Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[BrH:15].[CH2:16]([NH2:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[OH2:12].[BrH:15].[CH3:14][C:4]1[CH:3]=[C:2]([NH:24][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=1.[CH3:14][C:4]1[CH:3]=[C:2]([NH:24][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=1.[BrH:15]
Reactant: COc1ccc2nc(C)cc(Cl)c2c1
Reactant: CCCCCCCCN
Agent: Br
Product: CCCCCCCCNc1cc(C)nc2ccc(O)cc12
Product: O
Temperature: 25 °C
Yield: 12 %

Procedure:
In a 100 mL three-neck round bottom flask under a nitrogen atmosphere and with magnetic stirring, a solution of 1.0 g (4.8 mmol) of 4-chloro-6-methoxy-2-methylquinoline and 10 mL of n-octylamine was heated under reflux for three hours. Upon cooling to room temperature, the reaction mixture formed a glassy solid which was filtered. This was triturated under isopropyl ether filtered and washed with additional ether. The solid was stirred with a mixture of water and ethyl acetate; insolubles were filtered and discarded; the ethyl acetate layer eventually furnished 500 mg of 6-methoxy-2-methyl-N-octylquinolin-4-amine hydrochloride: m.p. 178°-179° C. Without further purification, a solution of 350 mg (1.04 mmol) of this material and 42 mL of 48% hydrobromic acid was heated reflux for 18 hours. Upon cooling, the reaction solution gave a precipitate which was filtered. The filtrate was evaporated to furnish a solid residue. The combined solids were recrystallized from hot water to give 45 mg (12%) of 2-methyl-4-octylaminoquinolin-6-ol hydrobromide hemihydrate: m.p. 176°-178° C.
Reaction SMILES: [CH3:1][CH2:2][OH:3].[O-:4][CH2:5][CH3:6].[Na+].Cl[C:9](Cl)(Cl)[C:10]([C:12]1[NH:13]C(CC)=[CH:15][CH:16]=1)=O.Cl>C(OCC)C>[CH2:16]([C:12]1[NH:13][C:1]([C:2]([O:4][CH2:5][CH3:6])=[O:3])=[CH:9][CH:10]=1)[CH3:15]
Reactant: CC[O-]
Reactant: CCc1ccc(C(=O)C(Cl)(Cl)Cl)[nH]1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)c1ccc(CC)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Absolute EtOH (6 ml) was added to a 21 wt % solution of sodium ethoxide in EtOH (0.33 ml, 1.05 mmol) followed by the portion-wise addition of 2,2,2-trichloro-1-(5-ethyl-1H-pyrrol-2-yl)ethanone (J. Chem. Soc. Perkin Trans 1, 1996, 03) (2.1 g, 8.75 mmol) under nitrogen. The resulting yellow solution was stirred at room temperature for 30 minutes. Then the reaction was concentrated to give light orange oil. Hydrochloric acid (3 M, 2.5 ml) and diethyl ether (8 ml) were added to the oil and layers separated. The aqueous layer was extracted with diethyl ether (×2) and the combined organic extracts were washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated to give the desired product as a white solid (1.27 g, 86%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:28](=[O:29])[N:12]2[C:13]([C:25]([OH:27])=[O:26])=[C:14]([CH2:17]OC(=O)CC(=O)C)[CH2:15][S:16][C@H:11]12)=[O:8].[S:30]([O-:33])([O-:32])=[O:31].[Na+:34].[Na+:35].Cl>O1CCCC1.O>[Na:34][Na:35].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:28](=[O:29])[N:12]2[C:13]([C:25]([OH:27])=[O:26])=[C:14]([CH2:17][S:30]([OH:33])(=[O:32])=[O:31])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=S([O-])[O-]
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: [Na+]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CS(=O)(=O)O)CS[C@H]12
Product: [Na][Na]
Yield: 37.1 %

