Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].C([Li])CCC.[C:15]1([CH3:23])[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=1>O1CCCC1>[OH:22][CH:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:23])=[CH:16][CH:17]=1)[C:2]#[C:1][C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C#CC1(O)CCCCC1
Reactant: Cc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)C#CC2(O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
To a solution of 1-ethynylcyclohexanol (500 mg, 4.02 mmol) in tetrahydrofuran (20 mL), 2.77 M n-butyllithium (solution in n-hexane, 3.6 mL, 9.90 mmol) was added dropwise at −78° C., and the obtained solution was stirred at the same temperature for 1 hour. To the reaction solution, p-tolualdehyde (0.52 mL, 4.40 mmol) was added at −78° C., and the obtained solution was allowed to warm gradually to room temperature with stirring. To the reaction solution, distilled water and 1 M hydrochloric acid were added to make the mixture acidic, and the resultant was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (598 mg, 2.44 mmol, 61%) as a pale yellow solid.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.Cl[CH2:39][C:40]1[CH:41]=[CH:42][C:43]2[O:48][CH2:47][C:46](=[O:49])[N:45]([CH2:50][CH2:51][CH2:52][CH2:53][O:54][Si:55]([CH:62]([CH3:64])[CH3:63])([CH:59]([CH3:61])[CH3:60])[CH:56]([CH3:58])[CH3:57])[C:44]=2[CH:65]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:29])[CH2:3][CH:2]2[O:1][CH2:39][C:40]2[CH:41]=[CH:42][C:43]3[O:48][CH2:47][C:46](=[O:49])[N:45]([CH2:50][CH2:51][CH2:52][CH2:53][O:54][Si:55]([CH:59]([CH3:61])[CH3:60])([CH:56]([CH3:58])[CH3:57])[CH:62]([CH3:63])[CH3:64])[C:44]=3[CH:65]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Reactant: CC(C)[Si](OCCCCN1C(=O)COc2ccc(CCl)cc21)(C(C)C)C(C)C
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(c2)N(CCCCO[Si](C(C)C)(C(C)C)C(C)C)C(=O)CO3)cc1

Procedure:
Analogously to Method D, 1.30 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]-phenyl}piperidine-1-carboxylate (Example 10f) and 1.30 g of 6-chloromethyl-4-(4-triisopropylsilanyloxybutyl)-4H-benzo[1,4]oxazin-3-one are reacted. The title compound is obtained as a yellowish oil. Rf=0.42 (1:1 EtOAc-heptane); Rt=7.54.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:17])[C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:6][CH:7]=1.[CH2:18]([O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.O>[F:17][C:4]1[C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:6][CH:7]=[C:2]([C:30]2[CH:31]=[CH:32][C:27]([O:26][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:28][CH:29]=2)[CH:3]=1
Reactant: CCCCCCCCOc1ncc(Br)cc1F
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2cnc(OCCCCCCCC)c(F)c2)cc1
Yield: 67.3 %

