Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=4)=[O:26])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[C:8]([O:10]C)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[ClH:44]>O1CCOCC1>[ClH:44].[C:1]1([CH:7]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][CH:34]=4)=[O:26])=[CH:20][CH:19]=3)[CH2:16][CH2:17]2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(c1ccccc1)C1CCN(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc(N2CCC(C(C(=O)O)c3ccccc3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of intermediate (23) (0.0014 mol) in concentrated HCl (25 ml) and dioxane (20 ml) was stirred and refluxed for 4 hours, cooled and poured out into water. The mixture was extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 0.48 g of α-phenyl-1-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-4-piperidineacetic acid monohydrochloride (intermediate 24, mp. 196° C.).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[C@H:14]3[CH2:15][N:16](CC4C=CC=CC=4)[CH2:17][C@@H:13]3[C:12]=2[CH:32]=1>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[C@H:14]3[CH2:15][N:16]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:17][C@@H:13]3[C:12]=2[CH:32]=1
Reactant: CCOC(=O)Cl
Reactant: Clc1ccc2c(c1)[C@H]1CN(Cc3ccccc3)C[C@@H]1c1ccccc1O2
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C[C@@H]2c3ccccc3Oc3ccc(Cl)cc3[C@H]2C1

Procedure:
Ethyl chloroformate (5 ml) was added to a solution of trans-5-chloro-2,3,3a,12b-tetrahydro-2-benzyl-1H-dibenz[2,3:6,7]-oxepino[4,5-c]pyrrole (470 mg, 1.3 mmol) in toluene (30 ml). The reaction mixture was heated to reflux overnight under inert nitrogen atmosphere to give complete conversion. The resulting dark reaction mixture was concentrated under vacuum to give crude title compound as a black oil. MS: M+1=344 found.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:21])[C:9]2[CH:20]=[CH:19][C:12]3[N:13]([CH3:18])[C:14]([S:16][CH3:17])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:22][S:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)(=[O:25])=[O:24]>C(O)(C)C>[CH3:22][S:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:2]2[N:7]=[C:6]([N:8]([CH3:21])[C:9]3[CH:20]=[CH:19][C:12]4[N:13]([CH3:18])[C:14]([S:16][CH3:17])=[N:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:29][CH:28]=1)(=[O:24])=[O:25]
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Reactant: CSc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C
Solvent: CC(C)O
Product: CSc1nc2cc(N(C)c3ccnc(Nc4ccc(CS(C)(=O)=O)cc4)n3)ccc2n1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of (2-Chloro-pyrimidin-4-yl)-methyl-(1-methyl-2-methylsulfanyl-1H-benzoimidazol-5-yl)-amine (3.19 g, 10 mmol), 4-Methanesulfonylmethyl-phenylamine (1.85 g, 10 mmol) and (833 ul, 12N, 10 mmol) was refluxed in isopropanol (100 ml) overnight. The mixture was then concentrated to dryness and the residual was taken into MeOH and stirred with NaHCO3 (3 g) at room temperature for 20 min. and filtered, the filtrate was concentrated and the residual was purified by silica flash gave 3.35 g as a pale yellow solid: LC/MS(m/e) 469.2 [M+H]+, Rt at 1.37 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]1[CH:32]=[CH:31][C:16]([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[C:21]([F:30])[CH:20]=2)=[CH:15][C:14]=1[O:33][CH:34]([CH3:36])[CH3:35].[OH-].[Na+].[Cl-].[Ca+2:41].[Cl-]>CO.O>[Ca+2:41].[CH3:1][C:2]1([CH3:37])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]1[CH:32]=[CH:31][C:16]([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O-:29])=[O:28])=[C:21]([F:30])[CH:20]=2)=[CH:15][C:14]=1[O:33][CH:34]([CH3:35])[CH3:36].[CH3:1][C:2]1([CH3:37])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]1[CH:32]=[CH:31][C:16]([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O-:29])=[O:28])=[C:21]([F:30])[CH:20]=2)=[CH:15][C:14]=1[O:33][CH:34]([CH3:35])[CH3:36]
Reactant: CC(C)Oc1cc(CNc2ccc(CCC(=O)O)c(F)c2)ccc1CN1c2ccccc2C=CC1(C)C
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)Oc1cc(CNc2ccc(CCC(=O)[O-])c(F)c2)ccc1CN1c2ccccc2C=CC1(C)C
Yield: 42.3 %

