Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:32][CH2:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[N:38]([CH:44]1[CH2:49][CH2:48][C:47](=[O:50])[NH:46][C:45]1=[O:51])[CH2:37]2.Cl>CN(C=O)C>[O:51]=[C:45]1[CH:44]([N:38]2[CH2:37][C:36]3[C:40](=[CH:41][CH:42]=[C:34]([CH2:33][NH:32][C:10](=[O:12])[C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:14][CH:13]=4)[CH:35]=3)[C:39]2=[O:43])[CH2:49][CH2:48][C:47](=[O:50])[NH:46]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(C(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
A mixture of 4-(ethylsulfonyl)benzoic acid (0.30 g, 1.4 mmol) and CDI (0.24 g, 1.5 mmol) in DMF (30 ml) was stirred at 40° C. for 4 hours. 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.50 g, 1.4 mmol) was added and the mixture was stirred at 40° C. for 2 h. 4% Aqueous HCl (30 mL) was added and the resulting precipitate was filtered, washed with water (30 mL) and dried in vacuo providing N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-ethanesulfonyl-benzamide as a white solid, (0.39 g, 66% yield); mp 222-224° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 6.39 (98.78%); 1H NMR (DMSO-d6) δ 1.11 (t, J=7.3 Hz, 3H, CH3), 1.92-2.09 (m, 1H, CHH), 2.28-2.46 (m, 1H, CHH), 2.54-2.67 (m, 1H, CHH), 2.82-3.02 (m, 1H, CHH), 3.37 (q, 2H, CH2), 4.31 (d, 1H, CHH), 4.42 (d, 1H, CHH), 4.62 (d, J=5.3 Hz, 2H, CHH), 5.11 (dd, J=4.8, 13.1 Hz, 1H, CH), 7.48 (d, 1H, Ar), 7.57 (s, 1H, Ar), 7.71 (d, 1H, Ar), 8.02 (s, 2H, Ar), 8.15 (d, J=8.1 Hz, 2H, Ar), 9.45 (t, 1H, NH), 10.96 (s, 1H, NH); 13C NMR (DMSO-d6) δ 7.05, 22.49, 31.20, 42.89, 47.13, 49.01, 51.58, 122.15, 122.97, 127.13, 127.94, 128.31, 130.46, 138.75, 140.71, 142.42, 143.45, 165.06, 167.89, 170.98, 172.85; LCMS: MH=470; Anal. Calcd for C23H23N3O6S+0.3 CH2Cl2: C, 56.54; H, 4.81; N, 8.49. Found: C, 56.51; H, 4.90; N, 8.84.
Reaction SMILES: [NH:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[CH2:4][CH2:3][C:2]1=[O:12].[CH2:13](O)[CH2:14][OH:15]>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[O:15]1[C:8]2([CH2:9][CH2:10][C:5]3([CH2:4][CH2:3][C:2](=[O:12])[NH:1]3)[CH2:6][CH2:7]2)[O:11][CH2:13][CH2:14]1
Reactant: O=C1CCC2(CC1)CCC(=O)N2
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1CCC2(CCC3(CC2)OCCO3)N1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A stirred mixture of 1-azaspiro[4.5]decane-2,8-dione (P1, 2.00 g, 12.0 mmol), ethylene glycol (2.96 g, 47.7 mmol), and 4-methylbenzenesulfonic acid (100 mg, 0.735 mmol) in toluene (100 mL) was refluxed for 20 h with Dean-Stark apparatus to remove water. After this time, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was mixed with saturated aqueous sodium bicarbonate (100 mL) and the resulting aqueous mixture was extracted with 5% methanol/ethyl acetate (4×150 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford compound P2 as an off-white solid (2.41 g, 95%): 1H NMR (300 MHz, DMSO-d6) δ 5.82 (bs, 1H), 3.95 (s, 4H), 2.41 (t, J=8.0 Hz, 2H), 1.99 (t, J=8.0 Hz, 2H), 1.80-1.65 (m, 8H). MS (M+H) 212.
Reaction SMILES: COC1C=CC=CC=1S(O[C:13]1[C:24]2=[C:25]3[N:20]([CH:21]([CH3:26])[CH2:22][CH2:23]2)[CH:19]=[C:18]([C:27]([OH:29])=[O:28])[C:17](=[O:30])[C:16]3=[CH:15][CH:14]=1)(=O)=O.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CS(C)=O>[N:31]1([C:13]2[C:24]3=[C:25]4[N:20]([CH:21]([CH3:26])[CH2:22][CH2:23]3)[CH:19]=[C:18]([C:27]([OH:29])=[O:28])[C:17](=[O:30])[C:16]4=[CH:15][CH:14]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1
Reactant: COc1ccccc1S(=O)(=O)Oc1ccc2c(=O)c(C(=O)O)cn3c2c1CCC3C
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: CC1CCc2c(N3CCNCC3)ccc3c(=O)c(C(=O)O)cn1c23
Yield: 15.8 %

