Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH3:30][O:31][CH2:32][CH2:33]Br>>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:33][CH2:32][O:31][CH3:30])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[C:4]([C:26]([F:29])([F:27])[F:28])[CH:3]=1
Reactant: COCCBr
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(ccn3Cc3ccc(F)cc3C(F)(F)F)c2)S1
Product: COCCN1C(=O)S/C(=C\c2ccc3c(ccn3Cc3ccc(F)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-[(1-{[4-Fluoro-2-(trifluoromethyl)phenyl]methyl}-1H-indol-5-yl)methylidene]-3-[2-(methyloxy)ethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-fluoro-2-(trifluoromethyl)benzyl]-1H-indol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 249) and 2-bromoethyl methyl ether following General Procedure H.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[NH:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])([O-:3])=[O:2].Cl.[C:31](Cl)(=[O:33])[CH3:32]>>[C:31]([N:22]([C:5]1[CH:6]=[C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]=2[Cl:21])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: COC(=O)CCCNc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: Cl
Product: COC(=O)CCCN(C(C)=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
10 g of methyl N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]-4-amino-n-butyrate (compound 2) are refluxed in 30 ml of acetyl chloride until the evolution of hydrogen chloride is complete. Excess acetyl chloride is removed in vacuo, affording the title compound in quantitative yield. nD21 =1.5437.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]([CH3:26])([CH3:25])[CH:14]([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N+:17]=2[O-:23])=[CH:10][CH:9]=1)#[N:7]>C(N(CC)CC)C.ClCCl>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]([CH3:26])([CH3:25])[CH:14]([O:24][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N+:17]=2[O-:23])=[CH:27][CH:28]=1)#[N:7]
Reactant: Cc1cccc(CC(O)C(C)(C)Oc2ccc(C#N)cc2)[n+]1[O-]
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(CC(OS(C)(=O)=O)C(C)(C)Oc2ccc(C#N)cc2)[n+]1[O-]
Yield: 92.3 %

Procedure:
573 mg of methanesulphonyl chloride were added to a stirred solution of 1.56 g of 2-[3-(4-cyanophenoxy)-2-hydroxy-3-methylbutyl]-6-methylpyridine N-oxide in 3 ml of triethylamine and 25 ml of dichloromethane at room temperature. After 1 hour a further 573 mg of methanesulphonyl chloride were added and the mixture was stirred until thin-layer chromatography indicated that the reaction was complete. The mixture was washed with dilute hydrochloric acid and 2M sodium hydroxide solution, dried over sodium sulphate and evaporated to give 1.8 g of 2-[3-(4-cyanophenoxy)-2-methanesulphonyloxy-3-methylbutyl]-6methylpyridine N-oxide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:12][CH2:13][CH:14]2[CH2:19][CH:18]=[CH:17][CH2:16][N:15]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](=[CH2:29])=[N-].C(OCC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12][CH2:13][C@@H:14]2[CH2:19][C@@H:18]3[C@@H:17]([CH2:29]3)[CH2:16][N:15]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC=CCC1COC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2C[C@H]1COC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.67 h

Procedure:
tert-Butyl 2-({[(4-nitrophenyl)carbonyl]oxy}methyl)-3,6-dihydropyridine-1(2H)-carboxylate (10.0 g) produced above was dissolved in 5% diazomethane/diethyl ether (1.4 L), palladium acetate (689 mg) was added at 10° C., and the mixture was stirred at the same temperature for 40 min. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give a mixture of tert-butyl 2-({[(4-nitrophenyl)carbonyl]oxy}methyl)-3,6-dihydropyridine-1(2H)-carboxylate and the title compound. The obtained mixture was subjected to 3 repeats of a similar reaction operation to give the title compound (8.4 g).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:5][CH:4]=1)=O.[NH2:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:16]=1[C:17]([NH2:19])=[O:18].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(N(C)C)=O.CCOC(C)=O>[CH3:27][O:26][C:20]1[CH:21]=[C:22]([O:24][CH3:25])[CH:23]=[C:15]2[C:16]=1[C:17](=[O:18])[NH:19][C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:5][CH:4]=1)=[N:14]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CS(=O)(=O)Nc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(NS(C)(=O)=O)cc3)nc2c1
Temperature: 155 °C
Yield: 113.5 %

