Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:27]=1[NH2:28])=O)C.CCOC(C)=O>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)=[N:28][C:27]3[N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:25]=[CH:24][C:23]=3[C:21]=2[OH:20])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1N
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: Oc1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)nc2c1cnn2-c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1,2-bis-(4-chloro-phenyl)-ethanone (100 mg, 0.38 mmol) in dichloroethane (1 mL) is stirred at room temperature while TiCL4 (143 mg, 0.75 mmol) is added in dropwise. After the addition, the mixture is stirred at room temperature for 5 min and a solution of 5-amino-1-phenyl-1H-pyrazole-4-carboxilic acid ethyl ester (97 mg, 0.42 mmol) in dichloroethane (1 mL) is added dropwise. After the addition, the mixture is heated to 125° C. for 5 h. After cooling down the mixture, it is poured into a mixture of ice cold saturated aqueous NaHCO3 solution (15 mL) and EtOAc (15 mL). The resulted mixture is filtered through celite to remove the precipitate and washed with EtOAc (2×5 mL). The filtrate is extracted by EtOAc (3×5 mL). The organic layers are combined and washed with brine and dried (MgSO4). After filtering off the drying agent, the filtrate is concentrated and purified by preparative LC/MS to provide the titled compound 5,6-bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ol as light yellow solid. (55 mg, 31%). 1H NMR (MeOD) δ(ppm) 8.37 (s, 1H), 8.23 (d, 2H), 7.53 (t, 2H), 7.34 (t, 1H), 7.31 (d, 2H), 7.29 (d, 2H), 7.23 (d, 2H), 7.15 (d, 2H); HPLC-MS calculated for C24H15C12N3O (M+1+): 432.1. Found: 432.2.
Reaction SMILES: [OH:1][C@H:2]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]2[CH:10]=[N:11][C:12]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:13][CH:14]=2)[N:4]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[C:37]1([C@H:2]([C@H:3]2[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]3[CH:10]=[N:11][C:12]([C:15]([N:17]4[CH2:18][CH2:19][N:20]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=5)[CH2:21][CH2:22]4)=[O:16])=[CH:13][CH:14]=3)[NH:4]2)[OH:1])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3CCN(Cc4ccccn4)CC3)nc2)CC[C@@H]1[C@H](O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2)cn1)N1CCN(Cc2ccccn2)CC1

Procedure:
A solution of 0.038 g (0.067 mmol) of the title compound from Step A above in 1 mL dichloromethane and 1 mL trifluoroacetic acid was stirred at ambient temperature for 1 h. All volatiles were removed in vacuo and the crude light brown residue was purified directly by reverse-phase HPLC to afford the title compound (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). 1H-NMR (500 MHz, CD4O)
Reaction SMILES: ClC(OC(Cl)=O)C.[S:8]1[CH:12]=[CH:11][C:10]2[C:13]([O:17][CH:18]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:19][CH2:20][N:21](CC3C=CC=CC=3)[CH3:22])=[CH:14][CH:15]=[CH:16][C:9]1=2.ClCCCl.N>CO>[S:8]1[CH:12]=[CH:11][C:10]2[C:13]([O:17][CH:18]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:19][CH2:20][NH:21][CH3:22])=[CH:14][CH:15]=[CH:16][C:9]1=2
Reactant: CC(C)CC(CCN(C)Cc1ccccc1)Oc1cccc2sccc12
Agent: CC(Cl)OC(=O)Cl
Agent: N
Solvent: ClCCCl
Solvent: CO
Product: CNCCC(CC(C)C)Oc1cccc2sccc12
Yield: 86.7 %

Procedure:
Add 1-chloroethylchloroformate (0.58 mL, 5.38 mmol) to a stirred solution of [3-(benzo[b]thiophen-4-yloxy)-5-methyl-hexyl]-benzyl-methyl-amine (0.9619 g, 2.62 mmol) and 1,2-dichloroethane (25 mL). Heat the reaction to reflux under nitrogen for 1.5 hours. Add methanol (30 mL) and heat the reaction at reflux for 30 minutes. Cool the reaction to room temperature and make it basic using 2M ammonia in methanol. Concentrate on a rotary evaporator to give the crude product. Purify the crude product by flash chromatography on silica gel eluting with 0.5% concentrated ammonium hydroxide/5% ethanol/chloroform to yield 0.6303 g (87%) of [3-(benzo[b]thiophen-4-yloxy)-5-methyl-hexyl]-methyl-amine: mass spectrum (ion spray) m/z=278.2(M+1); HPLC (90/5/5 to 0/95/5 water/acetonitrile/5% formic acid in water) XTerra MS C18 2.1 mm×50 mm×3.5 micron: Retention time: 2.52 minutes, Purity: >99.9%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13]3([CH2:17][O:16][C:15]([NH2:18])=[N:14]3)[C:10]3([CH2:12][CH2:11]3)[C:9]([CH3:20])([CH3:19])[O:8][C:5]2=[CH:6][CH:7]=1.O.C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C@@:13]3([CH2:17][O:16][C:15]([NH2:18])=[N:14]3)[C:10]3([CH2:12][CH2:11]3)[C:9]([CH3:20])([CH3:19])[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: CC1(C)Oc2ccc(Br)cc2C2(COC(N)=N2)C12CC2
