Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1([NH:9]C(=O)OC(C)(C)C)[CH2:8][CH2:7]1)(=[O:4])=[O:3].[ClH:17]>C(Cl)Cl.O1CCOCC1>[CH3:1][S:2]([CH2:5][C:6]1([NH2:9])[CH2:8][CH2:7]1)(=[O:4])=[O:3].[ClH:17]
Reactant: CC(C)(C)OC(=O)NC1(CS(C)(=O)=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)CC1(N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 1-(methylsulfonylmethyl)cyclopropylcarbamate (crude, 1.05 g) in DCM (7 ml) was added 4M HCl in 1,4-dioxane (16 ml) at r.t. It was stirred further at room temperature for 1 h, at which time LC/MS analysis confirmed full consumption of starting material. Solvent was removed in vacuo and the solid was washed with ether to get the desired 1-(methylsulfonylmethyl)cyclopropanamine as an HCl salt.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[NH:21][C:22]([C:24]1[S:25][C:26]3[CH2:27][NH:28][CH2:29][CH2:30][C:31]=3[N:32]=1)=[O:23])=[O:13])=[CH:6]2.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>N1C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[NH:21][C:22]([C:24]1[S:25][C:26]3[CH2:27][N:28]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:29][CH2:30][C:31]=3[N:32]=1)=[O:23])=[O:13])=[CH:6]2
Reactant: O=C(N[C@H]1CCCC[C@H]1NC(=O)c1nc2c(s1)CNCC2)c1cc2cc(Cl)ccc2[nH]1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (100 mg) obtained in Example 34 was dissolved in pyridine (3 mL), triethylamine (168 μl) and methanesulfonyl chloride (48 μl) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and methylene chloride and 1N hydrochloric acid were added to the residue to separate an organic layer. The resultant organic layer was dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride:methanol=100:1) to give the title compound (79 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:9]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>C(O)C.[Ni]>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:10]2[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A large excess of Raney® nickel was added in portions to a stirred solution of ethyl 1-benzyl-5-nitro-3-phenyl-1H-indole-2-carboxylate (1.20 g, 3 mmol) and hydrazine (1.5 mL, 47.9 mmol) in 50 mL of ethanol. After stirring at room temperature for 2 h the catalyst was then removed by filtering through a short pad of Celite®521. The filtrate was concentrated to give ethyl 5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate (1.0 g, 90%) as an off-white solid: 1H NMR (DMSO-d6) δ 0.91 (t, J=7.0 Hz, 3H, 4.03 (q, J=7.0 Hz, 2H, 4.77 (s, 2H, 5.71 (s, 2H, 6.61 (d, J=1.8 Hz, 1H, 6.75 (d, J=2.2 Hz, 1H, 7.21-7.45 (m, 11H); MS (EI) m/z 371.2 (MH+).
Reaction SMILES: [Na].[CH:2](=[O:10])[C:3]1[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=1)[OH:5].Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20]>CN(C)C=O>[OH:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[CH:2]=[O:10]
Reactant: O=Cc1ccccc1O
Reactant: OCCOCCOCCCl
Agent: [Na]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCCOCCOCCO

Procedure:
A solution of 10 g of sodium salt of salicylaldehyde and 10 g of 2-[2-(2-chloroethoxy)ethoxy]ethanol in dimethylformamide was refluxed for 50 hours. After evaporation, the residue was dissolved in ethyl acetate and the solution washed with water, dried over magnesium sulfate and evaporated. The compound was purified by chromatography (silica; ethyl acetate).
Reaction SMILES: [Cl-].[C:2]([C:4]1([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:9][CH2:8][NH2+:7][CH2:6][CH2:5]1)#[N:3].C(N(CC)CC)C.[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22]>ClCCl>[CH2:21]([S:23]([N:7]1[CH2:8][CH2:9][C:4]([CH2:10][CH:11]([CH3:13])[CH3:12])([C:2]#[N:3])[CH2:5][CH2:6]1)(=[O:25])=[O:24])[CH3:22]
Reactant: CC(C)CC1(C#N)CC[NH2+]CC1
Reactant: CCS(=O)(=O)Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(C#N)(CC(C)C)CC1
Reaction time: 1 h

