Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:9][CH:10]=1)\[NH2:4].[C:20](OC(=O)C)(=[O:22])[CH3:21]>ClCCl>[C:20]([O:1]/[N:2]=[C:3](/[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:9][CH:10]=1)\[NH2:4])(=[O:22])[CH3:21]
Reactant: COC(=O)CCC(=O)Nc1ccc(/C(N)=N/O)cn1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COC(=O)CCC(=O)Nc1ccc(/C(N)=N/OC(C)=O)cn1
Reaction time: 120 h

Procedure:
To a suspension of methyl 4-[[5-[(Z)—N′-hydroxycarbamimidoyl]-2-pyridyl]amino]-4-oxo-butanoate (obtained as described in step 1, 0.15 g, 0.56 mmol, 1 equiv.) in dichloromethane (30 mL) was added acetic anhydride (1.98 mL, 20.3 mmol, 36 equiv.). The mixture was stirred for 5 days, before concentration under vacuum giving methyl 4-[[5-[(Z)—N′-acetoxycarbamimidoyl]-2-pyridyl]amino]-4-oxo-butanoate which is used in the next step without extra purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:39])[C:12]=1[CH2:13][CH2:14][C:15]1[N:16]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:17]([C:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([O:30][CH3:31])[CH:24]=2)([CH3:22])[CH3:21])=[CH:18][N:19]=1)[C:5]([O:7]CC)=[O:6].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:39])[C:12]=1[CH2:13][CH2:14][C:15]1[N:16]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[C:17]([C:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([O:30][CH3:31])[CH:24]=2)([CH3:22])[CH3:21])=[CH:18][N:19]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1cc(F)c(CCc2ncc(C(C)(C)c3ccc(Cl)c(OC)c3)n2-c2ccc(F)cc2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(C)(C)c2cnc(CCc3c(F)cc(C(=O)O)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a solution of ethyl 3-chloro-4-(2-(5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)ethyl)-5-fluorobenzoate (151 mg, 0.263 mmol) in MeOH (1.0 mL) was added dropwise a 2N solution of NaOH in H2O (0.5 mL). After stirring 1 h, the reaction mixture was concentrated under reduced pressure, diluted with H2O (1.5 mL), neutralized with 1N HCl and then extracted with DCM (10 mL×2). The combined extracts were dried (MgSO4), filtered and concentrated to give the title compound (116 mg, 81%) as gray solid. 1H NMR (400 MHz, DMSO) δ 7.69 (s, 1H), 7.57 (d, J=9.6 Hz, 1H), 7.27-7.17 (m, 2H), 7.05 (d, J=8.6 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 6.69 (dd, J=8.6, 4.8 Hz, 2H), 6.54 (s, 1H), 6.53-6.48 (m, 1H), 3.69 (s, 3H), 2.94 (t, J=7.2 Hz, 2H), 2.57 (t, J=7.2 Hz, 2H), 1.48 (s, 6H).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][N:6]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:9]=2[N:8]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7]1=[O:30])C.[OH-].[Na+].O.Cl>C(O)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:9]2[N:8]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7](=[O:30])[N:6]([CH2:5][C:4]([OH:31])=[O:3])[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:10]=2[CH:20]=1
Reactant: CCOC(=O)CN1N=C(c2ccccc2Cl)c2cc(Cl)ccc2N(CC(C)(C)C)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)CN1C(=O)N(CC(=O)O)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
To a solution of 7-chloro-5-(2-chlorophenyl)-1-neopentyl-1,2-dihydro-2-oxo-3H-1,3,4-benzotriazepine-3-acetic acid ethyl ester obtained in Example 56 (0.16 g) in ethanol (3 ml) was added a 1N aqueous solution of sodium hydroxide (0.3 ml). The mixture was stirred for 4 hours at room temperature. To the reaction mixture was added water (50 ml), which was made acid with 1N HCl, then the solution was concentrated. To the concentrate was added dichloromethane (50 ml), which was washed with water, then the solvent was distilled off. The residue was recrystallized from dichloromethane--petroleum ether to give 91 mg of colorless crystals, m.p. 181°-183° C.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].[Li]CCCC.[I:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([OH:23])=[O:22].ICC>C1COCC1>[I:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([CH2:1][CH3:2])[C:21]([OH:23])=[O:22]
Reactant: CC(C)NC(C)C
Reactant: O=C(O)Cc1ccccc1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCI
Product: CCC(C(=O)O)c1ccccc1I
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of diisopropylamine (5.6 mL, 40 mmol) in dry THF (60 mL) at -10° C. was added 1.6M BuLi (25 mL, 40 mmol). After 30 min, a solution of 2-iodophenylacetic acid (5.24 g, 20 mmol) in THF (20 mL) was slowly added. The solution was stirred for 1 h, at which point iodoethane (1.6 mL, 117 mmol) was added. After 2 h at r.t. the reaction was quenched with 0.5M NH4OAc solution and 6M HCl (10 mL) and the product was extracted with EtOAc. The organic layer was dried (MgSO4) and evaporated to give an oily residue which was purified by flash chromatography (15:85 EtOAc:hexane containing 5% AcOH) to give 4.37 g of the title compound as an off-white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:15][CH2:16][CH3:17])=[C:7]([O:12][CH2:13][CH3:14])[CH:8]=2)[N:3]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>>[F:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][C:6]([O:15][CH2:16][CH3:17])=[C:7]([O:12][CH2:13][CH3:14])[CH:8]=3)[N:3]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: CCOc1cc2ncc(Cl)nc2cc1OCC
Reactant: Nc1cccc(F)c1
Product: CCOc1cc2ncc(Nc3cccc(F)c3)nc2cc1OCC
Yield: 54.1 %

Procedure:
To 0.25 g (0.989 mmol) of 2-chloro-6,7-diethoxyquinoxaline is added 2 mL of m-fluoroaniline. This mixture is heated under nitrogen overnight to 120° C. The resulting mixture is chromatographed (30:1 CH2Cl2: EtOH) to yield partially purified product. This solid is triturated with ethyl acetate to give 0.175 g of the product as a brownish yellow solid in 54.1% yield (m.p. 193° C.). Anal. Calcd for C18H18N3O2F.0.25H2O: C, 65.15; H, 5.62; N, 12.66. Found: C, 65.30; H, 5.30; N, 12.41.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[S:21][C:22]([C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:24]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:32]1[C:41]([CH3:42])=[CH:40][C:39]2[C:38]([CH3:44])([CH3:43])[CH2:37][CH2:36][C:35]([CH3:46])([CH3:45])[C:34]=2[CH:33]=1>>[CH3:42][C:41]1[C:32](/[C:26](/[Si:27]([CH3:28])([CH3:29])[CH3:30])=[CH:25]/[C:22]2[S:21][C:20]([CH2:19][OH:18])=[CH:24][CH:23]=2)=[CH:33][C:34]2[C:35]([CH3:46])([CH3:45])[CH2:36][CH2:37][C:38]([CH3:44])([CH3:43])[C:39]=2[CH:40]=1
Reactant: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Reactant: CC(C)(C)[Si](OCc1ccc(C#C[Si](C)(C)C)s1)(c1ccccc1)c1ccccc1
Product: Cc1cc2c(cc1/C(=C/c1ccc(CO)s1)[Si](C)(C)C)C(C)(C)CCC2(C)C

Procedure:
Following General Procedure A, 5-[(trimethylsilyl)ethynyl]thiophen-2-ylmethyl tert-butyldiphenylsilyl Ether (Compound 13, 0.75 g, 1.8 mmol) and 2-bromo-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (0.45 g, 1.67 mmol) were coupled to give the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C@H:5]1[CH2:24][C@@:23]2([CH3:25])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:22]2[C:21](=[O:26])[CH2:20][C@@:19]2([CH3:27])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:16](=[O:18])[CH3:17])[CH2:7][C@@H:6]1[OH:28].[CH2:29](O)[CH2:30][OH:31].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][O:4][C@H:5]1[CH2:24][C@@:23]2([CH3:25])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:22]2[C:21](=[O:26])[CH2:20][C@@:19]2([CH3:27])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:16]2([O:31][CH2:30][CH2:29][O:18]2)[CH3:17])[CH2:7][C@@H:6]1[OH:28]
Reactant: OCCO
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCl)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](OCCCl)C[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1

Procedure:
2β-(2'-Chloroethoxy)-3α-hydroxy-5α-pregnane-11,20-dione (600 mg.) was dissolved in benzene (50 ml.), ethylene glycol (5 ml.) and toluene-p-sulphonic acid (2 mg.) added, and the vigorously stirred mixture refluxed under a Dean and Stark head for 20 hours. The cooled mixture was washed with sodium bicarbonate solution (5 ml.), water (2 × 100 ml.) and dried over anhydrous sodium sulphate. The dried solution was evaporated in vacuo to give the title compound (605 mg.) as a pale yellow foam, [α]D + 47.2° (c 1.11).
