Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:37])[C:35]#[CH:36])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.ClCCl.CO.N>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:37])[C:35]#[C:36][C:2]3[CH:19]=[CH:18][C:5]([CH2:6][N:7]4[CH2:12][CH2:11][CH:10]([N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[CH2:9][CH2:8]4)=[CH:4][CH:3]=3)=[CH:29][CH:28]=2)=[CH:25][CH:26]=1
Reactant: Ic1ccc(CN2CCC(N3CCCC3)CC2)cc1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: O=C(C#Cc1ccc(CN2CCC(N3CCCC3)CC2)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
Prepared analogously to Example 1.1.d. from 1-(4-iodobenzyl)-4-pyrrolidin-1-ylpiperidine and propynoic acid-(4′-chlorobiphenyl-4-yl)amide. Yield: 15 mg (7% of theory); melting point: 191° C.-192° C.; C31H32ClN3O (M=498.07); calc.: molecular ion peak (M+H)+: 498/500; found: molecular ion peak (M+H)+: 498/500; Rf value: 0.45 (silica gel, dichloromethane/methanol/ammonia (10:1:0.1)).
Reaction SMILES: C([CH:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][CH3:17])[C:12]2[C:7](=[C:8]([O:18][CH3:19])[CH:9]=[CH:10][CH:11]=2)[CH:6]=1)O)C.CS([Cl:24])(=O)=O>C(Cl)Cl>[Cl:24][CH2:3][C:5]1[CH:14]=[C:13]([O:15][CH2:16][CH3:17])[C:12]2[C:7]([CH:6]=1)=[C:8]([O:18][CH3:19])[CH:9]=[CH:10][CH:11]=2
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1cc(C(O)CC)cc2c(OC)cccc12
Solvent: ClCCl
Product: CCOc1cc(CCl)cc2c(OC)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
To a solution of ethyl (4-ethoxy-8-methoxynaphthalen-2-yl)methanol (0.136 g, 0.59 mmol) and TEA (0.25 mL, 1.76 mmol) in dry CH2Cl2 (6 mL) was added MsCl (0.068 mL, 0.88 mmol). The resulting reaction mixture was stirred at room temperature overnight and was then diluted with CH2Cl2 (25 mL) and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified on a silica gel column eluting with a gradient of 100% hexanes to 10% EtOAc/hexanes to give the title intermediate (23 mg) as a white solid.
Reaction SMILES: O(C1C=CC([N+]([O-])=O)=CC=1)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O.C([O-])(=O)C.[Na+].[CH2:27]1[CH2:35][N:34]2[CH:30]([CH:31]([OH:37])[CH:32]([OH:36])[CH2:33]2)[CH:29]([OH:38])[CH2:28]1>>[CH2:27]1[CH2:35][N:34]2[C@@H:30]([C@H:31]([OH:37])[C@H:32]([OH:36])[CH2:33]2)[C@H:29]([OH:38])[CH2:28]1
Reactant: OC1CN2CCCC(O)C2C1O
Agent: CC(=O)[O-]
Agent: O=[N+]([O-])c1ccc(OC2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)cc1
Agent: [Na+]
Product: O[C@H]1[C@H]2[C@H](O)CCCN2C[C@H]1O

Procedure:
The test compound swainsonine is prepared by 0.4 serial dilution of a 40 μM stock. Present in each determination is 10 μl diluted test compound, 25 μl of 10 mM paranitrophenyl mannopyranoside, 200 mM sodium acetate, pH 5.6 and 15 μl of purified rat liver Golgi mannosidase II. After incubating the reaction for 60 minutes at 37° C., the reaction is quenched with 50 μl of 0.5 M sodium carbonate. Absorption is read at 405 mn. After subtracting the blank from positive controls and samples, the samples are normalized against the positive control mean using a variable slope, sigmoidal curve fit, with bottom=0, top=100. The signal is proportional to the amount of products from the uninhibited reaction. The calculated IC50 for inhibition of purified Golgi mannosidase II by swainsonine hydrochloride is 0.068±0.021 μM.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=O)[C:10]3([CH2:13][S:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:13][S:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2C12CSC2
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)NCC21CSC1
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
To a solution of 6-bromospiro[indoline-3,3′-thietan]-2-one (0.260 g, 0.962 mmol) in toluene (39 mL) was added sodium bis(2-methoxyethoxy)aluminium hydride (60% in toluene, 1.47 mL, 4.81 mmol) dropwise under an atmosphere of argon gas. The solution was stirred at 80° C. for 40 min, cooled in an ice bath, quenched with aqueous 2N NaOH and treated with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give 6-bromo-1,2-dihydrospiro[indole-3,3′-thietane] as a tan solid. Mass Spectrum (ESI) m/e=256.0 [(M+1) (79Br)] and 258.0 [(M+1) (81Br)].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:14](=[O:17])[NH:15][CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:16][NH:15][C:14]([C:11]1([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:17]
Reactant: CNC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)C1(Cc2ccccc2)CCNCC1
Reaction time: 0.67 h
Yield: 76.7 %