Procedure:
In a dry round bottom flask was placed 4-cyano-4-isobutylpiperidinium chloride (3, 4.49 g, 44.4 mmol) dichloromethane (150 ml) and triethylamine (6.1 ml, 44.4 mmol). To this was added dropwise ethanesulfonyl chloride (2.1 ml, 22.2 mmol). This was stirred 1 hour and quenched with water (100 ml). The mixture was extracted with dichloromethane (3×50 ml) and the combined organic fractions dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexanes to give 1-(ethylsulfonyl)-4-isobutylpiperidine-4-carbonitrile (4) as a white solid. MS 259 (M+1)
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C@@H:19]2[OH:23])[C@H:15]2[C@@:6]1([F:26])[C@:7]1([CH3:25])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:24])[CH:9]=[CH:8]1)(=[O:3])[CH3:2].O.[CH3:28][S:29]([CH3:31])=O>C(O)(=O)C.C(OC(=O)C)(=O)C>[C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C@@H:19]2[O:23][CH2:28][S:29][CH3:31])[C@H:15]2[C@@:6]1([F:26])[C@:7]1([CH3:25])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:24])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]
Reactant: CS(C)=O
Reactant: CC(=O)O[C@H]1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CSCO[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@]12C

Procedure:
To a solution of (11β,17β)-11-(acetyloxy)-9-fluoro-17-hydroxyandrosta-1,4-dien-3-one (1.6 g, 4.42 mmole) in dry dimethylsulfoxide (30 ml), acetic acid (10 ml) and acetic anhydride (20 ml) were added. The starting steroid disappeared in 20 hours. The mixture was added into water and was extracted with chloroform (3×100 ml). The chloroform extracts were combined, washed with dilute brine and water, dried (anhydrous magnesium sulfate) and was evaporated in vacuo. The residue was dissolved in chloroform-hexane (1:1) and was absorbed on a column of silica gel (45 g). Elutions of the column successively with the same solvent mixture, chloroform and chloroform-ethyl acetate mixtures (2,3,5 and 10% ethyl acetate) gave (i) the homogeneous (tlc) title compound (1.1 g), (ii) a mixture of the 17α-isomer of the title compound and (11β)-11-(acetyloxy)-9-fluoroandrosta-1,4-dien-3,17-dione (300 mg), and (iii) (11β)-11-(acetyloxy)-9-fluoroandrosta-1,4-dien-3,17-dione (280 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>C(N(CC)CC)C.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.[Cu]I>[CH3:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:3][CH:4]=1)[CH3:10]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-iodoisopropylbenzene (12.3 g, 50 mmol, Lancaster Chemical Co.) in triethylamine (150 mL) was added trimethylsilylacetylene (5.89 g, 60 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.70 g, 1 mmol, Aldrich), and copper(I) iodide (1.5 g). The reaction was stirred at room temperature for 18 hours, diluted with hexanes and filtered. The filtrate was evaporated under reduced pressure to give crude 1-(4-(2-propyl)phenyl)-2-trimethylsilyl acetylene.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[C:25]2[CH:26]=[C:27]([CH:29]3[CH2:33][CH2:32][O:31][CH2:30]3)[O:28][C:24]=2[C:23]([O:34][Si](C(C)(C)C)(C)C)=[CH:22][CH:21]=1>O1CCCC1>[Br:19][C:20]1[C:25]2[CH:26]=[C:27]([CH:29]3[CH2:33][CH2:32][O:31][CH2:30]3)[O:28][C:24]=2[C:23]([OH:34])=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c2cc(C3CCOC3)oc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1ccc(Br)c2cc(C3CCOC3)oc12
Reaction time: 0.75 h
Yield: 52.2 %

