Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].I[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][N:36]=1.O=O.Cl>O1CCOCC1.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]>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][N:36]=3)=[CH:16][CH:17]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Reactant: COc1ccc(I)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cc(COc2ccc(-c3ccc(OC)cn3)cc2)c(C)o1
Temperature: 95 °C
Yield: 58.5 %

Procedure:
A mixture of 5-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-furan-2-carboxylic acid methyl ester (51) (126 mg), 2M aqueous cesium carbonate (0.6 mL) and 2-iodo-5-methoxypyridine (95 mg) in 1,4-dioxan (10 mL) under an argon atmosphere was sonicated to expel traces of oxygen. [1,1′-Bis-(diphenylphoshino)ferrocene]dichloropalladium (II) (8 mg) was added and the mixture heated at 95° C. for 18 hours. After cooling, the mixture was acidified to pH6 with 1M aqueous hydrochloric acid and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated to give compound 52 as an oil (70 mg), which was used directly in the next step. LC/MS System A: Rt=3.23 mins, m/z=354 ((M+H) for C20H19NO5).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[C:14]([CH:16]=O)[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OP([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:34][C:35]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:36]=3[N:37]=2)=[CH:29][CH:28]=1)(OCC)=O)C.O>CN(C)C=O>[C:1]1([C:7]2[O:8][C:9]3[CH:15]=[C:14]([CH:16]=[CH:26][C:27]4[CH:28]=[CH:29][C:30]([C:33]5[O:34][C:35]6[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:36]=6[N:37]=5)=[CH:31][CH:32]=4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOP(=O)(Cc1ccc(-c2nc3cc(Cl)ccc3o2)cc1)OCC
Reactant: O=Cc1ccc2nc(-c3ccccc3)oc2c1
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2oc(-c3ccc(C=Cc4ccc5nc(-c6ccccc6)oc5c4)cc3)nc2c1
Yield: 33.4 %

Procedure:
A solution of 4.46 g (0.02 mole) of 2-phenyl-6-formyl-benzoxazole of the formula ##STR29## (melting point: 133°-135° C.) and 7.59 g (0.02 mole) of 2-(p-diethylphosphonomethylphenyl)-5-chloro-benzoxazole of the formula ##STR30## (melting point: 96°-98°) in 80 ml of dimethyl formamide is heated to 40° C. Then 2.1 g (0.022 mole) of sodium tert.butylate are added in small amounts to the solution over the course of 30 minutes and the resultant suspension is further stirred for 4 hours at 40° C. The reaction mixture is poured into water and the precipitate is collected by filtration, washed with water and subsequently with a total amount of 110 ml of methanol. The product is recrystallised form a solvent mixture of nonane/xylene (1:1) with the addition of fuller's earth, affording 3 g (30% of theory) of 1-(2-phenylbenzoxazol-6-yl)-2-[4'-(5-chlorbenzoxazol-2-yl)-phenyl]-ethylene of the formula ##STR31## in the form of pale yellow flakes having a melting point of 241°-242° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32])[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)=[CH:37][C:36]=1[Cl:51].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:42]=[CH:43][C:44]([C:47]([F:48])([F:50])[F:49])=[CH:45][CH:46]=2)=[CH:37][C:36]=1[Cl:51])[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1ccc(-c2ccc(CBr)c(Cl)c2)cc1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1O)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1Cl)C(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A suspension of 51.21 g (116.24 mmol) of ethyl 5-{(tert-butoxycarbonyl)[2-(2-hydroxyphenyl)-ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 69A), 44.70 g (127.86 mmol) of 4-(bromomethyl)-3-chloro-4′-(trifluoromethyl)biphenyl and 40.16 g (290.60 mmol) of potassium carbonate in 1420 ml of acetonitrile was heated to 110° C. and stirred at this temperature overnight. After cooling, the reaction mixture was filtered, the filter cake was washed repeatedly with acetonitrile and the combined filtrates were concentrated to dryness on a rotary evaporator. The residue obtained was purified chromatographically on silica gel (2.5 kg) (mobile phase: petroleum ether/ethyl acetate 4:1). This gave 79 g (111.39 mmol, 96% of theory) of the target compound.
Reaction SMILES: Br[C:2]1[C:12]([CH3:13])=[CH:11][C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1.FC1(F)OC2C=C(C)C(C3N=C[C:27]([NH:30][C:31](=O)[C:32]4[CH:37]=[CH:36]C=CC=4F)=[N:28]C=3)=CC=2O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O1CCOCC1.O>[CH3:9][C:8]1([CH3:10])[CH2:7][O:6][C:5]2[CH:11]=[C:12]([CH3:13])[C:2]([C:32]3[CH:37]=[CH:36][C:27]([NH2:28])=[N:30][CH:31]=3)=[CH:3][C:4]1=2
Reactant: Cc1cc2c(cc1-c1cnc(NC(=O)c3ccccc3F)cn1)OC(F)(F)O2
Reactant: Cc1cc2c(cc1Br)C(C)(C)CO2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc2c(cc1-c1ccc(N)nc1)C(C)(C)CO2
Temperature: 85 °C
Yield: 90.8 %

