Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[C:23]([O:25]C)=[O:24])[CH2:14][C:13](=[O:27])[NH:12][CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[C:23]([OH:25])=[O:24])[CH2:14][C:13](=[O:27])[NH:12][CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2C(=O)OC)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 70 °C
Yield: 57 %

Procedure:
To a mixture of racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-methoxycarbonyl-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (60 mg, 0.13 mmol) in methanol (3.5 mL) was added a solution of NaOH (26 mg, 0.6 mmol) in water (1.5 mL). The mixture was heated at 70° C. for 3 h, concentrated to remove most of methanol, cooled to room temperature, and acidified to “pH” 2 with aqueous HCl solution. The precipitate was collected and dried to give title compound as a white solid (33 mg). m/z (M+H)+: 445
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[CH:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH2:24][S:25]([NH2:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=1.O(C(C)(C)C)[Na].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:17][C:18]3[CH:19]=[C:20]([CH2:24][S:25]([NH2:28])(=[O:26])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:7]=2)=[C:9]([O:15][CH3:16])[CH:10]=1
Reactant: COc1cc(F)ccc1-c1ccnc(Cl)c1
Reactant: Nc1cccc(CS(N)(=O)=O)c1
Agent: CC(C)(C)O[Na]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1-c1ccnc(Nc2cccc(CS(N)(=O)=O)c2)c1
Temperature: 110 °C

Procedure:
Intermediate A2 (119 mg, 0.5 mmol), (3-aminophenyl)methanesulfonamide (112 mg, 0.6 mmol), NaOC(CH3)3 (67 mg, 0.7 mmol), PdCl2(CH3CN)2 (6.5 mg, 0.025 mmol, 5 mol %), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) [Xantphos] (23 mg, 0.04 mmol, 8 mol %) were dissolved in dry DMF (4 mL) and purged for 10 minutes with nitrogen. After heating at 110° C. for 18 hours the reaction mixture was filtered and the residue washed with toluene. The filtrate was concentrated under reduced pressure and purified by automated column chromatography (ISCO, gradient MeOH/DCM). The collected fractions which contained the title compound were further purified by preparative HPLC to yield 24 mg (12%) of G1 as an off-white solid. 1H NMR (300 MHz, d6-DMSO, 298K) δ 3.84 (s, 3H), 4.22 (s, 2H), 6.81-6.94 (m, 5H), 6.98 (s, 1H), 7.07 (dd, J=11.7 Hz, J=4.2 Hz, 1H), 7.26 (t, J=6.6 Hz, 1H), 7.39 (dd, J=6.9 Hz, J=6.0 Hz, 1H), 7.56-7.61 (m, 1H), 7.79 (d, J=7.5 Hz, 1H), 8.16 (d, J=6.0 Hz, 1H), 9.12 (s, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C@@H:13]2[C@H:18]([NH2:19])[CH2:17][CH2:16][S:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH3:3].[CH3:20][O:21][C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28])=[O:23].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(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C@@H:13]2[C@H:18]([NH:19][C:27]([C:26]3[CH:25]=[C:24]([CH:32]=[CH:31][CH:30]=3)[C:22]([O:21][CH3:20])=[O:23])=[O:28])[CH2:17][CH2:16][S:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH3:3]
Reactant: CCOc1cc([C@H]2CSCC[C@H]2N)ccc1OC
Reactant: COC(=O)c1cccc(C(=O)O)c1
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: CCOc1cc([C@H]2CSCC[C@H]2NC(=O)c2cccc(C(=O)OC)c2)ccc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of (3R,4R)-3-(3-ethoxy-4-methoxyphenyl)tetrahydro-2H-thiopyran-4-amine hydrochloride (1.82 g; compound C13), 3-(methoxycarbonyl)benzoic acid (1.08 g) and HBTU (2.50 g) in DCM (50 ml) is added DIPEA (4.2 ml) and the mixture is stirred for 1 h at RT. A saturated aqueous solution of sodium hydrogen carbonate (30 ml) is added, the organic phase is separated and dried over sodium sulfate. After filtration the solvent is removed in vacuo and the resulting residue is purified by flash column chromatography [silica gel, eluation gradient: DCM/MeOH, 100/0 to 95/5 (v/v)] to give the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[CH:9]([B-](F)(F)F)=[CH2:10].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.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>[F:8][C:5]1[CH:4]=[CH:3][C:2]([CH:9]=[CH2:10])=[CH:7][N:6]=1
Reactant: C=C[B-](F)(F)F
Reactant: Fc1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(F)nc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
