layer and the residue refluxed in benzene (300 mL) with p-toluenesulfonic acid (0.12 g) using a Dean-Stark apparatus until no more H2O was evolved. The mixture was then washed with 1 M NaHCO3 (2×100 mL) and the volatiles were removed from the organic layer resulting in the isolation of a yellow oil. Recrystallization from MeOH (0° C.) resulted in the isolation of the desired product as off-white crystals (10.37 g, 74.3 percent yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]2[NH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:33])C(=O)C1>C(Cl)Cl>[I:33][C:15]1[C:13]2[N:14]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:10]=[C:11]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]=2[NH:17][CH:16]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ccc(COc2nc(OCc3ccccc3)c3[nH]ccc3n2)cc1
Solvent: ClCCl
Product: Ic1c[nH]c2c(OCc3ccccc3)nc(OCc3ccccc3)nc12
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a stirred solution of 2,4-bis-O-benzyl-5H-pyrrolo[3,2-d]pyrimidine 15 (1.43 g, 4.3 mmol) in anhydrous CH2Cl2 (15 mL) under N2, NIS (1.069 g, 4.7 mmol) was added at which point the reaction mixture turned from pink to orange. The mixture was stirred overnight until the TLC indicated the absence of starting material. The reaction mixture was washed with aqueous Na2S2O3 (15 mL) followed by brine (15 mL). The organic layer was dried over MgSO4, loaded onto silica and purified using column chromatography eluting with 4:1 then 1:1 hexanes/EtOAc to obtain compound 16 as a pale-yellow solid (1.77 g, 3.88 mmol, 90%). Rf 0.4 in 1:3 hexanes/EtOAc. Mp 157.8-158.4° C. 1H NMR (400 MHz, CDCl3): δ 5.53 (s, 4H), 7.32-7.41 (m, 9H), 7.55-7.57 (m, 2H), 8.71 (br s, 1H, NH). 13C NMR: 57.3, 68.7, 69.3, 111.9, 127.9, 128.3, 128.6, 128.66, 128.7, 128.9, 132.4, 135.8, 137.2, 152.0, 156.9, 160.1. FAB-MS m/z for C20H16IN3O2 calculated [M+H]+ 458.0360. found 458.0357.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=3[CH3:24])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:24][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[NH:14][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:3]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cncc(Br)c2)n1
Reactant: C1CCNC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cncc(N3CCCC3)c2)n1
Temperature: 160 °C

Procedure:
(2-Meth yl-5-nitro-phenyl)-[4-(5-pyrrolidin-1-yl-pyridin-3-yl)-pyrimidin-2-yl]-amine 9 is prepared by mixing 8 (0.40 g, 1.04 mmol), pyrrolidine (3.12 mmol), K3PO4 (0.44 g, 2.08 mmol), CuI (38.5 mg, 0.10 mmol) and L-proline amino acid (48.1 mg, 0.21 mmol) in DMSO (8 ml) and heating at 160° C. in a microwave oven for 20 min. The cooled mixture is partitioned between water and ethyl acetate. The organic layer is separated, and the aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue is dissolved in DMSO (4 mL) and purified with HPLC to afford pure product 9. 1H NMR (400 MHz, d-CDCl3) δ 9.23 (d, J=2.4 Hz, 1H), 8.63 (d, J=5.2 Hz, 1H), 8.58 (s, 1H), 8.10 (s, 1H), 8.04 (s, 1H), 7.90 (dd, J=8.4, 2.4 Hz, 1H), 7.44 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.30 (d, J=5.2 Hz, 1H), 3.43-3.48 (m, 4H), 2.49 (s, 3H), 2.12-2.16 (m, 4H). LC/MS (m/z) (M+1)+: 377.2.
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:26])[C@@H:16]([C:17](=[O:25])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@H:9]2[S:8][C:7]=1[NH2:27])(=O)C.[C:28]1([O:35][CH3:36])[C:29](=[CH:31][CH:32]=[CH:33][CH:34]=1)[OH:30]>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[OH:30][C:29]1[CH:31]=[CH:32][C:33]([CH2:5][C:6]2[CH:11]([C:12]([OH:14])=[O:13])[N:10]3[C:15](=[O:26])[C@@H:16]([C:17](=[O:25])[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C@H:9]3[S:8][C:7]=2[NH2:27])=[CH:34][C:28]=1[O:35][CH3:36]
Reactant: COc1ccccc1O
Reactant: CC(=O)OCC1=C(N)S[C@@H]2[C@H](C(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1cc(CC2=C(N)S[C@@H]3[C@H](C(=O)Cc4ccccc4)C(=O)N3C2C(=O)O)ccc1O
Reaction time: 0.25 h