Procedure:
A mixture of N-(4-formylphenyl)methanesulfonamide (0.161 g, 0.0800 mmol), 2-amino-4,6-dimethoxybenzamide (0.159 g, 0.0800 mmol), NaHSO3 (94%, 0.00460 g, 0.0240 mmol), and p-TsOH.H2O (0.0125 g, 0.120 mmol) in DMA (1.00 mL) was heated at 155° C. for 16 hours. The mixture was diluted with EtOAc (50 mL), washed with water (2×50 mL), then brine (50 mL), dried over Na2SO4, filtered, and the solvent was removed under vacuum. The residue was purified over silica gel (12 g, CH2Cl2/MeOH) and the product was freeze-dried from MeCN/H2O to provide the title compound (0.0341 g, 11%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 11.94 (s, 1H), 10.21 (s, 1H), 8.16 (d, J=8.76 Hz, 2H), 7.30 (d, J=8.76 Hz, 2H), 6.72 (d, J=2.25 Hz, 1H), 6.52 (d, J=2.25 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.09 (s, 3H). MS (ESI) m/z 376 [C17H17N3O5S+H]+.
Reaction SMILES: O.[OH-].[Na+].[OH:4][C@H:5]([CH3:12])[CH2:6][C:7]([O:9]CC)=[O:8].[Cl-].[Na+].[CH2:15]([OH:17])[CH3:16]>>[C:15]([O:4][CH:5]([CH3:12])[CH2:6][C:7]([OH:9])=[O:8])(=[O:17])[CH3:16]
Reactant: CCOC(=O)C[C@@H](C)O
Reactant: CCO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)OC(C)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a liquid mixture comprising 15 ml of water, 15 ml of ethanol and sodium hydroxide was dissolved 4.0 of ethyl (R)-β-hydroxybutanoate, and the solution was refluxed under heating, cooled and passed through an ion exchange resin (Amberlite1/2 IR-120B). The solvent was removed under a reduced pressure, 10 ml of anhydrous pyridine and 3 ml of anhydrous acetic acid were added to the residue, and the mixture was stirred at room temperature overnight. Dilute hydrochloric acid was added to the reaction liquid to adjust the pH value to 1, and the reaction liquid was saturated with sodium chloride and extracted with chloroform. The extract was washed with a saturated aqueous sodium chloride solution and dehydrated on magnesium sulfate. Then, chloroform was removed under a reduced pressure to obtain 3.6 g of the intended compound having [α]24 of -5.7°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:12])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(C1C=CC([N+]([O-])=O)=CC=1)=O.[N+](C1C=CC([C@@H](O)C)=CC=1)([O-])=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C@H:10]([OH:12])[CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: C[C@H](O)c1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O)c1ccc([N+](=O)[O-])cc1
Reaction time: 96 h
Yield: 38 %

Procedure:
As shown here, the biochemical conversion reaction of immobilized green pea protein for the substrate (±)-1-(4-nitrophenyl)ethanol (200 mg) requires 4 days by going through bioconversion to 4-nitroacetophenone accompanying sterically selective oxidation of (S)-1-(4-nitrophenyl)ethanol to obtain 76 mg of (R)-1-(4-nitrophenyl)ethanol at a yield of 38%. Optical purity was obtained at 54% e.e. HPLC conditions were set at a flow rate of 0.5 ml/min, while GC conditions were set to an oven temperature of 190° C.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[C:11]([C:13]1[CH:14]=[CH:15][C:16]([F:21])=[C:17]([CH:20]=1)[C:18]#[N:19])#[CH:12].N>>[F:21][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[N:8][CH:7]=[CH:6][N:5]=3)[CH:12]=2)=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: C#Cc1ccc(F)c(C#N)c1
Reactant: ON=C(Cl)c1cnccn1
Agent: N
Product: N#Cc1cc(-c2cc(-c3cnccn3)no2)ccc1F

