Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:19][C:18](=[O:20])[N:17]([CH3:21])[C:16]=2[CH:22]=1)C1C=CC=CC=1>[Pd].CO.O1CCCC1>[OH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:19][C:18](=[O:20])[N:17]([CH3:21])[C:16]=2[CH:22]=1
Reactant: Cn1c(=O)[nH]c2ccc(OCCOCc3ccccc3)cc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(=O)[nH]c2ccc(OCCO)cc21
Reaction time: 2 h
Yield: 95.6 %

Procedure:
A mixture of 6-(2-benzyloxy-ethoxy)-1-methyl-1,3-dihydro-benzoimidazol-2-one (0.69 g, 2.31 mmol) and 20% palladium on carbon (0.10 g) in methanol (10 ml) and tetrahydrofuran (10 ml) was stirred under a hydrogen atmosphere (1 atm) for 2 h. After removal of the catalyst, the catalyst was washed with boiling methanol (50 ml). The filtrate was evaporated to give 6-(2-hydroxy-ethoxy)-1-methyl-1,3-dihydro-benzoimidazol-2-one (0.46 g, 96%) as a solid. 1H NMR (DMSO) 10.54 (1H, s), 6.78 (1H, d, J=8.3), 6.70 (H, d, J=632.2), 6.50 (1H, dd, J=8.3, 2.4), 4.79 (1H, t, J=5.6), 3.90 (2H, t, J=5.0), 3.64 (2H, q, J=5.2), 3.18 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([Cl:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(Cl)c1O
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Product: Cc1cc(Br)cc(Cl)c1Oc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Into a 100 mL round bottom flask was added 4-bromo-2-chloro-6-methylphenol (1.00 g, 4.52 mmol), benzeneboronic acid (1.10 g, 9.04 mmol), cupric acetate (1.4 g, 7.70 mmol) and DCM (50 mL). TEA (4.0 mL, 29.0 mmol) was then added followed by 4 A° molecular sieves and the reaction mixture was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:9](=[N:10][C:11](C#N)=[C:12]([C:15]#[N:16])[N:13]=2)[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.C([O-])(=O)C.[NH4+:23].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[NH2:23][C:11]1[N:10]=[C:9]2[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:2](=[O:1])[C:14]2=[N:13][C:12]=1[C:15]#[N:16]
Reactant: [NH4+]
Reactant: N#Cc1nc2c(nc1C#N)-c1ccccc1C2=O
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1nc2c(nc1N)-c1ccccc1C2=O
Temperature: 70 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
A mixture of 1 (201 mg, 0.86 mmol), ammonium acetate (331 mg, 4.3 mmol) and Na2SO4 (200 mg) in THF (2.9 ml) was stirred at 70° C. in sealed tube for 18 hours. The solvent was evaporated, water (5 ml) was added and the precipitate filtered, washed with water and dried under vacuum, affording 7 (171 mg, 90%) as green solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([C:8]2([CH2:11][NH2:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([C:8]2([CH2:11][NH:12][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[C:22]([F:21])([F:32])[F:33])[CH2:9][CH2:10]2)=[N:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: NCC1(c2ncc(Br)cc2Cl)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1(c2ncc(Br)cc2Cl)CC1)c1ccccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
3 g C-[1-(5-bromo-3-chloro-pyridin-2-yl)-cyclopropyl]-methylamine (step 3) was dissolved in 20 ml of dichloromethane and was cooled down to 0° C. 2.32 g of triethylamine was added, then a solution of 2.87 g 2-(trifluoromethyl)benzoyl chloride 5 ml dichloromethane was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours. Then water was added and the mixture was extracted twice with dichloromethane. The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated. Crude material was obtained as a pale yellow sticky solid, which was purified by flash chromatography on silica gel with heptane/ethyl acetate as a solvent. Thus, 4.74 g of N—[[1-(5-bromo-3-chloro-2-pyridyl)cyclopropyl]methyl]-2-(trifluoromethyl)benzamide was obtained as a colourless sticky solid. 1H-NMR (CDCl3): 8.45 ppm (s, 1H), 7.87 ppm (s, 1H), 7.65 ppm (d, 1H), 7.52 ppm (m, 2H), 7.41 ppm (d, 1H), 6.10 ppm (s, 1H, broad), 3.70 ppm (d, 2H), 1.10 ppm (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:27][CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)[OH:29])[CH:9]([CH3:26])[CH2:10][C:11]1[CH:25]=[CH:24][C:14]2[O:15][C:16]([C:21]([OH:23])=[O:22])([C:18]([OH:20])=[O:19])[O:17][C:13]=2[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:38][C:39]([O:41][CH2:42][CH2:43][CH3:44])=[O:40]>>[CH2:42]([O:41][C:39]([CH:38]([O:19][C:18]([C:16]1([C:21]([OH:23])=[O:22])[O:15][C:14]2[CH:24]=[CH:25][C:11]([CH2:10][CH:9]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:27][CH:28]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[OH:29])[CH3:26])=[CH:12][C:13]=2[O:17]1)=[O:20])[C:16]([O:15][CH2:14][CH2:13][CH3:12])=[O:17])=[O:40])[CH2:43][CH3:44]