Procedure:
3-[4-({4-[(2,2-Dimethylquinolin-1(2H)-yl)methyl]-3-isopropoxybenzyl}amino)-2-fluorophenyl]propanoic acid (0.12 g, 0.24 mmol) was dissolved in methanol (2 mL), and 1 N aqueous sodium hydroxide solution (0.24 mL, 0.24 mmol) was added. A solution of calcium chloride (13 mg, 0.12 mmol) in water (1 mL) was added, and the precipitated solid was collected by filtration, washed with water and methanol and dried to give the title compound (53 mg, yield 43%) as a colorless powder.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].O>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: O
Product: CCCCc1nc(Cl)c(C=O)[nH]1
Yield: 86.3 %

Procedure:
A stirred mixture of 2-n-butyl-4-chloro-5-hydroxymethylimidazole (15.00 g, 0.0795 mol) and activated manganese dioxide (40.00 g) in 600 ml of methylene chloride was refluxed for 24 h using a water separator. The mixture was filtered hot through a Celite® pad. The Celite® pad was washed several times with hot methylene chloride. The washings were combined with the filtrate and concentrated in vacuo to give 12.81 g (86%) of the aldehyde as a white solid; mp 97-98° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:3]1.[CH3:27][Si:28]([CH3:38])([CH3:37])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>O>[O:1]=[C:2]1[C@H:7]([CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([Si:28]([CH3:27])([CH3:38])[CH3:37])[CH:30]=2)[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:3]1
Reactant: C[Si](C)(C)c1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CC(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2cccc([Si](C)(C)C)c2)C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 85.7 %

Procedure:
A dry 250 ml 3-necked flask equipped with a magnetic stirrer and a nitrogen inlet was charged with 2.08 g of t-butyl (2R, 3S)-(−)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate (Aldrich), 1.43 g of 3-(trimethylsilyl)benzyl bromide (Yamakawa, T., et al, J. Med. Chem., 1990, 33, 1430), and 45 mL of anhydrous THF. The solution was cooled to −780° C. and was treated with 6.17 mL of 1 M sodium bis(trimethylsilyl)amide/THF (Aldrich) via syringe through a rubber septum. The solution was stirred at −78° C. for 3.5 h and was then poured into 150 mL of water. The resulting mixture was extracted with EtOAc (4×50 mL). The combined EtOAc extracts were washed with saturated brine (3×50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give a light yellow oil. The crude material was purified by flash chromatography on silica gel (9:1 hexane:EtOAc) to afford 2.6 g (88%) of tert-butyl (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-(trimethylsilyl)benzyl)-4-morpholinecarboxylate as a white powder, m.p. 88-90° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:9][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:12][C:13]=3[O:14][C:4]=2[CH:3]=1.[C:22]1([S:28]([O-:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na+]>>[C:22]1([S:28]([C:2]2[CH:7]=[CH:6][C:5]3[C:8]4[CH2:9][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:12][C:13]=4[O:14][C:4]=3[CH:3]=2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3cc(Br)ccc3c2C1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3cc(S(=O)(=O)c4ccccc4)ccc3c2C1
Yield: 29 %

Procedure:
The product of step C was coupled with sodium benzenesulfinate following the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 85:15 hexanes/ethyl acetate) provided tert-butyl 7-(phenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (31 mg, 29%) as light yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.06 (d, J=1.2 Hz, 1H), 7.98-7.91 (m, 2H), 7.81 (dd, J=8.1 Hz, 1.2 Hz, 1H), 7.56-7.45 (m, 4H), 4.54 (s, 2H), 3.82 (t, J=5.4 Hz, 2H), 2.88 (t, J=5.7 Hz, 2H), 1.49 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH2:29]([NH2:37])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N1CCN2CCN(CCCC)P1N(CCCC)CC2)CCC.CC(C)([O-])C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([NH:37][CH2:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: NCCc1ccccc1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(NCCc4ccccc4)ccc2OCC3)c(F)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), Pd(OAc)2 (49 mg, 0.3 mmol), phenethylamine (174 mg, 1.44 mmol), 2,8,9-tributyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (99 mg, 0.29 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 120° C. for 1 h under the irradition of microwave. The mixture was filtered over ceilite. The filtrate was concentrated to dryness and purified by pre-HPLC to afford 90 mg of 126 (yield=25%). 1H NMR (CDCl3, 400 MHz): δ8.02 (s, 1H), 7.47-7.45 (m, 1H), 7.40-7.32 (m, 2H), 7.20-7.12 (m, 2H), 7.09 (s, 1H), 7.00-7.90 (m, 3H), 6.11 (d, J=8.4 Hz, 1H), 4.18-4.16 (m, 2H), 3.53-3.47 (m, 2H), 3.07-3.03 (m, 2H), 2.87-2.82 (m, 2H). LC-MS (ESI): m/z=502 [M+H]+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@H:29]([CH3:34])[C:30]([O:32]C)=O)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:34][C@@H:29]([O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2)[C:30](=[O:32])[N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Reactant: C1CCNC1
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)C(=O)N1CCCC1
Yield: 70 %

