Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH2:25][C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[O:34][CH3:35])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[OH-].[Li+]>C1COCC1.O>[CH3:35][O:34][C:27]1[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:26]=1[CH2:25][NH:24][C:20]1[N:19]=[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:36])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)[CH:23]=[CH:22][N:21]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(NCc4cc(OC)ccc4OC)n3)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(OC)c(CNc2nccc(Oc3cc(C)c4c(c3)B(O)OC4CC(=O)O)n2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A solution of {6-[2-(2,5-dimethoxy-benzylamino)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid ethyl ester (0.35 g, 0.71 mmol) in THF (5 mL) was treated with lithium hydroxide (0.081 g, 3.55 mmol) in water (5 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour then at room temperature for 1 hour. The mixture was quenched with 2N HCl to pH 2 then concentrated to approximately ½ the entire volume, diluted with brine and extracted with ethyl acetate. The organic extracts were dried (Na2SO4), filtered and concentrated to give {6-[2-(2,5-dimethoxy-benzylamino)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid as a yellow solid (0.32 g, 97%). 1H NMR (400 MHz, CD3OD) δ8.11 (d, J=6.64 Hz, 1H), 7.25 (s, 1H), 7.13 (s, 1H), 6.60-6.20 (m, 4H), 5.75-5.65 (m, 1H), 4.20-4.10 (m, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.21-3.10 (m, 1H), 2.40 (s, 3H), 2.39-2.20 (m, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:10][CH:9]([CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7][CH:6]=1)=O.CC(C[AlH]CC(C)C)C>C1COCC1>[CH2:14]([O:13][CH2:12][CH2:11][CH:9]1[CH2:10][C:5]([CH2:3][OH:2])=[CH:6][CH2:7][CH2:8]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C1=CCCC(CCOCc2ccccc2)C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCC1=CCCC(CCOCc2ccccc2)C1
Yield: 78.8 %

Procedure:
Intermediate A3 (6.5 g) was dissolved in THF (100 mL) and added to a solution of DIBAL (70 mL, 1M in hexanes) (available from Aldrich) in THF (160 mL) at −35° C. for 35 m. The mixture was quenched with Rochelle's salt solution, and extracted with ether. The dried residue was purified by chromatography on SiO2 with 30% EtOAc:Hx to yield [5-(2-benzyloxy-ethyl)-cyclohex-1-enyl]-methanol 4.6 g (80%). A solution of the alcohol (4.0 g, 18.7 mmol) in DMF (60 mL) was treated with triethylamine (3 mL) followed by TBSCl (3.0 g, 22.4 mol) for 20 m at rt. The residue was isolated from an aqueous work-up and purified by chromatography to give [5-(2-benzyloxy-ethyl)-cyclohex-1-enylmethoxy]-tert-butyl-dimethyl-silane (Intermediate A4) 3.6 g (63%).
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:2]2=[O:1])[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCNC1=O
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCCN(c2cccc(Cl)c2)C1=O
Temperature: 25 °C
Reaction time: 36 h
Yield: 10.1 %

