Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:25]=[CH:24][C:10]([CH2:11][O:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].CNN>ClCCl>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][O:12][NH2:13])=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Agent: CNN
Solvent: ClCCl
Product: CCCCCOc1ccc(CON)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a stirred solution N-hydroxyphthalimide (2.45 g), 4-pentyloxybenzyl alcohol (Aldrich, 2.92 g) and triphenylphosphine (4.72 g) in THF was added drop-wise diethyl azodicarboxylate (1.2 eq.). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was subjected to column chromatography on silica gel (petroleum ether/EtOAc, 1/2, v/v) and gave 2-(4-pentyloxy-benzyloxy)-isoindole-1,3-dione. This phthalimide intermediate (4.35 g) was dissolved in dichloromethane and methyl-hydrazine (1.1 eq.) was added. The reaction mixture stirred at room temperature for 60 minutes and the formed solid material was removed by filtration. The filtrate was evaporated under reduced pressure and the residue was subjected to column chromatography on silica gel (petroleum ether/EtOAc, 5/1, v/v), and gave the title compound (2.55 g). 13C-NMR (CDCl3) δ 159.1, 130.1, 129.2, 114.5, 77.7, 68.0, 29.0, 28.2, 22.5, 14.0.
Reaction SMILES: C[Si](Cl)(C)C.Cl[C:7]([F:18])([F:17])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:9].[I:19]I.O>C(#N)C.[Zn]>[F:17][C:7]([F:18])([I:19])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:9]
Reactant: Cc1ccccc1C(=O)C(F)(F)Cl
Reactant: II
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: O
Solvent: CC#N
Product: Cc1ccccc1C(=O)C(F)(F)I
Temperature: 55 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
To a suspension of zinc (1.6 g) in acetonitrile (40 mL) were added trimethylsilyl chloride (3.1 mL) and 2-chloro-2,2-difluoro-1-(2-methylphenyl)ethanone (4.0 g), and the mixture was stirred at 55° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, iodine (3.5 g) was added, and the mixture was further stirred for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with aqueous sodium hydrogen sulfite solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane) to give the title compound as a yellow oil (yield 2.6 g, 46%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][C:10]([OH:12])=O.C([Cl:16])(=O)C.P(Cl)(Cl)(Cl)(Cl)Cl>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][C:10]([Cl:16])=[O:12]
Reactant: O=C(O)COc1ccccn1
Reactant: CC(=O)Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=C(Cl)COc1ccccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-(2-pyridyloxy)acetic acid hydrochloride (1.5 g) and acetyl chloride (8 ml) was added at -30° C. phosphorus pentachloride (3.3 g), and the mixture was stirred at room temperature for 18 hours. Precipitated crystals were collected by filtration and washed with a small amount of acetyl chloride and diethyl ether and dried to give 2-(2-pyridyloxy)acetyl chloride (1.3 g). A mixture of 7-(D-2-phenylglycinamido)-3-methyl-3-cephem-4-carboxylic acid (2.5 g) and trimethylsilylacetamide (0.0288 mole) in methylene chloride (70 ml) was stirred for 1.5 hours. The solution was cooled to 3° C. and the above obtained 2-(2-Pyridyloxy)acetyl chloride was added thereto. The resultant mixture was stirred under ice-cooling for 2 hours and concentrated. To the residue was added ice-water and the resultant powder was filtrated and washed with acetone containing water and acetone in turn to give powder (1.4 g). The filtrate and washings were collected together and extracted with ethyl acetate four times. The ethyl acetate extracts were washed with water, dried and concentrated to give powder (0.4 g). Thus obtained powders (1.4 g) and (0.4 g) were combined together and recrystallized from methanol to give crystals (0.9 g) of 7-{D-2-[2-(2-pyridyloxy)acetamido]-2-phenylacetamido}-3-methyl-3-cephem-4-carboxylic acid, mp 209° to 211° C. (dec).