Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH2:29]=[O:30]>C1COCC1>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]([S:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])[CH2:29][OH:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(C=C(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=S(=O)(C(CO)=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To a stirred solution of 1.25 g (3.90 mmol) of 2,2-diphenyl1-(phenylsulfonyl) ethene in 20 mL of dry THF at -78° C., was added dropwise under a nitrogen atmosphere 2.8 mL of 1.4 M n-BuLi (3.90 mmol). The dark black solution was stirred at -78° C. for 30 minutes. Gaseous fomaldehyde, generated by heating paraformaldehyde at 170° C., was passed through a 5-mm tube into the reaction mixture with the aid of a slow stream of nitrogen at -78° C. for 30 minutes. The mixture was allowed to come to room temperature over a period of 30 minutes while continuing to pass formaldehyde through the reaction mixture until a pale yellow color was observed. The mixture was stirred overnight at room temperature. The mixture was quenched with 50 mL of 5% HCl, and extracted with three 25-mL portions of CH2Cl2. The organic layer was dried over MgSO4, filtered, and the solvent removed in vacuo from a water bath at 45° C. The resulting crude oil was flash chromatographed on silica gel (230-400 mesh, 5×16-cm column) with 30% ether/Skelly B as eluant to give 0.47 g (34%) of the colorless alcohol. In a melting point capillary the compound does not melt but decomposes above 290° C. with blackening; IR (KBr) cm-1 3480, 3040, 1590, 1480, 1440, 1370, 1280, 1130, 1020, 960, 790, 730, 700, 680, 610; 1H NMR (CDCl3) δ3.47 (t, 1H, OH), 4.61 (d, 2H, CH2O), 6.75-7.58 (m, 15H, phenyl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[C:9](=[O:17])[C:10](=[N:15][NH2:16])[C:11]([O:13][CH3:14])=[O:12]>COCCOCCOCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:9](=[O:17])[C:10]([C:11]([O:13][CH3:14])=[O:12])=[N:15][NH:16]2
Reactant: COC(=O)C(=NN)C(=O)c1c(F)cccc1Cl
Solvent: COCCOCCOCCOC
Product: COC(=O)c1n[nH]c2cccc(Cl)c2c1=O
Temperature: 140 °C
Yield: 66.8 %

Procedure:
A mixture of 4.2 g (16 mmol) of methyl 3-(2-chloro-6-fluorophenyl)-2-hydrazono-3-oxopropionate in 12 mL of triglyme was heated to 140° C. for 48 h. The slurry was then cooled to room temperature and the precipitate was collected by filtration. The precipitate was washed with diisopropyl ether and dried in vacuo to give 2.55 g (66%) of the title compound as a tan powder.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:24][O:25][C:26](=[O:47])[C@H:27]([CH2:39][C:40]1[CH:45]=[CH:44][C:43](Br)=[CH:42][CH:41]=1)[NH:28][C:29](=[O:38])[C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:37]>COCCOC.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.O.CCOC(C)=O>[CH3:24][O:25][C:26](=[O:47])[C@H:27]([CH2:39][C:40]1[CH:41]=[CH:42][C:43]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:8])(=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:44][CH:45]=1)[NH:28][C:29](=[O:38])[C:30]1[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Yield: 76.5 %

Procedure:
2-[N-(tert-Butyl)sulfamoyl]benzeneboronic acid (0.4 g) was dissolved in DME (10 mL). To this solution was added K2CO3 (0.1 g), N-(2,6-dichlorobenzoyl)-4-bromo-L-phenylalanine methyl ester (0.1 g), Pd(Ph3P)4 (0.1 g) and water (0.2 mL). The mixture was heated at 80° C. overnight. After cooling, EtOAc and water were added to the mixture. The EtOAc phase was dried (MgSO4), filtered and evaporated. The residue was purified by flash column chromatography (silica gel; eluent: EtOAc/hexanes 1:2) to give 100 mg of the title compound. ESMS: m/z 585 ([M+Na]+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@H:5]([NH:26]C(=O)OC(C)(C)C)[CH2:6][NH:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[C:11]2[C:22](=[O:25])[NH:23][CH2:24][C:10]=2[CH:9]=1)[CH3:2].CCOC(C)=O.C1COCC1>C(Cl)Cl>[NH2:26][C@@H:5]([CH2:4][O:3][CH2:1][CH3:2])[CH2:6][NH:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[C:11]2[C:22](=[O:25])[NH:23][CH2:24][C:10]=2[CH:9]=1
Reactant: CCOC[C@@H](CNc1cc2c(c(Nc3cccc(C)c3)n1)C(=O)NC2)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC[C@H](N)CNc1cc2c(c(Nc3cccc(C)c3)n1)C(=O)NC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.9 %