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and the product of Example 68A (73 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) 57.57 (t, J=8.9 Hz, 1H), 7.55 (s, 1H), 8.30 (ddd, J=8.9, 5.0, 2.4 Hz, 1H), 8.40 (dd, J=5.9, 2.0 Hz, 1H), 8.71 (d, J=2.8 Hz, 1H), 8.74-8.80 (m, 1H), 9.30 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 267 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:47][O:48][C:49](=[O:53])[CH2:50][NH:51][CH3:52]>CN(C=O)C.O>[CH3:47][O:48][C:49](=[O:53])[CH2:50][N:51]([C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:18])[CH3:52]
Reactant: CNCC(=O)OC
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN(C)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
DIPEA (880 mg, 1.2 mL, 6.8 mmol) was added to a stirred solution of biphenyl-4-carboxylic acid (300 mg, 1.5 mmol) in DMF (5 mL). HOBT (224 mg, 1.66 mmol) and EDCI (725 mg, 3.7 mmol) were then added at room temperature. After 2 minutes methylamino-acetic acid methyl ester hydrochloride salt (253 mg, 1.8 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 20% EtOAc in hexane as eluent) filtered the solid precipitated out to afford 330 mg (76.96% yield) of [(biphenyl-4-carbonyl)-methyl-amino]-acetic acid methyl ester.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1.[O:10]1[C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1.[NH4+].[Cl-]>C1COCC1>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([C:17]2([OH:20])[CH2:18][CH2:19][C:14]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:15][CH2:16]2)=[CH:4][CH:5]=1
Reactant: Brc1ccc(Br)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)cc2)CCC2(CC1)OCCO2
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 174.7 %

Procedure:
Magnesium (0.60 g, 24.6 mmol) and THF (5 ml) were added to 2-neck flask, and the reaction was initiated with addition of small amount of THF (25 ml) a solution including 1,4-dibromobenzene (5.30 g, 22.4 mmol). Then, the remaining THF solution including 1,4-dibromobenzene was slowly added dropwise with maintaining at 20-25° C. and was stirred for 2 hours. THF solution (8 ml) of 1,4-Dioxaspiro[4.5]decan-8-one (2.60 g, 17.0 mmol) was added slowly dropwise with maintaining 10-15° C., warmed to a room temperature and then stirred for 24 hours at a room temperature. The reacting solution was poured to NH4Cl aqueous solution (50 ml), and extracted by toluene (50 ml×3 time). The organic layer was washed by distilled water (20 ml×2 times) and concentrated under reduced pressure concentrate to obtain 8-(4-bromophenyl)-1,4-dioxaspiro[4.5]decane-8-ol (9.30 g).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[C:24]([O:28][C:29](=[O:35])[N:30]([CH2:32][CH2:33][NH2:34])[CH3:31])([CH3:27])([CH3:26])[CH3:25]>CCO>[C:24]([O:28][C:29](=[O:35])[N:30]([CH2:32][CH2:33][NH:34][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4])[CH3:31])([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: CN(CCN)C(=O)OC(C)(C)C
Solvent: CCO
Product: CN(CCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 97.4 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (100 mg, 0.32 mmol) and (2-amino-ethyl)-methyl-carbamic acid tert-butyl ester (67 mg, 0.39 mmol) in EtOH (9 mL) was refluxed for 16 h. After cooling to r.t., the mixture was concentrated in vacuo. The residue was dissolved in EtOAc and washed with 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-2% MeOH/CH2Cl2) to give 141 mg of the title compound. MS: (−) m/z 451.37 (M−1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:6][C:7]1[C:8]([C:5]#[C:4][CH2:3][NH:2][CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1Nc2ccc(F)c(I)c2/C1=C/c1ccc[nH]1
Reactant: C#CCNC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1ccc[nH]1)C(=O)N2