Procedure:
A mixture of 5-bromo-3,3,6-trimethyl-2,3-dihydrobenzo[b]furan (171) (241 mg, 1 mmol), 2-aminopyridine-5-boronic acid pinacol ester (11) (330 mg, 1.5 mmol), bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (106 mg), and K3PO4 (636 mg) in 3 ml ACN, 3 ml dioxane, 1.5 ml H2O was bubbled with argon before heated at 85° C. for 2.5 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine. Org. phase was dried over Na2SO4, concentrated and then subjected silica gel column purification to give 231 mg 5-(3,3,6-trimethyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)-2-pyridylamine (172) (yield: 90.8%, purity>95%) as thick yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH2:9]([O:11][C:12](=[O:35])[CH2:13][CH2:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:10].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:15][CH2:14][CH2:13][C:12]([O:11][CH2:9][CH3:10])=[O:35]
Reactant: CCOC(=O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCC=Cc1ccccn1
Yield: 40 %

Procedure:
2-Pyridinecarbaldehyde (3.0 g, 28.0 mmol) and (4-ethoxy-4-oxobutyl)triphenylphosphonium (16.7 g, 36.5 mmol) were dissolved in 1,4-dioxane (60 ml), and a solution of potassium carbonate (5.8 g, 42.0 mmol) in water (6 ml) was added thereto. The reaction mixture was refluxed for 18 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (100 g) column chromatography. The fractions eluted with hexane-ethyl acetate (4:1, v/v) were collected and concentrated to give Z-form of the titled compound (2.3 g, 40%). And the fractions eluted with hexane-ethyl acetate (2:1, v/v) were collected and concentrated to give E-form of the titled compound (1.2 g, 21%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH2:13][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:16][CH:17]=1)=[O:11].CCN(CC)CC>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:8][C:6]1[CH:7]=[C:2]2[C:12]3([CH2:17][CH:16]=[CH:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[C:10](=[O:11])[NH:9][C:3]2=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC=C(C(=O)Nc2ccc(F)cc2Br)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C=CCC2(C1)C(=O)Nc1ccc(F)cc12
Temperature: 100 °C
Yield: 70.6 %

Procedure:
To a stirred solution of tert-butyl 3-(2-bromo-4-fluorophenylcarbamoyl)-5,6-dihydropyridine-1(2H)-carboxylate (1.30 g, 3.56 mmol) in DMF (18 mL) under N2 was added successively Et3N (1.13 mL, 8.14 mmol), tetrabutylammonium bromide (1.26 g, 3.91 mmol) and Pd(OAc)2 (0.146 g, 0.651 mmol). The resulting mixture was heated at about 100° C. for 3 h. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with 1N HCl and brine, dried and concentrated. The residue was purified by column chromatography (hexanes:EtOAc, 4:1) to give tert-butyl 5-fluoro-2-oxo-2′,4′-dihydro-1′H-spiro[indoline-3,3′-pyridine]-1′-carboxylate (0.80 g, 77%). LCMS (APCI+) m/z 219 [M+H-Boc]+; Rt=3.41 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:14][CH2:15][CH2:16]Br>ClCCl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2([C:9]#[N:10])[CH2:16][CH2:15][CH2:14]2)[CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1cccc(Cl)n1
Reactant: BrCCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: N#CC1(c2cccc(Cl)n2)CCC1
Temperature: 25 °C