Procedure:
20.7 g of 8-(o-methoxybenzenesulfonyloxy)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid and 12.9 g of piperazine were added to 200 ml of anhydrous dimethyl sulfoxide and the mixture was heated in autoclave under flow of nitrogen at 10 atm. at a temperature of 150° to 160° C. for 18 hours while stirring. Treatment in an analogous manner as in Example 17 gave 2.5 g of 8-(1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white amorphous crystals having a melting point of not lower than 300° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[Cl:32])=[O:9])=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:40])[CH2:35][CH2:36][CH2:37][NH:38][CH3:39]>>[Cl:32][C:12]1[CH:13]=[CH:14][C:15]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:21]=2)=[O:19])=[CH:16][C:11]=1[NH:10][C:8]([C:5]1[CH:6]=[N:7][C:2]([N:38]([CH2:37][CH2:36][CH2:35][N:34]([CH3:40])[CH3:33])[CH3:39])=[CH:3][CH:4]=1)=[O:9]
Reactant: CNCCCN(C)C
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(Cl)nc2)c1)c1ccnc(N2CCOCC2)c1
Product: CN(C)CCCN(C)c1ccc(C(=O)Nc2cc(NC(=O)c3ccnc(N4CCOCC4)c3)ccc2Cl)cn1
Yield: 73 %

Procedure:
Using an analogous procedure to that described in Example 21, 6-chloro-N-[2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-3-carboxamide was reacted with N-(3-dimethylaminopropyl)-N-methylamine to give the title compound in 73% yield; NMR Spectrum: (DMSOd6) 1.67 (m, 2H), 2.12 (s, 6H), 2.21 (t, 2H), 3.07 (s, 3H), 3.51 (m, 4H), 3.58 (m, 2H), 3.71 (m, 4H), 6.69 (d, 1H), 7.1 (d, 1H), 7.23 (s, 1H), 7.5 (d, 1H), 8.04 (m, 2H), 8.28 (d, 1H), 8.72 (s, 1H), 9.7 (s, 1H), 10.44 (s, 1H); Mass Spectrum: M+H+ 552 and 554.
Reaction SMILES: [C:1]([N:8]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH:15]=[CH:16][CH2:17][CH:18]([CH3:20])[CH3:19])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C(O)C.[Pd]>[C:1]([N:8]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CC(C)CC=C[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)CCC[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C

Procedure:
A solution of trans-N-Boc-2-(1-isohexenyl)-6-methylpiperidine (1.35, 4.79 mmol) in 4 mL of ethanol was shaken under 58 psi of H2 pressure over 0.34 g Pd/C catalyst overnight, and then the mixture was filtered through Celite and concentrated to give 1.40 g (quantitative) of the product. No further purification was necessary. 1H NMR (250 MHz) δ3.92-3.90 (m, 1 H), 3.79-3.76 (m, 1 H), 1.84-1.14 (m, 28 H), 0.87-0.82 (d, 6 H); 13C NMR (62.7 MHz) 154.7, 78.6, 51.6, 46.9, 38.9, 34.5, 28.5, 27.9, 26.8, 24.8, 23.2, 22.6, 22.5, 20.8, 13.7 ppm.
Reaction SMILES: [Cl-].Cl[CH2:3][CH2:4][NH2+:5][CH:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:7].[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[S:26]>>[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]1[N:5]([CH:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH3:7])[CH2:4][CH2:3][S:26]1
Reactant: CC([NH2+]CCCl)C1CCCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1C(C)C1CCCCC1

