Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6](=O)[C:7]([OH:9])=[O:8])[CH:3]=[N:2]1.[OH-].[Mg+2].[OH-].[OH:14][NH:15]Cl>C(O)C.O>[OH:14][N:15]=[C:6]([C:4]1[CH:3]=[N:2][S:1][CH:5]=1)[C:7]([OH:9])=[O:8]
Reactant: ONCl
Reactant: O=C(O)C(=O)c1cnsc1
Agent: [Mg+2]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(=NO)c1cnsc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
A suspension of 2-(isothiazol-4-yl)glyoxylic acid (240 mg.), magnesium hydroxide (290 mg.) and hydroxylamino hydrochloride (140 mg.) in a mixture of ethanol (2 ml.) and water (10 ml.) was stirred for 2 hours at ambient temperature and allowed to stand overnight at ambient temperature. Ethanol was distilled off and to the residue was added ethyl acetate. The mixture was adjusted to pH 1 with 10% hydrochloric acid and the ethyl acetate layer was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 2-hydroxyimino-2-(isothiazol-4-yl)acetic acid (syn isomer) (0.20 g.), mp 159° to 161° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH3:2].O[C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C@@H:16]1[CH2:17][CH2:12][CH2:13][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1)[CH3:2]
Reactant: CCOc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOc1ccccc1O[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h
Yield: 45.9 %

Procedure:
To a solution of 2-ethoxyphenol (13.72 g, 99 mmol), tert-butyl (S)-3-hydroxypiperidine-1-carboxylate (20 g, 99 mmol), and triphenylphosphine (29 g, 111 mmol) in toluene (150 mL) at 20-25° C. was added a solution of DIAD (20 mL, 104 mmol) in toluene (50 mL) over 2 hours. After 2 hours, the reaction mixture was filtered and washed with diethyl ether (300 mL). The filtrate was washed with 3N NaOH (150 mL), dried over Na2SO4, and concentrated. The crude residue was purified via column chromatography to afford tert-butyl (R)-3-(2-ethoxyphenoxy)piperidine-1-carboxylate (14.6 g, 45%). MS (ES+) 222.2 (M-100+H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].C(N(CC)CC)C.S=[C:20]1[CH2:24][S:23][C:22](=[O:25])[NH:21]1>C(O)C>[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH:6][C:20]1[CH2:24][S:23][C:22](=[O:25])[N:21]=1
Reactant: O=C1NC(=S)CS1
Reactant: CC(C)[C@H](N)C(=O)N(C)C
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the crude product (19.6 g) containing N,N-dimethyl-L-valinamide hydrochloride obtained in B) and triethylamine (44.0 g) in ethanol (150 mL) was added 4-thioxothiazolidin-2-one (14.4 g) at room temperature, and the reaction mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, the obtained solid was suspended in THF, and the suspension was filtered through celite pad and silica gel pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/petroleum ether) to give the title compound (4.2 g).
Reaction SMILES: FC(F)(F)S(O[CH2:7][CH2:8][N:9]([CH2:22][CH2:23]OS(C(F)(F)F)(=O)=O)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])(=O)=O.Cl.[NH2:35][C:36]1([C:39]([O:41][CH3:42])=[O:40])[CH2:38][CH2:37]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([N:9]1[CH2:8][CH2:7][N:35]([C:36]2([C:39]([O:41][CH3:42])=[O:40])[CH2:38][CH2:37]2)[CH2:23][CH2:22]1)(=[O:11])=[O:12])([O-:21])=[O:20]
Reactant: COC(=O)C1(N)CC1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCOS(=O)(=O)C(F)(F)F)CCOS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)C1(N2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])CC2)CC1
Temperature: 60 °C

