Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]C1C=CC(Cl)=CC=1C=O.COC1C=C(C=CC=1)C=O.[ClH:21].[CH2:22]([CH:29]([CH2:40][N:41]([CH3:43])[CH3:42])[C:30]([C:32]1[CH:37]=[CH:36][C:35](Cl)=[CH:34][C:33]=1[Cl:39])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[ClH:1].[CH2:22]([CH:29]([CH2:40][N:41]([CH3:43])[CH3:42])[C:30]([C:32]1[CH:37]=[C:36]([Cl:21])[CH:35]=[CH:34][C:33]=1[Cl:39])=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=Cc1cc(Cl)ccc1Cl
Reactant: CN(C)CC(Cc1ccccc1)C(=O)c1ccc(Cl)cc1Cl
Agent: COc1cccc(C=O)c1
Agent: Cl
Product: CN(C)CC(Cc1ccccc1)C(=O)c1cc(Cl)ccc1Cl

Procedure:
The synthesis was carried out according to the procedure of Example 1, except that 5.0 g (0.028 mole) of 2,5-dichlorobenzaldehyde were used instead of 3-methoxybenzaldehyde. The reaction steps involving Grignard reaction, oxidation and Mannich reaction led to a total yield of 1.4 g (14%) of (2RS)-2-benzyl-1-(2,4-dichlorophenyl)-3-dimethylaminopropan-1-one hydrochloride with a melting point of 140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]CC)=[O:24])=[CH:18][C:17]=3[C:28]([F:31])([F:30])[F:29])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.O[Li].O>CO.C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[C:28]([F:29])([F:30])[F:31])=[CH:13][CH:12]=2)=[O:10])=[CH:34][CH:35]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C(F)(F)F)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C(F)(F)F)c1
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a solution of ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-(trifluoromethyl)phenyl)acetate (0.165 g, 0.326 mmol) in methanol/THF (1:1), 5 ml was added LiOH—H2O (0.0684 g, 1.63 mmol) and 3 drops of water, and the reaction was stirred for 1 hour The reaction was diluted with ethyl acetate, washed with 2N HCl and brine, dried over magnesium sulfate and concentrated. The crude material was purified by silica gel chromatography, eluting with a gradient of 0.5% methanol/dichloromethane containing 0.5% AcOH to 7% methanol/dichloromethane containing 0.5% AcOH to provide 2-(4-(4-((4-chlorophenethyl) carbamoyl)phenoxy)-3-(trifluoromethyl)phenyl)acetic acid (0.112 g). MS +478.3 [M+1]. 1H NMR (400 MHz, CD3OD) δ 8.49 (bt, NH), 7.79 (d, J=8.7 Hz, 2H), 7.68 (s, 1H), 7.53 (d, J=4.3 Hz, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 7.02-7.06 (m, 3H), 3.71 (s, 2H), 3.56 (t, J=6.8 Hz, 2H), 2.90 (t, J=7.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[N:14][C:15]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1.IC.I[CH2:30][CH2:31][CH2:32][CH3:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[N:14][C:15]=3[NH:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:10]([CH2:30][CH2:31][CH2:32][CH3:33])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1c(-c2ccc(Cl)cc2)c[nH]c2ccnc(NCc3ccccc3)c12
Reactant: CCCCI
Solvent: CI
Product: CCCCn1cc(-c2ccc(Cl)cc2)c(=O)c2c(NCc3ccccc3)nccc21