Procedure:
Tetrabutylammonium fluoride (8.1 ml, 1M in tetrahydrofuran) was added to a stirred solution of [4-bromo-2-(tetrahydrofuran-3-yl)-benzofuran-7-yloxy]-tert-butyldimethylsilane (2.69 g) in dry tetrahydrofuran (80 ml) at 0° C. under a dry nitrogen atmosphere. After stirring at this temperature for 45 minutes the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (75 ml) and water (75 ml). The organic extract was dried over magnesium sulphate, filtered and concentrated in vacuo. Purification by column chromatography on silica eluting with 50% ethyl acetate in heptane afforded the title compound as a clear oil (1 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]S(F)(=O)=O)=[CH:10][CH:9]=1.[Cl:19][C:20]1[CH:29]=[CH:28][C:23]([C:24](=[O:27])[CH2:25]Br)=[CH:22][CH:21]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl:19][C:20]1[CH:29]=[CH:28][C:23]([C:24](=[O:27])/[CH:25]=[CH:14]/[C:11]2[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=2)=[CH:22][CH:21]=1
Reactant: O=S(=O)(F)Cc1ccc(Cl)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
A catalytic amount (about 300 mg) of tetrabutylammonium bromide and 68 g of powdered anydrous potassium carbonate were added to a solution of 21.8 g 4-chlorophenylmethanesulphonyl fluoride and 23.3 g of 4-chlorophenacyl bromide in 200 ml of tetrahydrofuran at room temperature, while stirring. The mixture was stirred for a further 8 hours at 50° C. The reaction mixture was allowed to cool down to room temperature and was then filtered to remove inorganic substances which had precipitated. The organic phase was concentrated by stripping off the solvent under reduced pressure. The residue was recrystallized from ethanol. In this manner, 19.0 g of trans-1,3-di-(4-chlorophenyl)-prop-2-en-1-one were obtained in the form of yellow crystals of melting point 156° C.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([Cl:20])[CH:12]=[C:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:7]=2[O:6]1)=[N+]=[N-]>[Pt]>[Cl:20][C:11]1[CH:12]=[C:13]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[C:7]2[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=2[CH:10]=1
Reactant: [N-]=[N+]=NCC1Cc2cc(Cl)cc(C3CCCCC3)c2O1
Agent: [Pt]
Product: NCC1Cc2cc(Cl)cc(C3CCCCC3)c2O1
Yield: 60 %

Procedure:
Treatment of (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methanol (4.5 g, 0.017 mol) with p-toluenesulfonyl chloride (4.8 g, 0.025 mol), diisopropylethylamine (4.36 g, 0.034 mol), and 4-(dimethylamino)pyridine (0.12 g, 0.98 mmol) generally according to the procedure described for Intermediate 45 gave (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of the tosylate with sodium azide (4.03 g, 61.99 mmol) generally according to the procedure described for Intermediate 98 provided 3.45 g of (±)-2-(azidomethyl)-5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.75 g, 5 wt. %) generally according to the procedure described for Example 1 afforded 2.70 g (60%) of (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp 210-213° C.; Anal. calcd for C15H20ClNOHCl: C, 59.61; H, 7.00; N, 4.63. Found: C, 57.29; H, 7.14; N, 4.78.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Br[CH2:11][C:12]([NH:14][C:15]1[C:16]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[N:17][C:18]([CH3:27])=[CH:19][C:20]=1[O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:13].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:31][C:30]([F:33])([F:32])[CH2:29][O:28][C:16]1[C:15]([NH:14][C:12](=[O:13])[CH2:11][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]2)=[C:20]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[C:18]([CH3:27])[N:17]=1
Reactant: OCCN1CCNCC1
Reactant: Cc1cc(OCC(F)(F)F)c(NC(=O)CBr)c(OCC(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(OCC(F)(F)F)c(NC(=O)CN2CCN(CCO)CC2)c(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.1 %

Procedure:
1-(2-Hydroxyethyl)piperazine (1.95 g, 15.0 mmol) and 2-bromo-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide (5.00 g, 12.5 mmol) were dissolved in acetonitrile (30 mL). Potassium carbonate (2.25 g, 16.3 mmol) was added to the solution, followed by stirring for 5 hours at room temperature. The reaction mixture was dilluted with water, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, followed by drying over sodium sulfate anhydrate and concentration under reduced pressure. The obtained residue was purified through silica gel column chromatography (eluent: ammonia-saturated methanol/chloroform=1/20), to thereby yield 5.40 g of N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide as colorless crystals (yield 91%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27](=[O:30])(=[O:29])[CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH2:32]([N:34]1[N:38]=[N:37][C:36]([CH2:39][N:40]2[C:45]3[CH:46]=[C:47]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[S:48][C:44]=3[C:43](=[O:55])[N:42]([CH:56]3[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]3)[C:41]2=[O:62])=[N:35]1)[CH3:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:59]4[CH2:60][CH2:61][CH:56]([N:42]5[C:43](=[O:55])[C:44]6[S:48][C:47]([C:49]7[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=7)=[CH:46][C:45]=6[N:40]([CH2:39][C:36]6[N:37]=[N:38][N:34]([CH2:32][CH3:33])[N:35]=6)[C:41]5=[O:62])[CH2:57][CH2:58]4)=[O:21])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27](=[O:29])(=[O:30])[CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCS(=O)(=O)C[C@H]21
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nnn(CC)n5)c4=O)CC3)cc1)=N[C@@H]1CCS(=O)(=O)C[C@H]21
Reaction time: 12 h