Procedure:
2-(6-Chloropyridin-2-yl)acetonitrile (5.7 g, 37.4 mmol) was dissolved in dichloromethane (25 ml). 50% aqueous sodium hydroxide solution (26.5 mL) was added dropwise. Benzyltriethylammonium chloride (0.17 g, 0.747 mmol) was added. 1,3-Dibromopropane (7.54 g, 37.4 mmol) were added dropwise and the reaction mixture was stirred over night at room temperature. The reaction mixture was diluted with dichloromethane and washed with water (3×). The organic layer was dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography (silica, dichloromethane, methanol). Yield: 2.4 g (10.9 mmol, 29%).
Reaction SMILES: CS(O[C@H:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([F:20])[F:19])=[CH:14][CH:13]=2)[C:7]1=[O:21])(=O)=O.Cl.[F:23][C@H:24]1[C@H:29]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH2:28][CH2:27][NH:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[F:19][CH:18]([F:20])[C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][CH:6]([N:26]3[CH2:27][CH2:28][C@@H:29]([C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=4)[C@H:24]([F:23])[CH2:25]3)[C:7]2=[O:21])=[CH:13][CH:14]=1
Reactant: Oc1ccc([C@@H]2CCNC[C@H]2F)cc1
Reactant: CS(=O)(=O)O[C@H]1CCN(Cc2ccc(C(F)F)cc2)C1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1C(N2CC[C@@H](c3ccc(O)cc3)[C@H](F)C2)CCN1Cc1ccc(C(F)F)cc1
Temperature: 85 °C
Reaction time: 16 h
Yield: 35.8 %

Procedure:
A solution of (S)-1-(4-(difluoromethyl)benzyl)-2-oxopyrrolidin-3-yl methanesulfonate (500 mg, 1.57 mmol, intermediate M) in 5.0 mL of acetonitrile was added dropwise over 1.5 h to a stirred mixture of 4-((3S,4S)-3-fluoropiperidin-4-yl)phenol, hydrochloride (363 mg, 1.57 mmol, intermediate F) and N,N-diisopropylethylamine (1.09 mL, 6.26 mmol) in 5.0 mL of acetonitrile maintained at 85° C. After complete addition, the reaction mixture was stirred at 85° C. for 16 h. The reaction mixture was concentrated in vacuo. The residue was purified using silica gel column chromatography (0-100% EtOAc/hexanes) to afford a diasteromeric mixture (partial epimerization of the lactam stereocenter) of 1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one (235 mg, 35% yield). A sample of the diastereomeric mixture (780 mg) was separated by preparative chiral SFC (column=Lux Cellulose-2 (21×250 mm, 5 μm); isocratic solvent=20% methanol (with 15 mM ammonia)/80% CO2; temp=35° C.; flow rate=60 mL/min; injection volumn=1.0 mL (˜20 mg/mL in MeOH) stacked @ 13 min intervals; λ=210 nM; Peak 1=19.6 min, Peak 2=24.5 min) to afford the titled compounds of example 6 (Peak-1, 389 mg) and (S)-1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one (Peak 2, 242 mg). Data for Example 6: LC-MS m/z 419.3 (M+H); 1H NMR (500 MHz, chloroform-d) δ 7.50 (d, J=7.9 Hz, 2H), 7.34 (d, J=7.9 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 6.91-6.80 (m, 2H), 6.65 (t, J=56.4 Hz, 1H), 4.96 (s, 1H), 4.77-4.43 (m, 3H), 3.68 (t, J=8.8 Hz, 1H), 3.42-3.33 (m, 1H), 3.29-3.14 (m, 2H), 2.85 (d, J=10.4 Hz, 1H), 2.78-2.69 (m, 1H), 2.69-2.57 (m, 1H), 2.48 (td, J=9.9, 4.9 Hz, 1H), 2.21-2.11 (m, 1H), 2.04 (dq, J=13.0, 8.6 Hz, 1H), 1.94-1.82 (m, 2H)). The relative and absolute configuration of Example 114, P-1 was confirmed by single crystal X-ray analysis.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16]C1C([N+]([O-])=O)=CC2NC(=O)COC=2C=1.C[Mg]Br>>[CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH3:16])[C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: Cc1cc2c(cc1[N+](=O)[O-])NC(=O)CO2
Reactant: Cc1c([N+](=O)[O-])ccc2c1NC(=O)CO2
Agent: C[Mg]Br
Product: Cc1cc2c(c(C)c1[N+](=O)[O-])NC(=O)CO2