Reactant: CCCOC(=O)CBr
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)N(CC(O)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Product: CCCOC(=O)C(OC(=O)C1(C(=O)O)Oc2ccc(CC(C)N(CC(O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2O1)C(=O)OCCC

Procedure:
The title compound was prepared from 5-(2-{tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino}-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid and propyl 2-bromoacetate according to the procedure of Example 24, step 3 as a colorless oil: 1H NMR (300 MHz, CDCl3): δ 0.91 (t, J=7.4 Hz, 6H), 1.21 (d, J=6.9 Hz, 3H), 1.40 (s, 9H), 1.55-1.72 (m, 4H), 2.47-2.70 (m, 1H), 3.05-3.17 (m, 1H), 3.46-3.60 (m, 1H), 4.11 (t, J=6.6 Hz, 4H), 4.70-4.85 (m, 4H), 5.47 (s, 1H), 6.60-6.92 (m, 3H), 7.20-7.35 (m, 3H), 7.41 (s, 1H); MS (ES) m/z (relative intensity): 722 (M+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:26]1([CH2:32][S:33][CH:34]([C:38](O)=[O:39])[C:35](O)=[O:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[OH:39][C:38]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])[O:10][C:35](=[O:36])[C:34]=1[S:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)c1ccccc1O
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccccc2O)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared by Method A using 2'-hydroxyacetophenone (0.722 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (1.95 g, 11.6 mmol), chlorotrimethylsilane (1.48 mL, 11.6 mmol), THF (116 ml), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 189° C.; 1H NMR (400 MHz, DMSO-d6) δ4.01 (s, 2 H), 6.97 (s, 1 H), 7.25 (m, 7 H), 7.71 (d, 1 H), 10.75 (s, 1 H), 11.85 (bs, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:13][C@H:12]1[CH2:22][OH:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:25].[Na+].O1CCOCC1.O=O>[Pt].O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:13][C@H:12]1[C:22]([OH:25])=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: O=C(OCc1ccccc1)N1C[C@H](C2CCCCC2)C[C@H]1CO
Agent: [Pt]
Agent: O=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@@H]1C[C@@H](C2CCCCC2)CN1C(=O)OCc1ccccc1

Procedure:
To a mixture of (2S-trans)-1-[(benzyloxy)carbonyl]-4-cyclohexyl-2-pyrrolidinemethanol (0.65 g), sodium bicarbonate (0.5 g), dioxane (20 ml), and water (20 ml) was added freshly prepared platinum black (prepared by hydrogenating 0.3 g of platinum oxide). Oxygen was passed through the solution at room temperature for 16 hours with vigorous stirring. Filtration and acidification, followed by extractive work-up yielded (trans)-1-[(benzyloxy)carbonyl]-4-cyclohexyl-L-proline as a glassy solid. This compound can be deprotected using catalytic hydrogenation as described in Method I.
Reaction SMILES: [CH2:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][CH2:2]1)=[CH:10][C:9]([S:14][C:15]1[CH:16]=[C:17]([C:21]2([OH:27])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1)=[CH:8][CH:7]=3.[H-].[Na+].[CH3:30]N(C=O)C>IC>[CH3:30][O:27][C:21]1([C:17]2[CH:16]=[C:15]([S:14][C:9]3[CH:10]=[C:11]4[C:6](=[CH:7][CH:8]=3)[N:5]3[CH2:1][CH2:2][N:3]=[C:4]3[CH:13]=[CH:12]4)[CH:20]=[CH:19][CH:18]=2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: OC1(c2cccc(Sc3ccc4c(c3)C=CC3=NCCN34)c2)CCOCC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COC1(c2cccc(Sc3ccc4c(c3)C=CC3=NCCN34)c2)CCOCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2c (42 mg, 0.11 mmol) in DMF was added sodium hydride (5 mg, 0.12 mmol). Iodomethane (one drop) was added, and the mixture was stirred at room temperature for 5 hours. The reaction was quenched with water, extracted with EtOAc, and purified by preparative HPLC to give the desired product, 2d.