Procedure:
A solution of N,N-bis-(2-trifluoromethanesulfonyloxyethyl)-2-nitrobenzenesulfonamide (1.83 g, 3.30 mmol) from Example 16B and methyl 1-aminocyclopropane-1-carboxylate HCl (0.50 g, 3.30 mmol) in anhydrous acetonitrile (10 mL) was treated with sodium carbonate (1.40 g, 13.2 mmol) and heated overnight at 60° C. (J. A. Kozlowski, et al., Bioorg. Med. Chem. Lett. 12: 791-794, 2002). Reaction diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal phase HPLC on a Biotage pre-packed silica gel column eluting with 3:1 hexane:ethyl acetate to afford the title compound. MS (ESI) m/z 370 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])SC)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:20]>CO>[C:1]([O:5][C:6]([NH:8][C:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[NH:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 74 %

Procedure:
15 g of 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (0.052 mol) were suspended in 150 mL of gaseous ammonia in methanol and the mixture was stirred at room temperature in a close bottle at room temperature. The resulting solution was concentrated in vacuo until 10 g (74% yield) of the title compound precipitated which were collected by filtration.
Reaction SMILES: [ClH:1].Br[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[ClH:1].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]3[CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)=[O:11])=[CH:5][CH:4]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(Nc1ccc(Br)cc1)C1CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: O=C(Nc1ccc(-c2ccc(F)cc2)cc1)C1CN2CCC1CC2

Procedure:
90 mg (0.26 mmol) of N-(4-bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide hydrochloride, 40 mg (0.31 mmol) of 4-fluorophenylboronic acid, 190 mg (0.57 mmol) of cesium carbonate and 20 mg (0.03 mmol) of bis(diphenylphosphino)ferrocenepalladium(II) chloride are reacted in 1 ml of 1,2-dimethoxyethane by the general method. 17.6 mg (19% of theory) of the title compound are obtained.
Reaction SMILES: C(=[C:5]1[CH:10]=[C:9]([CH2:11][NH2:12])[CH:8]=[CH:7][NH:6]1)C(C)C.[CH3:13][C:14]([O-])([CH3:16])[CH3:15].[K+]>C1(C)C=CC=CC=1>[N:6]1[CH:5]=[CH:10][C:9]([CH:11]=[N:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:8][CH:7]=1
Reactant: CC(C)C=C1C=C(CN)C=CN1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)CN=Cc1ccncc1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 2933 %

Procedure:
96 g (0.593 mol) of isobutylidene-4-aminomethylpyridine is added dropwise at 40° C. in the course of 30 minutes, with stirring, to a suspension of 2 g (0.0179 mol) of potassium tert-butylate in 100 ml of toluene. The reaction mixture becomes in the process darkish red-brown. It is stirred at 40° C. for a further 1.5 hours, and the toluene is distilled off in a water-jet vacuum. The residue is then distilled in an oil-pump vacuum to obtain 85 g (0.525 mol) of 4-pyridylmethylidene-isobutylamine as a slightly yellowish liquid, corresponding to a yield of 88.5% of theory; b.p. 62°-63° C./1.3 Pa; nD20 =1.5166.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]2[O:18][C:17](=[O:19])[CH2:16][C@@H:15]([CH:20]=[CH2:21])[CH2:14]2)=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O.C(#[N:31])C>>[NH2:31][N:2]=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]2[O:18][C:17](=[O:19])[CH2:16][C@@H:15]([CH:20]=[CH2:21])[CH2:14]2)=[CH:5][CH:4]=1
Reactant: C=C[C@@H]1CC(=O)O[C@H](CCCCc2ccc(C#N)cc2)C1
Reactant: CC#N
Solvent: O=C(O)C(F)(F)F
Product: C=C[C@@H]1CC(=O)O[C@H](CCCCc2ccc(C=NN)cc2)C1