Procedure:
The title compound is synthesized from 5-methyl-6-nitro-3-oxo-3,4-dihydro-(2H)-1,4-benzoxazine or from 7-methyl-6-nitro-3-oxo-3,4-dihydro-(2H)-1,4-benzoxazine and methyl magnesium bromide using the method illustrated in Example 37.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH2:19]1[O:28][C:27]2[CH:26]=[CH:25][C:23](N)=[CH:22][C:21]=2[O:20]1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[O:20]1[C:21]2[CH:22]=[CH:23][C:25]([NH:13][C:12]3[C:11]4[C:10](=[CH:9][CH:8]=[C:6]5[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]5=4)[N:14]=[CH:15][N:16]=3)=[CH:26][C:27]=2[O:28][CH2:19]1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccc2c(c1)OCO2
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc5c(c4)OCO5)c3c2s1
Yield: 49 %

Procedure:
Prepared from VII and 3,4-(methylenedioxy)aniline. Flash chromatography eluent (DCM-EtOAc, 9:1). Yield: 49%; orange solid; mp>260° C.; IR (KBr) νmax/cm−1 2894, 2226, 1734, 1706, 1645, 1609, 1581, 1555, 1499, 1471, 1377, 1354, 1304, 1264, 1236, 1211, 1188, 1162, 1125, 1086, 1037, 972, 938, 924, 859, 829, 809; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=9.0 Hz), 8.14 (m, 1H), 7.76 (m, 1H), 6.94 (d, 2H, J=9.0 Hz), 6.72 (m, 1H), 6.02 (s, 2H); HRMS calcd for C17H9N5O2S (M+H+): 348.0555, found 348.0566.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:16]2=[O:31])[C@H:11]([CH2:32][CH2:33][CH3:34])[CH2:10]1)(C(C)(C)C)(C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOCC>CC(O)=O.C1COCC1.O>[O:31]=[C:16]1[C@@H:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:19][N:15]1[C@H:12]1[CH2:13][CH2:14][C:9](=[O:8])[CH2:10][C@H:11]1[CH2:32][CH2:33][CH3:34]
Reactant: CCC[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCC[C@@H]1CC(=O)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 37.3 %

Procedure:
A sample of benzyl (S)-1-((1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-propylcyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (0.4 g, 0.82 mmol) was dissolved in 36 mL of 4:1:1 HOAc/THF/water and stirred at RT for 5 days. The volatiles were removed in vacuo and the residue was dissolved in EtOAc. The organic phase was washed with sat. NaHCO3, dried (MgSO4), filtered, and concentrated in vacuo. The residue was dissolved in methylene chloride (4 mL) and the resultant solution was cooled to 0° C. and charged with Dess-Martin periodinane (0.54 g, 1.27 mmol). After stirring for 2 h at RT, the solution was again cooled to 0° C. and charged with Dess-Martin periodinane (0.27 g). The reaction was stirred at RT for 14 h and treated with Et2O. The resultant suspension was washed with 1 N NaOH, sat. Na2S2O3, and sat. NaHCO3. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo to afford benzyl (S)-2-oxo-1-((1S,2R)-4-oxo-2-propylcyclohexyl)pyrrolidin-3-ylcarbamate (114 mg). MS found: (M+Na)+=395.4.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][CH:8]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(N(CC)CC)C.O>C(Cl)Cl.CS(C)=O>[C:17]1([CH2:16][CH2:15][C:8](=[O:7])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC(CCc1ccccc1)Cn1ccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(CCc1ccccc1)Cn1ccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (2.0 ml) in methylene chloride (40 ml) was placed in a flask and cooled to -50° C. to -60° C. Dimethyl sulfoxide (3.0 ml) in 10 ml of methylene chloride was then added followed by 2.3 g of 1-(2-hydroxy-4-phenylbutyl)imidazole dissolved in 20 ml of methylene chloride containing 0.5 ml of dimethyl sulfoxide. The reaction mixture was stirred for 30 minutes at the initial temperature. Triethylamine (7 ml) was added to the reaction mixture which was then allowed to warm to room temperature. Water was added, the organic layer separated and the aqueous layer extracted with methylene chloride (2×50 ml). The organic layers were dried over MgSO4, the solvent removed and the residue recrystallized from ethyl acetate to give 1-(4-phenylbutan-2-on-1-yl)imidazole. The hydrochloride salt crystallized from methanol/ethyl acetate had a melting point of 172°-173° C.
Reaction SMILES: [Li][CH:2](CC)C.C1CCCCC1.CN(CCN(C)C)C.[CH3:20][C:21]([N:24]([CH3:38])[C:25](=[O:37])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Si:33]([CH3:36])([CH3:35])[CH3:34])([CH3:23])[CH3:22].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:23][C:21]([N:24]([CH3:38])[C:25](=[O:37])[C:26]1[C:31]([CH3:2])=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Si:33]([CH3:34])([CH3:35])[CH3:36])([CH3:20])[CH3:22]
Reactant: CN(C(=O)c1cccc(F)c1[Si](C)(C)C)C(C)(C)C
Reactant: [Li]C(C)CC
Agent: CN(C)CCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CI
Product: Cc1ccc(F)c([Si](C)(C)C)c1C(=O)N(C)C(C)(C)C
Temperature: -100 °C
Yield: 99 %