Procedure:
1-Cyclohexyl-1-ethylamine was converted to N-(2-hydroxyethyl)-N-(1-cyclohexyl-1-ethyl)amine according to Method B5a. The alcohol was reacted with SOCl2 according to Method B7a to give N-(2-chloroethyl)-N-(1-cyclohexyl -1-ethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-methyl-4-nitrophenylimino)-3-(1-cyclohexyl-1-ethyl)-1,3-thiazolidine.
Reaction SMILES: [CH3:1][Mg]Cl.[C:4]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([F:15])[CH:8]=1)(=[O:6])[CH3:5]>C1COCC1>[F:15][C:9]1[CH:8]=[C:7]([C:4]([OH:6])([CH3:1])[CH3:5])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: C[Mg]Cl
Reactant: CC(=O)c1ccc(C#N)c(F)c1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C#N)c(F)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of 4.7 g (0.019 mol) anhydrous CeCl3 in 30 mL anhydrous THF at 0° C. was added 6 mL of 3.0M CH3MgCl dropwise. Stirred at 0° C. for 45 minutes. Next a solution of 2.5 g (0.015 mol) 4-Acetyl-2-fluoro-benzonitrile in 200 mL anhydrous THF was added dropwise at 0° C. Stirred at 0° C. for 1 hour, then quenched with 2N acetic acid added dropwise. The mixture was poured into 200 mL water and acidified to pH 2 with 2N acetic acid. The aqueous layer was extracted with ethyl acetate (2×200 mL). The ethyl acetate extracts were combined, washed with water (2×40 mL), brine (1×40 mL), dried over MgSO4 and concentrated to give an oil, which was then chromatographed on silica gel eluted with 50% ethyl acetate/50% hexanes to give 1.95 g of an amber oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>C(#N)C>[O:13]1[C:14]2[CH:18]=[CH:17][S:16][C:15]=2[C:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[O:4][CH2:3][CH2:2][NH:32][CH2:31][C:30]2[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:35])[F:36])=[CH:34][CH:33]=2)=[N:12]1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1ccc(CNCCOc2cccc(-c3noc4ccsc34)c2)cc1
Reaction time: 8 h

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 4-(trifluoromethyl)benzylamine and acetonitrile essentially as described above in example 18 except that the reaction is run overnight and the compound is purified by column chromatography using a solvent gradient of 5% ethyl acetate in dichloromethane to 10% methanol in ethyl acetate. Purity by LC/MS (APCI)=98%, [M+H]+=419.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Br)C.[CH3:24][C:25]1([CH3:33])[C:27]([CH3:29])([CH3:28])[CH:26]1[C:30](Cl)=[O:31]>[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][CH:13]=[C:12]2[C:30]([CH:26]1[C:27]([CH3:29])([CH3:28])[C:25]1([CH3:33])[CH3:24])=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: COc1cc2[nH]ccc2cc1OCc1ccccc1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Product: COc1cc2[nH]cc(C(=O)C3C(C)(C)C3(C)C)c2cc1OCc1ccccc1
Yield: 65.8 %