Procedure:
4-Benzyl-4-methylcarbamoylpiperidine-1-carboxylic acid tert-butyl ester (2.8 g) was dissolved in a mixture of TFA and methylene chloride and stirred for 40 min. The solvent was removed in vacuo and the residue was dissolved in water (30 ml) and pH was adjusted to 13 with aqueous sodium hydroxide (1N). The aqueous phase was extracted with methylene chloride (3×75 ml) and the combined organic phases were dried (MgSO4) and evaporated in vacuo to afford 1.50 g of 4-benzylpiperidine-4-carboxylic acid methylamide.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[CH2:12]SC2=O)=[CH:5][CH:4]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=O)[CH2:21][CH2:20]1>CN(C)C=O>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=[CH:12][C:13]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][CH:7]=2)=[O:14])[CH2:21][CH2:20]1
Reactant: CN1CCN(c2ccccc2C=O)CC1
Reactant: O=C1CSC(=O)N1c1ccc(C(F)(F)F)cc1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccccc2C=CC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame-dried 3-neck round bottom flask equipped with a magnetic stir bar, sodium hydride (50 mg, 1.25 mmol of a 60% oil dispersion) was washed with hexane and covered with 6.0 mL of anhydrous dimethylformamide (DMF). To this was added a solution of 3-(4-trifluoromethylphenyl)-thiazolidine-2,4-dione (240 mg, 0.92 mmol) and 2-(4-methylpiperazin-1-yl)benzaldehyde (170 mg, 0.84 mmol) in 2 mL of DMF. After stirring at room temperature overnight the mixture was heated to reflux for 4 hours and cooled. The solvent was removed in vacuo and the residue partitioned between saturated aqueous ammonium chloride and chloroform. The organic layer was washed with saturated NaCl, dried and filtered. The residue was absorbed onto silica gel (640 mg) and flash chromatographed on a 4×0.75 in column eluting with ethyl acetate: hexanes (3:1) followed by 100% ethyl acetate. The crude product oil was dissolved in hot EtOAc and allowed to cool to deposit 30 mg of yellow crystals which were filtered and dried, m.p. 207-209° C.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[C:11](N2CC[C@H](O)C2)=[N:12][CH:13]=[C:14]([CH:29]=1)[C:15]([NH:17]C1C=CC(OC(Cl)(F)F)=CC=1)=[O:16].[O:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[N:42]1[C:46](B2OC(C)(C)C(C)(C)O2)=[CH:45][CH:44]=[N:43]1>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[N:42]1[C:46]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:29]=2)[C:15]([NH2:17])=[O:16])=[CH:45][CH:44]=[N:43]1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: NC(=O)c1cncc(-c2ccnn2C2CCCCO2)c1
Temperature: 110 °C

Procedure:
K3PO4 (41.3 mg, 0.195 mmol) was added to a solution of (S)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 8.1, 30 mg, 0.067 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (36.2 mg, 0.13 mmol) in toluene (0.32 mL) in a vial which was flushed with argon. Pd(PPh3)4 (3.75 mg, 0.032 mmol) was added. The vial was sealed and heated at 110° C. for 18 h. After cooling at RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH) to afford N-(4-(chlorodifluoromethoxy)phenyl)-6-(S)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide, a portion of which (21 mg, 0.039 mmol) was dissolved in DCM (0.5 mL), treated with TFA (0.141 mL, 1.82 mmol) and stirred at RT for 3 h. The RM was poured into 10% aq. Na2CO3 (10 mL) and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH) to afford the title compound. HPLC (Condition 4) tR=4.49 min, HPLC Chiral (CHIRALCEL® OD-H, 250×4.6 mm, eluent:n-heptane/EtOH/MeOH (85:10:5), 1 mL/min, UV DAD, tR=13.32 min, UPLC-MS (Condition 3) tR=0.92 min, m/z=450.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.76 (m, 1H) 1.77-1.92 (m, 1H) 2.86-2.97 (m, 1H) 3.18-3.35 (m, 2H) 3.34-3.47 (m, 1H) 4.10-4.24 (m, 1H) 4.66-4.93 (m, 1H) 6.28-6.42 (m, 1H) 7.31 (d, J=8.99 Hz, 2H) 7.85 (d, J=8.99 Hz, 3H) 7.96-8.05 (m, 1H) 8.64-8.81 (m, 1H) 10.17 (s, 1H) 12.80-13.14 (m, 1H).
Reaction SMILES: [CH:1]([N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13])=[CH2:2].C1(=O)N(C(C)[CH:20]=[O:21])C(=O)C2=CC=CC=C12>>[C:7]1(=[O:8])[N:3]([CH2:1][CH2:2][CH:20]=[O:21])[C:4](=[O:13])[C:5]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:6]12
Reactant: CC(C=O)N1C(=O)c2ccccc2C1=O
Reactant: C=CN1C(=O)c2ccccc2C1=O
Product: O=CCCN1C(=O)c2ccccc2C1=O
Yield: 78 %