5-Bromo-2-fluoropyridine (Aldrich 99%, 5.14 g, 29.2 mmol) and potassium vinyltrifluoroborate (Aldrich, St. Louis, Mo., 4.23 g, 31.6 mmol) were suspended in THF (80 mL) and water (9.0 mL) and dichlorobis(triphenyl-phosphine)palladium (II) (0.627 g, 0.893 mmol) and cesium carbonate (28.5 g, 87.6 mmol) were added. The reaction flask was fitted with a reflux condenser and placed in a preheated oil bath (85° C.) and stirred overnight under nitrogen. Then, the reaction was cooled to room temperature and diluted with water (125 mL). The layers were separated, and the aqueous phase was extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated (using an unheated water bath and a rotary evaporator pressure of 43-70 torr). The crude material was purified on a silica gel filter (about 3 inches) with DCM, and the fractions with product were collected, concentrated, and dried briefly under high vacuum. The material was triturated with Et2O and filtered, and the solid was washed with Et2O. The filtrate was concentrated and dried on two separate occasions on the high vacuum for about 10 seconds each to afford 2-fluoro-5-vinylpyridine, which was taken to the next step.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][CH:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:30][C:31]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][CH:34]=3)=[O:32])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)CBr)cc1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1ccc(C(=O)Cn2c(=O)c3cc(CC)sc3n(Cc3ccc(-c4ccccc4C#N)cc3)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1 g), 2-bromo-1-(4-ethylphenyl)ethanone (0.88 g) and N,N-dimethylformamide (40 mL) was added 60% sodium hydride (0.15 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.87 g, 63%).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:43]=[CH:44][C:45]=1[Cl:46])[CH2:8][O:9][CH:10]1[CH:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:18][CH:17]=2)[CH2:14][CH2:13][N:12]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11]1)C=C.[BH4-].[Li+].C(=O)([O-])O.[Na+]>O1CCCC1.CC([O-])=O.CC([O-])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd+2]>[Cl:46][C:45]1[CH:44]=[CH:43][C:7]([CH2:8][O:9][CH:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:18][CH:17]=3)[CH2:14][CH2:13][N:12]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:11]2)=[CH:6][C:5]=1[OH:4]
Reactant: C=CCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(Cl)c(O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The solution of 1.53 g of tert-butyl 3-(3-allyloxy-4-chlorobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 15 ml of tetrahydrofuran is admixed with stirring successively with 0.018 g of bis(triphenylphosphine)palladium(II) acetate and 0.053 g of lithium borohydride. The reaction mixture is stirred at room temperature over 16 hours, subsequently poured onto saturated aqueous sodium hydrogencarbonate solution and extracted with tert-butyl methyl ether (2×100 ml). The organic phases are washed with water (100 ml) and brine (100 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.45 (1:1 EtOAc-heptane); Rt=5.88.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH3:20])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([O:22][CH3:23])[CH2:10][CH2:11][C:12](=[O:21])[CH2:13]4.[N:24]#CBr.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:20]([N:19]1[CH2:18][CH2:17][C@@:14]23[C:15]4[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[CH2:7][C@@H:8]1[C@:9]2([O:22][CH3:23])[CH2:10][CH2:11][C:12](=[O:21])[CH2:13]3)#[N:24]
Reactant: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@]1(OC)CCC(=O)C3
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc2c(c1)[C@]13CCN(C#N)[C@H](C2)[C@]1(OC)CCC(=O)C3

Procedure:
A solution of 3,14-dimethoxy-17-methylmorphinan-6-one (0.490 g, 1.55 mmol) in methylene chloride (25 ml) was treated with cyanogen bromide (0.977 g, 9.3 mmol) and anhydrous potassium carbonate (1.285 g, 9.3 mmol). The mixture was refluxed for 22 hours, filtered through Celite and the filtrate washed with water (3×50 ml). The organic solution was separated, dried over MgSO4, filtered and concentrated under reduced pressure to give 0.463 g (92% theory) of the desired product as a yellow solid (m.p. 172°-176°). Recrystallization from ethanol gave 0.427 g (85% theory) of the product as a white solid, m.p. 176°-177° C.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:30][O:31][C:32](=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH2:38]>C(Cl)Cl>[NH:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C@@H:9]([C:11]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][C:32]([O:31][CH3:30])=[O:39])=[O:13])[CH3:10]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)CCCCCN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)CCCCCNC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 25 h

Procedure:
Boc-(D)-alanine (5.1 g, 26.9 mmol) in 100 ml of methylene chloride (CH2Cl2) was cooled to 0° C. and 5.9 ml (53.8 mmol) of N-methylmorpholine (NMM) were added. After cooling this vigorously stirred solution to -78° C., 3.5 ml (26.9 mmol) of isobutylchloroformate (IBCF) were added to this reaction which was run entirely under an Ar atmosphere. The mixture was allowed to warm slowly to 20° before it was again cooled to -78° C. and 4.9 g (26.9 mmol) of 6-aminohexanoic acid methylester hydrochloride were added in a single portion. Following warming this mixture to room temperature, it was allowed to stir 25 hour (h). Precipitated N-methylmorpholine hydrochloride was filtered off and the filtrate, after diluting with CH2Cl2 (200 ml), was washed 3×100 ml of 0.5N potassium bisulfate (KHSO4). The combined aqueous washes were extracted with a 100 ml portion of CH2Cl2 and the combined organics were washed 1×75 ml of brine, dried over Na2SO4 (anhy.), and stripped of all solvent under reduced pressure. By thin layer chromatography (10% ethanol (EtOH)/chloroform (CHCl3)) the yellow liquid title product was essentially one spot and used in subsequent reactions without further purification. Optical rotation [α]D +21.5° and +93.7° (365 nm) CHCl3. NMR shift of the (D)Ala methyl=1.34 δ (CDCl3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:10]([N:23]1[CH2:24][CH2:25][CH:20]([OH:19])[CH2:21][CH2:22]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC(O)CC1

Procedure:
(R)-2-(N-t-butoxycarbonylamino)-3-phenyl-propan-1-one (14 mmol) and 4-hydroxypiperidine (21.5 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, washed with acid first then base) and the product used without further purification. Yield 4.7 g, 94%; HPLC (60/40) 3.52 minutes (98%).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[O:22])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][C:15]([N+:19]([O-:21])=[O:20])=[CH:16][CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:25][N:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]1.[ClH:39]>C(Cl)Cl.O1CCOCC1>[ClH:39].[ClH:39].[OH:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[O:22])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][C:15]([N+:19]([O-:21])=[O:20])=[CH:16][CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4cc([N+](=O)[O-])ccc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1/C(=C/c2c[nH]c3cc([N+](=O)[O-])ccc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of tert-butyl (Z)-4-({6-hydroxy-2-[(6-nitro-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.020 g, 0.038 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in a mixed solvent of methylene chloride and diethyl ether and thereby washed to obtain (Z)-6-hydroxy-2-[(6-nitro-1H-indol-3-yl)methylene]-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.014 g, 75%).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][CH:3]1C(OCC)=O.[OH-].[Na+].Cl>O1CCOCC1.O>[O:1]=[C:2]1[CH2:3][CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
To a solution 1-tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (compound 82.1, 19.0 g, 66.6 mmol) in 1,4-dioxane (190 mL) was added drop-wise a solution of sodium hydroxide (4.00 g, 100 mmol) in water (100 mL). The resulting mixture was stirred at room temperature overnight. The pH was then adjusted to 4-5 with hydrogen chloride (aq. 3 M) and the resulting solution was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (2×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:3) as the eluent to furnish 11 g (77%) of the title compound as a yellow oil.
