Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][C:3]=1[NH2:4].[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2[CH2:22][CH2:23][CH2:24][CH2:25][C:17]1=2.O>C(OCC)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][C:3]=1[N:4]1[C:19](=[O:20])[C:18]2[CH2:22][CH2:23][CH2:24][CH2:25][C:17]=2[C:16]1=[O:21]
Reactant: Nc1cc(OC2CCCC2)c(Cl)cc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Yield: 65 %

Procedure:
A solution of 2-fluoro-4-chloro-5-cyclopentyloxyaniline (0.50 g, 2.18 mmol) and 3,4,5,6-tetrahydrophthalic anhydride (0.398 g, 2.61 mmol) in ethyl acetate (3.0 ml) was stirred under refluxing for 3 hours. Water (20 ml) was added to the resulting reaction solution, and the mixture was extracted with ethyl acetate (20 ml×3). After drying the organic layer, the solvent was distilled off under reduced pressure, and the resulting light yellow oily substance was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=8/1) to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophathalimide as a colorless transparent oily substance (0.513 g, 1.41 mmol, 65% yield). The product was recrystallized by adding ethanol (1.0 ml) thereto to obtain the product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][SH:11].[ClH:12].[C:13]([NH:15][C:16](=[N:19][CH3:20])SC)#[N:14]>N1C=CC=CC=1.O>[ClH:12].[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][S:11][C:16](=[N:19][CH3:20])[NH:15][C:13]#[N:14]
Reactant: CN=C(NC#N)SC
Reactant: Cc1[nH]cnc1CSCCS
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CN=C(NC#N)SCCSCc1nc[nH]c1C

Procedure:
2-(5-Methyl-4-imidazolylmethylthio)ethanethiol (4.0 g) (prepared from the hydrochloride as in Example 1 (b) and N-cyano-N', S-dimethylisothiourea (4.0 g) were heated together under nitrogen in pyridine (100 ml) at 100° for 20 hours. After this time the mixture was evaporated to dryness to give the crude title product. This residue taken up in water acidified to pH2 with concentrated hydrochloric acid. After extracting with ethyl acetate the volume of the aqueous fraction was reduced and on cooling gave S-[2-(5-methyl-4-imidazolylmethylthio)-ethyl]-N-cyano-N'-methylisothiourea hydrochloride, m.p. 225°.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=1.[NH:11]1[CH2:19][CH2:18][CH:14]([C:15]([OH:17])=[O:16])[CH2:13][CH2:12]1.C(N(CC)CC)C>C(O)C>[B:8]([C:5]1[CH:4]=[N:3][C:2]([N:11]2[CH2:19][CH2:18][CH:14]([C:15]([OH:17])=[O:16])[CH2:13][CH2:12]2)=[N:7][CH:6]=1)([OH:10])[OH:9]
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: O=C(O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)C1CCN(c2ncc(B(O)O)cn2)CC1
Temperature: 80 °C
Yield: 60.3 %