Procedure:
To a solution of (R)-tert-butyl 1-ethoxy-3-(3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)propan-2-ylcarbamate (109 mg, 0.239 mmol) in DCM (1 mL) was added a TFA/DCM solution (1/1, 10 mL). The mixture was stirred at RT for 2 h. After removal of the solvent, the resulting crude material was reconstituted in a solution of MeOH/DCM (1/1, 5 mL) and was purified via reverse phase preparative HPLC. The fractions were collected, and ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3, washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to give the title compound (11 mg, 13%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.18 (m, 3H), 1.25-1.44 (m, 4H), 2.26-2.32 (m, 3H), 4.07-4.17 (m, 3H), 4.19-4.29 (m, 2H), 6.03 (s, 1H), 6.78 (d, J=7.83 Hz, 1H), 7.06 (br s, 1H), 7.12-7.22 (m, 1H), 7.48 (s, 1H), 7.60 (d, J=7.83 Hz, 1H), 7.66-7.75 (m, 2H), 7.99 (s, 1H), 8.83-8.97 (m, 1H). [M+H] calc'd for C19H25N5O2, 356. found, 356.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1([F:29])[CH2:24][CH:23]1[C:25]([NH:27][NH2:28])=[O:26].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:28][NH:27][C:25]([CH:23]1[CH2:24][C:22]1([F:29])[F:21])=[O:26])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)C1CC1(F)F
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C1CC1(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added 2,2-difluorocyclopropanecarbohydrazide 267 (0.184 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 268 (0.36 g, quant. yield) as a white foam.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[O:16]1CCC[CH2:17]1.C([Li])CCC.CN(C)C=O>O>[F:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[N:6]=[CH:7][C:2]([CH:17]=[O:16])=[CH:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: C1CCOC1
Reactant: Fc1ccc(Oc2ccc(Br)cn2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(F)cc2)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a mixture of 5-bromo-2-(4-fluoro-phenoxy)-pyridine (940 mg, 3.5 mmol) described in Manufacturing Example 75-1-1 and tetrahydrofuran (10 mL) was added n-butyl lithium (1.7 mL, 1.5 M n-hexane solution, 2.6 mmol) under nitrogen atmosphere at −78° C., which was stirred for 30 minutes at that temperature. N,N-dimethylformamide (0.54 mL, 7.0 mmol) was added to the reaction mixture at the same temperature, and the temperature was gradually raised to 0° C. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (280 mg, 36%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=3)[CH:15]=2)=[C:9]([CH3:34])[CH:8]=1)[CH3:2].[N+](=[CH2:37])=[N-].CN(N=O)C(N[N+]([O-])=O)=N.[OH-].[K+]>O1CCCC1.C(OCC)C.C(O)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:34])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:23]=[CH:24][C:25]([CH:28]4[CH2:37][CH:29]4[C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:27]=3)[CH:15]=2)=[C:11]([CH3:13])[CH:12]=1)[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CCOCCOc1cc(C)c(-c2cccc(COc3ccc(/C=C/C(=O)OC)cc3)c2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(N=O)C(=N)N[N+](=O)[O-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOCCOc1cc(C)c(-c2cccc(COc3ccc(C4CC4C(=O)OC)cc3)c2)c(C)c1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A solution of methyl (2E)-3-(4-{[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methoxy}phenyl)acrylate (1.50 g, 3.26 mmol) in tetrahydrofuran (50 mL) was stirred under ice-cooling, and a solution of diazomethane prepared from N-methyl-N′-nitro-N-nitrosoguanidine (50% water-containing product, 4.98 g, 16.9 mmol) and 9.5 M aqueous potassium hydroxide solution (12.0 mL, 114 mmol) in diethyl ether (25 mL), and palladium(II) acetate (36.6 mg, 0.163 mmol) were alternately added thereto over 10 min in small portions. The reaction mixture was stirred for 5 hr, and acetic acid (3 drops) was added. The insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-30:70) to give the title compound (1.53 g, yield 99%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH2:11]([C@@H:13]1[NH:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)[CH3:12].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:11]([C@@H:13]1[N:18]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:14]1)[CH3:12]
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])nc1
Temperature: 100 °C
Yield: 20.8 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (50 mL), 5-bromo-2-nitropyridine (2.02 g, 10 mmol), (S)-tert-butyl 3-ethylpiperazine-1-carboxylate (2.14 g, 10.0 mmol), Pd2(dba)3 (458 mg, 0.50 mmol), XantPhos (576 mg, 1.0 mmol), and cesium carbonate (6.52 g, 20 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. overnight. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 3:1 petroleum ether/ethyl acetate to afford 114a (700 mg, 22%) as a yellow solid. MS: [M+H]+ 336
Reaction SMILES: Cl.ClCC([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([Cl:18])=[C:15]([Cl:17])[Cl:16])=[CH:10][C:9]=1[OH:19])=O>C(O)C>[NH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([Cl:18])=[C:15]([Cl:17])[Cl:16])=[CH:10][C:9]=1[OH:19]
Reactant: O=C(CCl)NCc1ccc(C(Cl)=C(Cl)Cl)cc1O
Agent: Cl
Solvent: CCO
Product: NCc1ccc(C(Cl)=C(Cl)Cl)cc1O
Temperature: 85 °C