Reaction SMILES: FC1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:26]2[CH2:35][CH:34](O)[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=3)[O:27]2)[CH:23]=[CH:24][CH:25]=1>>[OH:19][C:20]1[CH:21]=[C:22]([CH:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=3)[O:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: Oc1cccc(C2CC(O)c3cc(O)ccc3O2)c1
Agent: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Product: Oc1cccc(C2CCc3cc(O)ccc3O2)c1

Procedure:
2-(3-Hydroxyphenyl)chroman-6-ol was prepared as described for 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 2-(3-hydroxyphenyl)chroman-4,6-diol. 1H NMR (400 MHz, d6-DMSO) δ: 9.38 (s, 1H), 8.77 (s, 1H), 7.17-7.13 (m, 1H), 6.82-6.79 (m, 2H), 6.70-6.67 (m, 1H), 6.62 (d, 1H, J 8.6 Hz), 6.52-6.47 (m, 2H), 4.89 (dd, 1H, J 2.1, 9.9Hz), 2.86-2.82 (m, 1H), 2.65-2.59 (m, 1H), 2.09-2.04 (m, 1H), 1.91-1.85 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][O:25][C:26](=[O:30])[CH:27](C)C)=[CH:18][C:17]=3[CH2:31][NH:32][CH3:33])[CH2:12][CH2:11]2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.ClC1C=CC(C(N([C@H]2CC[C@H](C3C=CC(CCCO)=CC=3CNC)CC2)C)=O)=CC=1.C(Cl)(=O)C(C)C>>[C:26]([O:25][CH2:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C@H:13]2[CH2:12][CH2:11][C@H:10]([N:8]([C:6](=[O:7])[C:5]3[CH:34]=[CH:35][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[C:17]([CH2:31][NH:32][CH3:33])[CH:18]=1)(=[O:30])[CH3:27]
Reactant: CNCc1cc(CCCOC(=O)C(C)C)ccc1[C@H]1CC[C@H](N(C)C(=O)c2ccc(Cl)cc2)CC1
Agent: CC(C)C(=O)Cl
Agent: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](N(C)C(=O)c2ccc(Cl)cc2)CC1
Product: CNCc1cc(CCCOC(C)=O)ccc1[C@H]1CC[C@H](N(C)C(=O)c2ccc(Cl)cc2)CC1

Procedure:
trans-N-(4-chlorobenzoyl)-N-methyl-4-[4-(3-isobutyryloxypropyl)methylaminomethylphenyl]-cyclohexylamine from trans-N-(4-chlorobenzoyl)-N-methyl-4-[4-(3-hydroxypropyl)methylaminomethylphenyl]cyclohexylamine and isobutyrylchloride. Melting point: 79°-81° C.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[N+:8]([C:11]1[CH:12]=[C:13]([NH2:22])[CH:14]=[C:15]([N:17]2[CH:21]=[CH:20][CH:19]=[CH:18]2)[CH:16]=1)([O-:10])=[O:9]>>[N+:8]([C:11]1[CH:12]=[C:13]([NH:22][C:5](=[O:7])[CH3:6])[CH:14]=[C:15]([N:17]2[CH:18]=[CH:19][CH:20]=[CH:21]2)[CH:16]=1)([O-:10])=[O:9]
Reactant: Nc1cc(-n2cccc2)cc([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(-n2cccc2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Acetic anhydride (7.0 ml) was added to 3-nitro-5-pyrrol-1-yl-phenylamine (7.0 g, 34.48 mmol). The mixture was stirred for 30 min at RT and subsequently quenched by the addition of crushed ice. The precipitate formed was filtered and was washed with cold water to obtain off-white solid. The solid was dried under high vacuum to give the product in 89% yield (7.52 g). LC-MS (ESI): Calculated mass: 245.23; Observed mass: 244.1 [M−H]+ (rt: 0.24 min).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][C@@H:4]([CH2:6][CH:7]2OCO[O:8]2)[N:3]1[C:12](=[O:17])[C:13]([O:15][CH3:16])=[O:14].CSC>ClCCl.CO>[O:1]=[C:2]1[CH2:5][C@@H:4]([CH2:6][CH:7]=[O:8])[N:3]1[C:12](=[O:17])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(=O)N1C(=O)C[C@H]1CC1OCOO1
Solvent: CO
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)C(=O)N1C(=O)C[C@H]1CC=O
Temperature: 5 °C
Reaction time: 15 h

Procedure:
A solution of methyl [(4R)-2-oxo-4-(1,2,4-trioxolan-3-ylmethyl)azetidin-1-yl]glyoxylate (320 mg) and dimethyl sulfide (2 ml) in a mixture of dichloromethane (9 ml) and methanol (10 ml) was stirred at 5° C. for 6 hours and at room temperature for 15 hours. The mixture was then heated at 50° for 4 hours and evaporated to give methyl [(4R)-2-oxo-4-(2-oxoethyl)-azetidin-1-yl]glyoxylate.