Reaction SMILES: [Li+].[OH-].[F:3][C:4]1[C:5]([NH:20][CH:21]([C:28]2([CH3:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:22][C:23]([O:25]CC)=[O:24])=[N:6][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([F:19])[CH:17]=3)[NH:12][CH:11]=2)=[N:8][CH:9]=1>O.C1COCC1>[F:3][C:4]1[C:5]([NH:20][CH:21]([C:28]2([CH3:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:22][C:23]([OH:25])=[O:24])=[N:6][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([F:19])[CH:17]=3)[NH:12][CH:11]=2)=[N:8][CH:9]=1
Reactant: CCOC(=O)CC(Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F)C1(C)CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C(CC(=O)O)Nc2nc(-c3c[nH]c4ncc(F)cc34)ncc2F)CCCCC1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
LiOH (0.118 mg, 4.927 mmol) was added to a solution of ethyl 3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3-(1-methylcyclohexyl)-propanoate, 77, (0.23 g, 0.49 mmol) in water (5 mL) and THF (5 mL). The solution was stirred at 95° C. for 18 hours and then cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water (10 mL) and neutralized with 2N HCl. The resulting precipitate was extracted with EtOAc (3×10 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo to afford 210 mg of the desired product as an off-white solid: 1H NMR (400 MHz, CD3OD) δ 8.78 (dd, J=9.7, 2.7 Hz, 1H), 8.16 (s, 2H), 7.99 (d, J=4.1 Hz, 1H), 5.20 (d, J=9.9 Hz, 1H), 2.86-2.69 (m, 1H), 2.53 (dd, J=14.7, 11.0 Hz, 1H), 1.76-1.56 (m, 2H), 1.53 (m, 4H), 1.29 (m, 4H), 1.02 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.20 minutes (M+H) 416.27.