Agent: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: CO
Solvent: O
Product: CC1(C)Oc2ccc(Br)cc2[C@@]2(COC(N)=N2)C12CC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40.4 %

Procedure:
To a solution of 6′-bromo-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-amine (3.7 g, 11 mmol) in methanol (50 ml) was added (+)-dibenzoyl-D-tartaric acid monohydrate (4.1 g, 11 mmol). The mixture was stirred at room temperature for 5 minutes and concentrated in vacuo. To the residue was added dioxane (25 ml). The mixture was heated under reflux for 5 minutes, cooled to room temperature and stirred at room temperature overnight. The resulting precipitate was collected, washed with dioxane, and dried in vacuo. The resulting powder was dissolved in saturated aqueous sodium hydrogen carbonate and chloroform. The mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford (4′R)-6′-bromo-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-amine (1.5 g). The mother liquor was concentrated in vacuo and purified by NH-silica gel column chromatography (CHCl3/MeOH=20:1). The purified material was treated with (−)-dibenzoyl-L-tartaric acid monohydrate (2.0 g, 5.4 mmol) in the same manner as described above which lead to isolation of (4′S)-6′-bromo-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-amine (1.2 g).
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].O[CH:6]=[C:7]1[C:16](=[S:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[CH:14]=2)[O:9][CH:8]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O.C(Cl)(Cl)Cl>C(O)C.C(O)(=O)C>[CH2:2]([O:3][CH:6]=[C:7]1[C:16](=[S:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[CH:14]=2)[O:9][CH:8]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:1]
Reactant: CC[O-]
Reactant: Cc1ccc2c(c1)C(=S)C(=CO)C(c1ccccc1)O2
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCOC=C1C(=S)c2cc(C)ccc2OC1c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 5.5 g sodium ethylate in 40 ml absolute ethanol is added to a suspension of 29.5 g 3-hydroxymethylidene-6-methyl-thioflavanone in 400 ml absolute ethanol. After stirring for one day at room temperature the suspension is poured into a mixture of water and chloroform containing acetic acid. The organic layer is separated and the aqueous layer is extracted with chloroform. The combined organic extracts are washed with water, dried over magnesium sulfate, filtered and evaporated. The residue is recrystallised from a mixture of light petroleum and chloroform. Pure 3-ethoxymethylidene-6-methyl-thioflavanone is obtained as yellow crystals; m.p. 140°-142° C.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1>C(Cl)Cl.CO.C(Cl)Cl.O=[Mn]=O>[O:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH:10]=[O:11])=[CH:12][CH:13]=2)=[CH:4][N:3]=[CH:2]1
Reactant: OCc1ccc(-c2cnco2)cc1
Agent: O=[Mn]=O
Solvent: CO
Solvent: ClCCl
Product: O=Cc1ccc(-c2cnco2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the 4-(oxazol-5-yl)benzyl alcohol (prepared as described by Tanaka, A.; Terasawa, T.; Hagihara, H.; Sakuma, Y.; Ishibe, N.; Sawada, M.; Takasugi, H.; Tanaka, H. J. Med. Chem. 1998, 41, 2390-2410) (0.23 g, 1.31 mmol) in CH2Cl2/MeOH (20:1, 10.5 mL) was added activated MnO2 (1.01 g, 11.6 mmol) and the mixture stirred at room temperature overnight. The reaction was then diluted with CH2Cl2 (10 mL) and filtered through Celite®, washing with CHCl3. The filtrate was concentrated to give the crude aldehyde as a beige solid (0.164 g) which used without further purification in the next reaction. 1H NMR (CDCl3) δ7.52 (s, 1H), 7.82 (d, 2H, J=9 Hz), 7.95 (d, 2H, J=9 Hz), 7.99 (s, 1H), 10.02 (s, 1H).