Procedure:
Using Method C above, N-methylpropargylamine (48.4 mg, 0.7 mmol) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.28 mmol) (Starting Material 5, supra) using (Ph3P)4Pd (32 mg) and CuI (5.3 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-Dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 10 mg, 12%).
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:30](Cl)(=[O:32])[CH3:31].O>C1COCC1.CCN(CC)CC>[C:30]([N:12]1[CH2:13][CH2:14][C@H:9]([O:8][CH2:7][C:6]2[CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=[C:4]([C:3]([F:2])([F:28])[F:29])[CH:5]=2)[C@H:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11]1)(=[O:32])[CH3:31]
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of the compound (0.15 g) obtained in Example 1 in THF (5.0 ml), Et3N (0.15 ml) was added, acetyl chloride (0.040 ml) was added at 0° C., and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 10% citric acid solution and saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (ethyl acetate:hexane=1:1→1:0) to obtain the title compound as colorless oil (0.10 g, 66%).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37]([CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:38]=2)O1>>[N:41]1([CH2:40][CH2:39][N:37]2[CH:38]=[C:34]([C:25]3[CH:2]=[CH:3][C:4]4[O:13][CH2:12][CH2:11][C:10]5[S:9][C:8]([C:14]6[N:15]([CH2:19][C:20]([F:21])([F:22])[F:23])[N:16]=[CH:17][N:18]=6)=[N:7][C:6]=5[C:5]=4[CH:24]=3)[CH:35]=[N:36]2)[CH2:42][CH2:43][O:44][CH2:45][CH2:46]1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
Product: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cnn(CCN4CCOCC4)c3)cc1-2
Yield: 17 %

