Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14](=[O:15])[CH2:13][C:12]2([C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[NH:17][C:16]2=[O:25])[C:11]1=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:27]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:30])[CH:28]=[CH2:29].O>O1CCCC1>[C:32]([O:31][C:27](=[O:30])[CH2:28][CH2:29][N:17]1[C:18]2[C:23](=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:12]2([CH2:13][C:14](=[O:15])[N:10]([CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:11]2=[O:26])[C:16]1=[O:25])([CH3:35])([CH3:34])[CH3:33]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=C1CC2(C(=O)Nc3ccc(Cl)cc32)C(=O)N1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCN1C(=O)C2(CC(=O)N(Cc3ccccc3)C2=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred suspension of sodium hydride (60% dispersion in oil, 7 mg, 0.16 mmol) in anhydrous tetrahydrofuran (2 ml) was treated with 1′-benzyl-5-chloro-1H-spiro[indole-3,3′-pyrrolidine]-2,2′,5′-trione, intermediate 14 (50 mg, 0.15 mmol). After stirring at ambient temperature for 30 minutes, tert-butyl acrylate (0.03 ml, 0.19 mmol) was added and the resultant mixture stirred for 2 hours and left to stand at ambient temperature for 18 hours. Water (15 ml) was added and the mixture extracted with ethyl acetate (3×15 ml). The combined extracts were washed with brine (15 ml), dried (MgSO4) and the solvent removed in vacuo to give the crude 3-(1′-Benzyl-5-chloro-2,2′,5′-trioxo-spiro[indole-3,3′-pyrrolidin]-1-yl)-propionic acid tert-butyl ester. This was purified by flash chromatography (silica) eluting with petroleum ether (40-60) containing an increasing amount (0 to 50%) of ethyl acetate to give a white solid (37 mg 54%). This was sufficiently pure by 1H NMR to take on to the final hydrolysis step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[O:21][CH2:20]3)=[CH:13][CH:12]=2)[C:9]([C:22]([O:24][CH3:25])=[O:23])=[C:8]([CH3:26])[N:7]([CH3:27])[C:6]=1[CH3:28])=[O:4].[CH:29]([NH2:32])([CH3:31])[CH3:30]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]([OH:21])[CH2:20][NH:32][CH:29]([CH3:31])[CH3:30])=[CH:15][CH:16]=2)[C:9]([C:22]([O:24][CH3:25])=[O:23])=[C:8]([CH3:26])[N:7]([CH3:27])[C:6]=1[CH3:28])=[O:4]
Reactant: COC(=O)C1=C(C)N(C)C(C)=C(C(=O)OC)C1c1ccc(OCC2CO2)cc1
Reactant: CC(C)N
Product: COC(=O)C1=C(C)N(C)C(C)=C(C(=O)OC)C1c1ccc(OCC(O)CNC(C)C)cc1
Yield: 90 %

Procedure:
Eleven grams of 1,2,6-trimethyl-4-[4-(2,3-epoxypropoxy)-phenyl]-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (melting point 126°), 3 g of isopropylamine and 40 ml of alcohol are heated at reflux overnight, concentrated in vacuo and treated with acetone. The product precipitates as the hydrochloride salt, white crystals of melting point 211°-212°C, in a yield of 90% of theory.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[S:4][CH:5]=[C:6]([CH2:8]O)[N:7]=1.P(Br)(Br)[Br:13]>C(Cl)Cl>[Br:13][CH2:8][C:6]1[N:7]=[C:3]([C:2]([F:11])([F:10])[F:1])[S:4][CH:5]=1
Reactant: BrP(Br)Br
Reactant: OCc1csc(C(F)(F)F)n1
Solvent: ClCCl
Product: FC(F)(F)c1nc(CBr)cs1
Reaction time: 1 h
Yield: 36 %

Procedure:
To a stirring solution of (2-(trifluoromethyl)thiazol-4-yl)methanol (550 mg, 3.00 mmol) in DCM (5 ml) was added PBr3 (0.283 ml, 3.00 mmol) at 0-5° C. in 5-10 min. and stirring continued for 1 h. Reaction mixture was diluted with DCM and washed with water. Organic layer was separated and distilled out to get crude product which was column purified using 0-2% EtOAC in hexane to get title compound in 36% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C@@H:13]([CH3:23])[CH2:12][N:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[NH:30][C:31]([C:33]2[C:42]([NH:43]C(=O)OCC3C=CC=CC=3)=[CH:41][C:40]3[C:35](=[CH:36][C:37]([C:54]4[CH2:55][CH2:56][N:57]([CH3:60])[CH2:58][CH:59]=4)=[CH:38][CH:39]=3)[N:34]=2)=[O:32])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:43][C:42]1[C:33]([C:31]([NH:30][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][C:24]=2[N:11]2[CH2:12][C@H:13]([CH3:23])[C@@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:20])[CH3:21])([CH3:18])[CH3:17])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10]2)=[O:32])=[N:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[C:37]([CH:54]1[CH2:59][CH2:58][N:57]([CH3:60])[CH2:56][CH2:55]1)[CH:36]=2
Reactant: [H][H]
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(C4=CCN(C)CC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(C4CCN(C)CC4)ccc3cc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 66.6 %