Procedure:
Starting from N-vinylphthalimide, a 78% yield of the 3-phthalimidopropanaldehyde and 2-phthalimidopropanaldehyde in a ratio of 2.5:1 was obtained. The Rh-related catalyst afforded a relatively reverse selectivity.
Reaction SMILES: [NH+]1([O-])CCOCC1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[C:11]([CH2:17][CH3:18])[CH:10]=1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[C:11]([CH2:17][CH3:18])[CH:10]=1
Reactant: CCc1cc(Br)ccc1CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: [O-][NH+]1CCOCC1
Solvent: ClCCl
Product: CCc1cc(Br)ccc1C=O
Reaction time: 2 h
Yield: 110.8 %

Procedure:
Morpholine-N-oxide (5.0 g, 43 mmol) was stirred in dichloromethane (30 mL) over 3A sieves 30 min under N2 atmosphere. (4-Bromo-2-ethyl-phenyl)-methanol (3.1 g, 14.4 mmol), then tetrapropylammonium perruthenate (250 mg, 0.72 mmol) was added. The solution was stirred 2 h then filtered through a plug of silica. The silica was washed with 30% ethyl acetate in hexanes, and the organics were pooled. The solution was concentrated in vacuo to give a light yellow oil (3.4 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)=[C:9]1[CH:20]=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[BH4-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([I:19])=[CH:17][CH:18]=2)=[C:9]1[CH2:20][OH:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc(-c2ccc(I)cc2)c1C=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc(-c2ccc(I)cc2)c1CO
Yield: 82.7 %

Procedure:
A solution of 6 (400 mg, 1.0 mmol) in anhydrous THF (12 mL) under argon was cooled to −20 to −25° C. and LiBH4 (55 mg, 2.5 mmol) was added in portions. The reaction was monitored by TLC (silica, hexanes/ethyl acetate (4:1)), and when no starting material was detected (20-25 min), the reaction was quenched with cold water (30 mL). The aqueous layer was extracted with CH2Cl2 and the organic layer was dried (Na2SO4), concentrated, and purified by flash column chromatography [silica, hexanes/ethyl acetate containing 1% Et3N (3:1)] yielding a gum (330 mg, 82%). 1H NMR δ 1.62 (s, 9H), 3.61 (br, 1H), 4.66 (d, J=7.2 Hz, 2H), 6.25 (d, J=3.6 Hz, 1H), 7.18 (d, J=8.1 Hz, 2H), 7.22 (d, J=3.6 Hz, 1H), 7.71 (d, J=8.1 Hz, 2H); 13C NMR δ 27.8, 55.3, 84.7, 92.4, 111.2, 121.3, 127.9, 130.0, 130.4, 134.1, 137.5, 149.8; FAB-MS obsd 399.0336, calcd 399.0331 (C16H18INO3).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].[CH2:6](O)[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(N=C=NC2CCCCC2)CCCCC1>CCOCC.CN(C)C1C=CN=CC=1>[C:1]([O:5][CH2:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:4])[C:2]#[CH:3]
Reactant: C#CC(=O)O
Reactant: OCC=Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: C#CC(=O)OCC=Cc1ccccc1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
2.71 mg (44 mmol) of propiolic acid and 5.14 ml (40 mmol) of cinnamyl alcohol were dissolved in 20 ml of dry ether. The obtained solution was cooled to −20° C. 100 ml of a solution of 9.27 g (45 mmol) of dicyclohexylcarbodiimide and 0.36 g (30 mmol) of 4-dimethylaminopyridine in dry ether was dropped into the solution. The temperature of the obtained mixture was elevated to room temperature. After stirring overnight, the insoluble matter was filtered out. The filtrate was washed with 2 N hydrochloric acid and saturated aqueous salt solution, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1) to obtain the title compound.
Reaction SMILES: CO[C:3](=[O:15])[NH:4][C:5]1[NH:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[N:6]=1.[CH3:16][O:17][CH2:18][CH2:19][NH2:20].O>CN1CCCC1=O>[OH:14][C:11]1[CH:12]=[CH:13][C:7]2[N:6]=[C:5]([NH:4][C:3]([NH:20][CH2:19][CH2:18][O:17][CH3:16])=[O:15])[NH:9][C:8]=2[CH:10]=1
Reactant: COC(=O)Nc1nc2ccc(O)cc2[nH]1
Reactant: COCCN
Solvent: O
Solvent: CN1CCCC1=O
Product: COCCNC(=O)Nc1nc2ccc(O)cc2[nH]1