Procedure:
8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene and 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine were reacted under palladium Suzuki conditions to give 115 (17% yield). LC/MS (ESI+): m/z 532 (M+H). 1H NMR (400 MHz, DMSO) δ 8.48 (d, J=2.1, OH), 8.30 (s, OH), 8.07 (s, OH), 7.76 (s, OH), 7.49 (dd, J=8.3, 2.2, OH), 7.09 (d, J=8.3, OH), 5.89 (q, J=8.6, OH), 4.38 (t, J=4.9, OH), 4.25 (t, J=6.6, OH), 3.61-3.51 (m, 1H), 3.48 (t, J=4.9, OH), 2.75 (t, J=6.6, OH), 2.45-2.35 (m, 1H)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)(O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:26]2[CH:27]=[CH:28][C:23]([OH:29])=[CH:24][CH:25]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: COc1cccc(C2(O)CCCN(Cc3ccccc3)C2)c1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1cccc(C2(c3ccc(O)cc3)CCCN(Cc3ccccc3)C2)c1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
To a solution of 1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-ol (17.6 g, 73.1 mmol) in (CH2)2Cl2 (200 mL) was added phenol (16.7 g, 178 mmol) followed by portionwise addition (highly exothermic) of AlCl3 (23.3 g, 178 mmol). The reaction mixture was heated to reflux for 2 hours. The mixture was cooled to room temperature and was slowly poured into a mixture of crushed ice (50 mL) and 30% aq. NH4H (120 mL). The mixture was stirred vigorously for 20 mininutes and was then filtered through celite. The celite cake was washed with CH2Cl2 (200 mL). The organic layer was separated and the aqueous layer was washed with CH2Cl2 (3×100 mL). The combined organic layers were dried (MgSO4) and concentrated. The crude residue was purified by flash chromatography with hexanes/EtOAc (1:1) to afford 16.3 g of 4-[1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenol 1HNMR (400 MHz, CDCl13) δ 7.39-7.21 (comp, 5H), 7.19-7.05 (comp. 3H), 6.84 (s, 1H), 6.79 (d, 1H), 6.67-6.61 (comp, 3H), 3.73 (s, 3H), 3.50 (s, 2H), 2.86-2.79 (comp, 2H), 2.45-2.38 (comp, 2H), 2.21-2.19 (comp, 2H), 1.60-1.51 (comp, 2H); MS (M+1) 374.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[CH:14]([N:16]([CH:18]3[CH2:20][CH2:19]3)[CH3:17])[CH2:13][CH2:12][C:11]([CH3:22])([CH3:21])[C:10]=2[CH:9]=[C:8]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34]C)=[O:33])=[CH:27][CH:26]=2)[CH:7]=1)=[O:5])[CH3:2].[OH-].[Li+]>C(O)C.O1CCCC1.O>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[CH:14]([N:16]([CH:18]3[CH2:19][CH2:20]3)[CH3:17])[CH2:13][CH2:12][C:11]([CH3:22])([CH3:21])[C:10]=2[CH:9]=[C:8]([C:23]#[C:24][C:25]2[CH:26]=[CH:27][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:29][CH:30]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C#Cc2ccc(CC(=O)OC)cc2)cc2c1C(N(C)C1CC1)CCC2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1C(N(C)C1CC1)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A solution of 8-(cyclopropyl-methyl-amino)-3-(4-methoxycarbonylmethyl-phenylethynyl)-5,5-dimethyl-5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 78, 0.09 g, 0.19 mmol) in ethanol (2 mL), tetrahydrofuran (3 mL) and water (1.5 mL) was treated with lithium hydroxide (0.11 g, 2.62 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a white solid (0.085 g, 94%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.Cl[S:16](O)(=O)=O.C(Cl)(=O)C(Cl)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>C(Cl)Cl.CN(C)C=O.Cl>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][C:4]2[CH:3]=[CH:2][C:1]([SH:16])=[CH:6][CH:5]=2)=[CH:13][CH:12]=1
Reactant: O=S(=O)(O)Cl
Reactant: Brc1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Sc1ccc(Oc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
A solution of 4-bromodiphenyl ether (50 g, 200.7 mmol) in methylene chloride (118 mL) was cooled to 0° C. and chlorosulfonic acid (14.7 mL, 220.8 mmol) was added dropwise over a 20 minute period. The solution was stirred an additional 10 minutes, warmed to room temperature and stirred an additional 1 hour. To this mixture was added oxalyl chloride (23.6 mL, 270.9 mmol), followed by N,N-dimethylformamide (1.5 mL) as a catalyst, and the mixture refluxed for 2 hours. The mixture was cooled to room temperature, and additional oxalyl chloride (23.6 mL, 270.9 mmol) was added, the mixture refluxed for 3 hours, cooled to room temperature and stirred 12 hours more. The solution was concentrated to an oil, azeotroped several times using methylene chloride and put under high vacuum (1 torr) for several hours until the mixture had completely solidified. This mixture was immediately dissolved in methylene chloride (160 mL) which was added dropwise to a solution of triphenylphosphine (157.0 g, 602 mmol) in methylene chloride (160 mL) containing N,N-dimethylformamide (4 mL, 52.2 mmol). The mixture was stirred 2 hours, diluted with 1M aqueous hydrochloric acid (300 mL) and stirred for 1 hour. The aqueous layer was separated, extracted with methylene chloride (200 mL), and the organic layers were combined, washed with 200 mL of brine, dried (MgSO4) and concentrated in vacuo. The resulting solid was further purified through trituration with 750 mL of hexane. The solid was then dissolved in 750 mL of diethyl ether, extracted with 2M aqueous sodium hydroxide (2×350 mL), and the basic aqueous layer back extracted using diethyl ether (2×400 mL). The aqueous layer was adjusted to pH 2, extracted with diethyl ether (3×200 mL) and the combined organic layers dried (MgSO4) and concentrated to afford 4-(4-bromophenoxy)thiophenol (45.6 g, 81%). 1HNMR (CDCl3) δ 3.43 (s, 1H), 6.86 (d, J=8.9 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H), 7.28 (d, J=8.6 Hz, 2H), 7.43 (d, J=8.9 Hz, 2H).
Reaction SMILES: CS(O[CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1)(=O)=O.N12CCC(CC1)C(O)C2.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][SH:30])=[CH:27][CH:26]=1.[H-].[Na+]>>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][S:30][CH:6]2[CH:11]3[CH2:10][CH2:9][N:8]([CH2:13][CH2:12]3)[CH2:7]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(CS)cc1
Reactant: CS(=O)(=O)OC1CN2CCC1CC2
Agent: OC1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(CSC2CN3CCC2CC3)cc1

Procedure:
The procedure described in preparation 6-(2) was repeated, but using 3.7 g of 3-methanesulfonyloxyquinuclidine (prepared by the methanesulfonylation of 3-quinuclidinol), 3.0 ml of 4-methoxybenzyl mercaptan and 0.942 g of sodium hydride (as a 55% w/w suspension in mineral oil), to afford 1.74 g of the title compound as an oil.