Procedure:
A mixture of benzyl [2-({[4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)pyridin-3-yl]amino}carbonyl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl]carbamate (0.013 g, 0.016 mmol) in 1.5 mL of MeOH was hydrogenated in the presence of 10% Pd on carbon (10 mg) under a balloon of hydrogen at room temperature for 1 h. The reaction mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to yield the protected intermediate tert-butyl ((3R,4R,5S)-1-[3-({[3-amino-7-(1-methylpiperidin-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (0.0075 g, 68%). LCMS calc. for C38H58N7O4Si [M+H]+: m/z=704.4. found: 704.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCN1CCC(O[C@@H](c2ccc(Cl)cc2)c2ccccn2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCN1CCC(O[C@@H](c2ccc(Cl)cc2)c2ccccn2)CC1
Reaction time: 8 h

Procedure:
In 760 ml of ethanol was dissolved 126.0 g (0.302 mol) of ethyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy ]-piperidino]butanoate obtained according to Reference example 3(1), and then 120.8 ml of a 5N aqueous sodium hydroxide solution was added to the mixture and the mixture was allowed to stand at room temperature overnight. After confirming disappearance of the starting materials, the mixture was neutralized by adding 121.1 ml of a 5N hydrochloric acid. After the precipitated crystals were removed by filtration, the reaction mixture was concentrated under reduced pressure. To the residue was added 600 ml of methyl acetate, and the solution was again concentrated under reduced pressure. The residue was dissolved in 600 ml of dichloromethane and dried over anhydrous magnesium sulfate sufficiently. Insolubles were removed by filtration, the filtrate was concentrated to afford the desired compound as an orange syrupy product (125.3 g). When the syrupy product was further dried under reduced pressure, it became a foamy product (120.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27](OCC)=[O:28])[C:9]2=[O:32])=[CH:4][CH:3]=1.[CH3:33][O:34][CH2:35][CH2:36][NH2:37]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27]([NH:37][CH2:36][CH2:35][O:34][CH3:33])=[O:28])[C:9]2=[O:32])=[CH:6][CH:7]=1
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Solvent: CCO
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Temperature: 140 °C
Yield: 86 %