Procedure:
1.3M s-BuLi in cyclohexane (31.4 mL, 41 mmol) was added dropwise to THF (100 mL) and TMEDA (5.35 g, 46 mmol), cooled to -100° C. under nitrogen with stirring. To this mixture was added dropwise the compound of Example 5 (10.45 g, 37 mmol), dissolved in a minimum amount of THF. After stirring for 10 min, MeI (15.8 g, 0.1114 mol) was injected. The mixture was stirred for 1 h and 25% citric acid (15 mL) was added. The mixture was extracted three times with ether; the ether extracts were combined and washed twice with water, dried (MgSO4), and concentrated. The crude product was purified by RC, with 1:9 ethyl acetate/hexanes. The title compound was recovered as a light yellow solid, in 99% yield. m.p. 44-47° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][CH2:19][CH2:18]2.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH2:20]1[C:21]2[C:17](=[CH:16][C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])=[CH:23][CH:22]=2)[CH2:18][CH2:19]1
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Brc1ccc2c(c1)CCC2
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3c(c2)CCC3)C1=O
Yield: 18.1 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847 mmol) was reacted with 5-bromo-indan (248 mg, 1.0163 mmol), 1,4-dioxane (10 mL), copper iodide (0.0161 g, 0.0842 mmol), trans-1,2-diamino cyclohexane (0.028 g, 0.245 mmol) and potassium phosphate (538 mg, 2.537 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in CHCl3) afforded 45 mg of the product (20% yield).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][CH:27]([C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)[CH3:28]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:35]([C:32]4[CH:33]=[CH:34][C:29]([CH:27]([CH3:28])[CH3:26])=[CH:30][CH:31]=4)(=[O:37])=[O:36])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C(C)C)cc4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 4-(propan-2-yl)benzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.II.[Mg].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>CO.C1(C)C=CC=CC=1.CCOCC>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:21]([C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:25])[F:26])=[CH:24][CH:23]=2)=[NH:22])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Agent: II
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CO
Product: N=C(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Yield: 68.2 %

Procedure:
One part of 4-bromobenzotrifluoride (12.4 g, 55 mmol) and a small quantity of iodine were added to an Et2O suspension (10 mL) of magnesium (1.34 g, 55 mmol) under an argon atmosphere. And, they were heated appropriately. After the reaction start was observed, the remaining Et2O solution (15 mL) of the remaining 4-bromobenzotrifluoride was added slowly. After heat refluxing for one hour, a toluene solution (10 mL) of 4-(trifluoromethyl)benzonitrile (11.8 g, 86 mmol) was added slowly at room temperature. After heat refluxing for 20 hours, anhydrous methanol (12 mL) was added slowly at room temperature. And, the stirring-up was conducted for thirty minutes. Insoluble compounds were removed with the celite filtering. The filtrate was concentrated under reduced pressure. Thereafter, the obtained crude product was distillated under reduced pressure. And, the target product (11.9 g, 75%) was obtained. After distillation, the product was solidified.