Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:13](=[O:18])[NH:14][NH:15][C:16]=2[CH3:17])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:19][C:20]([O:22][CH2:23][C@H:24]1[O:29][C@H:28](Br)[C@H:27]([O:31][C:32]([CH3:34])=[O:33])[C@@H:26]([O:35][C:36]([CH3:38])=[O:37])[C@@H:25]1[O:39][C:40]([CH3:42])=[O:41])=[O:21]>O1CCCC1.C(=O)([O-])[O-].[Ag+2]>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]2[C:13]([O:18][C@@H:28]3[O:29][C@H:24]([CH2:23][O:22][C:20](=[O:21])[CH3:19])[C@@H:25]([O:39][C:40](=[O:41])[CH3:42])[C@H:26]([O:35][C:36](=[O:37])[CH3:38])[C@H:27]3[O:31][C:32](=[O:33])[CH3:34])=[N:14][NH:15][C:16]=2[CH3:17])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Cc1[nH][nH]c(=O)c1Cc1ccc(OC(C)C)cc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 39 %

Procedure:
To a suspension of 1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one (46 mg), acetobromo-α-D-glucose (99 mg) and 4A molecular sieves in tetrahydrofuran (3 mL) was added silver carbonate (66 mg), and the mixture was stirred under shading the light at 65° C. overnight. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: tetrahydrofuran). Further purification by preparative thin layer chromatography on silica gel (developing solvent: ethyl acetate/hexane=2/1) afforded 4-[(4-isopropoxy-phenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (42 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH:37]1[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]1>CN(C=O)C.O.C(=O)(O)[O-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([N:37]1[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]1)=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.7 %

Procedure:
A mixture of (R)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2 g, 9.3 mmol), EDAC (3.5 g, 16 mmol), HOBt (1.4 g, 18 mmol), TEA (2.5 mL) and piperidin-4-ol (1.8 g, 16 mmol) in DMF (20 mL) was stirred at rt for 20 hours. The reaction was diluted with water and sodium bicarbonate, extracted with 5% methanol in DCM. The DCM was concentrated and purified on a silica gel column to give 2.6 g of (R)-2-(4-hydroxy-piperidine-1-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:16]([O:18]CC)=[O:17])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:8]=1)[CH3:2].[OH-].[K+]>CCO.C(Cl)Cl.O>[CH2:1]([O:3][C:4]1[C:5]([C:16]([OH:18])=[O:17])=[N:6][N:7]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)c1nn(-c2ccc(F)cc2)cc1OCC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCOc1cn(-c2ccc(F)cc2)nc1C(=O)O
Temperature: 25 °C
Yield: 93.4 %

Procedure:
D2 (38 mmol, 1.0 eq.) and aq. KOH-solution (3M, 190 mmol, 5.0 eq.) in EtOH (152 mL) were heated for 45 min at 50° C. The mixture was cooled to RT and diluted with DCM and water. The aq. phase was washed a second time with DCM. The aq. phase was acidified with aq. HCl-solution (1N) to pH=1 and extracted with EtOAc. The combined organic phase was washed with brine and dried over Na2SO4. Removal of the solvent yielded the product D3 as a brown solid (8.88 g, 93% over 2 steps). 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.34 (t, J=7.0 Hz, 3H), 4.02 (q, J=7.0 Hz, 2H), 7.37 (dd, J=J=9.0 Hz, 2H), 7.87 (dd, J=9.0 Hz, J=4.6 Hz, 2H), 8.38 (s, 1H), 12.68 (br s, 1H). MS (ES) C12H11FN2O3 requires: 250. Found: 251 (M+H)+ and 273 (M+Na)+.
Reaction SMILES: [NH2:1][C@H:2]([CH3:7])[C:3]([CH3:6])([OH:5])[CH3:4].Cl.N[C@@H](C)C(OC)=O.[Cl:16][C:17]1[C:24]([C:25]#[C:26][Si](C)(C)C)=[C:23](F)[CH:22]=[CH:21][C:18]=1[C:19]#[N:20].C1CCN2C(=NCCC2)CC1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[Cl:16][C:17]1[C:18]([C:19]#[N:20])=[CH:21][CH:22]=[C:23]2[C:24]=1[CH:25]=[CH:26][N:1]2[C@@H:2]([C:3]([OH:5])([CH3:6])[CH3:4])[CH3:7]
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1Cl
Reactant: C[C@@H](N)C(C)(C)O
Agent: COC(=O)[C@H](C)N
Agent: Cl
Agent: O=C([O-])O
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H](n1ccc2c(Cl)c(C#N)ccc21)C(C)(C)O
Temperature: 140 °C
Yield: 7 %