Procedure:
2-Chloropyrimidin-5-ylboronic acid (2.00 g, 12.6 mmol) and isonipecotic acid (1.63 g, 12.6 mmol) were suspended in ethanol (25 mL). Triethylamine (1.78 mL, 12.6 mmol) was added and the mixture was heated at 80° C. for 16 h. The reaction mixture was cooled and concentrated in vacuo to dryness. Water (30 mL) was added and the reaction mixture was swirled until the product completely dissolved. On standing, crystallisation occurred. The mixture was cooled in an ice bath for 30 minutes, then filtered. The resultant solid was washed sparingly with water and dried under suction, then freeze-dried, to give the title compound (1.90 g, 7.6 mmol, 60%) as a white solid. δH (d6-DMSO) 8.60 (s, 2H), 8.06 (br s, 2H), 4.60-4.52 (m, 2H), 3.14-3.02 (m, 2H), 2.60-2.54 (m, 1H), 1.90-1.80 (m, 2H), 1.55-1.39 (m, 2H). LCMS (ES+) 252 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([F:14])[C:11]([Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:9]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:3]=1[Cl:24].[Br:25]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[C:7]([Br:25])=[C:6]([C:8]2[CH:13]=[C:12]([F:14])[C:11]([Si:15]([CH3:17])([CH3:18])[CH3:16])=[CH:10][C:9]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:3]=1[Cl:24]
Reactant: BrBr
Reactant: COC(=O)c1nc(-c2cc(F)c([Si](C)(C)C)cc2F)cc(N)c1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1nc(-c2cc(F)c([Si](C)(C)C)cc2F)c(Br)c(N)c1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of methyl 4-amino-3-chloro-6-(2,5-difluoro-4-(trimethylsilyl)phenyl)picolinate (0.210 g, 0.566 mmol) in CH2Cl2 (2.265 mL) at 20° C. was added bromine (0.117 mL, 2.265 mmol). The reaction mixture was stirred at 20° C. overnight. The mixture was then poured into a saturated aqueous solution of Na2S2O3 and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, hexanes/EtOAc gradient) to provide the title compound as a white solid (0.125 g, 49.1%): mp 165-166° C.; 1H NMR (400 MHz, CDCl3) δ 7.10 (dd, J=8.9, 4.0 Hz, 1H), 7.03 (dd, J=7.6, 5.1 Hz, 1H), 5.43 (s, 2H), 3.96 (s, 3H), 0.33 (d, J=0.7 Hz, 9H); ESIMS m/z 450 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]1[N:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]2)(=[O:16])=[O:17])=[CH:11][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1cc(S(=O)(=O)N2CCN(CC)CC2)cnc1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinoate (10.2 g, 0.0275 mol) was dissolved in toluene (50 mL) and a solution of sodium hydroxide (1.1 g, 0.0275 mol) in water (20 mL) added to it. This two phase mixture was then stirred vigorously at ambient temperature overnight. The aqueous phase was separated off and adjusted to pH=5.6 by addition of c. hydrochloric acid. The precipitated product was slurried with ice cooling for 15 minutes, filtered, water washed and dried under vacuo at 50° C. to afford the title compound as an off-white solid. Mpt 206-207° C. δ (CDCl3): 1.25 (3H, t), 1.39 (3H, t), 2.82 (2H, q), 3.03 (4H, m), 3.25 (4H, m), 4.50 (2H, q), 8.25 (1H, d), 8.56 (1H, d). m/z (Found:344 [M+H]+, 100%. C14H22N3O5S requires 344.38).
Reaction SMILES: Cl.Cl.C[O:4][C:5]1[CH:24]=[CH:23][C:8]([CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[CH2:15][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=1.B(Br)(Br)[Br:26].CO>C(Cl)Cl>[BrH:26].[BrH:26].[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[CH2:15][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(Cn2ccnc2CNc2ccccc2)cc1
Reactant: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Br
Product: Oc1ccc(Cn2ccnc2CNc2ccccc2)cc1
Reaction time: 3 h

Procedure:
A suspension of 1.6 g (0.0044 mole) of 1-(4-methoxybenzyl)-2-phenylaminomethyl imidazole dihydrochloride in 100 ml of CH2Cl2 was converted to its free base by washing with aqueous NaHCO3. The CH2Cl2 was dried (K2CO3), and filtered, and the filtrate was treated with a solution of 3.3 g (0.013 mole) of BBr3 in 9 ml of CH2Cl2. After 3 hr, methanol was cautiously added and all the solvents were evaporated. The residue was recrystallized from methanol and diethyl ether to give 1-(4-hydroxybenzyl)-2-phenylaminomethyl imidazole dihydrobromide, 0.73 gm (39%), mp 198°-200°.
Reaction SMILES: C[Al](C)C.Cl.[CH3:6][NH2:7].C([O:10][C:11]([C:13]1[O:14][C:15]2[C:21]([F:22])=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]([CH3:29])=[C:18]([C:30]#[N:31])[C:16]=2[N:17]=1)=O)C.Cl>ClCCl>[C:30]([C:18]1[C:16]2[N:17]=[C:13]([C:11]([NH:7][CH3:6])=[O:10])[O:14][C:15]=2[C:21]([F:22])=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]=1[CH3:29])#[N:31]
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CN
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reaction time: 0.67 h
Yield: 64 %

Procedure:
Under nitrogen atmosphere, trimethylaluminium (1.03 M n-hexane solution, 1.80 ml, 1.85 mmol) was dropwise added to a dichloromethane (2 ml) solution of methylamine hydrochloride (125 mg, 1.85 mmol) at room temperature, and stirred for 40 minutes. Subsequently, a dichloromethane (2 ml) solution of ethyl-4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (200 mg, 617 μl) was dropwise added and stirred for 63 hours. After the reaction, aqueous 1 N hydrochloric acid solution was added to the reaction liquid with cooling with ice, followed by stirring at room temperature. The reaction liquid was extracted with chloroform. Next, the obtained organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with dichloromethane/methanol (100:1, v/v) gave the entitled compound (122 mg, 64%) as a pale green solid.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][S:11]([CH3:14])(=[O:13])=[O:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:4]([C:3]1[C:2]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[N:9][CH:8]=[CH:7][CH:6]=1)#[N:5]
Reactant: CS(N)(=O)=O
Reactant: N#Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ncccc1C#N
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 2-chloro-nicotinonitrile (2 g), H2NSO2Me (1.73 g) and K2CO3 (4.44 g) in DMF (100 ml) was stirred at 100° C. for 18 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel in dichloromethane/methanol=98/2 (v/v) as eluent. Yield: 1.32 g. MS-ESI: [M+H]+=198.2
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:18][C:19]([CH3:24])([CH2:22]O)[CH2:20][OH:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C.O>[OH:13][C:12]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]([CH:8]2[O:21][CH2:20][C:19]([CH3:24])([CH3:22])[CH2:18][O:9]2)=[CH:10][C:11]=1[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(CO)CO
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)COC(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)OC1

