Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[O:11][C:10](=[O:21])[NH:9]2)[CH:5]=[N:6][CH:7]=1.[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[CH:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[C@H:12]1[O:11][C:10](=[O:21])[NH:9][C@@H:8]1[C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:23]#[C:22][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:3]=1
Reactant: O=C1N[C@H](c2cncc(Br)c2)[C@@H](c2cc(F)ccc2F)O1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C1N[C@H](c2cncc(C#Cc3ccccc3)c2)[C@@H](c2cc(F)ccc2F)O1
Temperature: 25 °C

Procedure:
To a stirred solution of optically enriched (4R,5R)-4-(5-bromopyridin-3-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one (1.25 g, 3.25 mmol) in triethylamine (70 mL) was added ethynylbenzene (0.592 mL, 5.28 mmol), copper(I) iodide (67 mg, 0.352 mmol), and triphenylphosphine (653 mg, 2.464 mmol). Nitrogen was bubbled through the mixture for 10 minutes before adding dichlorobis(triphenylphosphine)-palladium(II) (202 mg, 0.282 mmol) with continued nitrogen gas bubbling. After an additional 10 minutes the reaction mixture was heated to reflux for 16 hours, cooled to ambient temperature, diluted with EtOAc, washed with water (3×), brine, dried over magnesium sulfate, and concentrated in vacuo. Column chromatography (25%-->40% EtOAc/Hex) provided optically enriched (4R,5R)-5-(2,5-difluorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one which was separated by chiral SFC chromatography (Chiralcel OJ-H preparative column, 30×250 mm, 5 μm, Mobile Phase: 40% MeOH (0.1% DEA) in CO2 @ 150 Bar, Temp: 35° C., Flow rate: 70.0 mL/min. for 16 min, UV monitored @ 280 nM. tR=9.23 min) to provide (1.38 g, 2.99 mmol, 85% yield) of pure single enantiomer (4R,5R)-5-(2,5-difluorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.77 (d, J=2.21 Hz, 1H) 8.57 (s, 1H) 8.56 (d, J=2.20 Hz, 1H) 8.07 (t, J=2.05 Hz, 1H) 7.58-7.66 (m, 2H) 7.44-7.52 (m, 3H) 7.39-7.45 (m, 1H) 7.28-7.39 (m, 2H) 5.67 (d, J=6.62 Hz, 1H) 5.04 (d, J=6.62 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ ppm 157.28; 157.24 (d, J=240.70 Hz) 155.92 (d, J=245.20 Hz) 151.63; 147.70; 136.78; 135.02; 131.57; 129.43; 128.89; 126.63 (dd, J=14.99, 7.72 Hz) 121.51; 119.47; 117.83 (dd, J=23.60, 9.10 Hz) 117.50 (dd, J=24.50, 8.20 Hz); 114.60 (dd, J=26.34, 4.54 Hz); 92.86; 85.76; 78.12; 59.43; LCMS (ESI) m/z calcd for C22H15F2N2O2: 377.11. found 377.20 [M+H]+; HRMS (ESI) m/z calcd for C22H15F2N2O2: 377.1096. found 377.1096 [M+H]+.
Reaction SMILES: C(N[C:5](=[CH:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=1)[C:6]([O:8]C)=[O:7])(=O)C.Cl.[O:26]1CCOCC1>>[F:22][C:21]([F:24])([F:23])[C:13]1[CH:12]=[C:11]([CH2:10][C:5](=[O:26])[C:6]([OH:8])=[O:7])[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=1
Reactant: COC(=O)C(=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC(C)=O
Reactant: C1COCCO1
Agent: Cl
Product: O=C(O)C(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
19.5 g (54.9 mmol) methyl 2-acetylamino-3-(3,5-bis-trifluoromethyl-phenyl)-acrylate in 100 mL 1,4-dioxane were heated to 100° C. bath temperature, combined with 100 mL 4 M HCl and stirred for 8 h at 100° C. bath temperature. The reaction mixture was evaporated down i. vac., the crystals were suction filtered, washed with water and dried in the drying cupboard at 50° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=O)=[O:13])=[C:4]1[CH3:23])[CH3:2].[NH:24]([C:31]1[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2([N:24]([C:31]3[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=3[C:33]([O:35][CH3:36])=[O:34])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16](=[O:18])[O:13]2)=[C:4]1[CH3:23])[CH3:2]
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Reactant: COC(=O)c1ccccc1Nc1ccccc1
Product: CCn1c(C)c(C2(N(c3ccccc3)c3ccccc3C(=O)OC)OC(=O)c3ccccc32)c2ccccc21
Yield: 7.7 %