Reaction SMILES: [OH:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]([C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=2)[S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:26]([OH:29])[CH:27]=[CH2:28].C(=O)(O)[O-].[Na+].O>CN(C)C=O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([O-])=O.CC([O-])=O.[Pd+2].C(OCC)(=O)C>[OH:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]([C:17]2[CH:22]=[CH:21][C:20]([CH2:28][CH2:27][CH:26]=[O:29])=[CH:19][CH:18]=2)[S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C=CCO
Reactant: O=S(=O)(c1ccccc1)N(Cc1ccc(O)cc1)c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=CCCc1ccc(N(Cc2ccc(O)cc2)S(=O)(=O)c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 19 h
Yield: 77.9 %

Procedure:
To a solution of N-(4-hydroxy-benzyl)-N-(4-iodo-phenyl)-benzenesulfonamide (3.20 g, 6.88 mmol) in 16 mL dimethylformamide was added allyl alcohol (1.20 mL, 17.60 mmol), Pd(OAc)2 (0.094 g, 0.42 mmol), sodium bicarbonate (1.42 g, 16.9 mmol), and tetrabutylammonium chloride (1.95 g, 7.02 mmol). The reaction was stirred at 50° C. for 19 hr. The reaction mixture was cooled, water and ethyl acetate were added, and the mixture was filtered through diatomaceous earth. The aqueous layer was washed twice with ethyl acetate. The combined organic layers were dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography (25% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded 2.12 g (78%) of N-(4-hydroxy-benzyl)-N-[4-(3-oxo-propyl)-phenyl]-benzenesulfonamide.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=2)[C:10]([O:12]C)=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[CH3:21][NH2:22].C([Al](CC)CC)C.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[N:1]1([C:7]2[CH:8]=[C:9]([CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=2)[C:10]([NH:22][CH3:21])=[O:12])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Reactant: CN
Agent: CC[Al](CC)CC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 3-(4-morpholinyl)-5-nitro-benzoic acid, methyl ester (Example 86c; 0.53 g, 2 mmol) in toluene (5 mL) under an argon atmosphere, is treated with a mixture of methylamine hydrochloride (0.27 g, 4 mmol), triethylaluminium (2 mL of a 2 M solution in toluene, 4 mmol) in toluene (5 mL) and heated at 60° C. for 18 h. The cooled mixture is then treated with hydrochloric acid (10 mL of 2 M), stirred for 5 min and then treated with aqueous sodium hydroxide (5 mL of 4 M). The mixture is then treated with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts are washed with brine (2×50 mL), dried (MgSO4) and the solvent is evaporated off under reduced pressure to give the crude product which is purified by recrystallisation from ethyl acetate to afford the title compound as yellow crystalline solid, m.p. 204-207° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:27]C)=[C:4]([O:25][CH3:26])[C:5]([O:23][CH3:24])=[C:6]([O:21]C)[C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][C:17]#[C:18][CH2:19][OH:20].N1C(C(O)=O)=CC=CC=1C(O)=O>C(#N)C.O>[CH3:24][O:23][C:5]1[C:6](=[O:21])[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][C:17]#[C:18][CH2:19][OH:20])=[C:2]([CH3:1])[C:3](=[O:27])[C:4]=1[O:25][CH3:26]
Reactant: COc1c(C)c(CCCCC#CCCCC#CCO)c(OC)c(OC)c1OC
Agent: O=C(O)c1cccc(C(=O)O)n1
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(CCCCC#CCCCC#CCO)=C(C)C1=O
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
In a mixed solvent of acetonitrile (6 ml) and water (3 ml) were dissolved 5-methyl-1,2,3,4-tetramethoxy-6-(12-hydroxy-5,10-dodecadiynyl)benzene (II, 0.50 g, 1.29 mmole) and pyridine-2,6-dicarboxylic acid (0.65 g, 1.29×3 mmole), and the solution was stirred under cooling with ice, followed by adding dropwise and ice-cooled solution of ceric ammonium nitrate (2.12 g) in acetonitrile (4.5 ml) and water (4.5 ml) over a 15-minute period. The reaction was allowed to proceed under the same conditions for 15 minutes and further at room temperature for 15 minutes. After the completion of the reaction, the insolubles were filtered out, and the acetonitrile was distilled off under reduced pressure. By adding isopropyl ether (20 ml) and water (20 ml) to the residue, the product was extracted. The organic layer was washed with aqueous sodium bicarbonate solution and aqueous sodium chloride solution, successively, dried (over MgSO4) and concentrated under reduced pressure, resulting in a residue. The residue was chromatographed on a column of silica gel developing with a mixed solvent of isopropyl ether and ethyl acetate to give 2,3-dimethoxy-5-methyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (I, 0.42 g, 91%, oil).