Procedure:
A solution of 46.9 parts of 3,5-di-tert.butyl-4-hydroxybenzaldehyde, 21 parts of 2,2-dimethyl-1,3-propane diol and 0.5 parts of 4-toluene-sulphonic acid hydrate in 300 parts of toluene is raised to boiling temperature and reacted with removal of the water of reaction in a separator. After reaction for 6 hours, 85 parts of ethyl acetate are added. The reaction solution is dried over potassium carbonate and the solvent distilled, after which 60 parts of the crude product are obtained. This is recrystallized from hexane to give 2-(4'-hydroxy-3',5'-di-tert.butyl phenyl)-5,5-dimethyl-1,3-dioxane of formula IV, ##SPC3##
Reaction SMILES: Cl[CH:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH:7]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:6]3[CH2:5][C:4]=2[NH:3]1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.CCOC(C)=O>[C:17]1([N:23]2[CH2:28][CH2:27][N:26]([C:2]3[CH:11]=[CH:10][C:9]4[C:8](=[O:12])[CH:7]5[CH2:13][CH2:14][CH2:15][CH2:16][CH:6]5[CH2:5][C:4]=4[N:3]=3)[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1C2=C(CC3CCCCC13)NC(Cl)C=C2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2ccc(N3CCN(c4ccccc4)CC3)nc2CC2CCCCC12
Yield: 247.4 %

Procedure:
A mixture of 2-chloro-2,5a,6,7,8,9,9a,10-octahydro-1H-benzo[g]quinolin-5-one (0.29 g, 0.123 mmol) and 1-phenylpiperazine (2.0 g, 12.3 mmol) was stirred at 100° C. for 1 h (TLC control; hexane-EtOAc, 2:1). Then the mixture was separated by column chromatography on silica gel to give the title compound (0.11 g, 25%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1.O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:14][C:15]([OH:17])=[O:16])[CH:8]=[CH:9][CH:10]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 86.3 %

Procedure:
In an inert atmosphere, 3-(trifluoromethyl)benzaldehyde (13.26 g, 76.15 mmol) was dissolved in pyridine (58 ml) and malonic acid (15 g, 145 mmol) was added and the mixture was warmed to 50° C. followed by slow addition (over 5 minutes) of piperidine (5.8 ml, 58.6 mmol). The resulting suspension was warmed to 75° C. and stirring was continued for 3.5 h. The reaction mixture was cooled to 0° C. and poured onto an ice-cold solution of concentrated hydrochloric acid (12 M, 32 ml) in water (400 ml). The precipitated product was filtered off and dried at HV to give 14.21 g (68%) of 3-(3-trifluoromethyl-phenyl)-acrylic acid. LC-MS: tR=0.88 min; [M+H]+=no ionisation.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C(#N)C.C(N(CC)CC)C.FC(F)(F)S(O[CH2:45][C:46]([F:52])([F:51])[C:47]([F:50])([F:49])[F:48])(=O)=O>>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][N:21]([CH2:45][C:46]([F:52])([F:51])[C:47]([F:50])([F:49])[F:48])[CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(CC(F)(F)C(F)(F)F)C4)c3)n2)cn1
Temperature: 45 °C
Yield: 5.9 %