Reaction SMILES: [C:1]1([C:7]2([C:10]([C:12]3[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=3[C:14](OCC)=[O:15])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:24][NH2:25]>C(O)C>[C:1]1([C:7]2([C:10]3[C:12]4[C:13](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:14](=[O:15])[NH:25][N:24]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccccc1C(=O)C1(c2ccccc2)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(C2(c3ccccc3)CC2)c2ccccc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
A solution of (2-(ethoxycarbonyl)phenyl)zinc(II) bromide (2.2 mL, 1.1 mmol) was added to a mixture of 1-phenylcyclopropanecarbonyl chloride (0.200 g, 1.1 mmol) and Pd(PPh3)4 (0.0644 g, 0.056 mmol) in THF (1.1 mL), stirred for 2 hours, diluted with EtOAc, washed with 1N HCl and brine, dried (Na2SO4), filtered, and chromatographed (20% Et2O/hexanes) to give 216.2 mg of impure ethyl 2-(1-phenylcyclopropanecarbonyl)benzoate. A mixture of impure ethyl 2-(1-phenylcyclopropanecarbonyl)benzoate (0.216 g, 0.735 mmol) and hydrazine hydrate (0.13 mL, 2.298 mmol) in ethanol (3 mL) was stirred at 75° C. overnight, and concentrated to give 179.7 mg of impure 4-(1-phenylcyclopropyl)phthalazin-1(2H)-one, which was treated with O-(diphenylphosphoryl)hydroxylamine using a method similar to that described in Example 1B to give impure 2-amino-4-(1-phenylcyclopropyl)phthalazin-1(2H)-one.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH2:18])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25]>C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH:18][C:27]([NH:26][CH2:22][CH2:23][CH2:24][CH3:25])=[O:28])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:20][CH3:21]
Reactant: CCCCN=C=O
Reactant: CCCN(CCC)C1CCc2cccc(OCCN)c2C1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCNC(=O)NCCOc1cccc2c1CC(N(CCC)CCC)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.45 g (5 mmol) of 2-dipropylamino-8-(2-aminoethoxy)-1,2,3,4-tetrahydronaphthalene were initially introduced into 25 ml of toluene. The reaction was catalyzed using 3 drops of triethylamine, and 0.63 ml (5.5 mmol) of butyl isocyanate was then added dropwise. The mixture was stirred for 2 h at room temperature. The mixture was evaporated to dryness, and the residue was crystallized from petroleum ether/diisopropyl ether.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].C(N(CC)CC)C.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>ClCCl>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:18]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:23])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=Cc1cc(O)ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2,5-dihydroxybenzaldehyde (10 g) in dichloromethane (50 ml) at 0° C. was added triethylamine (5 ml) and pivaloyl chloride (4.4 ml). The mixture was stirred at room temperature for 18 hours, filtered and the filtrates washed with 2M HCl (100 ml), brine (100 ml) and sodium bicarbonate (100 m), dried (magnesium sulphate) filtered and evaporated. The residue was purified by chromatography on silica gel using dichloromethane:hexane (0:1 to 1:1 gradient) then ethyl acetate:hexane (1:9 to 3:7 gradient) as eluants to give 2-hydroxy-5-(t-butylcarbonyloxy)benzaldehyde (4 g) and some 2,5-dihydroxy-benzaldehyde.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][CH3:14])[CH:10]([N:15]2[CH:19]=[N:18][N:17]=[C:16]2[C:20]2[C:25]([NH:26][S:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=3)(=[O:29])=[O:28])=[CH:24][C:23]([Cl:41])=[CH:22][N:21]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([S:27]([NH:26][C:25]2[C:20]([C:16]3[N:15]([CH:10]4[CH:11]([O:13][CH3:14])[CH2:12][NH:8][CH2:9]4)[CH:19]=[N:18][N:17]=3)=[N:21][CH:22]=[C:23]([Cl:41])[CH:24]=2)(=[O:29])=[O:28])=[CH:31][C:32]=1[C:37]([F:39])([F:40])[F:38]
Reactant: COC1CN(C(=O)OC(C)(C)C)CC1n1cnnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1CNCC1n1cnnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