Procedure:
In a mixture of tetrahydrofuran (5 ml) and water (10 ml) were dissolved 7β-(2-thienylacetamido)-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid (876 mg) and sodium sulfite (504 mg) and the resultant solution was stirred for 120 minutes at 60° C. To the reaction mixture was added water (10 ml) and the mixture was adjusted its pH to 7.2 with 2 N-HCl, followed by condensation under reduced pressure. The residue was subjected to column-chromatography of silica-gel and eluted with acetonitrile-water (7:1-5:1). The fractions containing the objective compound were combined and the mixture was subjected to distillation of acetonitrile. The residue was chromatographed on column packed with Amberlite XAD-2 and eluted with water and then water-methanol. The fractions containing the objective compound were combined and the mixture was condensed under reduced pressure, followed by freeze-drying to give disodium salt of 7β-(2-thienylacetamido)-3-sulfomethyl-3-cephem-4-carboxylic acid (310 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]=12.[Cl:12][C:13]1[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([CH2:20]Cl)[C:14]=1[CH3:22].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[N:9]([CH2:20][C:15]3[C:14]([CH3:22])=[C:13]([Cl:12])[C:18]([CH3:19])=[CH:17][N:16]=3)[N:10]=[CH:11][C:3]=12
Reactant: Cc1cnc(CCl)c(C)c1Cl
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cnc(Cn2ncc3c(Cl)nc(N)nc32)c(C)c1Cl
Temperature: 80 °C

Procedure:
A mixture of 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (158 mg), crude 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine (204 mg), Cs2CO3 (660 mg) and DMF was heated to 80° C. for 1.5 h, diluted with EtOAc and washed with water. The crude material was concentrated and suspended in MeOH/DCM. Filtration gave a 2:1 mixture of regioisomers which was further purified by preparative silica gel plate (EtOAc 100%). The major (less polar) isomer corresponded to the title compound. R.t. 5.45 min. 1H-NMR (CDCl3) δ 8.22 (s, 1H), 7.90 (s, 1H), 5.57 (s, 2H), 5.28 (s, 2H), 2.43 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: S(=O)(=O)(O)O.C(OC[O:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]2[CH:25]=[C:26]([C:30]([OH:47])([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([CH3:46])([O:39]C3CCCCO3)[CH3:38])[CH3:31])[CH:27]=[CH:28][CH:29]=2)[CH:14]=[C:15]([O:17]COCC)[CH:16]=1)C.[CH3:48]O>C1COCC1>[OH:39][C:37]([CH3:38])([CH3:46])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][C:30]([C:26]1[CH:25]=[C:24]([CH:23]=[CH:22][C:13]2[CH:14]=[C:15]([OH:17])[CH:16]=[C:11]([OH:10])[CH:12]=2)[CH:29]=[CH:28][CH:27]=1)([O:47][CH3:48])[CH3:31]
Reactant: CCOCOc1cc(C=Cc2cccc(C(C)(O)CCCCCC(C)(C)OC3CCCCO3)c2)cc(OCOCC)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: COC(C)(CCCCCC(C)(C)O)c1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 1(j), by reacting 0.2 ml of concentrated sulphuric acid in 3 ml of methanol with 350 mg (0.6 mmol) of 2-{3-[2-(3,5-bis-ethoxymethoxyphenyl)vinyl]phenyl}-8-methyl-8-(tetrahydropyran-2-yloxy)nonan-2-ol in 3 ml of methanol and 3 ml of THF, after purification on a silica column (ethyl acetate 60-heptane 40), white crystals (m=76 mg; Y=32%) are obtained. m.p.=65-75° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:42]([O:49][C:50]([CH2:52][O:53][C:54](=[O:75])[C@@:55]([CH2:73][OH:74])([CH3:72])[CH2:56][C@H:57]([NH2:71])[CH2:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)=[CH:61][CH:60]=1)=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH2:42]([O:49][C:50]([CH2:52][O:53][C:54](=[O:75])[C@@:55]([CH2:73][OH:74])([CH3:72])[CH2:56][C@H:57]([NH:71][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:58][C:59]1[CH:60]=[CH:61][C:62]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)=[CH:63][CH:64]=1)=[O:51])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCC(=O)OCc1ccccc1
Reactant: O=C(O)c1c[nH]nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)OCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.5 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid benzyloxycarbonylmethyl ester (57.2 mg, 124 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (19 mg; purity 95%). MS m/z [M+H]+ calc'd for C31H32N4O6, 557.23. found 557.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[OH:11])[CH3:2].Cl[CH2:13][CH2:14][CH2:15][O:16][CH3:17]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH3:2]
Reactant: COCCCCl
Reactant: CCOc1ccc(C)cc1O
Product: CCOc1ccc(C)cc1OCCCOC