Procedure:
The title compound was prepared as described in Example 2 above except that 3-(4-chlorophenyl)-1,4-dihydro-4-oxo-5-(2-phenethylamino)-1,6-naphthyridine was replaced with 3-(4-chlorophenyl)-1,4-dihydro-4-oxo-5-benzylamino-1,6-naphthyridine and iodomethane was replaced with iodobutane. MS 428 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11][OH:12])=[CH:8][C:7]=2[CH:13]=1>O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]=[O:12])=[CH:8][C:7]=2[CH:13]=1
Reactant: COc1ccc2oc(CO)cc2c1
Agent: O=[Mn]=O
Product: COc1ccc2oc(C=O)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
To a solution of 5-methoxy-2-hydroxymethylbenzofuran (16.0 gm; 90 mmoles) in ethyl acetatel (1 L) was added MnO2 (78 gm, 900 mmoles). The reaction mixture was stirred at room temperature for 3 hours. Then this suspension was filtered through celite and concentrate in vacuo. The filtrate yielded the title Compound E9, (9.5 gm, 60%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=2[C:18](=[O:20])[CH3:19])[CH2:3][CH2:2]1.Cl[C:22](=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1C=CC=CC=1.C(OCC)(=O)C>[C:18]([C:9]1[CH:10]=[CH:11][C:12]([C:14]([F:15])([F:17])[F:16])=[CH:13][C:8]=1[N:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C:22](=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1NC1CCOCC1
Reactant: CCOC(=O)CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)CC(=O)N(c1cc(C(F)(F)F)ccc1C(C)=O)C1CCOCC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
To a stirred solution of 400 mg (1.39 mmol) 1-(2-(tetrahydro-2H-pyran-4-ylamino)-4-(trifluoromethyl)phenyl)ethanone in benzene (5 ml) was added 360 μl (2.78 mmol) ethyl 3-chloro-3-oxopropanoate at 0° C. The reaction mixture was stirred at 80° C. for 4 h. Then the mixture was diluted with ethyl acetate (20 ml) and washed with water (20 ml), brine (20 ml), a sat. aq. Na2CO3 sol. (2×30 ml), dried over anhydrous Na2SO4 and concentrated in vacuo to yield 550 mg (1.37 mmol, 98%) ethyl 3-((2-acetyl-5-(trifluoromethyl)phenyl)(tetrahydro-2H-pyran-4-yl)amino)-3-oxopropanoate, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]2[CH2:15][CH2:16][N:2]1[CH2:3][CH2:4]2.Br[C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][CH:24]=[N:25]2)=[CH:20][CH:19]=1>>[N:25]1[C:26]2[C:21](=[CH:20][CH:19]=[C:18]([N:7]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14]4[CH2:1][N:2]5[CH2:3][CH2:4][CH:5]([C:6]3=4)[CH2:15][CH2:16]5)[CH:27]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Brc1ccc2cccnc2c1
Reactant: c1ccc2c3c([nH]c2c1)C1CCN(CC1)C3
Product: c1cnc2cc(-n3c4c(c5ccccc53)CN3CCC4CC3)ccc2c1

Procedure:
The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (212 mg, 1.0 mmol; Example 187A) and 7-bromoquinoline (312 mg, 1.5 mmol; Ark Pharm) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.96-2.23 (m, 4H) 2.99-3.05 (m, 1H) 3.10-3.30 (m, 4H) 4.37 (s, 2H) 7.07-7.21 (m, 3H) 7.40-7.49 (m, 1H) 7.59-7.69 (m, 2H) 7.97 (d, J=2 Hz, 1H) 8.17 (d, J=9 Hz, 1H) 8.50 (d, J=7 Hz, 1H) 8.95 (dd, J=4, 2 Hz, 1H); MS (DCI/NH3) m/z 340 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]3[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=3[CH:11]=2)=[CH:6][CH:7]=1.[CH:22](OCC)(OCC)OCC>C(O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[CH:22]=[N:21][C:4]=2[CH:3]=1
Reactant: CSc1nc2ccc(CNc3ccc(C)cc3N)cc2s1
Reactant: CCOC(OCC)OCC
Solvent: O=CO
Product: CSc1nc2ccc(Cn3cnc4cc(C)ccc43)cc2s1
Temperature: 100 °C
Yield: 85 %

Procedure:
A stirred mixture of crude 4-methyl-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine (0.7 g, 2.3 mmol), formic acid (0.5 mL) and triethyl orthoformate (5 mL) was heated at 100° C. for 1 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 3% MeOH in DCM to afford 6-((5-methyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (0.61 g, 85%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.94 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.62 (s, 1H), 7.49 (s, 1H), 7.26 (m, 1H), 7.14 (d, J=8.1 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 5.43 (s, 2H), 2.77 (s, 3H), 2.47 (s, 3H); LCMS (ESI) m/z 326 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[H-].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:3]=1
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc2c(Cl)n[nH]c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(Cl)c2ccc([N+](=O)[O-])cc21
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 56.6 %