Procedure:
11.7 Grams of 3-acetyloxymethyl-7β-phenylacetyl-amino-ceph-2-em-4ξ-carboxylic acid are dissolved in a solution of 18.6 g of guaiacol in 300 ml of trifluoroacetic acid and the mixture is left to stand to 15 minutes at room temperature, then diluted with an equal volume of toluene and evaporated under reduced pressure. The residue is partitioned between ethyl acetate and an aqueous dipotassium hydrogen phosphate buffer solution (pH 7.5) and the layers are separated. The aqueous layer is thoroughly washed with ethyl acetate, its pH then adjusted to 2.5 with 20% aqueous phosphoric acid and again extracted with ethyl acetate. The latter extracts are washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. The residue is recrystallised from ethyl acetate to yield the 3-(4-hydroxy-3-methoxy-benzyl)-7β-phenylacetyl-amino-ceph-2-em-4ξ-carboxylic acid, m.p. 198-199°; thin-layer chromatogram (silica gel): Rf = 0.76 (system n-butanol/acetic acid/water 67:10:23) and Rf = 0.43 (system n-butanol/ethanol/water 40:10:50); ultraviolet absorption spectrum (in methanol): λmax = 235 mμ (ε = 6800) and 282 mμ (ε = 1820); infrared absorption spectrum (in mineral oil): characteristic bands at 2,85μ, 2,99μ, 5,67μ, 5.74μ and 6.56μ. It is possible to obtain a further amount of the desired product from the mother liquor via the diphenylmethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:18](=[O:29])[NH:19][C:20]2[C:25]([F:26])=[CH:24][C:23]([F:27])=[CH:22][C:21]=2[F:28])=[CH:12][CH:11]=1)([O-])=O.[Sn](Cl)Cl>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:18](=[O:29])[NH:19][C:20]2[C:21]([F:28])=[CH:22][C:23]([F:27])=[CH:24][C:25]=2[F:26])=[CH:14][CH:15]=1
Reactant: CCCCCN(Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1)C(=O)Nc1c(F)cc(F)cc1F
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CCCCCN(Cc1ccc(-c2ccccc2N)cc1)C(=O)Nc1c(F)cc(F)cc1F
Yield: 97.6 %

Procedure:
N′-[(2′-Nitro-1,1′-biphenyl-4-yl)methyl]-N′-pentyl-N-(2,4,6-trifluorophenyl)urea (196.0 mg) and anhydrous tin(II) chloride (401.6 mg) were added to ethanol (4 mL), and the mixture was heated under reflux. One hour later, the solvent was distilled off, and ethyl acetate (15 mL) and a saturated sodium bicarbonate solution (15 mL) were added to the residue. The resultant precipitate was filtered off through Celite. The filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford N′-[(2′-amino-1,1′-biphenyl-4-yl)methyl]-N′-pentyl-N-(2,4,6-trifluorophenyl)urea (179.2 mg). Yield: 94%.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Cl[CH2:31][C:32]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[C:12]([O:14][CH2:31][C:32]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[O:33])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C(\Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Reactant: CCN(CC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1ncc(/C=C(\Cc2ccccc2)C(=O)OCC(=O)N(CC)CC)n1Cc1ccccc1Cl
Temperature: 70 °C
Yield: 78.1 %

Procedure:
A solution of (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(benzyl)-2-propenoic acid (Example 2) (2.05 g, 5 mmol) in dry dimethylformamide (10 mL) was treated with 2-chloro-N,N-diethylacetamide (0.825 g, 5.51 mmol) followed by powdered potassium carbonate. This mixture was heated at 70° C. for 7 hours, diluted with water and extracted with ethyl acetate. The water-washed, dried, concentrated product solidified and after trituration with ether/hexane afforded 2.04 g (78%) of the title ester; mp 76°-77° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(O[K])(C)(C)C>C1(C)C=CC=CC=1>[C:2]1([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C1COCCN1
Agent: CC(C)(C)O[K]
Solvent: Cc1ccccc1
Product: c1ccc(N2CCOCC2)cc1
Temperature: 100 °C
Yield: 62 %