Procedure:
To a solution of (R)-3-amino-2-methylbutan-2-ol (made in a manner similar to Example 21G using commercially available (S)-methyl 2-aminopropanoate, hydrochloride) (0.1084 g, 1.051 mmol) and 2-chloro-4-fluoro-3-((trimethylsilyl)ethynyl)benzonitrile (Example 32B) (0.212 g, 0.841 mmol) in anhyd NMP (4 mL) at rt was added DBU (0.475 mL, 3.15 mmol), dropwise via syringe. The reaction vial was sealed with a crimp top and subjected to microwave heating (140° C.) for 40 min. Upon cooling the mixture was poured into satd NaHCO3 and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (C18 stationary phase, MeCN/water gradient with 0.1% TFA additive) affording (R)-4-chloro-1-(3-hydroxy-3-methylbutan-2-yl)-1H-indole-5-carbonitrile (0.0188 g, 7% yield) as a tan film: 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=3.4 Hz, 1H), 7.41 (d, J=8.6 Hz, 1H), 7.37 (d, J=8.6 Hz, 1H), 6.74 (d, J=3.3 Hz, 1H), 4.41 (q, J=7.0 Hz, 1H), 1.60 (d, J=7.0 Hz, 3H), 1.33 (s, 3H), 1.10 (s, 3H); MS (LCMS ES+) m/z 263 ([M+H]+, 52%), 304 ({[M+H]+MeCN}+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][C:6]([CH:12]([C:17]([CH3:22])([CH3:21])[CH:18]([CH3:20])[CH3:19])[O:13][SiH:14]([CH3:16])[CH3:15])=[CH:5]2.[H-].[Na+].[C:25]([O:29][C:30]([N:32]1[CH2:36][C@H:35]([CH3:37])OS1(=O)=O)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O>[C:25]([O:29][C:30](=[O:31])[NH:32][CH2:36][C@H:35]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[C:10]([CH3:11])[CH:9]=2)[CH:5]=[C:6]1[CH:12]([C:17]([CH3:21])([CH3:22])[CH:18]([CH3:19])[CH3:20])[O:13][SiH:14]([CH3:15])[CH3:16])[CH3:37])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1cc2[nH]c(C(O[SiH](C)C)C(C)(C)C(C)C)cc2cc1Br
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1Br)cc(C(O[SiH](C)C)C(C)(C)C(C)C)n2[C@H](C)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To a solution of 0.95 g 5-bromo-2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-6-methyl-1H-indole in 10 ml N,N-dimethylformamide was added 0.143 g sodium hydride 55-65% in oil and the mixture was stirred 30 min at room temperature. To the resulting mixture was added (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (0.703 g) and the mixture was stirred 2 h at room temperature. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was washed with 10% citric acid and brine, dried over magnesium sulfate and purified by chromatography on silica gel with hexane:ethyl acetate=5:1 to yield 0.789 g (R)-(2-{5-bromo-2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-6-methyl-indol-1-yl}-propyl)-carbamic acid tert-butyl ester as a slightly yellow oil. ISP-MS: M+H=541.3
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C1C(=O)N([Br:27])C(=O)C1.C(OOCC1C=CC=CC=1)C1C=CC=CC=1>>[C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:14]([CH2:15][Br:27])=[CH:13][C:12]([C:16]([F:18])([F:19])[F:17])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: Cc1cc(C(F)(F)F)nn1-c1ccc(F)c(C#N)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(COOCc2ccccc2)cc1
Product: N#Cc1cc(-n2nc(C(F)(F)F)cc2CBr)ccc1F
Yield: 50.1 %