Procedure:
Following a procedure similar to that described in Example 1A but employing 3.1 g of 2-(1-ethyl-2-methyl-3-indolylcarbonyl)benzoic acid and 2.3 g of methyl 2-anilinobenzoate there was obtained 0.4 g of 3-(1-ethyl-2-methyl-3-indolyl)-3-[N-(2-methoxycarbonylphenyl)-N-phenylamino]phthalide, m.p. 80°-115°. A toluene solution of the product contacted with acidic clay or phenolic resin developed a pink-colored image.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)=[C:6]([CH3:15])[CH:5]=1)([O-])=O.O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)=[C:6]([CH3:15])[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1-c1cnco1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: Cc1cc(N)ccc1-c1cnco1

Procedure:
2Bromo-5-nitrotoluene (1.0 g, 4.54 mmol) and vinyltributyl tin (1.59 g, 4.99 mmol) were dissolved in toluene (25 mL) under argon. Palladium dibenzylidene acetone (4.15 g, 0.455 mmol) and triphenylphosphine (488 mg, 1.86 mmol) was added and the reaction refluxed overnight. The solvent was evaporated and the residue dissolved in 200 mL of methylene chloride and washed with 10% ammonium hydroxide, water, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography heptane-methylene chlolride 1:1) to yield 726 mg of 2-methyl-4-nitrostyrene. 2-methyl-4-nitrostyrene (700 mg, 4.5 mmol) was dissolved in methylene chloride (20 mL) and cooled to −78° C., and treated with ozone until a blue color remained, after 5 minutes the excess ozone was removed by passing a stream of oxygen through the solution. Dimethyl sulfide (1 mL) was added and the reaction mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by flash column chromatography to yield 580 mg of the 2-methyl-4-nitrobenzaldehyde. 2-Methyl-4-nitrobenzaldehyde (570 mg, 3.45 mmol) and potassium carbonate (476 mg, 3.45 mmol) were suspended in methanol. Tosylmethylisocyanide (674 mg, 3.45 mmol) was added and the reaction mixture refluxed for 3 h, cooled to room temperature and concentrated. The residue was dissolved in methylene chloride (200 mL) and the organic layer was washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to yield 710 mg (94%) of 5-(4-nitro-2-methylphenyl)oxazole. 5-(4-Nitro-2-methylphenyl)oxazole was dissolved in methanol (100 mL) and 10% palladium on carbon 200 mg was wetted with water and added. The reaction mixture was hydrogenated at 45 psi overnight. The catalyst was removed by filtration and 560 mg of 5-(4-amino-2-methylphenyl)oxazole was isolated in 92% purity by HPLC method A. Mass spectrum M+H+=175.1, 1H 400 MHz NMR (CDCl3): δ7.88 (s, 1H), 7.45 (m, 1H), 7.08 (s, 1H), 6.60 m(m, 2H), 2.38 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([O:7][C:8]2[CH:32]=[CH:31][C:11]([CH2:12][NH:13][C:14]([C:16]3([NH:19][C:20]([C:22]4[CH:23]=[N:24][C:25]([S:28]([CH3:30])=[O:29])=[N:26][CH:27]=4)=[O:21])[CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)=[C:5]([C:35]([F:38])([F:37])[F:36])[CH:4]=1.ClC1C=CC=C(C(OO)=[O:47])C=1>>[CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:12][NH:13][C:14]([C:16]3([NH:19][C:20]([C:22]4[CH:23]=[N:24][C:25]([S:28]([CH3:30])(=[O:47])=[O:29])=[N:26][CH:27]=4)=[O:21])[CH2:17][CH2:18]3)=[O:15])=[CH:31][CH:32]=2)=[C:5]([C:35]([F:36])([F:38])[F:37])[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cnc(S(C)=O)nc4)CC3)cc2)c(C(F)(F)F)c1
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cnc(S(C)(=O)=O)nc4)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Half the crude product mixture from Example 148 was combined with a further 186 mg 3-chloroperbenzoic acid and stirred for two hours at ambient temperature. After the solution had been evaporated down the crude product thus obtained was purified by chromatography (reversed phase HPLC).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11](Cl)=[O:12].Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:25]1[CH2:26][CH2:27][CH2:28][C@@H:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH3:15])[CH:18]=2)[CH2:24]1)=[O:12]
Reactant: COc1cccc(C2CCCNC2)c1
Reactant: O=C(Cl)[C@H]1COc2ccccc2O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc([C@@H]2CCCN(C(=O)[C@H]3COc4ccccc4O3)C2)c1
Reaction time: 1 h