Procedure:
3-chloro-6-nitroindazole (20 g) was dissolved in dry DMF (180cm3) and the solution cooled to 5° C. 50% sodium hydride (4.86 g) was added portionwise with stirring and cooling between 5° and 10° C. and then for an additional 15 minutes. Ethyl bromoacetate (16.91 g) was added slowly at 5° C., the reaction mixture warming to 30° C. The reaction mixture was then stirred at 20° C. for four hours. Water (lL) was added and the mixture acidified with diluted hydrochloric acid, shaken with ethyl acetate and filtered through hyflo. The organic phase was separated from the filtrate and the aqueous phase extracted (×2) with ethyl acetate. The combined organic phase was washed with water, dried (MgSO4) filtered and the solvent removed from the filtrate under vacuum. The residue was purified by flash chromatography (SiO2 ; hexane: TBME, 7:3 and then chloroform:ethyl acetate 95:5) to give ethyl 3-chloro-6-nitroindazol-1-ylacetate (16.25 g) as a pale yellow solid m.pt 109.1°-110.3° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:29][CH:30]([F:32])[F:31])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Li+]>CO>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:9]2[C:10]([CH2:17][CH3:18])=[N:11][C:12]3[C:7]([C:8]=2[O:29][CH:30]([F:32])[F:31])=[C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])[CH:15]=[CH:14][C:13]=3[F:16])=[CH:21][CH:22]=1)(=[O:28])[CH3:27]
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(C(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 158.7 %

Procedure:
A solution of [3-(4-acetylbenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (0.13 g) in methanol (5.0 mL) was treated with 1.0M aqueous lithium hydroxide solution (0.54 mL), and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, diluted with water and acidified by the addition of 0.1M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate, and the combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on C-18 column to afford title compound (0.20 g).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]2[C:13]3[C:18]([O:19][CH2:20][C:3]=12)=[CH:17][C:16]([OH:21])=[CH:15][CH:14]=3.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[OH:21][C:16]1[CH:17]=[C:18]2[O:19][CH2:20][C:3]3[C:4](=[N:5][C:6]4[C:11]([C:2]=3[C:27]3[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=3)=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=4)[C:13]2=[CH:14][CH:15]=1
Reactant: Oc1ccc2c(c1)OCc1c-2nc2ccc(O)cc2c1Br
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Oc1ccc2c(c1)OCc1c-2nc2ccc(O)cc2c1-c1ccc(C(F)(F)F)cc1
Yield: 95 %