Procedure:
A mixture of 5-benzyloxy-6-methoxyindole (Sigma, 2.0 g, 7.9 mmol), ethylmagnesium bromide (1.0 M solution in THF, 9.5 mL, 9.5 mmol), zinc chloride (1.0 M solution in Et2O, 9.5 mL, 9.5 mmol) and the product of Example 1A (12 mmol) was processed as described in Example 1B to provide the title compound (2.0 g, 5.2 mmol, 66% yield). MS (DCI/NH3) m/z 378 (M+H)+.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:19][C:20]1([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH2:44][C:43]([C:49]4[CH:54]=[C:53]([Cl:55])[C:52]([Cl:56])=[C:51]([Cl:57])[CH:50]=4)([C:45]([F:48])([F:47])[F:46])[O:42][N:41]=3)=[CH:36][CH:35]=2)[CH2:23][CH:22]([NH:24]C(=O)OCC[Si](C)(C)C)[CH2:21]1>C1COCC1>[F:19][C:20]1([C:34]2[CH:35]=[CH:36][C:37]([C:40]3[CH2:44][C:43]([C:49]4[CH:54]=[C:53]([Cl:55])[C:52]([Cl:56])=[C:51]([Cl:57])[CH:50]=4)([C:45]([F:46])([F:47])[F:48])[O:42][N:41]=3)=[CH:38][CH:39]=2)[CH2:23][CH:22]([NH2:24])[CH2:21]1
Reactant: C[Si](C)(C)CCOC(=O)NC1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: NC1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reaction time: 8 h
Yield: 109.3 %

Procedure:
1.0 M TBAF in THF (576 μL, 0.576 mmol) is added to a mixture of 2-(trimethylsilyl)ethyl (3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)cyclobutyl)carbamate (Preparation 15, 120.0 mg, 0.19 mmol) in THF (1.9 mL). After stirring overnight, the reaction mixture is partitioned between EtOAc (5 mL) and brine (5 mL), the organics were separated, dried over MgSO4 and filtered to give an oil which was further purified using regular silica eluting from neat heptane to neat EtOAc to give the title compound (100 mg): m/z (Cl) 480.
Reaction SMILES: CON(C)[C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1(P(=[CH:44][C:45]([O:47][CH3:48])=[O:46])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:48][O:47][C:45](=[O:46])[CH:44]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCNc1cc(F)ccc1C(=O)N(C)OC
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCNc1cc(F)ccc1C=CC(=O)OC
Temperature: -35 °C
Reaction time: 0.67 h
Yield: 30.3 %

Procedure:
To a solution of N-methoxy-N-methyl-4-fluoro-2-n-butylamino-benzamide (0.5 g, 1.97 mmol) in THF (8 mL) was added dropwise LiAlH4 (1 M in THF, 1.0 mL) at −45° C. The mixture was stirred for 40 minutes at −35° C. and then quenched by adding saturated aqueous KHSO4 solution. The mixture was diluted with EtOAc, washed with 3 N HCl, and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was reacted with methyl (triphenylphosphoranylidene)acetate (725 mg, 2.17 mmol) in toluene (4 mL) overnight at 100° C. The mixture was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.15 g, 30%) after purification by column chromatography (EtOAc:hexane=1:10).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:18]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:18])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cccc(Br)c1
Reaction time: 18 h
Yield: 89.9 %

Procedure:
To a solution of 114 g (447 mmol) of tert-butyl (3-bromophenyl)carbamate in 800 ml of DMF are added portionwise 19 g (475 mmol) of sodium hydride (60% in oil) and the reaction medium is stirred until the evolution of gas has ceased. 29.3 ml (470 mmol) of methyl iodide are added dropwise and stirring is continued for 18 hours. The reaction medium is poured into ice-cold water and extracted with ethyl acetate. The organic phase is separated out after settling of the phases, dried over magnesium sulfate and evaporated. 115 g of tert-butyl (3-bromophenyl)-N-methylcarbamate are obtained in a yield of 95%.
Reaction SMILES: [OH-].[K+].C(O)CO.[OH:7][C:8]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[O:39][CH2:40][CH2:41][O:42]C(=O)C)[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([O:19]C)=[O:18])[CH2:10][CH2:9]1.Cl>O>[OH:7][C:8]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[O:39][CH2:40][CH2:41][OH:42])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17]([OH:19])=[O:18])[CH2:10][CH2:9]1
Reactant: COC(=O)C(CCN1CCC(O)(c2ccccc2OCCOC(C)=O)CC1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: O=C(O)C(CCN1CCC(O)(c2ccccc2OCCO)CC1)(c1ccccc1)c1ccccc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
In a mixture of 4 mL of a 25% aqueous solution of potassium hydroxide and 5 mL of ethylene glycol was dissolved 350 mg (0.66 mmol) of methyl 4-(4-hydroxy-4-(2-(2-acetoxyethoxy)phenyl)piperidino)-2,2-diphenylbutyrate. The resulting solution was stirred at 130° C. for 2 hours. Water was added to the reaction mixture, followed by neutralization with hydrochloric acid under ice cooling. The crystals thus precipitated were collected by filtration and dried, whereby 230 mg (yield: 73.4%) of 4-(4-hydroxy-4-(2-(2-hydroxyethoxy)phenyl)piperidino)-2,2-diphenylbutyric acid was obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:12]=1[CH3:21]>C(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][CH2:21][C:12]1[CH:13]=[C:14]([CH2:17][C:18]([OH:20])=[O:19])[CH:15]=[CH:16][C:11]=1[O:10][CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(CC(=O)O)cc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: COc1ccc(CC(=O)O)cc1CBr
Yield: 96.2 %