Procedure:
To a solution of 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62; 30.0 mg, 0.0694 mmol) in acetonitrile (694 μL, 0.0694 mmol) was added triethylamine (38.7 μL, 0.278 mmol) and 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate (39.1 mg, 0.139 mmol). The reaction mixture was heated to 45° C. for 2 hours. The crude reaction mixture was purified by reverse phase HPLC to afford 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,3,3,3-pentafluoropropyl)azetidin-3-yl)acetonitrile (2.0 mg, 5.9% yield). MS (apci) m/z=492.2 (M+H).
Reaction SMILES: [BH4-].[Na+].C([C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[B:23]1[O:27][C:26](C)(C)C(C)(C)[O:24]1)[O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[C:11]([O:18][CH3:19])[N:10]=1)=O>CO.C(Cl)Cl>[OH:24][B:23]1[C:22]2[CH:21]=[CH:20][C:7]([O:8][C:9]3[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[C:11]([O:18][CH3:19])[N:10]=3)=[CH:6][C:5]=2[CH2:26][O:27]1
Reactant: COc1nc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2)ccc1C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1nc(Oc2ccc3c(c2)COB3O)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of NaBH4 (0.077 g, 2.0 mmol) in anhydrous methanol (10 mL) was added to a solution of 6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-methoxy-nicotinamide (2.51 g, 6.30 mmol) in CH2Cl2 (40 mL) and stirred at room temperature for 5 minutes. Solid NaBH4 (0.400 g, 10.6 mmol) was then added portionwise over 45 minutes at room temperature. The reaction was stirred for an additional 30 minutes then quenched by the addition of 50% aqueous acetic acid (1 mL). After stirring for an additional 30 minutes at room temperature, the solution was concentrated in vacuo. The residue was purified by silica gel flash column chromatography (AcOH/MeOH/CH2Cl2 1:3:100 v/v/v) to give the title compound as a white fluffy solid (0.220 g, 12% yield).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:9][OH:10])(C)(C)C.[CH2:19](O)[CH:20]([CH3:22])[CH3:21]>>[CH2:15]([O:14][C:12](=[O:13])[NH:11][CH:8]1[CH2:7][C:6](=[O:5])[O:18][CH:9]1[O:10][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:16]=[CH2:17]
Reactant: CC(C)CO
Reactant: C=CCOC(=O)NC(CO)CC(=O)OC(C)(C)C
Product: C=CCOC(=O)NC1CC(=O)OC1OCC(C)C
Yield: 7.3 %

Procedure:
Prepared from 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester as described for 40 using isobutanol to afford 190 mg (yield 7.3%) of the title compound as an anti diastereomer and 290 mg (yield 11%) of the syn diastereomer. 1H-NMR (500 MHz, CDCl3) for anti diastereomer: δ (higher Rf) 0.85-1.05 (m, 6H), 1.82-1.98 (m, H), 2.37-2.42 (d, H), 2.98-3.04 (m, H), 3.31-3.35 (m, H), 3.55-3.58 (m, H), 4.20-4.30 (t, H), 4.58 (br, 2H), 5.07 (br, H), 5.22-5.43 (m, 3H), 5.84-5.96 (m, H), for syn diastereomer (lower Rf) 0.85-1.05 (m, 6H), 1.88-1.95 (m, H), 2.40-2.51 (m, H), 2.83-2.90 (m, H), 3.33-3.36 (m, H), 3.61-3.65 (m, H), 3.87-3.88 (d, H), 4.40-4.68 (m, 3H), 5.20-5.40 (m, 2H), 5.42-5.43 (d, H), 5.80-5.97 (m, H); LC-MS: m/z=258 (M+H+) for both of diastereomers.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=1.C(N(CC)CC)C>C(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:13]=[CH:14][CH:15]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cccc(Nc2cc(Cl)ncn2)c1
Temperature: 80 °C