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[N:11](C2CCCCO2)[N:10]=[C:9]3[C:21]2[CH:22]=[C:23](O)[CH:24]=[CH:25][CH:26]=2)=[N:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[N:59]1[CH:64]=[CH:63][CH:62]=[C:61]([CH2:65][OH:66])[CH:60]=1.Cl>O1CCCC1>[NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:14]=[C:13]([O:66][CH2:65][C:61]3[CH:60]=[N:59][CH:64]=[CH:63][CH:62]=3)[CH:12]=[C:8]([C:9]3[C:21]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:11][N:10]=3)[CH:7]=2)=[N:2]1
Reactant: Oc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4nc[nH]n4)cc23)c1
Reactant: OCc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cncc(COc2cc(-c3nc[nH]n3)cc(-c3n[nH]c4ccccc34)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
The title compound was prepared from 3-(5-(1H-1,2,4-triazol-3-yl)-1-perhydro-2H-pyran-2-yl-1H-indazol-3-yl)phenol (0.394 g, 0.65 mmol), triphenyl phosphine (0.685 g, 2.61 mmol), diethyl azodicarboxylate (0.41 mL, 2.61 mmol), 3-pyridylcarbinol (0.26 mL, 2.67 mmol) in tetrahydrofuran (2.5 mL) and was allowed to stir at room temperature overnight. To this mixture 6 N hydrogen chloride (20 mL) was added and allowed to stir at room temperature for 5 hours. This reaction was extracted with diethyl ether (3×), basified to pH˜11 with 6 N sodium hydroxide (aqueous), extracted with ethyl acetate (3×). The organic fractions were combined and dried with sodium sulfate, filtered, and condensed. The compound was purified by column chromatography (SiO2, 100% ethyl acetate in hexanes to 95% ethyl acetate in 5% methanol) and preparative HPLC (15–80% acetonitrile to H2O, 30 min.) (0.028 g, 12% yield over 2 steps): 1H NMR (CD3OD) δ 8.72 (m, 2H), 8.51 (dd, 1H), 8.11 (br s, 1H), 8.03 (dd, 1H), 7.68 (m, 3H), 7.50 (m, 2H), 7.13 (ddd, 1H), 5.30 (s, 2H); ES-MS (m/z) 369 [M+1]+.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16]C)=[O:15])(C)C.C1COCC1.CO.O.[OH-].[Li+]>O>[C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([OH:16])=[O:15])#[CH:5]
Reactant: COC(=O)Cc1ccccc1C#C[Si](C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C#Cc1ccccc1CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
To a solution of ester 319 (4.65 g, 18.9 mmol) in 1:1 THF/methanol (100 mL) was added lithium hydroxide monohydrate (1.60 g, 38.1 mmol) in water (25 mL) and the mixture was stirred at r.t. for 30 min. It was then partially concentrated, the aqueous residue was washed with ether, then acidified with 3M HCl (aq) and extracted with ethyl acetate. The organic extract was washed with water, dried (anhydrous MgSO4), filtered and concentrated. The residue was dissolved in ethyl acetate, run through a short plug of silica gel, and concentrated to provide 320 (2.77 g, 92% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.40 (br s, 1H); 7.45 (d, J=8.0 Hz, 1H), 7.37-7.24 (m, 3H), 4.36 (s, 1H); 3.72 (s, 2H). LCMS: (M+Na) 183.1
Reaction SMILES: O=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH2:3]1.[CH3:10][C:11]1([CH3:32])[O:15][C@@H:14]2[C@@H:16]([CH2:29][NH:30][CH3:31])[O:17][C@@H:18]([N:19]3[CH:27]=[N:26][C:25]4[C:20]3=[N:21][CH:22]=[N:23][C:24]=4[NH2:28])[C@@H:13]2[O:12]1.[BH3-]C#N.[Na+]>CO>[CH3:9][O:8][C:6]([CH:4]1[CH2:5][CH:2]([N:30]([CH2:29][C@@H:16]2[C@@H:14]3[C@@H:13]([O:12][C:11]([CH3:32])([CH3:10])[O:15]3)[C@H:18]([N:19]3[CH:27]=[N:26][C:25]4[C:20]3=[N:21][CH:22]=[N:23][C:24]=4[NH2:28])[O:17]2)[CH3:31])[CH2:3]1)=[O:7]
Reactant: COC(=O)C1CC(=O)C1