Procedure:
Analogously to Method F, 5.05 g of 2-ethoxy-5-methylphenol and 4.03 g of 1-chloro-3-methoxypropane are reacted. The title compound is obtained as a slightly orange oil. Rf=0.32 (1:4 EtOAc-heptane); Rt=4.60
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:11][CH3:12])[C:6]=2[N:5]=[C:4]2[CH2:13][CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17](=[O:18])[C:3]=12.[CH3:23][NH2:24]>>[CH2:11]([N:10]1[C:6]2[N:5]=[C:4]3[CH2:13][CH2:14][C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[C:17](=[O:18])[C:3]3=[C:2]([NH:24][CH3:23])[C:7]=2[CH:8]=[N:9]1)[CH3:12]
Reactant: CN
Reactant: CCn1ncc2c(Cl)c3c(nc21)CCc1ccccc1C3=O
Product: CCn1ncc2c(NC)c3c(nc21)CCc1ccccc1C3=O
Reaction time: 5 h

Procedure:
8.4 g. of 4-chloro-1ethyl-10,11-dihydrobenzo [4,5]cyclohepta [1,2-b ]pyrazolo [4,3-e ]pyridin-5(1H)one (0.027 mol.) dissolved in 90 ml. of an alcoholic methylamine solution (270 g/1) are allowed to stand at room temperature for five hours. After this time, 7.1 g. of precipitated 1-ethyl-10,11-dihydro-4-(methylamino)benzo [4,5]cyclohepta [1,2-b ]pyrazolo-[4,3-e ]pyridin-5(1H)one are collected, m.p. 148°-150°. A sample recrystallized from absolute ethanol melts at 149°-150°.
Reaction SMILES: F[C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[NH:12][C:11]2=[NH:19])=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][N:24]=1.[Na+].[Br-]>CC(=O)CC>[ClH:22].[Cl:22][C:23]1[N:24]=[CH:25][C:26]([CH2:29][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH2:9][CH2:8][CH2:7][O:6][C:5]3[CH:20]=[CH:21][CH:2]=[CH:3][CH:4]=3)[C:11]2=[NH:19])=[CH:27][CH:28]=1
Reactant: N=c1[nH]c2ccccc2n1CCCOc1ccc(F)cc1
Reactant: ClCc1ccc(Cl)nc1
Agent: [Br-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: Cl
Product: N=c1n(CCCOc2ccccc2)c2ccccc2n1Cc1ccc(Cl)nc1
Temperature: 90 °C
Yield: 53.2 %

Procedure:
To a solution of 1-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (2.0 g, 7.01 mmol) in 2-butanone (25 ml) at rt was added 2-chloro-5-chloromethyl-pyridine (2.27 g, 14.0 mmol) followed by NaBr (0.715 g, 7.01 mmol). The reaction was heated to 90° C. where it was maintained for 4 d. After this time, the suspension was cooled to rt and filtered. The collected solid was washed with additional 2-butanone and then dried to give 1-(6-chloro-pyridin-3-ylmethyl)-3-(3-phenoxy-propyl)-1,3-dihydro-benzoimidazol-2-ylideneamine, hydrochloride salt (1.6 g, 51%) which was used without further purification. HPLC-MS 411, 413 [M+1]+.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:11]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC(OCC)OCC)C>[N:5]1[CH:6]=[CH:7][C:2]([C:1]2[O:8][CH:11]=[N:10][N:9]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NNC(=O)c1ccncc1
Solvent: CCOC(OCC)OCC
Product: c1cc(-c2nnco2)ccn1
Temperature: 130 °C
Yield: 57738.3 %

Procedure:
A mixture of the isonicotinic hydrazide (13.7 g, 100 mmol), triethylorthoformate (60 mL) and p-toluenesulfonic acid (30 mg) was heated at 130° C. for 12 h. Excess triethylorthoformate was removed under vacuum. The crude was crystallized from ethyl acetate to give 14.8 g of 5-pyridin-4-yl-[1,3,4]oxadiazole.
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].[Br:19][C:20]1[C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=[CH:23][C:21]=1N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Br:19][C:20]1[C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=[CH:23][C:21]=1[NH:13][C:12]1[C:11]2[C:10](=[CH:9][CH:8]=[C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]3=2)[N:14]=[CH:15][N:16]=1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccc2c(c1Br)OCO2
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc5c(c4Br)OCO5)c3c2s1
Yield: 21 %

