Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].[CH3:13][NH2:14]>C(Cl)CCl>[CH3:13][NH:14][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CN
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Solvent: ClCCCl
Product: CNC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Commercially available 3-nitrobenzoic acid is reacted with methylamine and EDC under standard conditions to afford N-methyl-3-nitrobenzamide, which is reduced with LAH under standard conditions to afford N-methyl(3-nitrophenyl)methanamine, which is protected with benzylchloroformate under standard conditions to yield t-butyl 3-nitrobenzylmethylcarbamate. This material is nitrosated and reduced to yield t-butyl 3-hydrzazinobenzylmethylcarbamate.
Reaction SMILES: [OH:1][CH:2]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]([C:10]2[S:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH2:5]1.S(=O)(=O)(O)O.[OH-].[Na+].[CH3:32]O>>[CH3:32][O:1][CH:2]([C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]([C:10]2[S:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH2:5]1
Reactant: CO
Reactant: COc1ccc(C(O)CN2CC=C(C3=NNC(=O)CS3)CC2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(CN2CC=C(C3=NNC(=O)CS3)CC2)OC)cc1
Temperature: 0 °C

Procedure:
2-[1-[2-Hydroxy-2-(4-methoxyphenyl)ethyl]-1,2,5,6-tetrahydropyrid-4-yl]-4H,6H-1,3,4-thiadiazin-5-one (150 mg, 0.43 mmol) was dissolved in methanol (5 ml), added with concentrated sulfuric acid (0.8 ml, 15 mmol) and refluxed with heating for four hours. The solution was poured into ice water and neutralized with 2N aqueous sodium hydroxide. The precipitated colorless crystals are filtered out and recrystallized from 60% aqueous ethanol solution to obtain the compound (110 mg) as light yellow fine needles.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][N:8](C)[C:9](=O)OCC1C=CC=CC=1.[ClH:20]>C(O)C.[Pd]>[ClH:20].[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][NH:8][CH3:9]
Reactant: CN(CC1COCCO1)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNCC1COCCO1
Reaction time: 12 h

Procedure:
Benzyl (1,4-dioxan-2-ylmethyl)methylcarbamate (Enantiomer A, 2.9 g, 10.9 mmol) was dissolved in 50 mL dry ethanol. 10% (w/w) palladium on carbon (0.29 g) and 1.0 mL 10N HCl were added. The flask was sealed and flushed with hydrogen. Stirred solution under a hydrogen balloon. After 12 hours, the solution was filtered through celite and concentrated in vacuo to afford the title compound. 1H NMR (600 MHz, D6-DMSO) 8.64 (s, 2H); 3.82-3.75 (m, 2H); 3.69 (d, 1H); 3.64 (d, 1H); 3.59 (m, 1H); 3.44 (m, 1H); 3.22 (t, 1H); 2.94-2.84 (m, 2H); 2.51 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C([O-])(=O)C.[Na+]>C(O)C>[C:2]1([NH:1][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1ccccc1
Temperature: 25 °C
Yield: 3.3 %

Procedure:
To a solution of aniline (9.7 g, 104 mmol) and ethyl bromoacetate (16.3 g, 98 mmol) in 150 mL of absolute ethanol was added solid sodium acetate (8.1 g, 99 mmol) in portions. After stirring at room temperature, the solvent was removed by rotary evaporator and the residue suspended in diethyl ether, filtered through Celite and concentrated. Chromatography of the crude residue on silica gel using 20-80 ethyl acetate-hexane as eluant gave the title compound (580 mg) as a light brown solid. The structure was supported by NMR, infrared spectroscopy, elemental analysis, and mass spectroscopy.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.Cl.[Cl:10][C:11]1[CH:36]=[CH:35][C:14]2[O:15][C:16]3[CH:34]=[CH:33][CH:32]=[CH:31][C:17]=3[C@@H:18]3[C@H:23]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:22][CH2:21][CH2:20][N:19]3[C:13]=2[CH:12]=1>CC(C)=O.C(OCC)(=O)C>[Br:1][C:36]1[C:11]([Cl:10])=[CH:12][C:13]2[N:19]3[CH2:20][CH2:21][CH2:22][C@@H:23]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[C@H:18]3[C:17]3[CH:31]=[CH:32][CH:33]=[CH:34][C:16]=3[O:15][C:14]=2[CH:35]=1
Reactant: O=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C(N[C@@H]1CCCN2c3cc(Cl)c(Br)cc3Oc3ccccc3[C@H]12)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 130.3 %