Reaction SMILES: [N+](C1C=CC(OCC(O)COC2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=O.NC1C=CC(OCC(O)COC2C=CC(N)=CC=2)=CC=1.C(OC=C(C(O)=O)C(O)=O)C.[C:56]([C:61]1[C:70](=[O:71])[C:69]2[C:64](=[CH:65][CH:66]=[C:67]([O:72][CH2:73][CH:74]([OH:93])[CH2:75][O:76][C:77]3[CH:78]=[C:79]4[C:84](=[CH:85][CH:86]=3)[NH:83][CH:82]=[C:81]([C:87]([O:89]CC)=[O:88])[C:80]4=[O:92])[CH:68]=2)[NH:63][CH:62]=1)([O:58]CC)=[O:57].[OH-].[Na+]>CO.[Pd].[C].O>[C:87]([C:81]1[C:80](=[O:92])[C:79]2[C:84](=[CH:85][CH:86]=[C:77]([O:76][CH2:75][CH:74]([OH:93])[CH2:73][O:72][C:67]3[CH:68]=[C:69]4[C:64](=[CH:65][CH:66]=3)[NH:63][CH:62]=[C:61]([C:56]([OH:58])=[O:57])[C:70]4=[O:71])[CH:78]=2)[NH:83][CH:82]=1)([OH:89])=[O:88]
Reactant: CCOC(=O)c1c[nH]c2ccc(OCC(O)COc3ccc4[nH]cc(C(=O)OCC)c(=O)c4c3)cc2c1=O
Agent: [Pd]
Agent: CCOC=C(C(=O)O)C(=O)O
Agent: Nc1ccc(OCC(O)COc2ccc(N)cc2)cc1
Solvent: CO
Solvent: O
Product: O=C(O)c1c[nH]c2ccc(OCC(O)COc3ccc4[nH]cc(C(=O)O)c(=O)c4c3)cc2c1=O
Reaction time: 0.5 h

Procedure:
10 g. (30 mmol) of 1,3-bis(4-nitrophenoxy)-2-propanol is hydrogenated in methanol in the presence of 1.6 g. of Pd-carbon (10%). The catalyst is filtered off, and the filtrate is evaporated, leaving 13 g. of crude, oily 1,3-bis-(4-aminophenoxy)-2-propanol. This product is heated with 100 ml. of the diethyl ester of ethoxymethylenemalonic acid for 3 hours to 100°, then for 1 hour to 100° in a water jet pump vacuum. The excess diethyl ester of ethoxymethylenemalonic acid is distilled off under vacuum. The remainder is refluxed in 150 ml. of "Dowtherm A" for 30 minutes. After cooling, the solution is combined with isopropyl ether, and the thus-separated solid product is filtered off, thus obtaining 4 g. of crude 1,3-bis(3-carbethoxy-1,4-dihydro-4-oxo-6-quinolyloxy)-2-propanol, which is refluxed for 1 hour in 100 ml. of 2 N NaOH. After cooling, the mixture is extracted with ethyl acetate, and the aqueous phase is acidified with hydrochloric acid. The thus-produced oily compound is separated and stirred with ether until it has become solid. The solid product is filtered off, recrystallized from dimethylformamide, and dried under vacuum at 100°.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][C:5](=O)[CH3:6].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1.C>C1CCCCC1.C(O)(=O)C>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]2[CH3:6])=[N:11][CH:12]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1ccc(Br)cn1
Solvent: C1CCCCC1
Solvent: CC(=O)O
Product: Cc1ccc(C)n1-c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
Hexane-2,5-dione (97 mL, 831 mmol) was added to a solution of 2-amino-5-bromo-pyridine (125 g, 722 mmol) in cyclohexane (625 mL) and acetic acid (20 mL). The solution was heated to reflux under argon atmosphere with a Dean-Stark trap. A total of 30 mL of water was collected from the Dean-Stark trap. The mixture was allowed to cool to room temperature, diluted with water, and extracted with diethyl ether. The organic phase was washed with 1 N hydrochloric acid (4×), saturated aqueous sodium bicarbonate solution (2×) and saturated aqueous sodium chloride solution (2×). The organic phase was dried (MgSO4) and concentrated in vacuo to yield a yellow solid. The product was dissolved in hot hexanes (200 mL). Charcoal was added and the mixture filtered. Crystallization proceeded over three hours at 0° C. The solid was collected by filtration to yield yellow crystals (145 g, 80%). Mp=69° C.; 1H NMR (CDCl3, 300 MHz) δ 8.66 (d, 9 Hz, 1H), 7.96 (dd, 9 Hz, 8 Hz, 1H), 7.15 (d, 8 Hz, 1H), 5.91 (s, 2H), 2.14 (s, 6H); MS (CI) m/z 251 (MH+); Anal. Calcd. for C11H11BrN2: C, 52.61; H, 4.42; N, 11.16; Br, 31.82. Found: C, 52.62; H, 4.56; N, 11.18; Rf=0.4 (60:40 dichloromethane/hexanes).