Procedure:
N-Bromosuccinimide (1.0 g) and 2,2′-azobis(2-methylpropionitrile) (20 mg) were added to a solution of (4-methoxy-3-methyl-phenyl)-acetic acid (1.1 g) in chloroform (25 mL) and heated to reflux for 4 hours. On cooling, the mixture was evaporated, the residue dissolved in ethyl acetate, washed sequentially with 2M aqueous hydrochloric acid (2×50 mL), brine (50 mL), dried (magnesium sulfate) and concentrated to give the subtitle compound as an oil (1.4 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:23](=[O:35])[CH2:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]=2O)=[O:26])[CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)C>[CH2:16]([O:15][C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)[C:23]1[O:35][C:32]2[C:27]([C:25](=[O:26])[CH:24]=1)=[CH:28][CH:29]=[C:30]([OH:33])[CH:31]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CC(=O)c1ccc(O)cc1O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Solvent: CC(C)O
Product: O=c1cc(-c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)oc2cc(O)ccc12

Procedure:
A solution of 20% lithiumhexamethyldisilazane in tetrahydrofuran (217.5 mL, 260 mmol) was added to a well-stirred solution of 2,4-dihydroxy acetophenone, 14 (9.88 g, 65 mmol) in tetrahydrofuran (150 mL) under nitrogen atmosphere at −78° C. for 30 min. The reaction mixture was stirred at −78° C. for 1 h and at −30° C. for 2 h. It was again cooled to −78° C. and a solution of ethyl-3,5-dibenzyloxy-benzoate 8 (23.5 g, 65 mmol) in tetrahydrofuran (100 mL) was added over a period of 30 min. It was further stirred at room temperature for overnight and poured into ice water containing hydrochloric acid. It was extracted with chloroform, dried over sodium sulphate, filtered and evaporated on rotavapor to afford 1-(3,5-bis-benzyloxy-phenyl)-3-(2,4-dihydroxy-phenyl)-propane-1,3-dione (16). The residue, 16 (37.8 g) was refluxed with Dowex-H+ (8 g) in 2-propanol (300 mL) for 34 h. 2-Propanol was evaporated on rotavapor, residue suspended in hot dimethyl formamide and filtered. The filtrate was 3,4-Dimethoxy-benzoic acid (10). Yield 2 g (8%); mp 179-181° C.; MS (FAB) 183 (M++1); IR (KBr) 2939, 2836, 1867, 1678; 1H NMR (200 MHz, CDCl3) δ 7.79 (dd, J=8.4 Hz, 1.9 Hz, 1H), 7.60 (d, J=1.8 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 3.96 (s, 6H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][CH2:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH2:4]1.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[O:20][CH3:21]>C(Cl)Cl>[CH3:21][O:20][C:19]([NH:2][CH:3]1[CH2:11][CH2:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH2:4]1)=[O:22]
Reactant: NC1CCc2sccc2C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NC1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To 3.79 g of 5-amino-4,5,6,7-tetrahydrobenzo[b]thiophene.hydrochloride and 4.04 g of triethylamine dissolved in 30 ml of methylene chloride was added dropwise 1.89 g of methyl chlorocarbonate under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, the organic layer was collected by separation and dried, and then the solvent was removed. The resulting crystals were recrystallized from isopropyl ether to obtain 3.80 g of 5-methoxycarbonylamino-4,5,6,7-tetrahydrobenzo[b]thiophene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[OH-].[K+].[C:12](#[N:15])[CH:13]=[CH2:14]>C(O)(C)(C)C.CCOCC>[C:12]([CH2:13][CH2:14][O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)#[N:15]
Reactant: C=CC#N
Reactant: COc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: COc1ccc(OCCC#N)cc1
Temperature: 75 °C
Reaction time: 5 h