Procedure:
3.00 g (9.86 mmol) of 5-bromo-3-fluoro-2-octyloxypyridine, 2.47 g (9.86 mmol) of 4-octyloxybenzeneboronic acid, 0.11 g (0.10 mmol) of tetrakis(triphenylphospine)palladium(0) and 2.09 g (19.72 mmol) of sodium carbonate are heated at 80° C. for 3 hours in 90 ml of toluene, 60 ml of ethanol and 30 ml of water. The mixture is subsequently partitioned between aqueous sodium chloride solution and ether and the organic phase is washed with aqueous sodium chloride solution, dried over sodium sulfate, evaporated and purified by chromatography (silica gel/hexane: ethyl acetate 9:1), giving 2.85 g of 3-fluoro-2-octyloxy-5-(4-octyloxyphenyl)pyridine. ##STR24##
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[N:19]=[CH:18]3)=[C:13]([F:31])[CH:12]=2)[CH2:6]1)=[N+]=[N-].C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(OCC)(=O)C.[Pd]>[Si:24]([O:23][CH2:22][C:20]1[N:19]=[CH:18][N:17]([C:14]2[CH:15]=[CH:16][C:11]([N:7]3[CH2:6][C@H:5]([CH2:4][NH:1][C:39](=[O:41])[CH3:40])[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[F:31])[CH:21]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)OCc1cn(-c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(CO[Si](C)(C)C(C)(C)C)c3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To (5R)-5-azidomethyl-3-(4-(4-t-butyldimethylsilyloxymethylimidazol-1-yl)-3-fluorophenyl)oxazolidin-2-one(10.0 g) in ethyl acetate (560 ml) was added triethylamine (13.3 ml), acetic anhydride (4.5 ml), and palladium catalyst (10% on charcoal, 1.5 g), and the mixture hydrogenated at ambient temperature for 17 hours. The mixture was filtered through celite, the celite washed well with ethyl acetate, and the organic layer stirred with a saturated solution of sodium bicarbonate (100 ml) at ambient temperature for 1 hour. The organic layer was separated, dried over magnesium sulfate, and evaporated. Crude product (15 g, from two batches) was dissolved in dichloromethane and chromatographed on silica, eluting with a gradient from dichloromethane (100%) to 10% methanol in dichloromethane. Product fractions were combined to give a gum (12.3 g).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[CH2:32][CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[CH2:32][CH:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN(CC(c2ccccc2)c2ccccc2)[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: c1ccc(C[C@@H]2C[C@@H](NCc3ccnc4ccccc34)CCN2CC(c2ccccc2)c2ccccc2)cc1

Procedure:
170 mg (0.280 mmol) of (2R*,4S*)-2-benzyl-1-(2,2-diphenylethyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 42 mg (1.12 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR41## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.28, FD-MS: M+ =511.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH2:35]([S:39](Cl)(=[O:41])=[O:40])[CH2:36][CH2:37][CH3:38]>CN(C=O)C>[CH2:35]([S:39]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:16]2[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[C:17]=2[N+:18]([O-:20])=[O:19])[CH2:23][CH2:24]1)(=[O:41])=[O:40])[CH2:36][CH2:37][CH3:38]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: CCCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCS(=O)(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1

Procedure:
Compound A29 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (20 μl), butane-1-sulfonyl chloride (8 mg, 0.056 mmol), DMF (0.6 mL), 1H NMR (CDCl3, 400 MHz) δ 0.98 (t, 3H), 1.51 (m, 2H), 1.83 (m, 2H), 2.07 (m, 4H), 2.97 (m, 2H), 3.08 (s, 3H), 3.40 (m, 2H), 3.58 (m, 2H), 5.68 (m, 1H), 7.87 (d, 2H), 7.98 (d, 2H), 8.41 (s, 1H), 10.21 (s, 1H). Exact mass calculated for C20H27N5O7S2 513.14, found 514.4 (MH+).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[CH3:8][CH:9]([CH2:12][CH2:13][CH3:14])C=O.N1CCCCC1.Cl>N1C=CC=CC=1>[CH3:8][CH:9]([CH2:12][CH2:13][CH3:14])/[CH:1]=[CH:2]/[C:3]([OH:5])=[O:4]
Reactant: CCCC(C)C=O
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCCC(C)/C=C/C(=O)O
Reaction time: 2 h
Yield: 46.4 %

Procedure:
Malonic acid (44 g, 0.42 mol), 2-methylpentan-1-al (14 g, 0.14 mol) and piperidine (1.7 ml) were suspended in 85 ml pyridine and heated under reflux. Gas formation was observed which ceased after two hours. Heating was continued for 1 hour. The cooled reaction mixture was poured into 2M hydrochloric acid (200 ml) after which two phases were obtained which were separated in a separating funnel. The aqueous phase was extracted once with dichloromethane (60 ml). The organic phases were combined and the solvent removed under reduced pressure. The residue was purified by column chromatography (pre-packed silica column, gradient of pentane/ethyl acetate). 9.3 g (0.065 mol, 47% yield) of (E)-4-methyl-hept-2-enoic acid were obtained as a solid. NMR (1H, CDCl3, 300 MHz): 11.86 (s, 1H), 7.00 (dd, 1H), 5.79 (d, 1H), 2.35 (m, 1H), 1.35 (m, 4H), 1.06 (d, 3H), 0.89 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13](O)[N:12]2[CH:16]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:18]=[C:11]2[CH:10]=1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:13]1[N:12]2[CH:16]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:18]=[C:11]2[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: CN1CCN(Cc2cn3c(O)nc(-c4ccc(Cl)cc4Cl)cc3n2)CC1
Reactant: O=P(Cl)(Cl)Cl
Product: CN1CCN(Cc2cn3c(Cl)nc(-c4ccc(Cl)cc4Cl)cc3n2)CC1