Procedure:
Prepared from VII and 2-bromo-3,4-(methylenedioxy)aniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 21%; yellow solid, mp>260° C.; IR (KBr) νmax/cm−1 2887, 2233, 1632, 1610, 1581, 1501, 1484, 1465, 1379, 1348, 1303, 1267, 1232, 1161, 1116, 1034, 970, 929, 829; 1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, 1H, J=9.0 Hz), 8.06 (s, 1H), 7.77 (d, 1H, J=9.0 Hz), 7.25 (s, 1H), 6.83 (s, 1H), 6.06 (s, 2H); HRMS calcd for C17H9N5O2SBr (M+H+): 425.9660, found 425.9646.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8](C)[CH2:9][CH2:10][C:11]([O:13]C)=O)[CH:5]=[CH:6][CH:7]=1.[CH3:16][NH:17][CH3:18].Cl>O>[CH3:16][N:17]([CH3:18])[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: COC(=O)CCC(C)c1cccc(O)c1
Reactant: CNC
Agent: Cl
Solvent: O
Product: CN(C)C(=O)CCCc1cccc(O)c1
Reaction time: 25 h
Yield: 41 %

Procedure:
A mixture of 3.7 g of methyl 4-(3-hydroxyphenyl)pentanoate and 40 mL of 40% dimethylamine in water was stirred for 25 hours. The mixture was acidified with 5N hydrochloric acid and extracted with dichloromethane. The organic phase was washed with a saturated sodium chloride solution, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with ethyl ether/methanol to provide 1.62 g (41%) of the title intermediate. NMR
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5](=[O:10])[CH:4]=[N:3]1.[Br:11]Br>O>[Br:11][C:4]1[C:5](=[O:10])[N:6]([CH3:9])[C:7](=[O:8])[N:2]([CH3:1])[N:3]=1
Reactant: BrBr
Reactant: Cn1ncc(=O)n(C)c1=O
Solvent: O
Product: Cn1nc(Br)c(=O)n(C)c1=O
Temperature: 60 °C

Procedure:
The compound 17a (13.3 g, 94.1 mmol) is placed in 100 ml of water in the presence of bromine (18 ml, 351 mmol) and then this mixture is heated at 60° C. for 12 h.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][C@H:11]([CH3:13])[NH:10][CH2:9][C@H:8]2[CH3:14])=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:27]=[C:26]2[C:21]([CH2:22][CH2:23][C:24](=[O:28])[O:25]2)=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C@@H:8]([CH3:14])[CH2:9][N:10]([C:24](=[O:28])[CH2:23][CH2:22][C:21]3[CH:20]=[CH:19][C:18]([CH3:17])=[CH:27][C:26]=3[OH:25])[C@H:11]([CH3:13])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccc(F)cc1
Reactant: Cc1ccc2c(c1)OC(=O)CC2
Solvent: Cc1ccccc1
Product: Cc1ccc(CCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(O)c1
Yield: 79 %