Procedure:
The title compound was prepared from the product of step C (1.00g, 3.53 mmol) in a manner similar to example 1 step G with a modification in the purification. The residue was dissolved in acetonitrile and TFA (402 mg, 3.53 mmol) was added. The solvent was evaporated under reduced pressure and the residue redissolved in a minimal amount of acetonitrile. Addition of Et2O caused the precipitation of the crude product which was filtered and washed with Et2O. The material was briefly suspended in ice water, filtered, washed with ice water and dried. Recrystallization from acetonitrile afforded 720 mg (50%) of product as the TFA salt (m.p. 186°-187° C. dec.). Anal. calc'd. for C20N25O4F3 0.3H2O: C, 57.14; H, 6.15; N, 6.66.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:31])[CH2:13][CH:14]2[C:19](=[O:20])[NH:18][CH:17]=[CH:16][N:15]2[S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:5][CH:4]=1.O=S(Cl)[Cl:34]>O1CCOCC1>[Cl:34][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:31])[CH2:13][CH:14]2[C:19](=[O:20])[NH:18][CH:17]=[CH:16][N:15]2[S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)N2C=CNC(=O)C2CC(=O)NCCc2ccc(CO)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N2C=CNC(=O)C2CC(=O)NCCc2ccc(CCl)cc2)cc1

Procedure:
To a suspension of N-[2-(4-hydroxymethyl-phenyl)-ethyl]-2-[3-oxo-1-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-pyrazin-2-yl]-acetamide (0.376 g, 0.85 mmol) in 1,4-dioxane (10 mL) was added SOCl2 (Aldrich, 0.25 mL, 3.4 mmol) at rt. The reaction mixture was concentrated in vacuo after 30 min. The crude product was used in next step without purification. MS (ESI): 464 (M+H)+.
Reaction SMILES: I[C:2]1[C:3]([NH:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26]>CN(C=O)C>[NH2:9][C:5]1[N:6]=[C:7]([CH3:8])[C:2](/[CH:26]=[CH:25]/[C:24]([O:28][CH2:29][CH3:30])=[O:27])=[C:3]([NH:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:4]=1
Reactant: C=CC(=O)OCC
Reactant: Cc1nc(N)nc(NC2CCOCC2)c1I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1c(C)nc(N)nc1NC1CCOCC1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
To a solution of 5-iodo-6-methyl-N4-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4-diamine (10.0 g, 30.0 mmol) in DMF (200 mL) was added triethylamine (12.50 mL, 90.0 mmol) and ethyl acrylate (9.80 mL, 90.0 mmol) successively at room temperature. The reaction was purged with nitrogen for 5 min. and Pd(PPh3)4 (10 mol %, 3.50 g) was added. The reaction was heated to 95° C., stirred for overnight under nitrogen, and then cooled to room temperature. Nearly all DMF was evaporated under reduced pressure. The reaction was poured into ethyl acetate (500 mL) and H2O (300 mL). The organic layer collected and dried over anhydrous sodium sulfate, and concentrated in vacuo to afford the crude product. The product was purified by a flash chromatography (70% ethyl acetate/hexanes to 10% EtOH/ethyl acetate) to afford (E)-ethyl 3-(2-amino-4-methyl-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-5-yl)acrylate, as a light yellow semicrystal (yield: 6.85 g, 75.0%). LC/MS: calculated for C15H22N4O3 (306.17). found: 307.2 (MH+). HPLC analytical purity: >97.0%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:37][CH3:38])=[C:7]([C:9]2[N:13]([CH:14]([CH3:16])[CH3:15])[C:12]3[CH:17]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=4[CH3:36])[N:18]([C:21]4[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[C:19](=[O:20])[C:11]=3[N:10]=2)[CH:8]=1.[C:39]([O:42][CH2:43][C:44](Cl)=[O:45])(=[O:41])[CH3:40]>C1COCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([CH:17]2[C:12]3[N:13]([CH:14]([CH3:15])[CH3:16])[C:9]([C:7]4[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=4[O:37][CH3:38])[CH2:2][NH:1][C:44]([CH2:43][O:42][C:39](=[O:41])[CH3:40])=[O:45])=[N:10][C:11]=3[C:19](=[O:20])[N:18]2[C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[CH3:28])=[C:30]([CH3:36])[CH:31]=1
Reactant: COc1ccc(CN)cc1-c1nc2c(n1C(C)C)C(c1ccc(Cl)cc1C)N(c1cc(Cl)ccc1C)C2=O
Reactant: CC(=O)OCC(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)COC(C)=O)cc1-c1nc2c(n1C(C)C)C(c1ccc(Cl)cc1C)N(c1cc(Cl)ccc1C)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product from example 16 (90 mg, 0.16 mmol) was dissolved in THF (1.6 mL) with TEA (27 μL, 0.20 mmol) and then acetoxyacetyl chloride (19 μL, 0.18 mmol) was added. The reaction mixture was stirred at RT for 30 min. It was then concentrated to give the title compound. tR: 1.24 min (LC-MS 2); ESI-MS: 649.3/651.2 [M+H]+ (LC-MS 2).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][O:8][CH:9]([O:13][CH3:14])[CH:10]([NH2:12])[CH3:11].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:7][O:8][CH:9]([O:13][CH3:14])[CH:10]([NH:12][C:2](=[O:3])[O:4][CH2:5][CH3:6])[CH3:11]
Reactant: COC(OC)C(C)N
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)NC(C)C(OC)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80 g (0.73 mol) of ethyl chloroformate are added dropwise with ice-cooling to 86.2 g (0.72 mol) of 2-aminopropionaldehyde dimethyl acetal in 350 ml of toluene and 32 g (0.8 mol) of NaOH in 300 ml of water. The mixture is stirred for a further 2 hours at room temperature, the organic phase is separated off, the aqueous phase is extracted using toluene and the toluene solutions are dried over K2CO3. The extracts are concentrated and the residue is distilled.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[C:27]([F:40])[CH:26]=1>>[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][N:34]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:33](=[O:37])[CH:32]=2)=[C:27]([F:40])[CH:26]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2F)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5F)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Yield: 48.5 %