Reaction SMILES: C([S:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH2:7][CH2:6]1)(=O)C.[ClH:24]>C(O)C>[ClH:24].[CH:21]1([C:19]([CH:11]([N:8]2[CH2:7][CH2:6][CH:5]([SH:4])[CH2:10][CH2:9]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[O:20])[CH2:23][CH2:22]1
Reactant: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)CC1
Agent: Cl
Solvent: CCO
Product: O=C(C1CC1)C(c1ccccc1F)N1CCC(S)CC1
Reaction time: 8 h

Procedure:
In 50 ml of ethanol, 2.00 g (5.97 mmol) of 4-acetylthio-1-(α-cyclopropylcarbonyl-2-fluorobenzyl)piperidine were dissolved. An adequate amount of hydrogen chloride gas was blown into this solution and the resulting solution was allowed to stand overnight at room temperature. The solvent was distilled off under reduced pressure. The residue was crystallized from diethyl ether, whereby 1.95 g of the title compound were obtained as slightly brown crystals (yield: 99%).
Reaction SMILES: [CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[NH:10][CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[C:36](O)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C.C(Cl)Cl>[CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[N:10]([C:36](=[O:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)NCC2
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)N(C(=O)c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
A mixture of the compound obtained in Example 3 (361 mg), methylene chloride (10 ml), triethylamine (85 mg), benzoic acid (103 mg), N-hydroxybenzotriazole (114 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (162 mg) is stirred at room temperature overnight. The reaction solution is washed, dried and evaporated to remove the solvent. The resulting oily residue is purified by silica gel column chromatography (solvent; chloroform/methanol=20:1) to give methyl 2-butyl-5-benzoyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (297 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][OH:17])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[CH3:23][N:24]=[C:25]=[S:26].[Cl-].[NH4+]>CCCCCC.O1CCCC1.CN(C)C=O>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][O:17][C:25](=[S:26])[NH:24][CH3:23])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CN=C=S
Reactant: CC(C)c1nc(CO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=S)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a dry tetrahydrofuran-dimethylformamide (1:1 v/v, 1 ml)solution of 50 mg (0.15 mmol)of [5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]-methanol (Compound I-8)was added 6.6 mg (0.17 mmol)of 60% sodium hydride under nitrogen atomosphere, and the mixture was stirred at room temperature for 30 minutes. Then, 22 mg (0.3 mmol)of methylisothiocyanate was added under ice-cooling. The mixture was stirred at the same temperature for 30 minutes, and at room temperature for 30 minutes. To the reaction mixture, an aqueous ammonium chloride solution was added to terminate the reaction. The mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate:n-hexane=1:1)to give 37 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-(N-methylthiocarbamoyl)oxymethyl-1H-imidazole (Compound I-44)(yield 60%). mp 119-121° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH:13]1([N:19]=[C:20]=[S:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CCOCC>[CH:13]1([NH:19][C:20]([N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)=[S:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: c1cnc(N2CCNCC2)cn1
Reactant: S=C=NC1CCCCC1
Solvent: CCOCC
Product: S=C(NC1CCCCC1)N1CCN(c2cnccn2)CC1
Reaction time: 0.58 h

Procedure:
To a solution of 4.92 g. of 1-(2-pyrazinyl)piperazine in 50 ml. of anhydrous ether is added dropwise a solution of 4.2 g. of cyclohexyl isothiocyanate in 50 ml. of anhydrous ether over 5 minutes. The mixture isstirred for 35 minutes and the resulting solid is collected and recrystallized from 50 ml. of ethanol, giving 7.58 g. of the desired product, m.p. 176°-178° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([O:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:20][CH2:19]3)[CH2:15][CH2:14]2)=[O:12])=[CH:7][C:6]=1[O:30][CH3:31])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].FC(F)(F)S(O[CH2:43][CH:44]([F:46])[F:45])(=O)=O>C(O)C>[F:45][CH:44]([F:46])[CH2:43][N:20]1[CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][O:23][C:16]2([CH2:15][CH2:14][N:13]([C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([O:30][CH3:31])[CH:7]=3)=[O:12])[CH2:18][CH2:17]2)[CH2:19]1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: COc1cc(C(=O)N2CCC3(CC2)CNC(c2ccccc2)CO3)ccc1OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C(=O)N2CCC3(CC2)CN(CC(F)F)C(c2ccccc2)CO3)ccc1OC(C)C
Temperature: 80 °C
Yield: 25.6 %

Procedure:
To a solution of (4-isopropoxy-3-methoxy-phenyl)-(9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)methanone (15 mg, 0.04 mmol) in ethanol (375 μL) was added NaHCO3 (12 mg, 0.14 mmol), followed by the addition of 2,2-difluoroethyl trifluoromethanesulfonate (11 mg, 0.05 mmol). The reaction mixture was heated at 80° C. for 16 hours. The reaction mixture was filtered and purified by Waters mass directed LC/MS: (1-99% ACN/H2O (5 mM HCl) to obtain [8-(2,2-difluoroethyl)-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methoxy-phenyl)methanone (5 mg, 29%). 1H NMR (400 MHz, CDCl3) δ 7.45-7.36 (m, 5H), 6.98-6.83 (m, 3H), 5.25 (d, J=10.4 Hz, 1H), 4.57 (dt, J=12.2, 6.1 Hz, 1H), 3.85 (s, 3H), 3.60 (d, J=10.9 Hz, 1H), 3.47-3.12 (m, 6H), 2.86-2.60 (m, 3H), 1.88-1.50 (m, 5H), 1.38 (d, J=6.1 Hz, 6H); ESI-MS m/z calc. 488.5. Found 489.7 (M+1)+; Retention time: 2.17 minutes (3 min run).
Reaction SMILES: [C:1]([OH:6])(=O)/[CH:2]=[CH:3]/[CH3:4].S(Cl)(Cl)=O.[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([Cl:20])[CH:13]=1>CC(N(C)C)=O.[Cl-].[Na+].O>[Cl:20][C:14]1[CH:13]=[C:12]([NH:11][C:1](=[O:6])/[CH:2]=[CH:3]/[CH3:4])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: C/C=C/C(=O)O
Reactant: N#Cc1ccc(N)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: C/C=C/C(=O)Nc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
A solution of crotonic acid (8.24 mL, 98.31 mmol) and thionyl chloride (7.18 mL, 98.31 mmol) in DMA (150 mL) was stirred at 0° C. for 1 hr. To the reaction mixture was added 4-amino-2-chlorobenzonitrile (15 g, 98.31 mmol), and the mixture was stirred at room temperature for additional 14 hr. To the reaction solution was added brine at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution and 1N hydrochloric acid, and dried, and the solvent was evaporated under reduced pressure to give (E)-N-(3-chloro-4-cyanophenyl)but-2-enamide (21.69 g, 98.31 mmol, quantitative) as a brownish-red powder.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@@H:8]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:12]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:11]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@:10]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[C:50]([F:56])[C:49]=3[F:57])[CH:41]=2)([O:38][CH3:39])[O:9]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[CH2:15]([O:14][C@H:13]1[C@H:12]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:11]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@:10]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[C:50]([F:56])[C:49]=3[F:57])[CH:41]=2)([O:38][CH3:39])[O:9][C@@H:8]1[CH2:7][OH:6])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.4 %

Procedure:
To a solution of tert-butyl-dimethyl-[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]silane 21j (72.7 g, 86 mmol) in tetrahydrofuran (300 mL) was added tetrabutylammonium fluoride (172 mL, 172 mmol, 1 M in tetrahydrofuran) at room temperature. The mixture was stirred at room temperature for 12 hours, and then ethyl acetate was added (300 mL). The resulting mixture was washed with water (400 mL×4), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=20/1 to give the title compound 21k as yellow oil (21.0 g, 33.4%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.42-7.29 (m, 13H), 7.27-7.17 (m, 3H), 7.01 (m, 2H), 6.74-6.66 (m, 1H), 6.63-6.53 (m, 1H), 4.99-4.88 (m, 3H), 4.72 (m, 1H), 4.54 (d, 1H), 4.15-4.09 (m, 2H), 3.99-3.89 (m, 3H), 3.87 (s, 3H), 3.83 (d, 1H), 3.78-3.66 (m, 2H), 3.34 (d, 1H), 3.10 (s, 3H).