Procedure:
Ethyl 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (21 mg, 0.048 mmol) was dissolved in ethanol (1 mL) and [2-(methyloxy)ethyl]amine (0.05 mL) was added. This solution was heated in a microwave at 140° C. for 20 minutes. The resulting suspension was concentrated under reduced pressure and 1 N hydrochloric acid was added to bring the mixture to a pH of 3. The resulting white solid was collected by vacuum filtration to yield 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(methyloxy)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (19.8 mg, 86%). 1H NMR (CDCl3) δ 10.07 (m, 1 H), 8.52 (s, 1 H), 7.30-7.28 (m, 2 H), 7.22-7.18 (m, 2 H), 7.02-6.92 (m, 4 H), 6.70 (s, 1 H), 3.95 (s, 2 H), 3.65-3.60 (m, 2 H), 3.55-3.52 (m, 2 H), 3.33 (s, 3 H); MS m/z 459 (M+23).
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:30])[C:13]([CH2:28][OH:29])([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH3:33]I>O1CCCC1>[C:1]12([NH:11][C:12](=[O:30])[C:13]([CH2:28][O:29][CH3:33])([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CI
Reactant: O=C(NC12CC3CC(CC(C3)C1)C2)C(CO)(Cc1ccncc1)Cc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(Cc1ccncc1)(Cc1ccncc1)C(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
To a well-stirred suspension of N-adamantan-1-yl-2-hydroxymethyl-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionamide (40 mg, 0.1 mmol) in anhydrous tetrahydrofuran (0.50 ml), sodium hydride (7.8 mg of 60% mineral oil dispersion; 0.2 mmol of sodium hydride) was added. After stirring at ambient temperature for 30 minutes, methyl iodide (12.5 μl, 0.2 mmol) was added. After stirring for 2 hours at ambient temperature, the reaction was quenched by the addition of water/methylene chloride (10 ml of each). The mixture was then extracted twice with 10 ml portions of methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to an oil (60 mg). Flash chromatography of the entire sample (silica gel, 40 micron mesh; elution with methanol/ethyl acetate=1:9 in volume) afforded the title compound (free base) as an amorphous solid (16 mg).
Reaction SMILES: Cl[C:2]1[C:7]2=[N:8][N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:6]2[CH:5]=[CH:4][N:3]=1.[OH-:25].[Na+]>C1COCC1.Cl>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:9]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:6]2[C:7]([C:2]([OH:25])=[N:3][CH:4]=[CH:5]2)=[N:8]1
Reactant: Clc1ccc(-c2c3ccnc(Cl)c3nn2-c2ccccc2Cl)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1nccc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A mixture of 7-chloro-2-(2-chlorophenyl)-3-(4-chlorophenyl)-2H-pyrazolo[3,4-c]pyridine (I-9A-1a, 420 mg, 1.12 mmol) in THF (12 ml) and 3M aqueous HCl (7.5 ml) was stirred overnight at 60° C. The reaction mixture was cooled, adjusted to pH=7.5 with 5M aqueous NaOH, and extracted into ethyl acetate. The combined organic layers were dried (Na2SO4), concentrated under reduced pressure, and then repulped from 40% ethyl acetate in isopropyl ether to give the desired product (I-9A-1a) as a colorless solid (320 mg, 80%): +ES MS (M+1) 356.3; 1H NMR (400 MHz, CD2Cl2): δ 9.64 (br s, 1H), 7.55-7.41 (m, 4H), 7.36-7.32 (m, 2H), 7.23-7.19 (m, 2H), 6.96 (dd, J=7.5, 5.8 Hz, 1H), 6.50 (d, J=7.5 Hz, 1H).
Reaction SMILES: [CH:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]5=[CH:15][C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:30]([F:33])([F:32])[F:31])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O-]S(C(F)(F)F)(=O)=O.F[N+:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl.CCOC(C)=O>[CH:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]5=[C:15]([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][N:43]=5)[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:30]([F:33])([F:31])[F:32])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCn2c1cc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Reactant: F[n+]1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O)CC1CCn2c1c(-c1ccccn1)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 0 °C
Yield: 9.4 %

Procedure:
The 1st enantiomer (described as the enantiomer isolated and having the retention time of 15 min per the conditions reported in Example 1.7) of 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid (0.100 g, 0.219 mmol) was dissolved in anhydrous DCM (2.2 mL) using a plastic vial. The reaction was cooled to 0° C., and N-fluoropyridinium triflate (0.073 g, 0.295 mmol) was added. The reaction was allowed to warm to 25° C. and after 4 h there was a dark solution. The reaction was diluted with EtOAc (40 mL), washed with water/brine (2×10 mL), brine (10 mL), and dried over MgSO4. The solvent was evaporated in vacuo. The residue was purified by HPLC to give the titled compound (0.011 g) as a yellow solid. LCMS m/z=535.5 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.54-1.78 (m, 4H), 1.79-1.92 (m, 2H), 2.05 (dd, J=9.92, 4.48 Hz, 2H), 2.43-2.53 (m, 2H), 2.57-2.73 (m, 2H), 3.29-3.41 (m, 1H), 4.09-4.28 (m, 3H), 5.17 (d, J=3.54 Hz, 2H), 6.99 (dd, J=8.84, 2.27 Hz, 1H), 7.34 (d, J=8.84 Hz, 1H), 7.44 (d, J=2.27 Hz, 1H), 7.53 (t, J=6.25 Hz, 1H), 7.56-7.61 (m, 1H), 7.64-7.69 (m, 1H), 7.73 (s, 1H), 7.90 (d, J=8.34 Hz, 1H), 8.23 (td, J=7.86, 1.58 Hz, 1H), 8.66 (d, J=4.42 Hz, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(=S)=S.O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:12]([C:11]2[CH:15]=[CH:16][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=2)=[O:13])=[CH:20][CH:19]=1
Reactant: Fc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: O=C(c1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 28.9 %