Procedure:
In analogy to Example 95A, 42 mg (17% of theory) of the product are obtained from 225 mg (0.49 mmol) of 7-(2,4-dichlorophenyl)-2-[(4-methylpiperazin-1-yl)methyl]imidazo[1,2-c]-pyrimidin-5-ol (Example 94A) by reaction with phosphoryl chloride.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:15][CH:14]([OH:16])[CH2:13]2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[N:12]1([CH:10]2[CH2:11][NH:8][CH2:9]2)[CH2:15][CH:14]([OH:16])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CC(O)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1CN(C2CNC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 3-hydroxy-[1,3]biazetidinyl-1′-carboxylic acid tert-butyl ester (0.69 g, 3.05 mmol) in DCM/TFA (4 mL/4 mL). The reaction mixture was stirred for 30 min at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give [1,3′]Biazetidinyl-3-ol as a colourless oil (0.225 g, 58%). LCMS (Method A): RT=0.29 min, [M+H]+ 288.9
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.Cl.Cl[CH2:16][C:17]1[CH:18]=[N:19][N:20]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:16][C:17]2[CH:18]=[N:19][N:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[CH:21]=2)[N:3]=1
Reactant: COc1ccc(Cn2cc(CCl)cn2)cc1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cc(Cn3nc(I)c4c([N+](=O)[O-])cccc43)cn2)cc1
Reaction time: 16 h
Yield: 79.9 %

Procedure:
To 3-iodo-4-nitro-1H-indazole (2.13 g, 7.37 mmol) in DMF (20 mL) was added 4-(chloromethyl)-1-(4-methoxybenzyl)-1H-pyrazole hydrochloride (2.21 g, 8.11 mmol) and K2CO3 (3.06 g, 22.1 mmol). The reaction mixture was stirred for 16 hours. The reaction mixture was diluted with EtOAc, washed with H2O, and brine, and the filtrate was concentrated under reduced pressure. Silica gel chromatography (hexanes/EtOAc 5:1) provided the desired product (2.88 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:13]3[C:14]([C:36]4[CH:41]=[CH:40][N:39]=[C:38]([C:42](O)=[O:43])[CH:37]=4)=[N:15][N:16]([C:17]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:12]=3[CH:11]=[CH:10][N:9]=2)[CH2:3][CH2:2]1.Cl.[CH3:46][NH:47][CH3:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.C(OCC)(=O)C>[CH3:46][N:47]([CH3:48])[C:42](=[O:43])[C:38]1[CH:37]=[C:36]([C:14]2[C:13]3[C:8]([O:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[N:9][CH:10]=[CH:11][C:12]=3[N:16]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:15]=2)[CH:41]=[CH:40][N:39]=1
Reactant: O=C(O)c1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccnc(OC4CCOCC4)c23)ccn1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccnc(OC4CCOCC4)c23)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
A mixture of 4-(4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)picolinic acid (100 mg, 0.17 mmole), dimethylamine hydrochloride (30 mg, 0.34 mmole), HATU (100 mg, 0.26 mole), DIPEA (0.2 mL) in DMF (20 mL) was stirred overnight at 25° C. Ethyl acetate (100 mL) and water (50 mL) were added. The organic layer was separated and washed with water (30 mL) and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude desired product as a yellowish oil (70 mg, 68%). LCMS (Method A): m/z=610 [M+H]+; 2.33 min.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([OH:12])[CH2:9][C@H:8]1[CH:13]=[C:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[O:6])[CH:2]=[CH2:3].N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([O:12][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:9][C@H:8]1[CH:13]=[C:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[O:6])[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCOC(=O)N1C[C@@H](O)C[C@H]1C=C(C)C(C)=O
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=C(C)C(C)=O
Reaction time: 2 h
Yield: 63.2 %