Procedure:
To a solution of 5 mL ethanol and 1.5 mL conc. hydrochloric acid was added 0.818 g (2.5 mmol) of the product of Step E and the reaction mixture was stirred and heated to 85° C. using an external oil bath overnight. The reaction mixture was then cooled to room temperature and evaporated in vacuo. The residue was triturated with ether and dried overnight in vacuo to afford the title compound as a white crystalline solid.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:16])[CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[C:17]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)#[N:18].Cl>O>[ClH:1].[C:17]([CH:19]1[CH2:24][CH2:23][N:22]([CH2:2][CH:3]([OH:16])[CH2:4][O:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)[CH2:21][CH2:20]1)#[N:18]
Reactant: N#CC1CCNCC1
Reactant: OC(CCl)COc1cccc2ccccc12
Agent: Cl
Solvent: O
Product: N#CC1CCN(CC(O)COc2cccc3ccccc23)CC1

Procedure:
4.0 Parts of 1-chloro-3-(1-naphthoxy)-2-propanol and 16.0 parts of 4-cyanopiperidine are heated in a sealed vessel for 10 hours at about 100° C. That reaction mixture is then diluted with 50 parts of water, acidified with concentrated hydrochloric acid, and extracted with 35 parts of ethyl ether. The aqueous phase is separated and made alkaline with the addition of 10 N sodium hydroxide. The resultant solid is filtered and converted to the hydrochloride salt by redissolving the solid in isopropanol and adding a solution of hydrochloric acid in isopropanol. The resulting salt is separated by filtration and crystallized from a mixture of ethanol and ethyl ether to give 3-(4-cyanopiperidino)-1-(1-naphthoxy)-2-propanol hydrochloride, identical to the product of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[N:24]=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]#[N:20]>CN(C=O)C.[Cu]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C:17]1[C:18]([C:19]#[N:20])=[CH:21][CH:22]=[CH:23][N:24]=1
Reactant: COc1cccc(O)c1
Reactant: N#Cc1cccnc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Oc2ncccc2C#N)c1
Reaction time: 0.75 h
Yield: 90.1 %