Procedure:
This compound was prepared from 7-bromo-3,9-dihydroxy-6H-chromeno[4,3-b]quinoline (7) using 4-trifluoromethylphenylboronic acid according to method M. Yellow powder; Yield: 95%; mp 175-177° C. (dec.); 1H-NMR (400 MHz, DMSOd-6) δ 5.00 (s, 2H), 6.36 (d, J=2.3 Hz, 1H), 6.56 (d, J=2.6 Hz, 1H), 6.61 (dd, J=8.6, 2.2 Hz, 1H), 7.26 (dd, J=9.1, 2.6 Hz, 1H), 7.64 (d, J=7.9 Hz, 2H), 7.92 (d, J=9.0 Hz, 1H), 7.98 (d, J=8.1 Hz, 2H), 8.16 (d, J=8.6 Hz, 1H), 9.84 (s, 1H), 10.00 (s, 1H); 19F-NMR (400 MHz, DMSOd-6) δ −61.43 (s); MS (ESI) m/z 408 ([M−H]−), 410 ([M+H]+); HRMS (ESI+) calcd for C23H14F3NO3 410.0999 ([M+H]+). Found: 410.0992.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH2:22][NH:21][CH2:20][CH2:19][C:11]=2[N:12]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[N:14]=1.C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl>[C:30]([N:21]1[CH2:20][CH2:19][C:11]2[N:12]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[N:14]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:10]=2[CH2:22]1)(=[O:32])[CH3:31]
Reactant: CS(=O)(=O)c1nc2c(c(-c3ccc(Cl)cc3Cl)n1)CNCC2
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2nc(S(C)(=O)=O)nc(-c3ccc(Cl)cc3Cl)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2,4-dichlorophenyl)-2-(methylsulfonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine (100 mg, 0.279 mmol), triethylamine (78 μl, 0.558 mmol) in dichloromethane (2 ml) was added acetic anhydride (53 μl, 0.558 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and water. Organic layer was separated and washed with brine, dried (MgSO4) and filtered. Concentration of filtrate afforded crude product 6-acetyl-4-(2,4-dichlorophenyl)-2-(methylsulfonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine in quantitative yield.
Reaction SMILES: [F:1][CH:2]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][CH2:5][CH:6]([N:10]1[CH:13]([S:14][CH3:15])[C:12]([CH2:18][CH3:19])([CH2:16][CH3:17])[C:11]1=[O:20])[C:7]([O-])=[O:8].C(C1(CC)C(SC)[N:33](CC(OC)=O)C1=O)C.FC1C=CC(CCCCCCO)=CC=1.C[O-].[Na+]>C1C=CC=CC=1>[F:1][CH:2]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][CH2:5][CH:6]([N:10]1[CH:13]([S:14][CH3:15])[C:12]([CH2:18][CH3:19])([CH2:16][CH3:17])[C:11]1=[O:20])[C:7]([NH2:33])=[O:8]
Reactant: CCC1(CC)C(=O)N(C(CCCC(F)CCc2ccccc2)C(=O)[O-])C1SC
Reactant: CCC1(CC)C(=O)N(CC(=O)OC)C1SC
Agent: C[O-]
Agent: OCCCCCCc1ccc(F)cc1
Agent: [Na+]
Solvent: c1ccccc1
Product: CCC1(CC)C(=O)N(C(CCCC(F)CCc2ccccc2)C(N)=O)C1SC
Reaction time: 2 h
Yield: 13 %

Procedure:
4-Fluorophenylhexyl(3,3-diethyl-4-methylthio-2-oxoazetidin-1-yl)acetate-Methyl (3,3-diethyl-4-methylthio-2-oxo-azetidin-1-yl)acetate (0.8 g, 3.2 mmol) was dissolved in benzene with 4-fluorophenylhexylalcohol (1.3 g, 6.5 mmol) and sodium methoxide (SOmg ,0.9 mmol) and the mixture refuxed for 2 h. The reaction mixture was evaporated and diluted with EtOAc, the solution washed with water, separated, dried (K2CO3) and flash chromatographed (hexane/ethyl acetate 9:1) to give 4-fluorophenylhexyl(3,3-diethyl-4-methylthio-2-oxoazetidin-1-yl)acetamide 0.17 g, 14% as an oil.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=2)[NH:3]1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][NH:25]2)[CH2:19][CH2:18]1>>[CH3:16][N:17]1[CH2:18][CH2:19][N:20]([CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2[S:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[C:10]3=[O:11])(=[O:14])=[O:13])[CH2:21][CH2:22]1
Reactant: CN1CCN(C[C@@H]2CCCN2)CC1
Reactant: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Product: CN1CCN(C[C@@H]2CCCN2S(=O)(=O)c2ccc3c(c2)C(=O)C(=O)N3)CC1

Procedure:
The title compound was prepared from 2,3-dioxo-2,3-dihydro-1H-indole-5-sulfonylchloride and 1-methyl-4-[(2S)-pyrrolidin-2-ylmethyl]piperazine according to a procedure similar to that of step 1 of Example 12. NMR (400 Mz, DMSO-d6): consistent.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([C:26]#[C:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)=[CH:30][N:29]=1)(C(C)(C)C)(C)C>C(Cl)Cl>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([C:31]2[CH:32]=[CH:33][C:28]([C:27]#[CH:26])=[N:29][CH:30]=2)=[CH:39][CH:38]=1
Reactant: CC(C)(C)[Si](C)(C)C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reaction time: 2 h