Procedure:
To a toluene solution (3 ml) containing iodobenzene (110 mg), morpholine (73.2 mg), and tert-butoxypotassium (110 mg) the mesh catalyst precursor (12 mm by 14 mm, wire diameter of 0.1 mm, opening of 0.154 mm) prepared in Example 3 was added to be heated for 24 hours at 100° C. The reaction mixture was cooled to room temperature, and the mesh catalyst precursor was washed with ethanol to be taken off from the mixture. The solvent was distilled away from the reaction mixture under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=9:1) to give an intended product, 4-phenylmorpholine with 62% yield. The mesh catalyst precursor taken off from the mixture was recycled in the same reaction to give the intended product, 4-phenyl-morpholine with respective yields of 61%, 57%, 58%, 54%, 58%, 58%, 53%, 53%, 53% from the second to the tenth reaction.
Reaction SMILES: [CH3:1][C:2]([OH:10])([C:5]([CH3:9])([CH3:8])[CH2:6][CH3:7])[C:3]#[CH:4].[H][H]>>[CH3:1][C:2]([OH:10])([C:5]([CH3:9])([CH3:8])[CH2:6][CH3:7])[CH:3]=[CH2:4]
Reactant: [H][H]
Reactant: C#CC(C)(O)C(C)(C)CC
Product: C=CC(C)(O)C(C)(C)CC

Procedure:
3,4,4-Trimethylhex-l-yn-3-ol can be hydrogenated at from 0° to 50° C., preferably 5° to 20° C., and from 0.01 to 50 bar, preferably 0.1 to 10 bar, particularly preferably 0.5 to 5 bar, in a hydrogen atmosphere, in the presence or absence of an inert solvent on partial hydrogenation catalysts, such as e.g. according to Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Volume 4/lc, pages 107 to 109. After hydrogen absorption is complete, the catalyst is as a rule filtered off and the solvent is removed by distillation. The crude product can be directly processed or distilled again.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 100 °C
Yield: 42.7 %

Procedure:
A mixture of (3-hydroxy-benzyl)-carbamic acid tert-butyl ester (250 mg, 1.12 mmol), 2-fluoro-5-nitro-pyridine (150 mg, 1.12 mmol) and K2CO3 (120 mg) in N,N-dimethylformamide (3 mL) was heated under microwave condition at 100° C. for 10 min. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographed using hexane/ethyl acetate (7:1) to give the title compound (165 mg, 43%). MS (DCI/NH3) m/z 346 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].CS(C)=O>O>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: NCCCCO
Reactant: Clc1ccc2ccccc2n1
Solvent: O
Solvent: CS(C)=O
Product: OCCCCNc1ccc2ccccc2n1
Temperature: 25 °C

Procedure:
2-Chloroquinoline (3.26 g, 20 mmol) and 4-amino-1-butanol are dissolved in anhyd. DMSO (10 mL) and heated to 140° C. for 4 hrs. The reaction is cooled to r.t., poured into water (250 mL) and extracted with ethyl acetate (3×100 mL). The organic fractions are pooled and washed with brine (3×150 mL), dried over MgSO4, filtered and reduced under vacuum to dryness. The crude material is purified by flash chromatography (silica, 7% methanol in dichloromethane) to give the title compound. MS (ESI) 217 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.[CH3:15][O:16][C:17](=[O:22])[CH2:18][C:19]([CH3:21])=O.C[O-].[Na+]>CO>[CH3:15][O:16][C:17]([C:18]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=2)=[N:2][O:1][C:19]=1[CH3:21])=[O:22]
Reactant: COC(=O)CC(C)=O
Reactant: ON=C(Cl)c1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2cccc(C(F)(F)F)c2)noc1C
Yield: 57 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), N-hydroxy-3-(trifluoromethyl)benzimidoylchloride (8.0 g, 35.78 mmol), methylacetoacetate (8.30 g, 71.56 mmol) and sodium methoxide (5.80 g, 107.34 mmol), a white solid required compound (5.82 g, 20.41 mmol, 57%) was obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[CH2:15][O:16][CH3:17].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl>[CH3:17][O:16][CH2:15][CH:3]1[CH:2]([NH:1][C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:25])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4]1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCC1CN(C(=O)OC(C)(C)C)CCC1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC1CN(C(=O)OC(C)(C)C)CCC1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,1-dimethylethyl 4-amino-3-[(methyloxy)methyl]-1-piperidinecarboxylate D33 (0.7 g), and benzoyl chloride (490 mg, 3.5 mmol, commercially available from e.g. Sigma-Aldrich, Fluka or Fisher) were dissolved in dichloromethane (30 ml) and then triethylamine (1.3 ml, 8.7 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours, then washed with water (2×), brine, dried with MgSO4, filtered and solvent removed to obtain a yellow oil of crude product which was purified by column chromatography on silica gel eluting with pet eth/EA (2/1) to give clean desired product D34 as a yellow oil in 0.8 g. LCMS [M-56+H] 293.1@1.62 min (5 min run)