Procedure:
Using the same procedure as in Example 5, methyl (2R)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.44 mmol) was reacted with pyrrolidine (0.22 ml, 2.6 mmol) to give the title compound as a beige solid (152 mg, 70%), except that 3 Å molecular sieve was added and that the crude material was purified on an HPLC column (C18, 5 microns, 19 mm diameter, 100 mm length) of a preparative HPLC-MS system eluting with a mixture of water and acetonitrile containing 2 g/l of ammonium carbonate (gradient). NMR Spectrum 1.60 (d, 3H), 1.81 (m, 2H), 1.94 (m, 2H), 3.47-3.30 (m, 3H), 3.77 (m, 1H), 5.62 (q, 1H), 5.77 (s, 2H), 6.95 (d, 1H), 7.28 (m, 2H), 7.35 (d, 1H), 7.74-7.68 (m, 3H), 7.82 (dd, 1H), 8.15 (s, 1H), 8.53 (m, 3H), 11.07 (br s, 1H); Mass spectrum MH+ 494.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20]C(=O)OC(C)(C)C.B(OC(C)C)(OC(C)C)OC(C)C.C(=O)([O-])[O-].[Na+].[Na+].I[C:48]1[CH:53]=[CH:52][C:51]([N:54]2[CH2:58][CH2:57][CH2:56][CH2:55]2)=[CH:50][CH:49]=1>C1COCC1.COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:54]1([C:51]2[CH:52]=[CH:53][C:48]([C:16]3[CH:15]([NH2:20])[NH:14][CH:19]=[CH:18][CH:17]=3)=[CH:49][CH:50]=2)[CH2:58][CH2:57][CH2:56][CH2:55]1
Reactant: Ic1ccc(N2CCCC2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: COCCOC
Product: NC1NC=CC=C1c1ccc(N2CCCC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 9.7 %

Procedure:
n-Butyllithium (1.6 M in hexane, 48.3 ml) was added dropwise to a solution of N,N,N′,N′-tetramethylethane-1,2-diamine (8.08 g) and tert-butyl pyridin-2-ylcarbamate (5.00 g) in THF (dry) (50 ml) at −78° C. The mixture was stirred at 0° C. under N2 for 2 hr. Triisopropyl borate (17.0 g) was added to the mixture at −78° C. The mixture was stirred at 0° C. under N2 for 30 min. The mixture was quenched with sat. NH4Cl aq. at 0° C. and added with Et2O to give a yellow precipitate (11.7 g, wet). A mixture of the precipitate (349 mg), sodium carbonate (155 mg), tetrakis(triphenylphosphine)palladium(0) (42.3 mg) and 1-(4-iodophenyl)pyrrolidine (200 mg) in DME (25 mL) and water (5 mL) was stirred at 80° C. under N2 overnight. NH silica gel was added and the mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (17.1 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:12])=O>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:7]([CH2:8][Cl:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccnc1Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: ClCc1cccnc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
To a solution of the compound (18.5 g) obtained in step 1 in a mixture of chloroform (95 mL) and DMF (0.63 mL) was added thionyl chloride (14.0 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was poured into a mixture of water and ethyl acetate. The solution was neutralized with sodium hydrogen carbonate, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine, and concentrated to give 2-chloro-3-(chloromethyl)pyridine (20.5 g, 89%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][CH2:7][CH2:8]Cl.[OH:14][C:15]1([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][CH2:7][CH2:8][N:18]1[CH2:19][CH2:20][C:15]([OH:14])([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:16][CH2:17]1
Reactant: ClCCCOc1ccc(Cl)c(Cl)c1
Reactant: OC1(c2ccc(Cl)c(Cl)c2)CCNCC1
Product: OC1(c2ccc(Cl)c(Cl)c2)CCN(CCCOc2ccc(Cl)c(Cl)c2)CC1
Yield: 97.4 %