To 3-{3-[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-[1,2,4]triazol-4-yl}-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (71 mg, 0.11 mmol) was added 1:1 mixture of TFA-CH2Cl2 (2 mL) at room temperature and stirred for 2 h. Solvents were evaporated, 1:1 mixture of CH3CN—H2O (5 mL) and lyophilized to obtain 4-chloro-N-{5-chloro-2-[4-(4-methoxy-pyrrolidin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide as a white solid in quantitative yield. MS (ES) [M+H]+ expected 537.0, found 537.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C@@H:12]3[CH2:16][CH2:15][NH:14][CH2:13]3)[CH2:9][C:8](=[O:17])[N:7]([CH2:18][CH3:19])[C:6]=2[CH:20]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][CH2:29][CH:30]=[C:31]1[C:37]2[CH:38]=[CH:39][CH:40]=[N:41][C:36]=2[CH2:35][O:34][C:33]2[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C@@H:12]3[CH2:16][CH2:15][N:14]([CH2:28][CH2:29][CH:30]=[C:31]4[C:37]5[CH:38]=[CH:39][CH:40]=[N:41][C:36]=5[CH2:35][O:34][C:33]5[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]4=5)[CH2:13]3)[CH2:9][C:8](=[O:17])[N:7]([CH2:18][CH3:19])[C:6]=2[CH:20]=1
Reactant: CCN1C(=O)CN([C@@H]2CCNC2)Cc2ccc(Cl)cc21
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN1C(=O)CN([C@@H]2CCN(CCC=C3c4cc(C(C)(C)O)ccc4OCc4ncccc43)C2)Cc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.8 %

Procedure:
To a solution of (R)-8-chloro-1-ethyl-4-pyrrolidin-3-yl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.121 g, 0.32 mmol) in acetonitrile/water (8:2) (3.2 mL) was added K2CO3 (0.368 g, 2.6 mmol) and 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.102 g, 0.27 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated down and partitioned between EtOAc/H2O, extracted with EtOAc (3×). The organics were collected together dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (5% methanol/95% methylene chloride to 10% methanol/90% methylene chloride to 15% methanol/85% methylene chloride) to yield the title compound (0.033 g, 21%). 1H-NMR (CDCl3): δ 1.17 (t, 3H), 1.55 (s, 6H), 1.73 (septet, 1H), 2.08 (m, 1H), 2.34 (pentet, 2H), 2.43-2.61 (m, 4H), 2.85 (t, 1H), 2.92 (d, 1H), 3.10 (q, 1H), 3.22 (m, 1H), 3.52 (q, 2H), 3.91 (septet, 2H), 5.29 (bs, 2H), 6.12 (t, 1H), 6.79 (dd, 1H), 7.15-7.28 (m, 5H), 7.44 (s, 1H), 7.56 (d, 1H), 8.47 (d, 1H). ESI-MS m/z: 587 (M+1), retention time 1.37.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]2[CH2:15][CH:14]3[N:16]([CH3:17])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH3:17][N:16]1[CH:14]2[CH2:13][CH2:12][CH:11]1[CH2:10][C:9](=[CH:8][C:4]1[CH:3]=[C:2]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([C:18]#[N:19])[CH:25]=3)[CH:7]=[CH:6][CH:5]=1)[CH2:15]2
Reactant: CN1C2CCC1CC(=Cc1cccc(Br)c1)C2
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN1C2CCC1CC(=Cc1cccc(-c3cccc(C#N)c3)c1)C2
Temperature: 130 °C
Yield: 97 %

Procedure:
To a solution of 3-[(3-bromophenyl)methylidene]-8-methyl-8-azabicyclo[3.2.1]octane (1.17 g, 4 mmol) in p-dioxane (15 mL) and H2O (5 mL) was added (3-cyanophenyl) boronic acid (0.705 g, 4.80 mmol), Pd(PPh3) (0.185 g, 0.16 mmol), and K2CO3 (1.658 g, 12 mmol) and then the mixture was heated in a microwave oven at 130° C. for 20 min. The organic layer of the reaction mixture was separated, concentrated and purified by Combiflash chromatograph to afford 1.22 g (97%) of the title compound. LC-MS m/z 315 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[Si:7]([O:14][C@@H:15]1[C@H:19]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:18][C@@H:17]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32](Cl)[CH:31]=2)[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[NH2:37][C@@H:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39]1>COCCOC.CCOC(C)=O>[Si:7]([O:14][C@@H:15]1[C@H:19]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:18][C@@H:17]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH:37][C@@H:38]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:40][CH2:39]3)[CH:31]=2)[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc(Cl)c2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: N[C@H]1CCc2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc(N[C@H]3CCc4ccccc43)c2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 0.08 h