Procedure:
To a stirred solution of (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (400 mg, 1.75 mmol) in DCM (7.5 mL) was added TEA (0.488 mL, 3.50 mmol) followed by copper (II) acetate (477 mg, 2.63 mmol) and 3-chlorophenylboronic acid (548 mg, 3.50 mmol) at rt under argon. Then, activated molecular sieves (˜1 gm) were added. The reaction mixture was stirred at rt for 36 hr. The reaction mixture was filtered through CELITE®. The filtrate was concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (S)-tert-butyl 1-(3-chlorophenyl)-2-oxoazepan-3-ylcarbamate (60.0 mg, 0.177 mmol, 10.1% yield) as white solid. Anal. Calcd. for C17H23ClN2O3 m/z 338.8. found: 339.1 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:28]([O:32][C:33](=[O:42])[N:34]([CH3:41])[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([CH3:31])([CH3:30])[CH3:29]>C(Cl)Cl>[C:28]([O:32][C:33](=[O:42])[N:34]([CH:35]1[CH2:36][CH2:37][N:38]([S:17]([C:13]2[S:14][C:15]([Br:16])=[C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])[CH:12]=2)(=[O:19])=[O:18])[CH2:39][CH2:40]1)[CH3:41])([CH3:31])([CH3:29])[CH3:30]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCC(N(C)C(=O)OC(C)(C)C)CC3)sc2Br)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (300 mg; 0.72 mmol; 1 eq), is dissolved in anhydrous DCM (20 ml). The reaction mixture is put under nitrogen. Triethylamine (0.5 ml; 3.61 mmol; 5 eq) and methyl-piperidine-4-yl-carbamic acid tert-butyl ester (773.2 mg; 3.61 mmol; 5 eq) are added successively and the reaction mixture is stirred for 30 minutes at room temperature. It is then washed with water, NaHCO3 sat., brine and dried over MgSO4, affording the title compound (470 mg; quantitative).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]Br)(=[O:3])[CH3:2].[N-:8]=[N+:9]=[N-:10].[Na+]>CN(C)C=O.O>[C:1]([O:4][CH2:5][CH2:6][N:8]=[N+:9]=[N-:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCN=[N+]=[N-]
Temperature: 70 °C

Procedure:
A mixture of 2-bromoethyl acetate (500 μl, 4.54 mmol) in N,N-dimethylformamide (DMF) (2.0 mL) was treated with sodium azide (295 mg, 4.54 mmol) and then heated to 70° C. for 2 hours. The mixture was diluted with water and then extracted with ether. The extracts were washed with water, then brine, dried over sodium sulfate, filtered and concentrated to afford the title compound as a colorless liquid. 1H NMR (400 MHz, CHLOROFORM-d) d=4.29-4.19 (m, 2 H), 3.53-3.44 (m, 2 H), 2.11 (s, 3 H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:8]#[N:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C=O)C.[Cl-].[Na+].O>[CH2:12]([O:1][CH2:2][C:3]1([C:8]#[N:9])[CH2:7][CH2:6][CH2:5][CH2:4]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: N#CC1(CO)CCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(COCc2ccccc2)CCCC1
Reaction time: 0.33 h
Yield: 76.6 %

Procedure:
To a solution of 1-(hydroxymethyl)cyclopentanecarbonitrile (0.30 g, 2.0 mmol) in DMF (4 mL) was added sodium hydride (60% dispersion in mineral oil, 0.101 g, 2.52 mol). The resulting mixture was stirred for 20 minutes, followed by the addition of benzyl bromide (0.28 mL, 2.4 mmol). The reaction was stirred at ambient temperature for 64 hours. Additional sodium hydride (60% dispersion in mineral oil, 0.060 g, 1.5 mmol) and benzyl bromide (0.18 mL, 1.5 mmol) were added and the reaction was stirred for an additional 30 minutes. Water was then added to the mixture, followed by brine, and the aqueous layer was extracted with ethyl acetate. The extracts were combined and dried over sodium sulfate, and the solvent was then removed in vacuo. To the resulting residue was added water. The product was isolated by extraction with diethyl ether. The ethereal extracts were dried over sodium sulfate, and the solvent was evaporated. Flash column chromatography (eluting with a gradient from 0-30% ethyl acetate in hexanes) afforded product (330 mg, 64%).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:9](S(C(F)(F)F)(=O)=O)[S:10]([C:13]([F:16])([F:15])[F:14])(=O)=[O:11]>N1C=CC=CC=1>[Br:1][C:2]1[C:7]([O:8][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Br
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: O=S(=O)(Oc1cccnc1Br)C(F)(F)F
Temperature: 23 °C
Reaction time: 1.25 h
Yield: 94 %