Procedure:
To a solution of 1-(3-cyano-4-fluoro-phenyl)-3-trifluoromethyl-5-methylpyrazole (4.0 g, 14.9 mmol) in CCl14 (75 mL) was added NBS (5.3 g, 29.7 mmol) and benzylperoxide (0.2 g, 1.49 mmol). The reaction was brought to reflux overnight. The next day the CCl4 was evaporated and the residue was partitioned between ethyl acetate and sodium bicarbonate (sat.). The organic phase was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography gave 1-(3-cyano-4-fluoro-phenyl)-3-trifluoromethyl-5-bromomethylpyrazole (2.6 g, 50% yield) as pure compound: MS (CI): 348 (M+H)+ (100%).
Reaction SMILES: Cl.Cl[C:3]1C=CC(NN)=CC=1.BrCCC1C=CC(C(F)(F)F)=NC=1.ClC1C=CC(N(CCC2C=NC(C(F)(F)F)=CC=2)N)=CC=1.C(OC(OCC)CCCNC)C.[Cl:57][C:58]1[CH:59]=[C:60]2[C:64](=[CH:65][CH:66]=1)[N:63]([CH2:67][CH2:68][C:69]1[CH:70]=[N:71][C:72]([C:75]([F:78])([F:77])[F:76])=[CH:73][CH:74]=1)[CH:62]=[C:61]2[CH2:79][CH2:80][NH:81][CH3:82].C=O.C(O)(C(F)(F)F)=O>C(#N)C.C(N(CC)CC)C>[Cl:57][C:58]1[CH:59]=[C:60]2[C:64](=[CH:65][CH:66]=1)[N:63]([CH2:67][CH2:68][C:69]1[CH:70]=[N:71][C:72]([C:75]([F:78])([F:77])[F:76])=[CH:73][CH:74]=1)[C:62]1[CH2:82][N:81]([CH3:3])[CH2:80][CH2:79][C:61]2=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CNCCc1cn(CCc2ccc(C(F)(F)F)nc2)c2ccc(Cl)cc12
Agent: C=O
Agent: CCOC(CCCNC)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN1CCc2c(n(CCc3ccc(C(F)(F)F)nc3)c3ccc(Cl)cc23)C1

Procedure:
The title compound is prepared by following General Methods 1, 3 and 4 using 4-chlorophenylhydrazine hydrochloride, 5-(2-bromoethyl)-2-(trifluoromethyl)pyridine, and triethylamine (General Method 1), 1-(4-chlorophenyl)-1-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)hydrazine and 4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and 2-(5-chloro-1-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-indol-3-yl)-N-methylethanamine, formaldehyde and TFA in acetonitrile (General Method 4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:12][CH2:13][CH2:14][N:7]21.[CH2:26]([Mg]Br)[CH3:27]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:25])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(C)n1
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
To a solution of 9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (673.0 mg, 1.886 mmol) in tetrahydrofuran (10.0 mL) was added ethylmagnesium bromide (3.0 M solution in diethyl ether, 0.94 mL, 2.829 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was washed with diisopropyl ether to give the title compound as a colorless solid (702.4 mg, 1.816 mmol, 97%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:40]=[C:41](F)[CH:42]=1)[CH2:5][C@H:6]([C:25](N1[C@@H](CC2C=CC=CC=2)COC1=O)=O)[C@@H:7]([C@H:9]1[CH2:13][C@@H:12](OCC=C)CN1C(OC(C)(C)C)=O)O.[F:44][C:45]1[CH:46]=[C:47]([CH:68]=[C:69]([F:71])[CH:70]=1)[CH2:48][C@H:49]1[C@@H:53]([CH:54]2[CH2:59][O:58][CH2:57][CH2:56][N:55]2C(OC(C)(C)C)=O)[O:52][C:51](=[O:67])[NH:50]1.FC1C=C(C=C(F)C=1)C[C@@H]([C@@H]([C@H]1C[C@@H](OCC=C)CN1C(OC(C)(C)C)=O)O)C(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(N(CC)CC)C>[F:71][C:69]1[CH:68]=[C:47]([CH:46]=[C:45]([F:44])[CH:70]=1)[CH2:48][C@H:49]1[C@@H:53]([C@H:54]2[CH2:59][C@H:57]([OH:58])[CH2:56][N:55]2[CH:5]([C:4]2[CH:3]=[CH:2][CH:42]=[CH:41][CH:40]=2)[C:6]2[CH:7]=[CH:9][CH:13]=[CH:12][CH:25]=2)[O:52][C:51](=[O:67])[NH:50]1
Reactant: CC(C)(C)OC(=O)N1CCOCC1[C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1
Reactant: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)N(C(=O)OC(C)(C)C)C1
Agent: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Step L (5): tert-Butyl 3-((4S,5S)-4-(3,5-difluorobenzyl)-2-oxooxazolidin-5-yl)morpholine-4-carboxylate. To a solution of (2S,3S)-2-(3,5-difluorobenzyl)-3-(4-(tert-butoxycarbonyl)morpholin-3-yl)-3-hydroxypropanoic acid (step L (6), 1.6 g, 4 mmol) in toluene (100 mL) was added diphenylphosphoryl azide (1.65 g, 6 mmol) and triethyl amine (1.01 g, 10 mmoL). This reaction mixture was stirred at 80° C. for 4 h. Ethyl acetate (500 mL) was added. The mixture was washed with sodium carbonate solution, H2O, dried over Na2SO4 and concentrated. The crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 30% to 50% to 70% EtOAc/Hexane step gradient) to give 800 mg of the title compound: MS (ESI) (M−H)− 397.12.
Reaction SMILES: [H-].[Na+].O[CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=1)[CH2:5][C:6]#[N:7].[H][H].C(OC(=O)C)(=O)C>O1CCCC1.O>[C:14]1([C:10]2[CH:9]=[C:8]([CH:4]=[CH:5][C:6]#[N:7])[CH:13]=[CH:12][CH:11]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: [H][H]
Reactant: N#CCC(O)c1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: N#CC=Cc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 40.6 %