Procedure:
3-Methoxyphenol (124 g) and anhydrous potassium carbonate (69 g) were heated together with stirring in dry DMF (500 ml) at 80° C. under an atmosphere of nitrogen. After 45 minutes, the greyish solution was cooled and 2-chloronicotinonitrile (138.5 g) and copper bronze (10 g) were added (washed in with 100 ml DMF). The resulting brown reaction mixture was heated to 125°-130° C. After 21/2 hours, the reaction mixture was cooled and filtered to remove excess copper bronze and undissolved solid material. The resulting solution was added to water (3 liters) and left to stand overnight. The resulting precipitate was filtered, washed with water then dissolved in ether. The ether solution was dried, filtered and evaporated to afford 2-(3-methoxyphenoxy)-3-cyanopyridine as an off-white solid (203.5 g, 90%).
Reaction SMILES: [C:1]([C:5]1[CH:39]=[CH:38][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:32][CH2:33][CH2:34][CH2:35][C:36]#[N:37])[CH2:20][CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N:44]=[N+:45]=[N-:46])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:39]=[CH:38][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:32][CH2:33][CH2:34][CH2:35][C:36]2[NH:46][N:45]=[N:44][N:37]=2)[CH2:20][CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCCCC#N)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCCCc2nnn[nH]2)cc1
Temperature: 80 °C

Procedure:
A solution of 200 mg (0.38 mmol) of methyl 4-[3-((E)-2-{2-[(4-tert-butylbenzyl)oxy]phenyl}vinyl)-7-cyanoheptyl)benzoate in 3 ml of toluene is mixed with 660 mg (5.73 mmol) of trimethylsilyl azide and 142.6 mg (0.57 mmol) of di-n-butyltin oxide and heated to 80° C. for 12 hours. After cooling to room temperature, the mixture is washed with saturated sodium bicarbonate solution. The organic phase is separated off, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate is concentrated to dryness. The resulting crude product is purified by chromatography on a silica gel column (mobile phase: cyclohexane/ethyl acetate 1:1). 103 mg (0.18 mmol, 46% of theory) of a white foam are obtained.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([O:10][C@H:11]2[CH2:15][CH2:14][O:13][CH2:12]2)[CH:7]=[C:6]([CH3:16])[C:5]=1[C:17]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]2[C:18]=1[CH2:19][CH2:20][C@H:21]2[O:27][C:28]1[CH:41]=[CH:40][C:31]2[C@H:32]([CH2:35][C:36]([O:38]C)=[O:37])[CH2:33][O:34][C:30]=2[CH:29]=1.Cl>CO.C(OCC)C.C(#N)C.O>[CH3:16][C:6]1[CH:7]=[C:8]([O:10][C@H:11]2[CH2:15][CH2:14][O:13][CH2:12]2)[CH:9]=[C:4]([CH3:3])[C:5]=1[C:17]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]2[C:18]=1[CH2:19][CH2:20][C@H:21]2[O:27][C:28]1[CH:41]=[CH:40][C:31]2[C@H:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:33][O:34][C:30]=2[CH:29]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O[C@H]6CCOC6)cc5C)ccc(F)c43)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: Cc1cc(O[C@H]2CCOC2)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 40 °C
Reaction time: 12 h

Procedure:
1 M aqueous NaOH solution (585 μL) is added to a solution of methyl 2-((S)-6-((R)-4-(2,6-dimethyl-4-((S)-tetrahydrofuran-3-yloxy)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (125 mg) in methanol (3 mL). The mixture is stirred at 40° C. for 12 hours. After addition of 1 N hydrochloric acid (585 μL) the mixture is diluted with diethylether and washed with water and brine. The organic phase is dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 70:30→20:80). The product thus obtained is dissolved in acetonitrile/water (1:1) and lyophilized to give the title compound. Yield: 55 mg; LC (method 4): tR=1.82 min; Mass spectrum (ESI+): m/z=519 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[H-].[Na+].[CH2:14](Br)[CH3:15].CO>C1COCC1.O>[CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH2:14][CH3:15])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCBr
Reactant: CCc1cccc(NC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCc1cccc(N(C#N)CC)c1
Temperature: 82.5 °C
Reaction time: 6 h
Yield: 0.1 %