Procedure:
To a solution of (2S,4S)-1-allyloxycarbonyl-4-hydroxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (4.00 g) in N,N-dimethylformamide (40 ml) were added imidazole (2.70 g) and t-butyldimethylsilyl chloride (4.80 g). The resulting mixture was allowed to stand at ambient temperature for 2 hours. The mixture was diluted with ethyl acetate (200 ml), washed in turn with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (100 ml) eluting with a mixture of n-hexane and ethyl acetate (9:1-8:2 V/V) to give (2S,4S)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(2-methyl-3-oxo-1-butenyl)-pyrrolidine (3.67 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27].[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:9][CH2:10][C:11](=[O:21])[N:12]([C@@H:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C@@H:13]2[C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1
Reactant: CCOC(=O)C(Br)CC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CC)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 15 g (46.8 mmol) of ((5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1, Step E) in 140 mL of DMF was added 3.75 g (94 mmol) of a dispersion of 60% sodium hydride in mineral oil at 0° C. After being stirred for 20 min, ethyl 2-bromobutanoate (17.2 mL, 117 mmol) was added at 0° C. and the resulting solution was stirred at 25° C. for 12 h until completion of the reaction. Then sat. aq. NH4Cl solution was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 30% EtOAc/hexanes, gradient elution) provided the title compound as the faster eluting isomer.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:8](COCCOC)[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:20][C:19]=3[CH2:30][N:31]3[CH2:35][CH2:34][C:33]([CH3:37])([CH3:36])[C:32]3=[O:38])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].C[Si](Cl)(C)C.[Na+].[I-].O>CC#N.CCOC(C)=O>[CH3:1][C:2]1[C:3]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:20][C:19]=3[CH2:30][N:31]3[CH2:35][CH2:34][C:33]([CH3:36])([CH3:37])[C:32]3=[O:38])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncccn2)cc1CN1CCC(C)(C)C1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: Cc1onc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncccn3)cc2CN2CCC(C)(C)C2=O)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-N-[(2-methoxyethoxy)methyl]-4'-(2-pyrimidinyl)[1,1'-biphenyl]-2-sulfonamide in 5.1 ml of CH3CN, trimethylsilyl chloride ("Me3SiCl", 166 mg, 1.53 mmol) was added, followed by NaI (229 mg, 1.53 mmol). The mixture was stirred at room temperature for 1 hr. Additional Me3SiCl (166 mg, 1.53 mmol) and NaI (229 mg, 1.53 mmol) were added in three portions and the reaction was stirred for an additional 1 hr and 20 minutes. The reaction mixture was then added to 5 ml H2O and 30 ml EtOAc. The organic layer was separated and washed with 2 ml saturated aqueous sodium thiosulfate, brine, dried and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 32% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 68% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (29 mg, 21% for two steps) as a white solid, m.p. 125°-132° C. (amorphous).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]([CH3:14])([CH3:13])[C:8](OCC)=[O:9])=[CH:4][CH:3]=1.O.[NH2:18][NH2:19].C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]([CH3:14])([CH3:13])[C:8]([NH:18][NH2:19])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(F)cc1
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(Oc1ccc(F)cc1)C(=O)NN
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Ethyl 2-(4-fluorophenoxy)-2-methylpropanoate (5.13 g) was dissolved in methanol (50 ml), hydrazine monohydrate (11 ml) and potassium carbonate (3.14 g) were added thereto, followed by stirring at 70° C. for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Water and saturated aqueous sodium bicarbonate were added to the residue, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=99:1) to obtain 2-(4-fluorophenoxy)-2-methylpropanohydrazide (1.98 g) as a colorless oily product.
Reaction SMILES: ClC1C=CC=CC=1CN1C(CC(O)=O)=CN=C1SCCC.ClC1C=CC=CC=1CN1C(/C=C(\CC2SC=CC=2)/C(O)=O)=CN=C1SCCC.[CH2:50]([C:54]1[N:55]([CH2:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=2[Cl:78])[C:56](/[C:59](/C)=C(\C2C=CN=CC=2)/C(O)=O)=[CH:57][N:58]=1)[CH2:51][CH2:52][CH3:53].[S:79]1[CH:83]=[CH:82][CH:81]=[C:80]1[CH:84]([CH2:90][CH2:91][CH2:92][CH3:93])[CH2:85][C:86]([O:88]C)=[O:87]>>[CH2:50]([C:54]1[N:55]([CH2:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=2[Cl:78])[C:56](/[CH:59]=[C:85](\[CH:84]([C:80]2[S:79][CH:83]=[CH:82][CH:81]=2)[CH2:90][CH2:91][CH2:92][CH3:93])/[C:86]([OH:88])=[O:87])=[CH:57][N:58]=1)[CH2:51][CH2:52][CH3:53]
Reactant: CCCCc1ncc(/C(C)=C(/C(=O)O)c2ccncc2)n1Cc1ccccc1Cl
Reactant: CCCCC(CC(=O)OC)c1cccs1
Agent: CCCSc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccccc1Cl
Agent: CCCSc1ncc(CC(=O)O)n1Cc1ccccc1Cl
Product: CCCCc1ncc(/C=C(/C(=O)O)C(CCCC)c2cccs2)n1Cc1ccccc1Cl