Procedure:
Under a nitrogen atmosphere a mixture of 1.9 grams (0.048 mole) of sodium hydride (60% in mineral oil) in 50 mL of tetrahydrofuran was stirred, and a solution of 10.7 grams (0.048 mole) of 3-hydroxy-3-(3-phenylphenyl)propanenitrile in 100 mL of tetrahydrofuran was added dropwise. Upon completion of addition, the reaction mixture was stirred until the evolution of hydrogen gas ceased. After this time the reaction mixture was cooled in an ice-bath, and 4.6 mL (0.048 mole) of acetic anhydride was added dropwise. Upon completion of addition, the reaction was allowed to warm to ambient temperature where it was stirred for about 18 hours. The reaction mixture was poured into 300 mL of water, and the mixture was extracted with 200 mL of diethyl ether. The extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel using methylene chloride as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 4.0 grams of 3-(3-phenylphenyl)-2-propenenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:25]C3CCCCO3)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH2:34][CH2:35][CH3:36])[C:5]=1[OH:37])(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO.ClCCl>C(OCC)(=O)C>[C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]([OH:25])[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:14][CH:15]=2)=[C:6]([CH2:34][CH2:35][CH3:36])[C:5]=1[OH:37])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1c(OCc2ccc(C(O)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Temperature: 0 °C
Yield: 92.2 %