Procedure:
Aluminum chloride (26.0 g, 195 mmol) was added in portions to a solution of 4-nitrobenzoyl chloride (27.8 g, 150 mL) and 4-fluorobenzene (15.8 g, 165 mmol) in carbon disulfide (100 mL). After 1 hour, the resulting yellow mixture was carefully treated with concentrated hydrochloric acid (60 mL) and stirred for 30 minutes. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with dilute sodium hydroxide solution, water and brine, dried (MgSO4), and the solvent removed in vacuo. Crystallization from ethyl ether/hexanes gave 4-(4-fluorobenzoyl)-nitrobenzene (10.6 g, 82%) as a white solid, m.p. 87–88° C.; Analysis for C13H8NO3F: Calc.: C, 63.69; H, 3.26; N, 5.7: Found: C, 63.89; H, 3.28; N, 5.78.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].[N+:14]([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)([O-:16])=[O:15]>CN(C)C=O.C(Cl)(Cl)Cl>[N+:14]([C:17]1[N:18]=[CH:19][N:20]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]2[OH:7])[CH:21]=1)([O-:16])=[O:15]
Reactant: C1CCC2OC2C1
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cn(C2CCCCC2O)cn1
Temperature: 100 °C
Yield: 63.8 %

Procedure:
40.0 ml (395 mmol) of cyclohexene oxide and 86.37 g (625 mmol) of potassium carbonate were added to a suspension of 50.08 g (443 mmol) of 4-nitroimidazole in 800 ml of N,N-dimethylformamide. The obtained mixture was stirred under heating at 100° C. for 3 days and 20 hours to give a yellowish-brown suspension. This suspension was cooled by allowing to stand, and filtered to remove insolubles. The filtrate was concentrated in a vacuum. Water was added to the obtained residue to form a crystalline precipitate. This crystalline precipitate was recovered by filtration and washed with water. The obtained crude crystal was dissolved in chloroform and the obtained solution was washed with a saturated aqueous solution of common salt. The organic phase was dried over anhydrous magnesium sulfate and concentrated in a vacuum. In the course of the concentration, a crystal began to precipitate. This crystal was recovered by filtration to give 53.26 g of the title compound as a colorless crystal. Further, the filtrate was recrystallized from dichloromethane/diisopropyl ether to give 5.14 g of the title compound as a light-brown crystal. Thus, 58.30 g of the title compound was obtained in total (yield: 70%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1[C:10]([CH2:18][C:19](O)=[O:20])=[CH:11][C:12]2[O:16][CH2:15][O:14][C:13]=2[CH:17]=1)[CH3:8].O>O1CCCC1>[CH2:7]([C:9]1[C:10]([CH2:18][CH2:19][OH:20])=[CH:11][C:12]2[O:16][CH2:15][O:14][C:13]=2[CH:17]=1)[CH3:8]
Reactant: CCc1cc2c(cc1CC(=O)O)OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc2c(cc1CCO)OCO2
Reaction time: 12 h
Yield: 90.6 %

Procedure:
62 g of lithium aluminum hydride was suspended in 1.5 l of anhydrous tetrahydrofuran. A solution of 200 g of (6-ethyl-1,3-benzodioxol-5-yl)acetic acid in 200 ml of tetrahydrofuran was added dropwise to the suspension and the reaction was conducted at room temperature for 12 h. After the completion of the reaction, water was added thereto and the precipitate was filtered off. The filtrate was concentrated under reduced pressure and water was added to the residue. After extraction with ethyl acetate, the extract was washed with water, dried over magnesium sulfate, concentrated under reduced pressure and purified according to silica gel column chromatography (ethyl acetate/hexane=1:4) to obtain 169 g of the intended compound in the form of a faint yellow oil.
Reaction SMILES: [OH:1][CH:2]([CH2:41][N:42]1[C:46](=[O:47])[C:45]2([CH2:52][C:51]([CH3:54])([CH3:53])[NH:50][C:49]([CH3:56])([CH3:55])[CH2:48]2)[NH:44][C:43]1=[O:57])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([OH:40])[CH2:23][N:24]3[C:28](=[O:29])[C:27]4([CH2:34][C:33]([CH3:36])([CH3:35])[NH:32][C:31]([CH3:38])([CH3:37])[CH2:30]4)[NH:26][C:25]3=[O:39])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:7][CH:6]=1.[CH3:58][N:59]=[C:60]=[O:61]>>[CH3:58][NH:59][C:60]([O:40][CH:22]([CH2:23][N:24]1[C:28](=[O:29])[C:27]2([CH2:34][C:33]([CH3:35])([CH3:36])[NH:32][C:31]([CH3:37])([CH3:38])[CH2:30]2)[NH:26][C:25]1=[O:39])[CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH:2]([O:1][C:25](=[O:39])[NH:24][CH3:23])[CH2:41][N:42]3[C:46](=[O:47])[C:45]4([CH2:48][C:49]([CH3:56])([CH3:55])[NH:50][C:51]([CH3:54])([CH3:53])[CH2:52]4)[NH:44][C:43]3=[O:57])=[CH:10][CH:9]=2)([CH3:13])[CH3:12])=[CH:15][CH:16]=1)=[O:61]
Reactant: CC1(C)CC2(CC(C)(C)N1)NC(=O)N(CC(O)COc1ccc(C(C)(C)c3ccc(OCC(O)CN4C(=O)NC5(CC(C)(C)NC(C)(C)C5)C4=O)cc3)cc1)C2=O
Reactant: CN=C=O
Product: CNC(=O)OC(COc1ccc(C(C)(C)c2ccc(OCC(CN3C(=O)NC4(CC(C)(C)NC(C)(C)C4)C3=O)OC(=O)NC)cc2)cc1)CN1C(=O)NC2(CC(C)(C)NC(C)(C)C2)C1=O