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (54 mg, 0.27 mmol) was dissolved in DCM (4 ml). 3-(3-Methoxyphenyl)piperidine HCl (72 mg, 0.26 mmol) and triethylamine (59 mg, 0.58 mmol) were added. After stirring for 1 h, acidic work-up as above gave the crude product, which was purified by flash chromatography using heptane/EtOAc as eluent. The second eluting diastereomer was collected to give 19 mg of A14.
Reaction SMILES: C([C:4]([CH:13]([F:15])[F:14])([CH2:10][CH:11]=[CH2:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)N.C(#[N:18])C>O>[NH2:18][C:4]([CH:13]([F:15])[F:14])([CH2:10][CH:11]=[CH2:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC#N
Reactant: C=CCC(C(N)=O)(C(=O)OCC)C(F)F
Solvent: O
Product: C=CCC(N)(C(=O)OCC)C(F)F
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of ethyl 2-carbamoyl-2-difluoromethyl-4-pentenoate prepared as in Step B (2.3 g) and iodo-benzene ditrifluoroacetate (3.5 g) in acetonitrile (14 mL) and water (14 mL) is stirred at 80° C. for 16 hours. Water (20 mL) is added and the mixture is extracted with ether (3×20 mL). The aqueous phase is concentrated and the residue suspended in saturated aqueous sodium bicarbonate (10 mL). The suspension is extracted with diethyl ether (3×20 mL). The organic layers are combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo to give ethyl 2-amino-2-difluoromethyl-4-pentenoate (0.6 g) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[N:6]=[C:5]([C:12]([O:14]CC)=O)[CH:4]=1)[CH3:2].CO.[OH-].[NH4+:20]>>[CH2:1]([C:3]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[N:6]=[C:5]([C:12]([NH2:20])=[O:14])[CH:4]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCCCn1nc(C(=O)OCC)cc1CC
Agent: [OH-]
Solvent: CO
Product: CCCCn1nc(C(N)=O)cc1CC
Temperature: 25 °C

Procedure:
Ethyl 5-ethyl-1-butyl-1H-pyrazole-3-carboxylate (13.27 g, 59.2 mmol) in concentrated ammonium hydroxide (50 mL) was heated at 125° C. for 14 hours in a pressure vessel. After the vessel was allowed to cool to ambient temperature, methanol (40 mL) was added and the vessel was heated at 125° C. for 1 day. After cooling to ambient temperature, the vessel was cooled in an ice bath and the product began to crystallize from the reaction mixture. Two crops of crystals were isolated to provide 5.50 g of 5-ethyl-1-butyl-1H-pyrazole-3-carboxamide as off-white crystals, mp 60-61° C. MS (APCI) m/z 196.1 (M+H)+; Anal. calcd for C10H17N3O: C, 61.51; H, 8.78; N, 21.52.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=1)[C@H:9]([OH:25])[CH2:10][NH:11][C@@H:12]1[C:21]2[C:16](=[C:17]([Br:24])[CH:18]=[C:19]([CH2:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][CH2:13]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:26][C:27]1[CH:28]=[C:29]([F:34])[CH:30]=[C:31]([F:33])[CH:32]=1)[C@H:9]([OH:25])[CH2:10][NH:11][C@@H:12]1[C:21]2[C:16](=[C:17]([Br:24])[CH:18]=[C:19]([CH2:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: CCc1cc(Br)c2c(c1)[C@@H](NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C)CCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(Br)c2c(c1)[C@@H](NC[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1)CCC2
Reaction time: 1.5 h
Yield: 106.1 %

Procedure:
Compound 3 (995 mg) is dissolved in 10 mL of anhydrous CH2Cl2 followed by the addition of 10 mL of trifluoroacetic acid (anhydrous). The solution stands for 90 min. then the volatiles are removed with a stream of nitrogen. The compound is desalted by extraction between ethyl acetate, 10 mL, and saturated aqueous sodium bicarbonate, 20 mL. The ethyl acetate phase is washed a second time with saturated sodium bicarbonate. The organic phase is then dried with MgSO4 (anhydrous), filtered, and evaporated of volatiles yielding 865 mg of 4 ([M+H]+=452.8).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=CN=1.[CH2:8]([O:10][C:11](=[O:14])[CH2:12]Br)C.C([O-])([O-])=O.[Na+].[Na+]>CC(C)=O>[CH3:8][O:10][C:11](=[O:14])[CH2:12][C@@H:2]1[CH2:7][CH2:6][CH2:5][O:1]1
Reactant: Oc1ccccn1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)C[C@@H]1CCCO1