Yield: 94.8 %

Procedure:
To a mixture of [1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-yl](chloro)[(2,3-η)-(1Z)-1-phenylprop-1-ene-2,3-diyl]palladium(2+) (7.8 mg, 0.000012 mol) and potassium tert-butoxide (73.7 mg, 0.000656 mol) under an atmosphere of argon was added 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentyl]oxy}-2-chloropyridine (281.8 mg, 0.0005968 mol) in 1 ml DME. The solution was stirred for 5 mins, then (S)-(+)-1-aminoindane (0.10 mL, 0.000776 mol) in 1.0 ml DME was added dropwise over 15 min. The solution was stirred overnight, then dissolved in 50 mL EtOAc, washed with water, and concentrated. The residue was purified by flash chromatography (30% EtOAc/hexanes) to afford the title compound (0.3219 g, 95%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Sn](CCCC)(CCCC)CCCC>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[F:21]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1F
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)c(F)cc21
Product: O=C1CCCc2cc(-c3ccccc3F)c(F)cc21
Yield: 53.2 %

Procedure:
Using 1.50 g (4.80 mmol) of 3,4-dihydro-7-fluoro-6-trifluoromethylsulfonyloxy-1(2H)-naphthalenone and 2.22 g (5.78 mmol) of 2-fluorophenyltributyltin, the same reaction as described in Reference Example 1 was carried out to obtain 0.66 g of the above-mentioned compound (yield 53%).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[OH-].[Na+].O>[CH2:20]([O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: OCCOCCOCCOCCOCCOCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of hexaethylene glycol (Aldrich, 100 g) and benzyl bromide (Aldrich, 12 g) in aqueous sodium hydroxide (50% (w/w), 80 ml) was stirred at 100° C. (oil bath) under nitrogen for 2 h. The reaction mixture was then cooled to ambient temperature, diluted with water to a total volume of 500 ml, and extracted with diethyl ether (200 ml) to remove dibenzylated product. Sodium chloride (100 g) was added to the aqueous layer, which was extracted further with diethyl ether (6×100 ml). These ether extracts were combined, dried (sodium sulfate), and concentrated to give hexaethylene glycol monobenzyl ether as an oil (25 g, 20% based on glycol), 1H-NMR (CDCl3) δ: 7.30 (m, 5, 5 phenyl CH), 4.53 (s, 2, benzyl CH2), 3.69-3.54 (m, 22, 11 OCH2), 3.06 (br s, 3, OH and CH2O).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5]([NH2:8])(=[O:7])=[O:6].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[OH:24])=[CH:12][CH:11]=1>CO>[Cl:9][C:10]1[CH:11]=[CH:12][C:13](/[C:16](=[N:1]\[CH2:2][CH2:3][CH2:4][S:5]([NH2:8])(=[O:7])=[O:6])/[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[OH:24])=[CH:14][CH:15]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cc(F)ccc1O
Reactant: NCCCS(N)(=O)=O
Solvent: CO
Product: NS(=O)(=O)CCC/N=C(\c1ccc(Cl)cc1)c1cc(F)ccc1O
Yield: 50.6 %

Procedure:
3-Amino-1-propanesulfonamide (0.55 g, 4 mmol; from step 4) was added to a solution of 4′-chloro-5-fluoro-2-hydroxy-benzophenone (1 g, 4 mmol) in methanol (50 mL). The reaction mixture was stirred under reflux for 5 h then concentrated under reduced pressure. The residual material was purified by column chromatography (silica gel, dichloromethane:methanol 90:10 then 80:20). The corresponding solid (after removal of solvent) was recrystallized in diethyl ether to afford 3-{[(1E)-(4-chlorophenyl)(5-fluoro-2-hydroxyphenyl)methylene]amino}propane-1-sulfonamide (0.75 g, 51%). 1H NMR (CDCl3, 500 MHz) δ 2.21 (m, 2H), 3.24 (t, J=7.0 Hz, 2H), 3.47 (t, J=7.0H, 2H), 4.63 (bs, 2H), 6.93 (m, 1H), 6.95 (m, 1H), 7.04 (m, 1H), 7.13 (d, J=8.2 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H), 14.71 (s, 1H). ES-MS (369 M-1).