Procedure:
4-Methoxyphenol (248 g), KOH (5.6 g) and acrylo-nitrile (397 ml) were dissolved in 1 liter of t-butanol and heated with stirring at 75° C. for 5 hours. The mixture was then cooled to room temperature and stripped in vacuo to solid residue, which was repulped in ether and insolubles recovered by filtration. The latter were taken up in 2 liters of ethyl acetate, washed in sequence with 1 liter each of H2O, saturated NaHCO3 and saturated NaCl, dried over MgSo4 and restripped to yield purified title product, 199.4 g, m.p. 62-64° C.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CC(C)=O.O>[CH:2]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:16])=[O:17])=[O:1]
Reactant: N#Cc1ccc(C2OCCCO2)c(S(=O)(=O)c2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1ccc(C=O)c(S(=O)(=O)c2ccccc2)c1
Temperature: 160 °C
Reaction time: 0.1 h

Procedure:
In an Emrys microwave, 4-(1,3-dioxan-2-yl)-3-(phenylsulfonyl)benzonitrile (260 mg, 0.789 mmol) and pyridinium 4-toluenesulfonate (149 mg, 0.592 mmol; 0.75 eq.) in acetone/water (1:1, 3 ml) were heated with stirring at 160° C. for 6 min. The reaction mixture was then added to water (50 ml) and extracted with ethyl acetate (8×20 ml). The combined organic phases were subsequently washed with saturated sodium chloride solution (2×30 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound was obtained as a solid (0.21 g, quant.).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][CH2:13][O:14][C:7]3=[CH:6][C:5]=2[CH:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])[C:3]1=[O:24].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([C:37]([O:39][CH3:40])=[O:38])#N.Cl>O1CCCC1>[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][CH2:13][O:14][C:7]3=[CH:6][C:5]=2[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])([C:37]([O:39][CH3:40])=[O:38])[C:3]1=[O:24]
Reactant: COC(=O)C#N
Reactant: CN1C(=O)C(c2ccccc2[N+](=O)[O-])c2cc3c(cc21)OCCO3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ccccc2[N+](=O)[O-])C(=O)N(C)c2cc3c(cc21)OCCO3
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45.5 %

Procedure:
To a stirred solution of 6-methyl-8-(2-nitrophenyl)-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one (0.40 g, 1.2 mmol) in tetrahydrofuran (10 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 1.5 mL, 1.5 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 min, methyl cyanoformate (0.12 mL, 1.5 mmol) was added and the mixture was stirred at ambient temperature for 18 h. 10% w/v hydrochloric acid (5 mL) was added at 0° C. and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography and eluted with ethyl acetate/hexanes (1/2) to afford methyl 6-methyl-8-(2-nitrophenyl)-7-oxo-2,3,7,8-tetrahydro-6H-[1,4]dioxino[2,3-f]indole-8-carboxylate (0.21 g, 44%): 1H NMR (300 MHz, CDCl3) δ 7.92-7.89 (m, 1H), 7.48-7.37 (m, 2H), 7.20-7.19 (m, 1H), 6.97 (s, 1H), 6.41 (s, 1H), 4.21-4.14 (m, 4H), 3.65 (s, 3H), 3.12 (s, 3H).