Procedure:
To a solution of 2-bromo-3-hydroxypyridine [CAS 6602-32-0, commercially available] (25.0 g, 144 mmol) in anhydrous pyridine (145 mL) at −10° C. (ice/NaCl) was drop wise added Tf2O (24.2 mL, 147 mmol) keeping the temperature below −5° C. (30 min). The cooling bath was removed and mixture was allowed to reach 23° C., stirred at 23° C. for 75 min, poured into sat. NaHCO3-sol., extracted with DCM, washed with brine, dried over Na2SO4. Removal of the solvent in vacuum left a brown oil, which was purified by vacuum distillation: bp 65° C. (0.82 mbar) (42 g colorless oil, with some solid); triturated with hexane, filtered the undesired solid off, washed with hexane, collected the mother liquor, evaporated the solvent to give the title compound as a colorless liquid (41.52 g, 94%). MS (TOF ESP) 306 [(M+H)+], 307.85 [(M+2+H)+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][NH:24][CH3:25]>C(#N)C>[CH3:23][N:24]([CH3:25])[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CCC(CC)Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC(CC)Nc1nc(N(C)C)ccc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 52.4 %

Procedure:
To a room-temperature mixture containing 6-chloro-3-nitro-N-(pentan-3-yl)pyridin-2-amine (250 mg, 0.90 mmol) and potassium carbonate (250 mg, 1.8 mmol) in acetonitrile (2 mL) was added dimethylamine (1.35 mL, 1.0 M, 1.35 mmol) by syringe. After 3 h, the reaction mixture was concentrated in vacuo and then re-dissolved in EtOAc and water. The organic layer was washed twice with water and once with brine, dried over sodium sulfate, filtered and concentrated In vacuo. Silica gel chromatography (5%-20% EtOAc/Hexanes) provided the title compound as a yellow solid (119 mg, 52%). m/z=253.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH3:37])=[C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:29]3[CH:30]=[C:25]([O:24][CH3:23])[CH:26]=[CH:27][C:28]=3[CH3:37])[CH2:36][CH2:35]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: COc1ccc(C)c(N2CCNCC2)c1
Product: COc1ccc(C)c(N2CCN(C(=O)Nc3cc4ccccc4nc3OC)CC2)c1
Yield: 82 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(5-methoxy-2-methylphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.[OH-].[K+]>O1CCCC1.CO>[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)/[CH:16]=[C:2]1/[C:1](=[O:11])[C:10]2[C:5]([CH2:4][CH2:3]/1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: O=C1CCCc2ccccc21
Reactant: O=Cc1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1/C(=C/c2cccc(Br)c2)CCc2ccccc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 92.4 %

Procedure:
A 250 mL flask was charged with tetralone (5.2 g, 35.6 mmol) and 3-bromobenzaldehyde (8.51 g, 56 mmol). This was dissolved in warm tetrahydrofuran (20 mL), and to this yellow solution was slowly added a 4 wt % solution of KOH in methanol (160 mL). The reaction was stirred for 4 days at room temperature. The mixture was concentrated and reduced to approx 10% vol. The residue was filtered and washed with MTBE (3*50 mL), dried, to afford a light yellow powder (10.3 g, 92%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:26](C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[N:8]([CH3:26])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: c1ccc(CNC(c2ccccn2)c2ccccn2)nc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(Cc1ccccn1)C(c1ccccn1)c1ccccn1
Yield: 93 %