Procedure:
A suspension of m-ethylphenylcyanamide (2.26 g, 15.45 mmol) and sodium hydride (820 mg, 34.2 mmol, pre-washed thrice with hexane) in anhydrous THF (20 ml) was heated at 80-85° C. for 2.5 hours. After it was allowed to cool to room temperature ethyl bromide (4.66 g, 42.76 mmol) was added and continued stirring at room temperature for 6 hours. Methanol (20 ml) followed by water (40 ml) were added and then extracted with dichloromethane (3×25 ml). Concentration of the organic layer followed by quick flash chromatography afforded the title compound (2.36 mg, 88%) as a light yellow liquid:
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:28]1([C:31]2[C:32]([O:41][CH2:42][C:43]3([CH:49]([F:51])[F:50])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36]([OH:38])=O)[CH2:30][CH2:29]1.CS(N)(=O)=O.[N:57]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59][CH2:58]1>>[N:57]1([S:61]([NH:64][C:36](=[O:38])[C:35]2[CH:39]=[C:31]([CH:28]3[CH2:29][CH2:30]3)[C:32]([O:41][CH2:42][C:43]3([CH:49]([F:50])[F:51])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[CH:33][C:34]=2[F:40])(=[O:63])=[O:62])[CH2:60][CH2:59][CH2:58]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2(C(F)F)CCCCC2)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2(C(F)F)CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-4-((1-(difluoromethyl)cyclohexyl)-methoxy)-2-fluorobenzoic acid, and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a yellow oil (0.085 g, 79%): 1H NMR (300 MHz, DMSO-d6) δ11.64 (s, 1H), 7.17-7.10 (m, 2H), 6.04 (t, J=56.4 Hz, 1H), 4.14 (s, 2H), 4.05 (t, J=7.7 Hz, 4H), 2.22-2.08 (m, 2H), 2.06-1.98 (m, 1H), 1.74-1.65 (m, 2H), 1.59-1.44 (m, 7H), 1.32-1.21 (m, 1H), 0.92-0.85 (m, 2H), 0.68-0.63 (m, 2H); MS (ES+) m/z 461.1 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@@:4]1([CH2:12][N:13]([CH3:23])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl.CC(O)(C)C.C(OCC)C>[CH:2]([C@@H:3]1[CH2:5][C@@:4]1([CH2:12][N:13]([CH3:23])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:15])=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:1]
Reactant: CN(C[C@@]1(c2ccccc2)C[C@H]1CO)S(=O)(=O)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C[C@@]1(c2ccccc2)C[C@H]1C=O)S(=O)(=O)c1ccccc1
Yield: 45.1 %

Procedure:
N-{[(1S,2R)-2-(hydroxymethyl)-1-phenylcyclopropyl]methyl}-N-methylbenzenesulfonamide (600 mg, 1.82 mmol), accessed via the method of preparation 7A, was dissolved in 18 mL DCM with 270 uL 2-methylpropan-2-ol and treated with Dess-Martin Periodinane (1.23 g, 2.90 mmol, 1.6 eq) at ambient temperature for 16 h. The reaction mixture was diluted with 42 mL diethyl ether and treated with 22 mL 1N NaOH at ambient temperature for 15 min. The organic phase was separated, the aqueous phase extracted twice with diethyl ether, the organic phases combined, washed with brine, dried over MgSO4, filtered and concentrated to a colorless oil. The crude material was purified by flash chromatography (SiO2, eluted successively with DCM, EtOAc/hexanes (1:4)) to the title product (270 mg, 0.82 mmol, 45%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 9.82 (d, J=3.8 Hz, 1H), 7.65-7.28 (m, 10H), 3.53-3.43 (m, 2H), 2.42 (s, 3H), 2.34-2.32 (m, 1H), 1.90-1.87 (m, 1H), 1.70-1.66 (m, 1H).