Reactant: CNC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CC(N(C)C[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@@H]3OC(C)(C)O[C@@H]32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A solution of methyl 3-oxocyclobutanecarboxylate (1.28 g crude), 9-((3aR,4R,6R,6aR)-2,2-dimethyl-6-((methylamino)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (2.0 g, 6.25 mmol) (Townsend et al Org Lett 2009, 11, 2976-2679) and Ti(iPrO)4 (1.78 g, 6.25 mmol) in MeOH (50 mL) was stirred at 45° C. for 2 h, then NaCNBH3 (0.79 g, 12.50 mmol) was added. The reaction was stirred at RT overnight. The reaction was quenched with aq. sat. NaHCO3 (40 mL), filtered, extracted with DCM (40 mL×3), dried over Na2SO4 and concentrated. The residue was purified by SGC (DCM:MeOH=12:1) to obtain title compound (1.7 g, Yield 63%). 1H NMR (500 MHz, MeOD): δH 8.28-8.27 (m, 1H), 8.21 (s, 1H), 6.20-6.18 (m, 1H), 5.52 (dd, J=1.5, 6.0 Hz, 1H), 5.00 (dd, J=3.0, 6.0 Hz, 1H), 5.33 (brs, 1H), 3.65-3.63 (m, 3H), 2.77-2.55 (m, 4H), 2.19-2.11 (m, 5H), 2.00-1.82 (m, 2H), 1.59 (s, 3H), 1.38 (s, 3H) ppm; ESI-MS (m/z): 433.2 [M+1]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)(=O)=O.[C:21]([C:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1)#[CH:22].C(N(CC)CC)C.N>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[S:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[CH2:13][C:12]1[C:7]([C:22]#[C:21][C:23]2([OH:31])[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: O=S(=O)(Oc1ncccc1Cc1cccs1)C(F)(F)F
Agent: [Pd]
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1(C#Cc2ncccc2Cc2cccs2)CN2CCC1CC2
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 98.5 %

Procedure:
A mixture of 89 mg of 3-(2-thienylmethyl)-2-pyridyl trifluoromethanesulfonate, 50 mg of 3-ethynyl-3-quinuclidinol, 64 mg of tetrakis (triphenylphosphine) palladium(0), 11 mg of cuprous iodide, 105 μl of triethylamine and 3.0 ml of N,N-dimethylformamide was heated under stirring at 70° C. for 1.5 hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia, followed by extracting with ethyl acetate. Then, the organic phase was washed with brine and the solvent was removed, and the residue was subjected to NH-silica gel (Fuji silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (15:1), to give 88 mg of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:15][O:14][C@H:13]([C:16]([F:19])([F:18])[F:17])[C@H:12]1[CH2:11][O:10][NH:9]2>C(O)(=O)C.CCOC(C)=O.[Zn]>[NH2:9][C@@:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:15][O:14][C@H:13]([C:16]([F:19])([F:17])[F:18])[C@H:12]1[CH2:11][OH:10]
Reactant: Fc1ccccc1[C@]12CO[C@H](C(F)(F)F)[C@H]1CON2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N[C@@]1(c2ccccc2F)CO[C@H](C(F)(F)F)[C@H]1CO
Temperature: 0 °C
Reaction time: 16 h
Yield: 107.4 %

Procedure:
(3aR,4S,6aS)-6a-(2-fluorophenyl)-4-(trifluoromethyl)hexahydrofuro[3,4-c]isoxazole (28.76 g) was dissolved in acetic acid (200 mL) and the solution was cooled to 0° C. Zinc (50 g) was added, and the reaction mixture was allowed to warm and stir at RT for 16 h. The reaction mixture was then diluted with EtOAc (500 mL) and filtered through celite, washing with a further 500 mL of EtOAc. The combined organic portions were evaporated, dissolved in chloroform (200 mL), and ammonia (28% aq., 250 mL) was added slowly. The layers were separated, and the aqueous portion was further extracted with chloroform (2×250 mL). The combined organic extracts were dried over anhydrous MgSO4 and evaporated to afford the title compound (31.12 g) which was used in the subsequent step without further purification. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.93 (ddd, J=7.7, 4.9, 2.5 Hz, 1H), 3.84 (dd, J=12.4, 4.8 Hz, 1H), 4.05 (dd, J=9.2, 3.2 Hz, 1H), 4.17 (dd, J=12.4, 2.3 Hz, 1H), 4.31 (d, J=9.3 Hz, 1H), 4.72 (quin, J=7.3 Hz, 1H), 7.13 (ddd, J=13.1, 8.8, 1.3 Hz, 1H), 7.22 (td, J=7.6, 1.3 Hz, 1H), 7.31-7.40 (m, 1H), 7.51 (td, J=8.0, 1.6 Hz, 1H)