Procedure:
43.66 g (156.0 mmol) of TBAF are added at RT to a solution of 46.50 g (142.0 mmol) of 2-[(tert-butyldimethylsilanyl)ethynyl]-5-(4-chlorophenyl)pyridine in 1 L of DCM and the mixture is stirred for 2 hours. The organic phase is washed with water, dried over sodium sulfate, and evaporated down in vacuo. The residue is stirred with DIPE, and the precipitate is filtered off and washed with PE. Yield: 26.0 g (86% of theoretical);C13H8CIN (M=213.662); calc.: molpeak (M+H)+: 214/216 (Cl); found: molpeak (M+H)+: 214/216 (Cl); Rf value: 0.30 (silica gel, Cyc/EtOAc 4:1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:12])[CH:3]=1.S(=O)(=O)(O)O.[CH3:18]O>>[Cl:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([O:8][CH3:18])=[O:7])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Cl)c(I)cc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(I)c(Cl)cc1C
Temperature: 75 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 4-chloro-5-iodo-2-methylbenzoic acid (compound 177.1, 20.0 g, 67.5 mmol, 1.00 equiv) in methanol (100 mL) was added sulfuric acid (5 mL) dropwise. The resulting mixture was stirred overnight at 75° C. After cooling to ambient temperature, the methanol was removed under reduced pressure. The pH value of the remaining aqueous layer was carefully adjusted to 7 with sodium bicarbonate (aq., 1 M. Note: significant gas evolution). The aqueous phase was extracted with 2×200 mL of ethyl acetate and the combined organic layers were washed with 2×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:50) as eluent to furnish 20.0 g (95%) of methyl 4-chloro-5-iodo-2-methylbenzoate as a light yellow liquid.
Reaction SMILES: [NH:1]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:2]([C:11]([N:13]1[CH2:25][CH2:24][CH2:23][C@H:14]1[C:15]([NH:17][C@@H:18]([C:20]([NH2:22])=[O:21])[CH3:19])=[O:16])=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][CH:8]([CH3:10])[CH3:9].[C:33](Cl)([O:35][CH2:36][CH:37]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34]>C1COCC1.CCOC(C)=O>[NH:1]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:2]([C:11]([N:13]1[CH2:25][CH2:24][CH2:23][C@H:14]1[C:15]([NH:17][C@@H:18]([C:20]([NH2:22])=[O:21])[CH3:19])=[O:16])=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]([C:33]([O:35][CH2:36][CH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:44]2[C:49]1=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:34])[CH:8]([CH3:10])[CH3:9]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C)C(N)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)N(CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C)C(N)=O)C(=O)OCC1c2ccccc2-c2ccccc21
Yield: 79.3 %

Procedure:
A solution of Boc-Lys(iPr)-Pro-D-Ala-NH2 (9.11 gm) in 10% Na2 CO3 (25 mL) and THF (30 mL) was cooled to 0° C. and treated with a solution of Fmoc-Cl (6.46 gm) in THF. After 1 hour at 0° C. the mixture was partitioned between EtOAc (200 mL) and water (100 mL) and the layers were separated. The organic layer was washed with water (100 mL), 10% citric acid (2×100 mL) and water (100 mL), then dried over Na2SO4 and evaporated to dryness to yield an oil. The residue was dissolved in EtOAc and precipitated from heptane to yield 11.66 gm of crude product. This material was dissolved in a small in EtOAc and loaded onto a silica gel (200 gm) column which was eluted with an EtOAc/heptane mixture (2/1), followed by EtOAc and finally by ethanol. The product-containing fractions were combined and evaporated in vacuo to dryness to yield an oil. The residue was dissolved in a small amount of EtOAc and precipitated from heptane to yield 10.75 gm of Boc-Lys(iPr,Fmoc)-Pro-D-Ala-NH2. HPLC: 98.1%, MS: (M+H)+ =678, (M+NH4)+ =695, [a]D=-12.2 (c=1, HOAc)
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH3:21])=[C:10]([CH2:12][O:13][C@@H:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([OH:20])[CH2:15]3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].C(O)(=O)C>CO>[C:1]1([C:7]2[O:8][C:9]([CH3:21])=[C:10]([CH2:12][O:13][C@H:14]3[CH2:19][CH2:18][CH2:17][C@@H:16]([OH:20])[CH2:15]3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1oc(-c2ccccc2)nc1CO[C@@H]1CCC[C@H](O)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CO[C@H]1CCC[C@@H](O)C1
Reaction time: 3 h
Yield: 87.5 %