Procedure:
tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (150 mg, 0.400 mmol) and 4-(4-chloro-2-fluorobenzyloxy)pyridin-2(1H)-one (101 mg, 0.400 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (107 mg, 48%) as a yellow oil: ESI MS m/z 552 [M+H]+.
Reaction SMILES: C1(S([C:10]2[CH:11]3[CH2:21][CH2:20][CH:18]([CH:19]=2)[C:17]2[C:12]3=[CH:13][CH:14]=[CH:15][CH:16]=2)(=O)=O)C=CC=CC=1.[N+:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])#[C-:23].C(O[K])(C)(C)C.Cl>C1COCC1>[CH2:28]([O:27][C:25]([C:24]1[NH:22][CH:23]=[C:19]2[C:10]=1[CH:11]1[CH2:21][CH2:20][CH:18]2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=21)=[O:26])[CH3:29]
Reactant: O=S(=O)(C1=CC2CCC1c1ccccc12)c1ccccc1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]cc2c1C1CCC2c2ccccc21
Temperature: 0 °C
Yield: 90.9 %

Procedure:
Under an argon atmosphere, 0.296 g (1.0 mmol) of the obtained 1,4-dihydro-2-phenylsulfonyl-1,4-ethanonaphthalene, 0.13 ml (1.15 mmol) of ethyl isocyano-acetate and 30 ml of anhydrous THF were charged and cooled to 0° C. Into the mixture, 1.7 ml of tert-BuOK (1 M THF solution) was dropped over two hours and the resultant mixture was stirred for three hours at room temperature. After the completion of reaction, the reaction mixture was added with dilute hydrochloric acid, washed in turn with an aqueous saturated sodium bicarbonate solution, distilled water and saturated saline and dried with anhydrous sodium sulfate. The product was purified with silica gel column chromatography (chloroform) to obtain ethyl-4,9-dihydro-4,9-ethano-2H-benz[f]isoindole-1-carboxylate (0.243 g, yield: 91%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[C:13]2[C:22]([CH3:23])=[CH:21][C:20]3[C:19]([CH3:25])([CH3:24])[C:18](=[O:26])[CH2:17][C:16]([CH3:28])([CH3:27])[C:15]=3[CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:29]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[C:13]2[C:22]([CH2:23][Br:29])=[CH:21][C:20]3[C:19]([CH3:24])([CH3:25])[C:18](=[O:26])[CH2:17][C:16]([CH3:28])([CH3:27])[C:15]=3[CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc2c(cc1/C=C/c1ccc(C(=O)O)c(C)c1)C(C)(C)CC(=O)C2(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(/C=C/c2cc3c(cc2CBr)C(C)(C)C(=O)CC3(C)C)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a solution of 1.4 g (3.7 mmol) of methyl-4-[(E)-2-(5,5,8,8-tetramethyl-3-methyl-6-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]-benzoic acid and 0.86 g (4.8 mmol) of N-bromosuccinimide in 50 ml carbon tetrachloride was added 45 mg (0.19 mmol) of benzoyl peroxide and the reaction was heated to reflux temperature. After 1 h, added additional 45 mg of benzoyl peroxide and 25 ml carbon tetrachloride. After 3 h total added 0.2 g N-bromosuccinimide. After 6 h total, cooled to room temperature, washed with 10% aqueous sodium bisulfite and brine, dried over sodium sulfate and adsorbed onto silica gel. Purified by flash chromatography (hexane-8% ethyl acetate/hexane) to give 1.0 g (59%) of methyl-4-[(E)-2-(5,5,8,8-tetramethyl-3-bromomethyl-6-oxo -5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]-benzoic acid.