Procedure:
The title compound was prepared using the procedure of Example 1 (i, ii, iii, iv [Method B]) replacing methyl 3-(2 -thienyl) propanoate with methyl 3-(2-thienyl)heptanoate; mp 161°-163° C.
Reaction SMILES: C([O:8][C:9]([C:11]1[C:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][C:18]2[C:13](=[CH:14][C:15]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:16][CH:17]=2)[CH:12]=1)=[O:10])C1C=CC=CC=1.[OH-].[Na+]>CCO>[CH2:22]([O:21][C:20]1[C:11]([C:9]([OH:10])=[O:8])=[CH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:14]=2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(OCc1ccccc1)c1cc2cc(OCc3ccccc3)ccc2cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2cc(OCc3ccccc3)ccc2cc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a suspension of 3,7-bis-benzyloxynaphthalene-2-carboxylic acid benzyl ester (4.0 g, 8.4 mmol) in EtOH (75 mL), is added 10 mL of 1.0N NaOH (1.2 eq.) and the mixture is stirred at 70° C. for 18 h. The solvent is removed under reduced pressure and the residual solid is dissolved in 250 mL of water. The solution is washed with EtOH and the aqueous phase is acidified with 2N HCl. The resulting precipitate is filtered, washed with water and dried to afford 3,7-bis-benzyloxynaphthalene-2-carboxylic acid as a pale-yellow solid: mp=163-165° C.; (M−H)−=383.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:30]C1C(OS(C2C=CC(C)=CC=2)(=O)=O)=C(I)C=CC=1>C(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH3:29])=[O:30])=[CH:26][CH:27]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Reactant: CSc1ccc(-c2cnn(Cc3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Solvent: ClCCl
Product: CS(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Yield: 100 %

Procedure:
A solution of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone, prepared according to the method of Example 4, (450 mg, 1.12 mmol) in CH2Cl2 (10 mL) was added dropwise to a suspension of hydroxy(tosyloxy)iodobenzene (439 mg, 1.12 mmol) in CH2Cl2 (15 mL) and the mixture was stirred until a clear solution was obtained (about 1 hour). The reaction mixture was then washed with water and dried with MgSO4. Removal of solvent in vacuo provided the corresponding sulfoxide (yield: 485 mg, about 100%). 1H NMR (300 MHz, CDCl3) δ 2.72 (s, 3H), 5.40 (s, 2H), 6.90 (m, 2H), 7.15 (m, 3H), 7.33 (m, 3H), 7.57 (m, 3H), 7.71 (m, 1H), 7.86 (s, 1H). MS (DCI/NH3) m/z 419 (M+H)+, 436 (M+NH4)+.