Procedure:
A solution of (6-hydroxy-1H-benzoimidazol-2-yl)-carbamic acid methyl ester (300 mg, example 61) and 2-methoxy-ethylamine (630 IA) in N-methylpyrrolidinone (8 ml) was heated at 90° C. in a sealed tube for 20 hours. The reaction mixture was poured into water (160 ml) and extracted three times with ethyl acetate (40 ml). The combined extracts were dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (95 C:5 C, v/v) to 1-(6-hydroxy-1H-benzoimidazol-2-yl)-3-(2-methoxy-ethyl)-urea as a yellow solid (180 mg). Mass spectrum: 251 [M+H]+; retention time=0.55 minutes.
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[C:3]([O:5]CC)=[O:4].C(O)C.[OH-].[K+]>O>[CH3:1]/[C:2](=[CH:8]\[CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)/[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)/C(C)=C/CCC#Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C/C(=C\CCC#Cc1ccccc1)C(=O)O
Yield: 94.9 %

Procedure:
The ethyl 2-methyl-7-phenyl-(2E)-heptene-6-ynoate (1.0 g, 4.13 mmol), ethanol (4 ml), potassium hydroxide (1 g) and water (4 ml) were heated together under a nitrogen atmosphere at 50° C. for 2 hours. The reaction mixture was worked up as in Example 1 to give 0.84 g (95% of theory) of 2-methyl-7-phenyl-(2E)-hepten-6-ynoic acid as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH:16]2[CH2:20][CH2:19][O:18][CH2:17]2)=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: OC1CCOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OC2CCOC2)nc1
Temperature: 90 °C

Procedure:
To a solution of 5-bromo-2-fluoropyridine (1.5 mL, 14.2 mmol) in DMF (14 mL) was added Cs2CO3 (9.3 g, 28.5 mmol) and 3-hydroxytetrahydrofuran (1.7 mL, 21.3 mmol). The reaction mixture was heated at 90° C. for 3 days then allowed to cool to room temperature (rt). Water was added and product was filtered off, washed with water, and dried under vacuum overnight (3.5 g, 100%). MS (ESI): mass calcd. for C9H10BrNO2, 243.0; m/z found, 244.3, 246.3 [M+H]+. 1H NMR (CDCl3): 8.17 (d, J=2.1 Hz, 1H), 7.64 (dd, J=8.8, 2.6 Hz, 1H), 6.66 (dd, J=8.7, 0.5 Hz, 1H) 5.52-5.48 (m, 1H), 4.04-3.95 (m, 2H), 3.93-3.86 (m, 2H), 2.30-2.19 (m, 1H), 2.15-2.08 (m, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][NH:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:28]([O:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1)=[O:29]>C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][N:12]([C:28]([O:30][C:31]2[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=2)=[O:29])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(=O)N2C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
A 16.28 g portion of (3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-phenylpyrrolidine and 18 ml of pyridine were dissolved in 100 ml of THF, and 14.6 g of methyl 4-[(chlorocarbonyl)oxy]benzoate (mfd. by Fluka) was added under ice cooling in one portion thereto in an atmosphere of argon. After 1Hour of stirring at room temperature, 2.5 g of methyl 4-[(chlorocarbonyl)oxy]benzoate was further added at room temperature. After 2Hours of further stirring, the reaction solution was concentrated under a reduced pressure. The residue was diluted with water and diisopropyl ether, the thus precipitated insoluble matter was removed by filtration, and then the filtrated was concentrated under a reduced pressure and the resulting residue was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried with anhydrous sodium sulfate. This was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-ethyl acetate) to obtain 23.80 g of 4-(methoxycarbonyl)phenyl (3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-phenylpyrrolidine-1-carboxylate as a colorless oily substance.
Reaction SMILES: Cl[C:2]([CH2:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[OH:12])=[CH2:3].Cl>CCOCC>[F:11][C:9]1[CH:8]=[CH:7][C:6]2[O:12][C:2]([CH3:3])=[CH:4][C:5]=2[CH:10]=1
Reactant: C=C(Cl)Cc1cc(F)ccc1O
Agent: Cl
Solvent: CCOCC
Product: Cc1cc2cc(F)ccc2o1
Yield: 73.7 %