Procedure:
N-bromosuccinimide (9.2 mg, 0.05 mmol) and 0.5 μL of 1N HCl were added to trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (20 mg, 0.05 mmol) in 512 μL of acetone. The resulting mixture was stirred at room temperature for 30 min. The mixture was diluted with ethyl acetate, washed with saturated aq. sodium bicarbonate and water, dried (Na2SO4) and evaporated to give trans-N-(8-bromo-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide as a white solid (31 mg, 100%). Data: 1H-NMR (400 MHz, CDCl3) 1.85 (m, 4H), 2.27 (m, 2H), 3.20 (m, 1H), 3.64 (m, 1H), 4.44 (d, J=8.0, 1H), 4.65 (m, 1H), 6.26 (b, 1H), 7.02 (s, 1H), 7.10 (dt, J=8.0, 2.0, 1H), 7.16 (m, 2H), 7.30 (dt, J=8.0, 3.0, 1H), 7.35 (s, 1H). (m/z)=477 (M+H)+.
Reaction SMILES: [Mg].C(I)C.II.[CH2:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:26]([O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:37]=[O:38])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>O1CCCC1.CCOCC>[CH2:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:37]([C:36]1[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:34]([O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:35]=1)[OH:38])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: ClCCCCCCCCCCOCc1ccccc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCI
Solvent: CCOCC
Product: OC(CCCCCCCCCCOCc1ccccc1)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
To a mixture of 1 ml of anhydrous ether and 0.6 g of metallic magnesium were added 0.1 ml of ethyl iodide and a piece of iodine crystal followed by heating to initiate the reaction and then a mixture of 6.7 g of 10-benzyloxy-1-chlorodecane and 10 ml of anhydrous ether was added dropwise to the aforesaid mixture. After the reaction was over, the reaction mixture was refluxed for 2 hours. After cooling, the reaction mixture was added dropwise to a solution of 6 g of 3,4-dibenzyloxybenzaldehyde dissolved in 30 ml of tetrahydrofuran at 0° to 5° C. Thereafter, the mixture was stirred for 30 minutes at room temperature and after adding 300 ml of an aqueous 1% hydrochloric acid solution to the reaction mixture, the product was extracted with 100 ml of toluene. The extract was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 30 ml of ethanol, the solution was allowed to stand overnight under cooling to 0° to 5° C., and the crystals thus precipitated were collected by filtration. By drying the crystals, 5 g of 11-benzyloxy-1-(3,4-dibenzyloxyphenyl)-1-undecanol was obtained. Melting point 50°-52° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl-:9].[Cl-].[Cl-].[Al+3].ClCl>ClC(Cl)Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[Cl:9]
Reactant: Clc1ccc(Cl)nn1
Reactant: [Cl-]
Agent: ClCl
Agent: [Al+3]
Solvent: ClC(Cl)Cl
Product: Clc1cc(Cl)c(Cl)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a dry three-necked flask equipped with a refluxing condensor and a ventiduct (connected with a safety flask), 3,6-dichloropyridazine (purchased from Nanjingtianzunzezhong Chemical Agents Company) and anhydrous aluminum trichloride were added, heated by using external heat source to 120° C. to melt reactants, Cl2 gas was fed at this temperature for 3 hours, then the reaction was stopped, cooled to room temperature, trichloromethane was added to dissolve the product, the trichloromethane solution was washed with saturated sodium chloride aqueous solution for twice, the water phase was extracted with trichloromethane for twice, all trichloromethane solutions were combined together and dried over anhydrous sodium sulfate, after trichloromethane was removed by evaporation under vacuum, a reduced pressure distillation was employed to collect fraction of 110-114° C./8 mmHg or 128˜9° C./18 mmHg, a white solid was coagulated in a receiving flask. Yield: 55%, m.p. 57˜58° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[N:23]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:21][C:19]=3[N:20]=2)[C:11]([Cl:28])=[CH:10][C:9]=1[F:29])(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:7][C:8]1[C:9]([F:29])=[CH:10][C:11]([Cl:28])=[C:12]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[N:23]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:21][C:19]=3[N:20]=2)[CH:13]=1
Reactant: CC(=O)Nc1nc2cnc(Nc3cc(NC(=O)OC(C)(C)C)c(F)cc3Cl)nc2s1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2cnc(Nc3cc(N)c(F)cc3Cl)nc2s1
Yield: 74 %