Reaction SMILES: [CH2:1]([N:5]([CH3:14])[C:6](=[O:13])[CH2:7][O:8][CH2:9][CH2:10][CH2:11]O)[CH2:2][CH2:3][CH3:4].[Br:15]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br:15][CH2:11][CH2:10][CH2:9][O:8][CH2:7][C:6]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH3:14])=[O:13]
Reactant: CCCCN(C)C(=O)COCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCN(C)C(=O)COCCCBr
Yield: 66.4 %

Procedure:
Using the procedure of Step C of the Preparation of Example 83, 1.56 g of the product of Step A, 3.18 g of tetrabromo methane and 2.51 g of triphenyl phosphine were reacted to obtain after chromatography, 1.356 g of the expected product.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH:19]=O)=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:21][CH2:22][CH2:23][CH2:24][P:25](=[O:28])([OH:27])[OH:26].[BH3-]C#N.[Na+]>CO>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:19][NH:21][CH2:22][CH2:23][CH2:24][P:25](=[O:26])([OH:28])[OH:27])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: NCCCP(=O)(O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=P(O)(O)CCCNCc1ccc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
General Procedure M. To a solution of 5,6-diphenylpyridine-2-carbaldehyde (Compound 54, 95 mg, 0.37 mmol) and (3-amino-propyl)-phosphonic acid (51 mg, 0.37 mmol) in MeOH (3 ml) was added Bu4NOH (0.4 ml, 0.37 mmol, 1M in MeOH) under argon. The mixture was stirred at 50° C. for 30 min. before adding NaCNBH3 (23 mg, 0.37 mmol) to the mixture. The solution was stirred at 50° C. for 3 hours, and then it was concentrated in vacuo. The resulting crude solid was purified MPLC column chromatography (silica gel, 0-100% MeOH in ethyl acetate) to obtain the title compound as a white solid.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH2:19]([N:26]([CH3:35])[CH2:27][CH2:28][CH:29]([OH:34])[CH2:30][CH:31]([CH3:33])[CH3:32])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O[C:37]1[C:42]2[CH:43]=[CH:44][S:45][C:41]=2[CH:40]=[CH:39][CH:38]=1.C(P(CCCC)CCCC)CCC>ClCCl.C1(C)C=CC=CC=1>[S:45]1[CH:44]=[CH:43][C:42]2[C:37]([O:34][CH:29]([CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:28][CH2:27][N:26]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:35])=[CH:38][CH:39]=[CH:40][C:41]1=2
Reactant: CC(C)CC(O)CCN(C)Cc1ccccc1
Reactant: Oc1cccc2sccc12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)CC(CCN(C)Cc1ccccc1)Oc1cccc2sccc12
Yield: 59.2 %