Procedure:
To a solution of N-[di(2-pyridinyl)methyl]-N-(2-pyridinylmethyl)amine (1.262 g, 4.59 mmol) in 1,2-dichloroethane (35 ml) was added formaldehyde (37% solution in water, 0.45 ml, 6.0 mmol). NaBH(OAc)3 (3.92 g, 18.5 mmol) was added in small portions. After stirring for 7 h at room temperature saturated NaHCO3(aq) (35 ml) was added and the 1,2-dichloroethane layer was separated. The aqueous layer is extracted with CH2Cl2 (3×20 ml). The combined organic layers were washed with 1N NaOH (20 ml) and brine (20 ml), dried (Na2SO4) and the solvent removed in vacuo to give N-[di(2-pyridinyl)methyl]-N-methyl-N-(2-pyridinylmethyl)amine (1.235 g, 4.27 mmol, 93%) as a slightly yellow oil. 1H NMR (CDCl3, 300 MHz) δ 2.19 (s, 3H), 3.72 (s, 2H), 4.96 (s, 1H), 7.14 (m, 3H), 7.71 (m, 6H), 8.56 (m, 3H); 13C NMR (CDCl3, 50 MHz) δ 40.32 (q), 61.04 (t), 77.87 (d), 121.76 (d), 122.10 (d), 122.92 (d), 123.21 (d), 136.29 (d), 136.43 (d), 148.86 (d), 149.22 (d), 159.37 (s), 160.59 (s), MS (CI): m/z 291 (M+1).
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:36][S:37]([N:20]1[CH2:19][CH2:18][N:17]([C:16]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][C:9]3[C:14]([N:15]=2)=[CH:13][C:12]([C:23]([O:25][CH3:26])=[O:24])=[CH:11][CH:10]=3)[CH2:22][CH2:21]1)(=[O:39])=[O:38]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCNCC3)nc2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(S(C)(=O)=O)CC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 2-phenyl-3-(piperazin-1-yl)quinoxaline-6-carboxylate (150 mg, 0.43 mmol, 1.00 equiv), DIEA (3 mL) in DCM (15 mL). This was followed by the addition of methanesulfonyl chloride (0.5 mL) at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was washed by sat. NaCl and concentrated under vacuum. This resulted in 0.17 g (93%) of methyl 3-(4-(methylsulfonyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylate as a brown yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.[H][H]>[Ni].CC(N(C)C)=O.CO>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CN(C)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CN(C)c1ccc(N)c(C(=O)O)c1

Procedure:
A mixture of 18 g. of 2-nitro-5-dimethylaminobenzoic acid, 1.0 liter of a 50:50 mixture of dimethylacetamide/methanol and 18 g. of Raney Nickel is hydrogenated at a hydrogen pressure of 40-50 psi for 2 hours. The resulting mixture is filtered, washed with methanol and the total filtrate evaporated to a solid which is broken up, washed with ether and dried to obtain 2-amino-5-dimethylaminobenzoic acid, m.p. 231°-234° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:7]2[CH2:6][C:5](C(OCC)=O)([C:13]([O:15]CC)=[O:14])[CH2:4][C:3]1=2.[OH-].[K+]>C(O)C.O>[CH3:11][C:8]1([CH3:12])[CH2:9][CH2:10][C:2]([CH3:1])([CH3:23])[C:3]2[CH2:4][CH:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1=2
Reactant: CCOC(=O)C1(C(=O)OCC)CC2=C(C1)C(C)(C)CCC2(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CCC(C)(C)C2=C1CC(C(=O)O)C2
Temperature: 160 °C
Yield: 51.2 %

Procedure:
18.4 g of diethyl 4,5,6,7-tetrahydro-4,4,7,7-tetramethyl-2,2-indanebiscarboxylate are dissolved in 500 ml of ethanol and treated with a solution of 64 g of potassium hydroxide in a mixture of 200 ml of ethanol and 50 ml of water. After heating at reflux temperature for 6 hours, the mixture is cooled, the majority of the alcohol is distilled off on a rotary evaporator, the residue is poured on to ice, acidified with 2N hydrochloric acid, extracted repeatedly with ethyl acetate, dried and evaporated. The thus-obtained crude product is heated to 160° C. for 5.5 hours and subsequently chromatographed on silica gel [eluting agent: hexane/ether (2:1)]. After recrystallization from pentane, there are obtained 6.5 g of 4,5,6,7-tetrahydro-4,4,7,7-tetramethyl-2-indanecarboxylic acid in the form of colourless crystals of melting point 125°-129° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CC(C)=O>[CH3:16][O:15][C:13]([CH2:12][O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1)=[O:14]
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2cc[nH]c2c1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
6-Hydroxyindole (2.9 g), methyl chloroacetate (2.7 g), potassium carbonate (5.5 g) and potassium iodide (0.2 g) are added to acetone (100 ml), and the mixture is refluxed for 8 hours. The reaction mixture is cooled to room temperature, and the insoluble materials are removed by filtration. The filtrate is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform) to give 6-methoxycarbonylmethoxyindole (2.83 g).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:46])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41]I)[C:24]=1[CH2:43][CH2:44][CH3:45])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:17][C:18](=[O:46])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:24]=1[CH2:43][CH2:44][CH3:45])[CH3:16]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCCCOCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCCOCCCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Reaction time: 25 h
Yield: 96.1 %