Procedure:
To a solution of (2R,5S)-1-(4-fluoro-benzyl)-2,5-dimethyl-piperazine (0.25 g, 1.12 mmol) in toluene (10 mL) was added 7-methyl-chroman-2-one (0.25 g, 1.54 mmol) and the resulting solution was heated to reflux for 48 hours. The reaction was cooled, concentrated in vacuo and purified via chromatography on silica gel to give the title compound (0.34 g).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[N+:9]([C:12]1[CH:13]=[C:14]([OH:22])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)([O-:11])=[O:10].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O>[N+:9]([C:12]1[CH:13]=[C:14]([CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:17]=1)[O:22][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)([O-:11])=[O:10]
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCCN2CCCC2)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A mixture of 1-(2-chloroethyl)pyrrolidine (0.355 g, 2.66 mmol), 3-nitro-5-(trifluoromethyl)phenol (0.500 g, 2.41 nmmol), Cs2CO3 (2.36 g, 7.24 mmol), and DMF (18.69 mL) was allowed to stir at rt until reaction was judged to be complete. The mixture was diluted with EtOAc and washed with water (3×25 mL). The organic solution was dried over Na2SO4, filtered, and concentrated to give 3-(2-pyrrohidin-1-ylethoxy)-5-(trifluoromethyl)anlline as a brown oil (0.49 g, 63%). LCMS: (FA) ES+ 304.3.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(N(CC)CC)C.[CH2:25]([CH:32]1[CH2:37][CH2:36][N:35]([C:38](=[O:42])[C:39](Cl)=[O:40])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[CH2:25]([CH:32]1[CH2:33][CH2:34][N:35]([C:38](=[O:42])[C:39]([NH:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][CH2:9][CH2:10]3)=[O:40])[CH2:36][CH2:37]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc21
Reactant: O=C(Cl)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(c1)CCN2)C(=O)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a stirred solution of 0.5 g (2.25 mmol) of 5-amino-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester and 0.4 ml (2.8 mmol) of triethylamine in 20 ml of chloroform 0.7 g (2.6 mmol) of (4-benzyl-piperidin-1-yl)-oxo-acetyl chloride in 10 ml of chloroform is added dropwise at 0° C. The reaction mixture is stirred at room temperature for 1 hour, then washed with water and the organic layer is concentrated. The residue is purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent to yield 0.9 g (88.7%) of the title compound as solid. The crude product is used in the next step.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:35][Mg]Cl>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([OH:34])([CH3:35])[CH3:33])=[CH:30][CH:31]=2)=[CH:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 1-{4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-ethanone (prepared as in Example 80, 450 mg, 0.95 mmol) in dry tetrahydrofuran (20 mL) at 0° C. was added methylmagnesium chloride solution in tetrahydrofuran (3.0 M, 0.7 mL, 2.1 mmol) dropwise. After stirring at 0° C. for 1 h, the reaction was quenched with a saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 2-{4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-propan-2-ol (440 mg, 94%) as a white solid: LC/MS m/e calcd for C29H30N2O3S [M+H]+ 487.64, observed 487.2.
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.O.[CH3:25][C:26]1([CH3:39])[O:31][C:30](=[O:32])[CH:29]=[C:28]([CH2:33][CH2:34][CH2:35][C:36](=[O:38])[CH3:37])[O:27]1>C(OCC)(=O)C>[CH3:39][C:26]1([CH3:25])[O:31][C:30](=[O:32])[CH:29]=[C:28]([CH2:33][CH2:34][CH2:35][CH:36]([OH:38])[CH3:37])[O:27]1
Reactant: CC(=O)CCCC1=CC(=O)OC(C)(C)O1
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(O)CCCC1=CC(=O)OC(C)(C)O1
Temperature: 32 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
30 g of baker's yeast (made by Oriental Yeast Co., Ltd.) and 15 g of saccharose were added in 30 ml of tap water, and the solution was then stirred at 32° C. for 30 minutes. Afterward, 300 mg of 2,2-dimethyl-6-(4-oxopentyl)-1,3-dioxin-4-one were added thereto, and the solution was then stirred overnight at the same temperature. 7.5 g of saccharose were further added thereto, followed by stirring overnight. Water of the reaction solution was then distilled off under reduced pressure, and the resultant residue was extracted with dichloromethane and then dried over anhydrous sodium sulfate. Afterward, the solvent was distilled off, and the resultant residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate=4:1), thereby obtaining 148 mg (yield 50%) of (-)-2,2-dimethyl-6-(4-hydroxypentyl)-1,3-dioxin-4-one [a compound having the formula (1) in which n is 3, X is a hydrogen atom, Y is a hydrogen atom, and a subtituent is present at the 6-position].
Reaction SMILES: [CH3:1][Mg]Cl.C(OC(=O)[C:8]([F:27])([F:26])[C@@:9]([C:18]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([Br:25])[N:19]=1)([NH:11][S@@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH3:10])C.[CH2:29]1[CH2:33][O:32]CC1>>[Br:25][C:20]1[N:19]=[C:18]([C@:9]([NH:11][S@@:12]([C:14]([CH3:16])([CH3:15])[CH3:17])=[O:13])([CH3:10])[C:8]([F:26])([F:27])[C:33]([OH:32])([CH3:29])[CH3:1])[C:23]([F:24])=[CH:22][CH:21]=1
Reactant: C1CCOC1
Reactant: C[Mg]Cl
Reactant: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)c1nc(Br)ccc1F
Product: CC(C)(C)[S@@](=O)N[C@](C)(c1nc(Br)ccc1F)C(F)(F)C(C)(C)O
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To methylmagnesium chloride 3M in THF (38.3 ml, 115 mmol) was added a solution of (R)-3-(6-bromo-3-fluoro-pyridin-2-yl)-2,2-difluoro-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester (5.12 g, 11.5 mmol, example 1e)) in THF (102 ml) at rt. After 2 hr stirring the reaction was quenched with addition of an aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude product (4.78 g) was chromatographed over silica gel (cyclohexane/ethyl acetate 6:4) to give the title compound as a colourless solid. 2.97 g (59.9% yield).