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][S:7][CH2:6][CH2:5]1.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]>O1CCOCC1>[S:7]1[CH2:8][CH2:9][CH:4]([O:3][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: OC1CCSCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccccc1OC1CCSCC1
Temperature: 90 °C
Yield: 83.7 %

Procedure:
To 50 ml of a dioxane suspension containing 0.96 g of 60% sodium hydride was added 3.6 g of 4-hydroxytetrahydrothiopyran at room temperature, and the mixture was stirred on heating at 90° C. with stirring for 6 hours. The temperature of the mixture was returned to room temperature, then 10 ml of a dioxane solution of 4.5 g of 2-fluoronitrobenzene was added dropwise, and the mixture was stirred overnight. The reaction solution was poured into ice water and extracted with ethyl ether, and the ethyl ether layer was washed, in turn, with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated, and 1.1 g of the resulting oil was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=10:1 ) to give 6.1 g of 2-(tetrahydro-4H-thiopyran-4-yloxy)nitrobenzene as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:26]=[N:25][NH:24][C:23]2=[O:27])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH:26]=[N:25][N:24]([C@H:12]([CH3:13])[C@:9]3([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[O:10][CH2:11]3)[C:23]2=[O:27])=[CH:20][CH:21]=1
Reactant: O=c1[nH]ncn1-c1ccc(Cl)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ncn(-c2ccc(Cl)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 18.5 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.66 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.65 g of 4-(4-chlorophenyl)-3(2H,4H)-1,2,4-triazolone, 0.23 g of 4-(4-chlorophenyl)-2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3(2H,4H)-1,2,4-triazolone was obtained as a colorless viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH:11]2[O:13][CH2:12]2)=[CH:5][CH:4]=1.[CH2:14]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH2:22]([N:21]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][CH:11]([OH:13])[CH2:10][O:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(OCC2CO2)cc1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCO
Product: COc1ccc(OCC(O)CN(Cc2ccccc2)Cc2ccccc2)cc1
Yield: 102.5 %

Procedure:
A solution of glycidyl 4-methoxyphenyl ether (1.10 g, 6.10 mmol), dibenzylamine (1.25 g, 6.33 mmol), and anhydrous ethyl alcohol (20 mL) was heated at 80° C. for 2 days. The solvent was evaporated under reduced pressure to give the title compound as a clear oil (2.36 g, 100%). 1H NMR (CDCl3) δ7.35-7.30 (m, 7 H), 7.28-7.25 (m, 3 H), 6.82-6.76 (m, 4 H), 4.10-4.07 (m 1 H), 3.83-3.81 (m, 3 H), 3.78-3.76 (m, 1 H), 3.76 (s, 3 H), 3.53 (d, 2 H, J=13.4 Hz), 2.66 (d, 2 H, J=6.5 Hz). Mass spectrum (LCMS, ESI) calcd. for C24H27NO3: 378 (M+H). Found: 378.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Br:24])[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH2:9][CH2:8]1)(=O)=O.Cl.[CH3:31][O:32][CH:33]1[CH2:37][CH2:36][NH:35][CH2:34]1.C([O-])([O-])=O.[K+].[K+].C(N(CC)C(C)C)(C)C>C(#N)C>[Br:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([C:25]([CH:27]1[CH2:28][CH2:29]1)=[O:26])=[C:14]2[NH:13][C@H:10]1[CH2:9][CH2:8][C@H:7]([CH2:6][N:35]2[CH2:36][CH2:37][CH:33]([O:32][CH3:31])[CH2:34]2)[CH2:12][CH2:11]1
Reactant: COC1CCNC1
Reactant: CS(=O)(=O)OC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC1CCN(C[C@H]2CC[C@H](Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)CC2)C1