Procedure:
The title compound is prepared analogously as described for example 1 (however, stirring is performed for 12 h at RT) using 4-[(4aR,10bR)-9-ethoxy-8-methoxy-2,2-dioxido-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (330 mg; compound C4), 1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (365 mg; hydrochloride salt of compound B39), HBTU (322 mg), DIPEA (0.65 ml) and DCM (20 ml). The crude product is purified by flash column chromatography [silica gel, eluant: DCM/MeOH, 19/1 (v/v)] to yield the title compound as a solid.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[C:19]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=1[OH:29])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:25]4[CH:26]=[C:27]([C:30]([CH3:31])([CH3:32])[CH3:33])[C:28]([OH:29])=[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:24]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: CC(C)(C)c1cc(B(O)O)cc(C(C)(C)C)c1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cc(C(C)(C)C)c(O)c(C(C)(C)C)c4)cc3CC[C@@H]12
Yield: 60.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) {23 mg, 0.02 mmol), 3,5-di(t-butyl)-4-hydroxyphenylboronic acid (195 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 16 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 170 mg (58%) of the title compound as a white solid. mp>265°. FDMS: m/e=433 α[D]589 =+46.45 (c=1.00, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[C:23]([C:25]1([CH3:39])[CH2:30][CH2:29][C:28]2[C:31]([CH3:38])=[C:32]([OH:37])[C:33]([CH3:36])=[C:34]([CH3:35])[C:27]=2[O:26]1)#[CH:24].C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:24]#[C:23][C:25]3([CH3:39])[CH2:30][CH2:29][C:28]4[C:31]([CH3:38])=[C:32]([OH:37])[C:33]([CH3:36])=[C:34]([CH3:35])[C:27]=4[O:26]3)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Solvent: ClCCl
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1cc3c(s1)-n1c(C)nnc1CN=C3c1ccccc1Cl)O2

Procedure:
The title compound was obtained by coupling 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][4,1]diazepine with rac-2-ethynyl-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol under the conditions described in Example 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride. The combined clean fractions were evaporated and the residue was crystallized from ethyl acetate to give colorless crystals of rac-2-{[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][4,1]diazepin-2-yl]ethynyl}-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with m.p. 155°-160° with foaming. These crystals contained 1.5 molar amounts of water on the basis of the analytical and spectral data.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21](OS(C(F)(F)F)(=O)=O)[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.[F:42][C:43]([F:54])([F:53])[C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[C:21]([C:47]4[CH:48]=[CH:49][C:44]([C:43]([F:54])([F:53])[F:42])=[CH:45][CH:46]=4)[C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[CH:23][CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(OS(=O)(=O)C(F)(F)F)c2)c1)C1CC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(-c3ccc(C(F)(F)F)cc3)c2)c1)C1CC1
Temperature: 90 °C
Reaction time: 15 h
Yield: 56.4 %

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-(((trifluoromethyl)sulfonyl)oxy)biphenyl-4-yl)oxy)methyl)phenyl)propanoate (173 mg) in toluene (5.0 mL) were added 4-(trifluoromethyl)phenylboronic acid (157 mg), tris(dibenzylideneacetone)dipalladium(0) (20 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (39 mg) and 2.0 M aqueous sodium carbonate solution (0.43 mL), and the mixture was stirred at 90° C. for 15 hr. The reaction mixture was filtered through celite, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (97 mg) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl>[C:40]([NH:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)(=[O:42])[CH3:41]
Reactant: Cc1cccc(-c2c(F)cccc2[C@H](OCCN)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCO[C@@H](c1cccc(F)c1-c1cccc(C)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To a solution of (3R)-tert-butyl 3-((R)-(2-aminoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)piperidine-1-carboxylate (86 mg, 0.2 mmol) in anhydrous CH2Cl2 (8 mL) was added Et3N (0.5 ml, 20 mmol). The mixture was cooled with an ice bath and acetyl chloride (15 mg, 0.2 mmol) in CH2Cl2 (4 mL) was added. The reaction mixture was stirred at rt for 0.5 h, then washed with water, dried over MgSO4, filtered and concentrated to give (3R)-tert-butyl 3-((R)-(2-acetamidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)piperidine-1-carboxylate (80 mg, 85%), which was used in the next step without purification.