Procedure:
0.96 g of the (1R,3S)-acetyl compound from Example 20 was dissolved in approx. 5–10 ml of MeOH, admixed with 0.1 ml of NaOMe (30%) and stirred at 20–23° C. After 3 h, the mixture was neutralized with acetic acid and concentrated under reduced pressure, taken up with ethyl acetate, washed with saturated NaHCO3, dried (MgSO4) and concentrated under reduced pressure. After filtration through silica gel (10:1–0:1 n-heptane/ethyl acetate), 0.84 g of the desired (1R,3S)-3-[2-phenyl-5-methyloxazol-4-ylmethoxy]cyclohexan-1-ol having 95% ee (HPLC on Chiralpak AD 250×4.6; 1 ml/min, 25:1:0.5 heptane/EtOH/CH3CN+0.1% TFA) was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].Br[CH2:24][C:25]1[CH:34]=[CH:33][C:28]2[O:29][CH2:30][CH2:31][O:32][C:27]=2[CH:26]=1.BrCC1CCCCO1>>[O:29]1[C:28]2[CH:33]=[CH:34][C:25]([CH2:24][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]4([C:21]5[C:12](=[CH:13][C:14]6[O:19][CH2:18][CH2:17][O:16][C:15]=6[CH:20]=5)[O:11][CH2:10]4)[C:2]3=[O:22])=[CH:26][C:27]=2[O:32][CH2:31][CH2:30]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: BrCc1ccc2c(c1)OCCO2
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc3c(c2)OCCO3)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 6-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxine (Capilla, A. S. et al., Tetrahedron, (2001), 57:8297-304) to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (100%) as a colorless solid: mp 120-123° C. (hexanes/diethyl ether); 1H NMR (300 MHz, CDCl3) δ7.20 (ddd, J=7.8, 7.5, 1.2 Hz, 1H), 7.15 (dd, J=7.4, 0.8 Hz, 1H), 7.01 (ddd, J=7.5, 7.4, 0.7 Hz, 1H), 6.85-6.79 (m, 4H), 6.50 (s, 1H), 6.24 (s, 1H), 4.93 (d, J=8.7 Hz, 1H), 4.92 (d, J=15.5 Hz, 1H), 4.76 (d, J=15.5 Hz, 1H), 4.65 (d, J=8.7 Hz, 1H), 4.23 (s, 4H), 4.22-4.17 (m, 2H), 4.14-4.10 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.5, 155.4, 144.7, 143.8, 143.3, 142.3, 138.4, 132.4, 129.0, 128.9, 123.9, 123.4, 121.2, 120.5, 117.8, 116.5, 111.8, 109.5, 99.5, 80.4, 64.6, 64.44, 64.41, 64.0, 58.2, 43.8; MS (ES+) m/z 444.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][C:18]1[CH:17]=[CH:16][C:15]([O:14][C:13]([F:12])([F:24])[F:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc([N+](=O)[O-])cc1Oc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
A mixture of 2-methyl-5-nitrophenol (765 mg, 5.00 mmol), 4-(trifluoromethoxy)benzeneboronic acid (1.24 g, 6.00 mmol), copper(II) acetate (999 mg, 5.50 mmol), triethylamine (3.48 ml, 25.0 mmol), molecular sieves 4A and dichloromethane (20.0 ml) was stirred at room temperature overnight under argon atmosphere. The reaction mixture was filtered through celite. The residue obtained by evaporation of the solvent of the filtrate under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=20:1) to give the title compound (323 mg, 20.6%) as a colorless oil.