Temperature: 80 °C

Procedure:
To a solution of (trans-4-((6-bromo-3-(cyclopropanecarbonyl)quinolin-4-yl)amino)cyclohexyl)methyl methanesulfonate (362 mg, 0.75 mmol) and 3-methoxypyrrolidine hydrochloride (410 mg, 2.98 mmol) in acetonitrile (15 mL) was added K2CO3 (1.24 g, 9 mmol) and KI (300 mg, 1.81 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.9 mmol) and the reaction mixture was heated at 50° C. for 16 h and 80° C. for 24 h. The solution was cooled to room temperature, diluted with satd. aq. NaHCO3 and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purification by column chromatography (silica, 0-20% methanol/dichloromethane) to afford the desired product (155 mg, 42%) as an off-white solid. ESI MS m/z 486 [C25H32BrN3O2+H]+
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1>CN(C=O)C>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([O:1][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(OCCOC2CCCCO2)c(C=O)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
To a vigorously stirred solution of 15,2 g (100 mmol) 2-hydroxy-5-methoxy-benzaldehyde and 42.4 g (130 mmol) caesium carbonate in 350 ml DMF at 0° C. was added 26.1 g (125 mmol) 2-(2-Bromo-ethoxy)-tetrahydro-pyran (J. Org. Chem.; 50; 22; (1985); 4238-4245) in 50 ml DMF dropwisely. The reaction mixture was stirred vigorously at 70° C. for 6 h. The solvent was evaporated. 200 ml water and 200 ml ethyl acetate were added. The organic phase was separated. The aqueous phase was extracted three times with 100 ml ethyl acetate each. The combined organic phases were washed with 50 ml water and 50 ml brine. The organic phase was dried with magnesium sulphate and evaporated. The crude product was purified by silica column chromatography (ethylacetate:hexane 1:3). The desired product 1a was obtained in 81% yield (22.7 g, 81 mmol) as yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.CN(C)C=O>O>[N+:8]([C:7]1[C:2]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccnc1Nc1ccc(O)cc1
Temperature: 50 °C

Procedure:
A mixture of 2-chloro-3-nitropyridine (2C3NP, 138.1 Kg), 4-aminophenol (2.5-3 equivalents) and N,N-dimethylformamide (DMF, 4.8 mL/g 2C3NP) was stirred until homogeneous, heated at 50° C. during which an exotherm raised the solution temperature to 70° C., warmed to 80-85° C., stirred until no 2-chloro-3-nitropyridine remained, cooled to 30° C., treated with water (10.6 mL/g 2C3NP) to precipitate product, then with acetic acid (1.2 mL/g 2C3NP), then with ethyl acetate (0.5 mL/g 2C3NP), cooled to 5° C., stirred for 2 hours and filtered. The filtrant was washed sequentially with distilled water (1.6 mL/g 2C3NP), cold ethanol (1.2 mL/g 2C3NP) and cold isopropyl ether (1.2 mL/g 2C3NP), and dried under vacuum.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[CH:2]1.[C:15]1([CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][NH2:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC#N>[C:24]1([CH:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:22][NH:23][C:11](=[O:12])[C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:14])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Solvent: CC#N
Product: O=C(NCC(c1ccccc1)c1ccccc1)C(=O)c1c[nH]c2ccccc12

Procedure:
N-(2,2-Diphenylethyl)-2-(1H-indol-3-yl)-2-oxo-acetamide was synthesized following the scheme I above starting from (1H-indol-3-yl)-oxo-acetyl chloride and 2,2-diphenyl-ethylamine. Yield (48%). HPLC ret. time 3.55 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.70 (t, J=5.9 Hz, 1H), 8.50 (s, 1H), 8.17 (m, 1H), 7.52 (m, 1H), 7.36-7.18 (m, 12H), 4.43 (t, J=8.0 Hz, 1H), 3.90 (dd, J=8.0, 6.0 Hz, 2H); ESI-MS 369.3 m/z (MH+).