Procedure:
3-(3,4-dichlorophenoxy)propylchloride 1.38 g and 4-hydroxy-4-(3,4-dichlorophenyl)piperidine 1.35 g are reacted in the same manner as Example 109 (1) to prepare 2.40 g (Yield: 97.5%) of 1-{3-(3,4-dichlorophenoxy)propyl}-4-hydroxy-4-(3,4-dichlorophenyl) piperidine (III-66). mp.118.0°-118.5° C.
Reaction SMILES: Cl.Cl.[CH:3]1([NH:6][C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[CH:23]=[C:24]([C:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=5)[S:25][C:18]=34)=[C:12]([F:32])[CH:11]=2)=[O:8])[CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].[CH3:39][S:40]([O-])(=[O:42])=[O:41]>CN(C=O)C.O>[CH:3]1([NH:6][C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[CH:23]=[C:24]([C:26]5[CH2:27][CH2:28][N:29]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:30][CH:31]=5)[S:25][C:18]=34)=[C:12]([F:32])[CH:11]=2)=[O:8])[CH2:5][CH2:4]1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(C4=CCNCC4)sc23)c(F)c1)NC1CC1
Reactant: CS(=O)(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)N1CC=C(c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 23.2 %

Procedure:
To a stirred suspension of compound 271 (150 mg, 0.302 mmol) and K2CO3 (180 mg, 1.302 mmol) in DMF (10 mL) was added 2,5,8,11-tetraoxamidecan-13-yl methanesulfonate (112 mg, 0.39 mmol, K. Fukase, et al., SynLett., 2005, 2342-2346). The reaction mixture was stirred at RT for 2.5 days, diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80 g cartridge; MeOH/DCM: 0/100 to 15/85 over 20 CV) tp produce a material that upon trituration with Et2O/hexane afforded an unexpected compound 275 (35 mg, 0.07 mmol, 21% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.71 (s, 1H), 8.45 (d, J-5.6 Hz, 1H), 7.71 (dd, J=2.8 and 13.6 Hz, 1H), 7.57 (s, 1H), 7.35 (t, J=8.8 Hz, 1H), 7.22-7.16 (m, 1H), 6.02-5.95 (m, 2H), 6.44 (t, J=3.2 Hz, 1H), 3.95-3.90 (m, 2H), 3.42 (t, J=6.4 Hz, 2H), 2.96 (s, 3H), 2.58-2.50 (m, 1H), 0.68-0.62 (m, 2H), 0.44-0.41 (m, 2H). MS (m/z): 503.3 (M+H).
Reaction SMILES: O[CH:2]([CH2:5][CH:6]=C)[CH:3]=[CH2:4].C(=O)CCCC=C.[C:15]([OH:21])(=[O:20])[CH2:16][C:17](O)=O>>[C:15]([OH:21])(=[O:20])[CH:16]=[CH:17][CH2:6][CH2:5][CH2:2][CH:3]=[CH2:4]
Reactant: C=CCC(O)C=C
Reactant: O=C(O)CC(=O)O
Agent: C=CCCCC=O
Product: C=CCCCC=CC(=O)O