Procedure:
Add 1,1′-(azodicarbonyl)dipiperidine (1.6901 g, 6.698 mmol) to a stirred solution of 1-(benzyl-methyl-amino)-5-methyl-hexan-3-ol (1.0463 g, 4.445 mmol), 4-hydroxybenzo-thiophene (1.0027 g, 6.676 mmol), tributylphosphine (1.70 mL, 6.82 mmol), and anhydrous toluene (15 mL). Heat the reaction to 70° C. under nitrogen for 18 hours. Cool the reaction to room temperature and dilute with dichloromethane. Filter off the solid material and concentrate the solvent off on a rotary evaporator to give the crude product. Purify the crude product by flash chromatography on silica gel eluting with 10% ethyl acetate /dichloromethane to yield 0.9674 g (59%) of [3-(benzo[b]thiophen-4-yloxy)-5-methyl-hexyl]-benzyl-methyl-amine: mass spectrum (ion spray) m/z=368.3(M+1); 1H NMR (CDCl3) δ 7.46-7.41 (m, 2H), 7.29-7.21 (m, 7H), 6.83 (d, 1H), 4.66-4.60 (m, 1H), 3.47 (s, 2H), 2.54-2.51 (m, 2H), 2.19 (s, 3H), 2.02-1.71 (m, 4H), 1.49-1.42 (m, 1H), 0.95 (d, 3H), 0.89 (d, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:23])=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=2)[C:5]([CH3:14])=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][O:11][CH2:10]1.O[C:25]1[CH:38]=[CH:37][C:28]2[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=2[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[F:1][C:2]1[C:3]([CH3:23])=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:25]3[CH:38]=[CH:37][C:28]4[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=4[CH:26]=3)[CH:16]=2)[C:5]([CH3:14])=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: Cc1cc(O[C@H]2CCOC2)c(F)c(C)c1-c1cccc(CO)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@H]5CCOC5)c(F)c4C)c3)ccc21
Reaction time: 2 h
Yield: 72.2 %

Procedure:
(S)-(3′-Fluoro-2′,6′-dimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 19c (130 mg, 0.41 mmol), methyl (S)-2-(6-hydroxyl-2,3-dihydrobenzofuran-3-yl)acetate (85 mg, 0.41 mmol) and triphenylphosphine (161 mg, 0.62 mmol) were dissolved in 10 mL of dichloromethane, followed by addition of diisopropyl azodicarboxylate (125 mg, 0.62 mmol). The reaction solution was stirred for 2 hours. The resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound methyl 2-((S)-6-((3′-fluoro-2′,6′-dimethyl-4′-(((S)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 19d (150 mg, yield 72.5%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:11][CH2:12][CH2:13]Br.O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCOc1ccc(Br)cc1
Reaction time: 24 h
Yield: 95.3 %

Procedure:
In 100 ml of dimethylsulfoxide was dissolved 17.3 g (100.0 mmol) of 4-bromophenol, and an aqueous solution of sodium hydroxide (NaOH/H2O: 4.0 g/25 ml) was added thereto. The resultant mixture was stirred until dissolving homogeneously. Next was added 12.3 g (100.0 mmol) of n-propyl bromide to the resultant mixture, and the reaction was carried out at a room temperature for 24 hours. The reaction mixture was poured into an iced water, and the resultant oil was extracted with hexane. After the hexane phase was washed with water, hexane was removed from the hexane phase to give 20.5 g (95.3 mmol) of 1-bromo-4-n-propyloxybenzene.