Reaction SMILES: [Li+].[BH4-].[C:3]1([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([CH2:18][CH2:19]O)[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BrH:21]>>[C:3]1([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([CH2:18][CH2:19][Br:21])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCC1CC(c2ccccc2)c2ccccc21
Reactant: Br
Agent: [BH4-]
Agent: [Li+]
Product: BrCCC1CC(c2ccccc2)c2ccccc21

Procedure:
Ethyl 3-phenylindan-1-acetate (84.3 g, 0.3 mol) in THF (300 ml) was added dropwise with stirring to LiAlH4 (10 g) in THF (200 ml) under N2 and the mixture stirred at 80° C. overnight. Processing by standard conditions yielded 2-(3-phenylindan-1-yl)ethanol as an oil (47.3 g), IR 3100-3600 cm-1 (OH). This alcohol could also obtained by reduction of the ester in THF using LiBH4. The alcohol (43.15 g, 0.18 mol) was refluxed overnight with 48% HBr (280 ml), cooled, extracted with ether which, with standard processing, gave 2-(3-phenylindan-1-yl) ethyl bromide (50.8 g) as an oil. This bromo-compound (41.8 g, 0.14 mol) in Me2CO (160 ml) was added to a solution of NaCN (7 g, 0.143 mol) in H2O (40 ml) and the solution stirred and refluxed for 64 hours. The solution was evaporated to dryness and the product extracted with a mixture of AcOEt and H2O. After drying (Na2SO4), filtration and evaporation 3-(3-phenylindan-1-yl)propionitrile (26.8 g) was obtained as a solid, IR 2250 cm-1 (CN). This nitrile (24.3 g, 0.1 mol) in hot EtOCH2CH2OH (100 ml) was treated with NaOH (24.3 g, 0.6 mol) in H2O (40 ml) and the solution refluxed for 6 hours. It was then poured into conc. HCl (50 ml) in H2O (250 ml), extracted with Et2O and the Et2O extracted with 2N NaOH. Acidification gave the title compound. NMR (CCl4)δ1.5-3.3 (7H, CH2), 4.12 (1H, CH), 6.8-7.3 (9H,Ar), 11.92 (1H, exchangeable). cl EXAMPLE 3
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.[CH2:17]([C:19]1[O:20][C:21]([C:25](O)=[O:26])=[C:22]([CH3:24])[N:23]=1)[CH3:18].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>CN(C=O)C.[Cl-].[Na+].O.O>[CH2:17]([C:19]1[O:20][C:21]([C:25]([NH:13][C:12]2[CH:14]=[CH:15][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)=[O:26])=[C:22]([CH3:24])[N:23]=1)[CH3:18]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CCc1nc(C)c(C(=O)O)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(C)c(C(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.1 %

Procedure:
To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (360 mg, 1.643 mmol) in anhydrous DMF (8.2 mL) was added 2-ethyl-4-methyloxazole-5-carboxylic acid (306 mg, 1.972 mmol), followed by DIPEA (0.86 mL, 4.93 mmol) and the mixture was stirred at room temperature for 10 minutes. HATU (750 mg, 1.972 mmol) was added and the mixture was stirred at room temperature for 16 hour. The mixture was taken up in 1:1 mixture of brine and water (40 mL) and extracted with EtOAc (60 mL). The organic portion was dried over sodium sulfate, filtered and concentrated to afford a brown oil, which was purified by flash column chromatography to afford the title compound (305 mg, 52% yield) as a white solid. LC/MS, ESI-MS (+): 357.1, RT: 1.35 (Condition E).