Procedure:
Stir a mixture of 3-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (13.4 g, 26.88 mmol), p-toluenesulfonic acid monohydrate (5.1 g, 26.88 mmol), methanol (100 mL), dichloromethane (50 mL), and ethyl acetate (50 mL) at room temperature for an hour. Concentrate the reaction mixture, dilute with ethyl acetate (150 mL) and wash with water (2×100 mL). Dry the organic phase over magnesium sulfate, filter, and concentrate. Dilute the residue with 5:1 hexanes:dichloromethane (50 mL), cool to 0° C. and filter. Collect a second and third crop to give the title compound (10.3 g, 93%), as a white solid. LCMS 416 M+1.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1.I[CH2:23][CH:24]1[CH2:28][CH2:27][CH:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:25]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:21])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:25]1
Reactant: ICC1CCC(OC2CCCCO2)C1
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CC1CCC(OC2CCCCO2)C1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 81.5 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (3,4-dichloro-phenyl)-acetic acid methyl ester (prepared as in Example 1, 1.42 g, 6.48 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16.15 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. A solution of 2-(3-iodomethyl-cyclopentyloxy)-tetrahydropyran (2.21 g, 7.13 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL) was then added. The reaction mixture was stirred at −78° C. for 2 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 18 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL). This mixture was poured into water (100 mL) and extracted with methylene chloride 3×50 mL). The organics were washed with a saturated aqueous lithium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-[3-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (2.12 g, 81.6%) as a clear oil: EI-HRMS m/e calcd for C20H26Cl2O4 (M+Na)+ 423.1106. found 423.1093.
Reaction SMILES: F[C:2](F)(F)[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.Cl.Cl[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][NH2:22]>C(O)(=O)C>[C:16]1([N:21]2[C:5](=[O:7])[CH2:4][C:3]([C:2]3[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=3)=[N:22]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:15]=1
Reactant: NNc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: Cl
Solvent: CC(=O)O
Product: O=C1CC(c2ccccc2)=NN1c1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
A mixture of 5 g (27.2 mmol) of ethyl trifluoroacetoacetate and 4.86 g (27.2 mmol) of 2-chlorophenylhydrazine hydrochloride in 50 ml of acetic acid was heated at 100° C. with stirring overnight. The mixture was concentrated in vacuo (70° C.), the residue was disolved in methanol and concentrated in vacuo. The residue was triturated in methylene chloride, cooled (0° C.), and the white solid was filtered to afford 3.01 g (42%) of 2,4-dihydro-2-(2-chlorophenyl)-5-trifluoromethyl-3H-pyrazol-3-one (Formula III: R1 =2-Cl--Ph; R2 =CF3 ; R3=H) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[C@@H:13]([NH:19][C:20]([C:22]1[O:23][C:24]3[C:30](Br)=[CH:29][C:28]([F:32])=[CH:27][C:25]=3[CH:26]=1)=[O:21])[CH2:12]2.[OH-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]1)[C@@H:13]([NH:19][C:20]([C:22]1[O:23][C:24]3[C:30]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:29][C:28]([F:32])=[CH:27][C:25]=3[CH:26]=1)=[O:21])[CH2:12]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(F)cc(Br)c2o1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(F)cc(-c3ccc(F)cc3)c2o1
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
A mixture of 40 mg (0.29 mmol) of 4-fluorophenylboronic acid, 70 mg (0.19 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-fluoro-7-bromo-1-benzofuran-2-carboxamide (Example 5A), 0.57 ml (0.57 mmol) of 1N sodium hydroxide solution, 14 mg (0.02 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 2 ml of DMF is heated at 85° C. overnight. The solvent is removed under reduced pressure. The crude product is mixed with 1N sodium hydroxide solution and extracted three times with a total of 100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate, and the solvent is removed under reduced pressure. The crude product is taken up in methanol and shaken together with acidic ion exchanger (Dowex® WX2-200) for about 20 min. The loaded ion exchanger is washed three times with 30 ml of methanol each time, then with water, again with methanol, with dichloromethane, again with methanol, with THF and finally once more with methanol. The product is eluted with methanol/triethylamine 95:5. The solvent is removed in a rotary evaporator under reduced pressure. Silica gel 60 (Merck, Darmstadt; eluent: dichloromethane/triethylamine 100:1, then dichloromethane/methanol/triethylamine 100:1:1 to dichloromethane/methanol/triethylamine 100:10:1) is used for final purification. The solvent is removed under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 51 mg (70% of theory) of the title compound are isolated.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:8][C:7]=1[CH2:15]Br)=[O:5])[CH3:2].[CH2:17]([O:19][C:20](=[O:34])[CH2:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[O:32][CH3:33])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:8][C:7]=1[CH2:15][N:22]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[O:32][CH3:33])[CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:34])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Reactant: CCOC(=O)c1sc(C(C)(C)C)nc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(C(C)(C)C)sc1C(=O)OCC
Yield: 66.2 %

Procedure:
A portion of the crude 4-bromomethyl-2-tert-butyl-thiazole-5-carboxylic acid ethyl ester (12.6 g, 41.0 mmol), N-(2,4-dimethoxy-benzyl)glycine ethyl ester (11.6 g, 41.0 mmol), and potassium carbonate (6.2 g, 45 mmol) in 100 ml of anhydrous DMF was stirred for 18 h. The mixture was partitioned into a biphasic water-ethyl acetate mixture and the isolated organic layer was then washed with brine, dried over anhydrous magnesium sulfate, concentrated to a residue, and purified by flash chromatography: eluting the desired product from silica gel with a gradient of 10-35% ethyl acetate in hexanes. 13 g of a yellow oil was isolated. MS (ESI+): 479.4 (M+1).