Procedure:
The first step in the sequence in the pyrolysis of 3-hydroxy-1,5-hexadiene to prepare 5-hexenal which is reacted with malonic acid to form 2,7-octadienoic acid. The foregoing acid is esterified by treatment with diazomethane and the resulting methyl ester is reacted with the sodium salt of ethyl acetoacetate under the influence of sodium methoxide in a methanol menstruum to yield the sodium salt of methyl 6-(4pentenyl)-β-dihydroresorcylate. The dihydroresorcylate sodium salt is then brominated at low temperature to form methyl 3 -bromo-6-(4 -pentenyl)-β-dihydroresorcylate which is de-hydrobrominated by treatment with sodium ethoxide in an anhydrous ethanol menstruum to prepare ethyl 6-(4-pentenyl)-β-resorcylate. The foregoing resorcylate is reacted with benzyl chloride to yield ethyl 6-(4-pentenyl)-β-resorcylate dibenzyl ether which is treated with the sodium alcoholate of 4-penten-2 -ol to produce 4 -penten-2-yl 6-(4-pentenyl)-β -resorcylate dibenzyl ether. The foregoing compound is treated successively with 2,3-dimethyl-2-butylborane, carbon monoxide, sodium acetate solution, and hydrogen peroxide to form zearalanone dibenzyl ether. On Hydrogenation zearalanone dibenzyl ether is converted to (R,S)-zearalanone.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7]([NH2:10])(=[O:9])=[O:8].[Br:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>N1C=CC=CC=1>[Br:11][C:12]1[CH:13]=[C:14]([S:18]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[S:7]([NH2:10])(=[O:9])=[O:8])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: Nc1ccsc1S(N)(=O)=O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1sccc1NS(=O)(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 66.3 %

Procedure:
A mixture of 3-amino-thiophene-2-sulfonic acid amide (100 mg, 0.56 mmol) and 3-bromo-benzenesulfonyl chloride (97 μL, 0.67 mmol) in anhydrous pyridine (3 mL) was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was taken up in dichloromethane (25 mL). The organic phase was washed with 1 M hydrochloric acid, saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography, using 4-6% methanol in dichloromethane as the eluent, gave 147.6 mg (66% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:23])[N:9]([C@@H:11]([CH2:14][C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)[CH2:12]O)[CH2:10][C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]1(=[O:53])[NH:47][C:46](=[O:48])[C:45]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:23])[N:9]([C@@H:11]([CH2:14][C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)[CH2:12][N:47]3[C:43](=[O:53])[C:44]4[C:45](=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:46]3=[O:48])[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1c2cnc(Cl)cc2CN1[C@H](CO)Cc1cc(F)cc(F)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C[C@H](Cc1cc(F)cc(F)c1)N1Cc2cc(Cl)ncc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a solution of 6-chloro-2-[(1S)-1-(3,5-difluorobenzyl)-2-hydroxyethyl]-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (0.340 g, 1.00 mmol), triphenylphosphine (0.263 g, 1.00 mmol) and phthalimide (0.148 g, 1.00 mmol) in tetrahydrofuran (10 mL) at 25° C. was added diethyl azodicarboxylate (0.514 mL, 1.30 mmol). The reaction was stirred at room temperature overnight. After concentration, the residue was purified by combi-flash chromatography eluting with EtOAc/hexane (10-60%). The purification gave 0.360 g (76.7% yield) of the desired product as light green solid. LC/MS found: 468.0 (M+1)+.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:15]([O:17][CH2:18][CH3:19])=[O:16].CI.CN(P(N(C)C)(N(C)C)=O)C.[Cl-].[NH4+]>C1COCC1>[CH3:13][C:14]([CH3:1])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCCCCCCC(C)C(=O)OCC
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CCCCCCCC(C)(C)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
To a solution of diisopropylamine (10.7 ml, 76.6 mmol) in anhydrous THF (100 ml) was added dropwise n-butyl lithium (1.61N, 47.6 ml, 76.6 mmol) at -78° C. under argon stream. After stirring the mixture at -78° C. for 30 minutes, ethyl 2-methylnonanoate (9.6028 g, 47.9 mmol) was added dropwise and the mixture was further stirred at -78° C. for 30 minutes. A solution of methyl iodide (5.5 ml, 88.3 mmol) in HMPA (2.5 ml, 14.4 mmol) was dropwise added and the mixture was stirred at -78° C. for 40 minutes, them at 0° C. for 40 minutes, and further at room temperature for 45 minutes. Saturated aqueous ammonium chloride solution (20 ml) was added and the reaction mixture was extracted with ethyl acetate (50 ml×4). The ethyl acetate layers were washed with water (50 ml) and with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated. Distillation gave ethyl 2,2-dimethylnonanoate (9.6627 g, 94.1% yield, b.p.: 53°-65.5° C./0.22 mmHg) as colorless liquid. The structure of this product was confirmed by the following data.