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[C:45]([C:47]1[CH:48]=[C:49]([CH:53]=[CH:54][CH:55]=1)[C:50](O)=[O:51])#[N:46]>CN(C=O)C.O>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:50](=[O:51])[C:49]2[CH:53]=[CH:54][CH:55]=[C:47]([C:45]#[N:46])[CH:48]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(C#N)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
DIEA (527 mg, 4.07 mmol), HOBt (322 mg, 2.45 mmol), EDCI.HCl (302 m, 1.5 mmol) and piperazine-1-carboxylic acid tert-butyl ester (456 mg, 2.45 mmol) were added to a stirred solution of 3-cyano-benzoicacid (300 mg, 2.03 mmol) in DMF (3 mL) and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure to afford 590 mg (92%) of 4-(3-cyano-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1(O)C=CC=CC=1.[OH-].[K+].[O:16]([C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([NH:32]C(N)=S)=[C:25]([CH:36]([CH3:38])[CH3:37])[CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.BrC1C=C(C(C)C)C(N)=C(C(C)C)C=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cu+2]>[O:16]([C:23]1[CH:24]=[C:25]([CH:36]([CH3:37])[CH3:38])[C:26]([NH2:32])=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)c1cc(Oc2ccccc2)cc(C(C)C)c1NC(N)=S
Agent: [Cu+2]
Agent: CC(C)c1cc(Br)cc(C(C)C)c1N
Agent: O=C([O-])[O-]
Solvent: Oc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)c1cc(Oc2ccccc2)cc(C(C)C)c1N
Reaction time: 10 h
Yield: 80 %

Procedure:
With stirring, 21 g (0.15 mol) of potassium carbonate are initially added to 141 g (1.5 mol) of phenol in 500 g of toluene, followed by the addition of 168 g (1.5 mol) of a 50% aqueous solution of potassium hydroxide. The entire water of reaction is then separated under reflux, and then ca. 400 g of toluene are removed by distillation. The residue is dissolved in 700 g of dimethyl formamide. After addition of 6 g (0.05 mol) of copper carbonate, solvent is distilled off until the temperature of the reaction mixture is 140° C. Then 256 g (1 mol) of 4-bromo-2,6-diisopropylaniline are added at 140° C. and the mixture is kept for 10 hours at 140° C. The dimethyl formamide is then removed by vacuum distillation, the residue is extracted with water, and the product is taken up in toluene. After stripping off the toluene, the crude product is purified by vacuum distillation, giving 215 g (80% of theory) of 4-phenoxy-2,6-diisopropylaniline with a boiling point of 142°-145° C./0.04 mbar and a melting point of 69°-71° C., in the form of a bright red product. Conversion to the hydrochloride is effected by dissolving the product in 300 g of butyl acetate, adding 115 g of a 37% solution of hydrochloric acid, and removing the water of reaction by vacuum distillation. The hydrochloride is isolated by filtration, washed with butyl acetate and dried under vacuum, giving 235 g (96% of theory, based on 4-phenoxy-2,6-diisopropylaniline) of 4-phenoxy-2,6-diisopropylaniline hydrochloride in the form of white crystals which melt at 247°-249° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[C:4]([CH3:9])[C:3]=1[O:10][CH3:11].C(OC(=O)C)(=[O:14])C.CO>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:9][OH:14])[C:3]=1[O:10][CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(Cl)cc[n+]([O-])c1C
Solvent: CC(=O)O
Solvent: CO
Product: COc1c(Cl)ccnc1CO
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
30 g (173mmol) of 4-chloro-3-methoxy-2-methylpyridine N-oxide (cf. Example 1a) were dissolved in 100 ml of glacial acetic acid, after which 150 ml of acetic anhydride were added dropwise, at 80° C. and while stirring, and the mixture was then stirred at 110° C. for 2 h. The mixture was then cooled down to 80° C. and 200 ml of methanol were added dropwise; the mixture was then heated to boiling for 15 min. and, after having been cooled down, concentrated in vacuo; the residue was taken up in methanol and this mixture was allowed to flow into 300 ml of 1.5N methanolic sodium hydroxide solution, with this mixture then being stirred at 20° C. for 30 min. and concentrated in vacuo; the residue was taken up in water, and this mixture extracted three times with dichloromethane, with the organic phase being dried and concentrated; the residue was crystallized using petroleum ether. 