Procedure:
A solution of hydroxy-pyridine 42d (1.5g, 5.6 mmol), ethylbromoacetate (0.95 mL, 8.4 mmol) and Na2CO3 (0.93 mg, 8.8 mmol) is refluxed (75° C.) in acetone (35 mL) for 6 h. The solution is concentrated, then diluted with H2O/DCM. The aqueous phase is extracted with DCM. The combined organic extracts are washed with brine, dried (MgSO4) and concentrated. Purification by chromatography (20-100% EtOAc in hexanes) afford affords ester 42e.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[OH:30][N:29]=[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)[CH2:9][CH:10]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1cc(C(=O)CC(c2ccc(C(=O)O)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2ccc(C(=O)O)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 4-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3.3:1) as a colorless oil, MS (ESI+): m/z=375.1702 ([M+H]+).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=[O:5].C=O.N1CCC[CH2:15]1.C(O)(=O)CC>C(O)(C)C>[CH3:1][C@@H:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:10])[CH3:11])[C:3](=[CH2:15])[CH:4]=[O:5]
Reactant: C1CCNC1
Reactant: CC(C)=CCC[C@H](C)CC=O
Agent: C=O
Solvent: CC(C)O
Solvent: CCC(=O)O
Product: C=C(C=O)[C@@H](C)CCC=C(C)C
Temperature: 45 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of (S)-3,7-dimethyloct-6-enal (3.0 g, 19.45 mmol) in isopropyl alcohol (20 mL) at room temperature. was added 37% aqueous formaldehyde (14.46 mL, 194.5 mmol), pyrrolidine (1.61 mL, 19.45 mmol) and propionic acid (1.45 mL, 19.45 mmol). The mixture was warmed to 45° C. and stirred for 2 hours. The reaction was then cooled to 0° C. and quenched with saturated aqueous sodium bicarbonate (100 mL). The mixture was extracted with dichloromethane and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:petroleum ether/ethyl acetate=160:1->110:1) to afford the title compound as a colorless oil (3.2 g, Yield: 98%). Rf=0.7 (10:1) petroleum ether/:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 6.22 (s, 1H), 5.98 (s, 1H), 5.09-5.05 (m, 1H), 2.73-2.67 (m, 1H), 1.94-1.90 (m, 2H), 1.67 (s, 3H), 1.57 (s, 3H), 1.54-1.48 (m, 1H), 1.42-1.37 (m, 1H), 1.06 (d, J=6.8 Hz, 3H) ppm.
Reaction SMILES: C([O:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)[CH2:6]1)(=O)C.[OH-].[K+]>O.C(O)C>[N:14]1([C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:12]=2[CH2:13][CH:5]([OH:4])[CH2:6]3)[CH:15]=[CH:16][CH:17]=[CH:18]1
Reactant: CC(=O)OC1Cc2cccc(-n3cccc3)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OC1Cc2cccc(-n3cccc3)c2C1
Yield: 52.7 %

Procedure:
In the manner of Example 1, step H, hydrolysis of 0.84 g (0.004 mole) of 4-(1-pyrrolyl)-2-indanyl acetate with 0.28 g (0.005 mole) of potassium hydroxide in 5 mL of water and 10 mL of ethanol gave 0.42 g of 4-(1-pyrrolyl)-2-indanol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23](OC)=[C:22]([C:28]3[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=3)[CH:21]=[N:20]2)=[CH:15][CH:14]=1.[NH2-].[Li+]>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:22]([C:28]3[CH:29]=[CH:30][C:31]([S:34][CH3:35])=[CH:32][CH:33]=3)[CH:21]=[N:20]2)=[CH:15][CH:14]=1
Reactant: C1CCNCC1
Reactant: COc1c(-c2ccc(SC)cc2)cnn(-c2ccc(F)cc2)c1=O
Agent: [Li+]
Agent: [Li]CCCC
Agent: [NH2-]
Solvent: Cc1ccccc1
Product: CSc1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2N2CCCCC2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 95.1 %