Procedure:
4,6-Dichloropyrimidine (1.5 g, 10 mmol), tert-butyl 3-aminophenylcarbamate (2.1 g, 10 mmol) and triethylamine (2.2 g, 20 mmol) were mixed in ethanol (20 mL), heated at 80° C. for 16 hr. The reaction mixture was cooled to RT and solvent was removed in vacuo. The gummy crude product was mixed with 20 mL of DCM and was stirred at RT to give an off-white solid, which was filtered and dried under vacuum (1.6 g, 5 mmol). MS (m/z): MH+=321, 323.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.C(OC([N:29]1[C:37]2[N:32]([C:33](=[O:39])[N:34]=[C:35](Cl)[CH:36]=2)[CH2:31][C:30]1([CH3:41])[CH3:40])=O)(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)[CH2:20][O:21][C:35]1[CH:36]=[C:37]2[NH:29][C:30]([CH3:41])([CH3:40])[CH2:31][N:32]2[C:33](=[O:39])[N:34]=1
Reactant: OCc1cc(F)c(Oc2ccnc(C(F)(F)F)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CC1(C)Cn2c(cc(OCc3cc(F)c(Oc4ccnc(C(F)(F)F)c4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol and tert-butyl-7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:14][C:13]([C:15]([F:18])([F:17])[F:16])=[N:12][C:11]=2[C:19]2[CH:24]=[CH:23][C:22](SC)=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O[O:28][S:29]([O-:31])=O.[K+].[CH3:33]O>O>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[NH:12][C:11]=2[C:19]2[CH:24]=[CH:23][C:22]([S:29]([CH3:33])(=[O:31])=[O:28])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2[nH]c(C(F)(F)F)nc2-c2ccc(SC)cc2)cc1F
Reactant: CO
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: COc1ccc(-c2nc(C(F)(F)F)[nH]c2-c2ccc(S(C)(=O)=O)cc2)cc1F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
4-(3-Fluoro-4-methoxyphenyl)-5-[4-(methylthio)phenyl]-2-(trifluoromethyl)-1H-imidazole (516 mg, 1.35 mmol) from step 4 was dissolved in methanol (10 ml) and cooled to 0° C. OXONE® (2.46 g, 4 mmol) in water (10 ml) was added. After the addition, the ice bath was removed and the reaction was stirred at ambient temperature for 3 hours. The mixture was extracted with chloroform (3×50 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography, affording 4-(3-fluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole as a solid (98 mg): m.p. 228-234° C. (DSC) The structure assignment was supported by NMR. Mass spectrum (EI, m/e): 414. Anal. Calc'd. for C18H14N2F4O3S: C, 52.17; H, 3.41; N, 6.76. Found: C, 52.30; H, 3.62; N, 6.53.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH2:14]([CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1)[C:15]#[CH:16]>>[CH2:14]([CH:17]1[CH2:22][CH2:21][N:20]([C:2]([O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)=[O:3])[CH2:19][CH2:18]1)[C:15]#[CH:16]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Product: C#CCC1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1

Procedure:
4-(nitro)phenyl chloroformate (5.0 g, 24.8 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (4.25 g, 19.0 mmol) according to general procedure 1. Yield=5.72 g, 80%. m/z MH+=289.04. HPLC rt=10.4 min.
Reaction SMILES: [C:1]([N:3]=[C:4]([S-:6])[S-:5])#[N:2].[K+].[K+].[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1.[OH:18]O>>[OH:18][C:1]1[N:3]=[C:4]([S:6][CH2:9][C:10]2[CH:17]=[CH:16][C:13]([CH3:14])=[CH:12][CH:11]=2)[S:5][N:2]=1
Reactant: OO
Reactant: Cc1ccc(CCl)cc1
Reactant: N#CN=C([S-])[S-]
Agent: [K+]
Product: Cc1ccc(CSc2nc(O)ns2)cc1

Procedure:
Using the procedure of Example 12, 58.2 g of dipotassium N-cyanodithioimidocarbonate and 42 g of p-methylbenzyl chloride were reacted and then were treated with 35 ml of 30% hydrogen peroxide to obtain 26 g of 3-hydroxy-5-p-methylbenzylthio-1,2,4-thiadiazole melting at 144° C.
Reaction SMILES: [C:1]([S:9][CH2:10][C@@H:11]([CH3:15])[C:12]([OH:14])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH:36]1[NH:40][C@H:39]([C:41]([OH:43])=[O:42])[CH2:38][S:37]1>O1CCCC1.O>[C:1]([S:9][CH2:10][C@@H:11]([CH3:15])[C:12]([N:40]1[C@H:39]([C:41]([OH:43])=[O:42])[CH2:38][S:37][CH:36]1[C:32]1[S:31][CH:35]=[CH:34][CH:33]=1)=[O:14])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](CSC(=O)c1ccccc1)C(=O)O
Reactant: O=C(O)[C@@H]1CSC(c2cccs2)N1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)N1C(c2cccs2)SC[C@H]1C(=O)O
Temperature: -5 °C

Procedure:
11.2 g of (2S)-S-benzoyl-3-mercapto-2-methylpropanoic acid and 5.1 g of triethylamine are dissolved in 100 ml of dehydrated tetrahydrofuran. To this solution, 6.8 g of isobutyl chloroformate is added dropwise while stirring at the temperature maintained -5° C. After the addition, the mixture is stirred at room temperature for 10 minutes. To this solution, 10.8 g of (4R)-2-(2-thienyl)-4-thiazolidinecarboxylic acid and 5.1 g of triethylamine dissolved in the mixed solution of 5 ml of tetrahydrofuran and 15 ml of water are added. The mixture is stirred at room temperature for 30 minutes. To this reaction mixture, 200 ml of water is added and the mixture is extracted with ethyl acetate. The aqueous layer is acidified with dilute hydrochloric acid and the produced oil is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the titled compound, yield 10.3 g (49%), mp. 136°-137° C. (benzene), [α]D25 +79.6° (c=1.0, methanol).