23 g of product were obtained, m.p. 64°-66° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[C:12]([C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:19][CH:18]=4)[CH:13]=[CH:14][CH:15]=3)[C:10]3([C:41]4[C:32](=[CH:33][C:34]5[O:39][CH2:38][CH2:37][O:36][C:35]=5[CH:40]=4)[O:31][CH2:30]3)[C:9]2=[O:42])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[O:23]([C:20]1[CH:21]=[CH:22][C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[C:10]2([C:41]4[C:32](=[CH:33][C:34]5[O:39][CH2:38][CH2:37][O:36][C:35]=5[CH:40]=4)[O:31][CH2:30]2)[C:9](=[O:42])[NH:8]3)=[CH:18][CH:19]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(-c3ccc(Oc4ccccc4)cc3)c2C12COc1cc3c(cc12)OCCO3
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1Nc2cccc(-c3ccc(Oc4ccccc4)cc3)c2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)-4′-(4-phenoxyphenyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 4′-(4-phenoxyphenyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (74%) as an off-white solid: mp 243-246° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ 8.63-8.53 (m, 2H), 8.07 (d, J=8.5 Hz, 1H), 7.74-7.64 (m, 2H), 7.57-7.39 (m, 2H), 7.36-7.19 (m, 3H), 7.02-6.93 (m, 2H), 6.50 (s, 1H), 5.96 (s, 1H), 5.28 (d, J=15.8 Hz, 1H), 4.98 (d, J=15.8 Hz, 1H), 4.69 (d, J=9.2 Hz, 1H), 4.34 (d, J=9.2 Hz, 1H), 4.32-4.08 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.8, 155.4, 150.3, 149.6, 147.2, 144.8, 142.7, 138.2, 137.2, 136.3, 135.7, 131.2, 130.4, 129.7, 129.2, 128.0, 126.9, 128.0, 126.9, 125.6, 122.9, 122.7, 121.8, 111.3, 109.5, 99.6, 64.6, 64.1, 58.4, 46.3; MS (ES+) m/z 463.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH:27]1([O:33][C:34]2[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([O:33][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[CH:35][CH:36]=1
Reactant: NCc1ccc(OC2CCCCC2)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(OC4CCCCC4)cc3)c2CC1)C(F)(F)F
Yield: 37.7 %

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (100 mg, 0.43 mmol) with 4-cyclohexyloxy-benzylamine (58 mg, 0.285 mol) in anhydrous toluene (1 mL). Purify the crude mixture by chromatography on silica gel eluting with cyclohexane/EtOAc (9:1) to give 7-chloro-6-(4-cyclohexyloxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (78 mg, 69%).
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.CSC.B.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](=[O:35])[CH3:34]>C1COCC1>[C:27]1([CH3:26])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C@H:33]([OH:35])[CH3:34]
Reactant: CC(=O)c1ccccc1C
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1ccccc1[C@@H](C)O
Temperature: 0 °C

Procedure:
(S)-(−)-2-Methyl-CBS-oxazaborolidine (3.72 g, 13.4 mmol) was dissolved in THF (60 mL). Borane methyl sulfide complex (2M in THF; 36.6 mL, 73.3 mmol) was added, and the mixture was cooled to 0° C. 2′-Methylacetophenone (15 g, 111 mmol) in THF (30 mL) was added over 1 hour, and the mixture was then worked-up to yield a liquid with a white precipitate. Hexanes was added, the suspension was filtered to remove the precipitate, and the resulting filtrate was concentrated to give the title compound in 93% e.e.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[CH2:9]([O:11][C:12](=[O:26])[C:13](=O)[C:14]1[C:22]2[C:17](=[C:18]([CH2:23][CH3:24])[CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[CH3:10]>O.C(O)C>[CH2:9]([O:11][C:12](=[O:26])[C:13](=[N:7][OH:8])[C:14]1[C:22]2[C:17](=[C:18]([CH2:23][CH3:24])[CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[CH3:10]
Reactant: NO
Reactant: CCOC(=O)C(=O)c1c[nH]c2c(CC)cccc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NO)c1c[nH]c2c(CC)cccc12
Yield: 75.7 %

Procedure:
Solutions of sodium acetate (43.7 g, 0.53 mol) in water (100 mL) and hydroxylamine hydrochloride (37 g, 0.53 mol) in water (100 mL) were added to 7-ethyl-α-oxo-1H-indole-3-acetic acid ethyl ester 4 (17.4 g, 0.07 mol), in ethanol (250 mL) and the mixture was heated at reflux for 12 hours. The ethanol was removed by distillation and the resultant precipitate was filtered and recrystalized from hot ethanol to give the product (13.8 g, 75%), m.p. 167°-169° C. as a mixture of isomers.