Procedure:
To a slightly heterogeneous solution of piperidine (99.7 mg, 1.17 mmol) and toluene (8 mL) cooled to −78° C. was slowly added dropwise an n-BuLi solution (0.235 mL, 0.59 mmol, 2.5 M in hexanes). After stirring at −78° C. for 10 minutes, the cooling bath was removed and the mixture stirred an additional 1 hour at 23° C. The 2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (400 mg, 1.17 mmol) was dissolved in portions in toluene (3×6-7 mL aliquots) with a heat gun and cooled to 0° C. prior to transfer via syringe to the lithium amide solution (cooled to −78° C.). The addition was made slowly along the interior wall of the reaction vessel. This reaction mixture was stirred overnight, slowly warming to 23° C. as the cooling bath evaporated. The reaction was quenched with water and diluted with a large excess of ethyl acetate. The layers were separated, and the ethyl acetate layer washed with additional water and brine and dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes 1:2) to provide 440 mg (95%) of 2-(4-fluorophenyl)-5-[4-(methylthio)phenyl]4-piperidino-3(2H)-pyridazinone.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[N+:12]([CH3:15])([O-:14])=[O:13].[O-]CC.[Na+]>C(O)C>[N+:12]([CH2:15][C:7]1([OH:10])[CH2:6][CH2:5][C:4]2([O:3][CH2:2][CH2:1][O:11]2)[CH2:9][CH2:8]1)([O-:14])=[O:13]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])CC1(O)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 120 h
Yield: 40 %

Procedure:
To a solution of 1,4-cyclohexanedione mono-ethylene ketal (30.0 g, 192 mmol) and nitromethane (15.6 mL, 288 mmol) in ethanol (18 mL) was added a solution of sodium ethoxide in ethanol (2.67 M, 3.4 mL, 9.6 mmol). The solution was stirred at room temperature (rt) for 5 days (d), then was concentrated under reduced pressure to a brown oil that was partitioned between water (100 mL) and dichloromethane (100 mL). The aqueous layer was extracted with dichloromethane (3×100 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to a light brown oil. Purification by flash chromatography (silica gel, 40% ethyl acetate/hexanes) provided the product 8-(nitromethyl)-1,4-dioxaspiro[4.5]decan-8-ol as a clear oil (16.7 g, 40%) that slowly formed clear crystals overnight.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([OH:41])=O)=[CH:35][CH:34]=2)=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.N1C(F)=NC(F)=NC=1[F:44].N1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:44])=[O:41])=[CH:35][CH:34]=2)=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1
Reactant: Fc1nc(F)nc(F)n1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Br)ccc2Oc2ccc(C(=O)O)cc2)N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Br)ccc2Oc2ccc(C(=O)F)cc2)N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To the solution of racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(4-hydroxycarbonyl-phenoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.18 g, 0.28 mmol) in dichloromethane (50 mL) at 0° C. was added cyanuric fluoride (120 mg, 0.88 mmol) (Alfa) and pyridine (100 mg, 1.3 mmol). After the mixture was stirred at 0° C. for 2 h, the mixture was partitioned between H2O and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over MgSO4, concentrated to give racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(4-fluorocarbonyl-phenoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow foam and used for the next step without further purification (Yield: 0. 18 g, 98%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1.Cl>CN(C=O)C.CCOC(C)=O>[CH:19]1([CH2:18][O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[OH:1])[CH2:21][CH2:20]1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: BrCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCC2CC2)c(O)c1
Temperature: 50 °C
Yield: 53.2 %

Procedure:
A mixture of 3,4-dihydroxybenzaldehyde (0.5 g, 3.62 mmol), K2CO3 (0.550 g, 3.98 mmol) and (bromomethyl)cyclopropane (0.386 ml, 3.98 mmol) in DMF (12 ml) was heated to 50° C. overnight. The reaction mixture was portioned between EtOAc and HCl 1N. The organic phase was washed several times with brine and dried over Na2SO4; the solvent was removed; and the crude was purified by flash chromatography on silica gel cartridge (petroleum ether:EtOAc=90:10 to 85:15) to give 4-(cyclopropylmethoxy)-3-hydroxybenzaldehyde (0.370 g, 1.925 mmol, 53.2% yield, MS/ESI+ 193.0 [MH]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[O:59]1[CH2:60][CH2:61][CH:56]([NH:55][C:20]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:23])=[N:19][CH:18]=2)=[O:22])[CH2:57][CH2:58]1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)NC2CCOCC2)s1
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a solution of 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) in DMF (1.5 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (88 mg, 0.28 mmol), N,N-diisopropyl ethyl amine (214 μL, 1.25 mmol) and 4-aminotetrahydropyran (28 mg, 0.28 mmol). The resulting reaction mixture was stirred for 1 h. The reaction mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (68 mg, 66%) as a white solid. MS: m/e=415.3 [M+H]+.