Procedure:
A mixture of 5.0 g of 2,2-bis{4-[2-hydroxy-3-(7,7,9,9-tetramethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-3-yl)propoxy]phenyl}propane (prepared as described in Example 2) and 25.0 g of methyl isocyanate was refluxed for 8.5 hours. After completion of the reaction, excess methyl isocyanate was evaporated from the reaction mixture and then the residue was purified by column chromatography through silica gel eluted with a 24:12:2:1 by volume mixture of ethyl acetate, benzene, triethylamine and ethanol and then by recrystallisation from ethanol. The desired Compound No. 31 was obtained in the form of white crystals, melting point 238°-242° C.
Reaction SMILES: [ClH:1].O1CCOCC1.O[C:9]1([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1>>[ClH:1].[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:9]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH:10]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(C2(O)CCCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(C2=CCNCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of HCl in dioxane (10 mL, 40 mmol) and tert-butyl 4-hydroxy-4-(4-methoxyphenyl)azepane-1-carboxylate (0.68 g, 2.1 mmol) was stirred at room temperature for 3 h. The reaction mixture was concentrated and washed with diethyl ether and dried over sodium sulfate to yield 0.36 g 5-(4-methoxyphenyl)-2,3,4,7-tetrahydro-1H-azepine hydrochloride. LCMS: R.T. 0.61 min. LCMS (ES-API), m/z 204.0 (M+H).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[Br:16][CH:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1COCC1>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]2[C:15]1=[CH:3][CH:4]=[CH:5][CH:6]=2
Reactant: CCCCCCCCCC(Br)Br
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: BrCCCCCCCCCCn1c2ccccc2c2ccccc21

Procedure:
10 g (0.25 mol) sodium hydride (60%) was added in several portions into a solution of 30.6 g (0.20 mol) carbazole in 200 mL THF. Then the mixture was transferred into a funnel from which it was added dropwisely into a solution of 180 g (0.6 mol) dibromodecane in 500 mL THF at 70° C. and the mixture was refluxed for 48 h. After cooling, it was filtered. The filtrate was distilled in order to remove remaining dibromodecane. The residue was diluted with water and extracted with CH2Cl2. The organics was washed with brine and dried over anhydrous MgSO4 overnight. After removed the solvent by rotary evaporator, it was purified by silica chromography to give 31.6 g (41%, yield, mp 38˜40° C.) white solid product. 1H NMR (500 MHz, CDCl3), δ (ppm): 8.14 (2H, d), 7.51 (2H, d), 7.44 (2H, d), 7.26 (2H, d), 4.30 (2H, t), 3.41 (2H, t), 1.27˜1.90 (16H, m).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[CH2:9]([O:11][C:12]([N:14]=[C:15]=[O:16])=[O:13])[CH3:10]>C(OCC)C>[CH3:7][O:6][C:4](=[O:5])[C:3]([C:15]([NH:14][C:12]([O:11][CH2:9][CH3:10])=[O:13])=[O:16])=[C:2]([NH2:1])[CH3:8]
Reactant: CCOC(=O)N=C=O
Reactant: COC(=O)/C=C(/C)N
Solvent: CCOCC
Product: CCOC(=O)NC(=O)C(C(=O)OC)=C(C)N
Reaction time: 4 h

Procedure:
To a solution of methyl 3-aminocrotonate (39.0 g, 0.339 mol) in anhydrous diethyl ether (200 mL) under nitrogen with magnetic stirring at 0-5° C. is added in dropwise fashion a solution of ethoxycarbonyl isocyanate (0.339 mol) in diethyl ether (40 mL). The resulting pale yellow colored suspension is stirred below 5° C. for 4 h. The solid is collected by suction filtration, rinsed with 50 mL of diethyl ether and dried under vacuum at room temperature for 30 h to obtain the title compound as an off-white solid.