Procedure:
According to the procedure of W. K. Anderson, et al., J. Chem. Soc., Perkin, 1, 1 (1976), a mixture of 2-(2-chloro-1-propen-3-yl)-4-fluorophenol (20.9 g, 0.112 mol) and concentrated hydrochloric acid (114 mL) was heated at 85°-89° C. for 24 hours. The mixture was cooled and diluted with ether. The ethereal layer was separated and washed with H2O, 5% KOH, and H2O, dried (MgSO4), and concentrated to give 12.40 g (74%) of product as a brown oil.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH2:6]([NH:13][C:14](=[O:25])[CH2:15][CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][CH2:15][C:14]([NH:13][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:25])=[S:4]
Reactant: O=C(CCC(=O)c1ccccc1)NCc1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=S)NN=C(CCC(=O)NCc1ccccc1)c1ccccc1
Yield: 87.9 %

Procedure:
Thiosemicarbazide (2.30 g, 25.2 mmol) was added to a solution of N-benzyl-4-oxo-4-phenyl-butyramide (4.12 g, 15.4 mmol), prepared in the previous step, in 100 ml of methanol plus 4.2 ml of 1 N HCl plus 4.2 ml of water and the reaction stirred at room temperature for 20 hours. The reaction was cooled in an ice bath and a white solid precipitated. The solid was collected by filtration and dried to give 4.61 g of a white solid. Recrystallization of the solid from ethyl acetate-methanol gave the title compound (2.05 g, 39%) as a white solid, mp 162-164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]=1[CH:4]=O.[OH-].[K+].[C:21](OC(=O)C)(=[O:23])[CH3:22].Cl>C(=O)C.O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]=1/[CH:4]=[CH:22]/[CH:21]=[O:23]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1c(Cl)cc(Cl)cc1OCc1ccccc1
Agent: CC=O
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Temperature: 5 °C
Yield: 33 %

Procedure:
A stirred suspension of 2,4-dichloro-6-phenylmethoxybenzaldehyde (15.5 g, 55.1 mmole) in acetaldehyde (30 ml) was cooled to 5° C. and treated with 25% methanolic potassium hydroxide (1.4 ml, 6.24 mmole) at such a rate that the internal temperature was maintained at 25°-30° C. The resulting solution was stirred for 30 minutes in the ice bath, treated with acetic anhydride (30 ml) and then heated at 100° C. for 30 minutes. After cooling to 30° C. the solution was treated with water (84 ml) and 12 N hydrochloric acid (7 ml). The resulting mixture was refluxed for 30 minutes and then cooled in an ice bath to give a gummy solid which was recrystallized from cyclohexane to give the title compound (5.6 g, 33%), mp 109°-112° C.: pmr (CDCl3) δ5.10 (2H, s), 7.33 (5H, s), 9.68 (H, d).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[N:21]1([C:27]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:28]=2[NH2:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)C1C=CN=CC=1.O>[N:21]1([C:27]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][C:28]=2[NH:29][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCCCC1
Reactant: O=C(Cl)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCCCC1)c1ccncc1
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 33.9 %

Procedure:
Isonicotinoyl chloride hydrochloride (151 mg, 0.850 mmol, commercially available product), triethylamine (450 μl, 3.23 mmol), and a catalytic amount of 4-(dimethylamino)pyridine were sequentially added at 0° C. to a dichloromethane (5 ml) solution of 2-(1-piperidinyl)-5-(trifluoromethyl)aniline (173 mg, 0.708 mmol), obtained as described in Referential Example 1-2A. The resulting mixture was warmed to room temperature and stirred for 19.5 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10 g, hexane/ethyl acetate=1.5/1) and recrystallization (hexane). Thus, N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (SRPIN-1, code name GIF-0340) (83.8 mg, 0.240 mmol, 33.9%) was yielded as a colorless solid.