Reaction SMILES: [CH3:1][C@:2]([OH:9])([CH:6]([CH3:8])[CH3:7])[C:3](O)=[O:4].N1C=CN=C1.Cl.[CH3:16][NH:17][O:18][CH3:19]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:19][O:18][N:17]([CH3:16])[C:3](=[O:4])[C@@:2]([CH3:1])([OH:9])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)[C@](C)(O)C(=O)O
Reactant: CNOC
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CON(C)C(=O)[C@@](C)(O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a magnetically stirred solution of (8) (59 g, 0.44 mol) in methylene chloride (880 mL) in a 3-L, two-neck, round-bottom flask at 0° C. under a nitrogen atmosphere was added 1,1-carbonyldiimidazole (87 g, 0.54 mol, 1.2 equivalents) in portions. The yellow solution was gradually warmed to room temperature and stirred under a nitrogen atmosphere overnight. To the reaction was added imidazole (60 g, 0.88 mol, 2 equivalents), 4-dimethylaminopyridine (1.6 g, 0.01 mol, 0.03 equivalents), and N,O-dimethylhydroxylamine hydrochloride (53 g, 0.54 mol, 1.2 equivalents). The solution was stirred overnight and then the resulting mixture was washed with 2N aqueous hydrochloric acid (2×600 mL), water (1×800 mL), and saturated aqueous sodium chloride solution (1×800 mL), dried over anhydrous magnesium sulfate, and filtered. The solvent was removed in vacuo to provide 73 g (94% yield) of (9) as a yellow oil. The 1H NMR spectrum of the product was consistent with the material previously prepared.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:23][CH3:24])=[CH:8][C:9]([CH3:22])=[C:10]([C:12](=[O:21])[C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[CH:11]=2)C[CH2:2]1.CCCBr.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:20])[C:13]=1[C:12]([C:10]1[CH:11]=[C:6]([O:5][CH2:4][CH2:1][CH3:2])[C:7]([O:23][CH3:24])=[CH:8][C:9]=1[CH3:22])=[O:21]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCCBr
Product: CCCOc1cc(C(=O)c2c(Cl)cccc2Cl)c(C)cc1OC
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 2,6-dichloro-5'-hydroxy-4'-methoxy-2'-methylbenzophenone (Compound 5; 1.0 g, 3.2 mmol), n-propyl bromide (0.5 g, 4 mmol), potassium carbonate (2.8 g, 20 mmol) and ethanol (10 ml) is stirred for 6 h at 80° C., filtered and the filtrate is evaporated in vacuo. The residue is applied onto a flash chromatography column (silica gel, 30 g). Elution with toluene (750 ml) yields Compound 6 as a brown oil, 800 mg, (70.7% y) which slowly crystallizes (mp 73°-75° C.).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:22]=[CH:21][C:11]2[C:12]3[CH2:13][CH2:14][C:15](=O)[NH:16][C:17]=3[CH2:18][CH2:19][C:10]=2[CH:9]=1.[OH-].[Na+]>O1CCCC1>[Cl:7][C:8]1[CH:22]=[CH:21][C:11]2[C:12]3[CH2:13][CH2:14][CH2:15][NH:16][C:17]=3[CH2:18][CH2:19][C:10]=2[CH:9]=1
Reactant: O=C1CCC2=C(CCc3cc(Cl)ccc32)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)CCC1=C2CCCN1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
147 g (1.94 mol) of lithium aluminum hydride were suspended in 4 l of tetrahydrofuran under argon, 454 g (1.94 mol) of 8-chloro-1,4,5,6-tetrahydrobenzo[f]quinolin-3(2H)-one were slowly added thereto and the mixture was boiled under reflux for 2.5 hours. The mixture was then cooled, 470 ml of 18 percent sodium hydroxide solution were added thereto, the resulting mixture was stirred at room temperature for 30 minutes, filtered and the filter residue was washed with tetrahydrofuran. Upon evaporation of the filtrate there was obtained 8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline as a yellow oil.