Procedure:
A mixture of 0.871 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.536 g of 4-[4-acetyl-3-[4-(4-iodobutoxy)butoxy]-2-propylphenoxy]butanoic acid ethyl ester and 0.94 g of anhydrous potassium carbonate in 40 ml of anhydrous acetone was stirred at reflux for 17 hours. An additional 1.0 g of potassium carbonate was added and reflux was continued for 25 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was chromatographed on 200 g of silica gel. Elution with 20% ethyl acetate-toluene gave 2.71 g (96% yield) of 4-[4-acetyl-3-[4-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]2=1.Cl[S:17]([C:20]1[CH:24]=[CH:23][S:22][C:21]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:19])=[O:18]>N1C=CC=CC=1>[O:15]=[C:11]1[C:12]2[NH:13][C:14]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1][S:17]([C:20]3[CH:24]=[CH:23][S:22][C:21]=3[C:25]([O:27][CH3:28])=[O:26])(=[O:18])=[O:19])[C:7]=2[CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: Nc1cccc2c3c([nH]c12)C(=O)CCC3
Solvent: c1ccncc1
Product: COC(=O)c1sccc1S(=O)(=O)Nc1cccc2c3c([nH]c12)C(=O)CCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a mixture of 8-amino-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.30 g) and pyridine (8 mL) was added methyl 3-(chlorosulfonyl)thiophene-2-carboxylate (0.43 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.47 g, yield 80%) was obtained as pale-yellow crystals from a fraction eluted with tetrahydrofuran-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 239-240° C. (decomposition).
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:11])[C:3]=1[C:12](=[O:18])[CH2:13]S(C)(=O)=O.C(O)(=O)C>[Zn].C(O)C>[CH3:13][C:12]([C:3]1[N:4]([CH3:11])[C:5]2[C:10]([C:2]=1[OH:1])=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:18]
Reactant: Cn1c(C(=O)CS(C)(=O)=O)c(O)c2ccccc21
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)c1c(O)c2ccccc2n1C
Temperature: 25 °C

Procedure:
A mixture of 17.0g (0.0637 mole) 1-(3-hydroxy-1-methyl-1H-indol-2-yl)-2-(methylsulfonyl) ethanone, 21.0g (0.32 mole) zinc dust, 40ml glacial acetic acid and 80ml ab. ethanol was stirred vigorously and heated at 45°-50° for 1 hour. After stirring an additional hour at room temperature, the mixture was filtered through diatomaceous earth and the filter cake washed several times with fresh ethanol. The combined filtrates were condensed to 150ml and 50ml of hot water was added. Cooling yielded a green solid which was filtered, washed with cold water and recrystallized from 70% aqueous methanol to yield green needles of mpt. 119°-121°.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:7]=1OCC(N)=O)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C[N:27]1CCCC1=O>C(OCC)(=O)C>[C:1]([NH:4][CH2:5][C:6]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:7]=1[NH2:27])(=[O:3])[CH3:2]
Reactant: CN1CCCC1=O
Reactant: CC(=O)NCc1cc([N+](=O)[O-])ccc1OCC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(=O)NCc1cc([N+](=O)[O-])ccc1N
Temperature: 100 °C

Procedure:
120 g of the 2-(N-acetylaminomethyl)-4-nitrophenoxyacetamide made in step 1 are dissolved in 450 ml of N-methylpyrrolidone, mixed with 155 g of potassium carbonate and heated for 4.5 hours at 100° C. Subsequently the reaction mixture is cooled to room temperature, diluted with 840 ml of ethyl acetate, filtered and the solvent is evaporated in vacuum at 60 to 80° C. The remaining residue is crystallized by addition of ethanol. The product is filtered with suction, taken up in 250 ml ethanol and heated briefly under reflux. Subsequently the solution is cooled, filtered and the residue is dried in vacuum. 46.6 g of a yellow powder are obtained with a melting point of 208 to 210° C.