Procedure:
A solution of the above-mentioned crude product of tert-butyl(5-{[2-(acetylamino)[1,3]thiazolo[5,4-d]pyrimidin-5-yl]amino}-4-chloro-2-fluorophenyl)carbamate and anisole (1 mL) in trifluoroacetic acid (15 mL) was stirred at 0° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the obtained residue, and the mixture was extracted with ethyl acetate/tetrahydrofuran mixture (1:1, 50 mL, 10 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (297 mg, 74%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.CCOC(C)=O>CO>[NH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=2)=[N:4][CH:5]=1
Reactant: CCCc1cccc(Oc2ncc([N+](=O)[O-])cc2C)c1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1cccc(Oc2ncc(N)cc2C)c1
Yield: 80.1 %

Procedure:
To a solution of 3-methyl-5-nitro-2-{[3-(2-methylethyl)phenyl]oxy}-pyridine (Intermediate 24, 279 mg, 1.03 mmol) in MeOH (20 mL) and EtOAc (20 mL) Pd/C (10%, 28 mg, 0.1 wet. e.q.) was added and the flask was evacuated and backfilled with H2. The resulting mixture was stirred at r. t. under H2 atmosphere overnight and filtered through a pad of Celite. The filtrate was concentrated in vacuo to afford the title compound (200 mg) as a grey solid.
Reaction SMILES: C1(C)C=CC(C2OC3C=CC=CC=3C=2)=CC=1.COC1C=CC(S(Cl)(=O)=O)=CC=1.C[O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([C:40]2[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[O:42][C:41]=2[C:49]2[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[OH:30][C:31]1[CH:32]=[CH:33][C:34]([S:37]([C:40]2[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[O:42][C:41]=2[C:49]2[CH:50]=[CH:51][C:52]([CH3:55])=[CH:53][CH:54]=2)(=[O:39])=[O:38])=[CH:35][CH:36]=1
Reactant: COc1ccc(S(=O)(=O)c2c(-c3ccc(C)cc3)oc3ccccc23)cc1
Agent: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(-c2cc3ccccc3o2)cc1
Product: Cc1ccc(-c2oc3ccccc3c2S(=O)(=O)c2ccc(O)cc2)cc1

Procedure:
3-(4-Hydroxyphenylsulfonyl)-2-(4-tolyl)benzofuran is prepared by acylation of 2-(4-tolyl)benzofuran with 4-methoxybenzenesulfonyl chloride followed by demethylation of the 3-(4-methoxyphenylsulfonyl)-2-(4-tolyl)benzofuran thus formed as described hereinabove.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]3[CH2:19][CH2:20][O:21][CH2:22][CH:23]=3)=[C:13](Cl)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Sn](C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2[C:15](=[CH:14][C:13]([CH3:24])=[C:12]([C:18]3[CH2:19][CH2:20][O:21][CH2:22][CH:23]=3)[CH:11]=2)[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(C3=CCOCC3)cc2C1
Reactant: C[Sn](C)(C)C
Product: Cc1cc2c(cc1C1=CCOCC1)CN(C(=O)OC(C)(C)C)C2

Procedure:
Prepared in analogy to Example A54(a) from 5-chloro-6-(3,6-dihydro-2H-pyran-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A61(a)) and tetramethystannane. White solid. MS (m/e): 260.3 ([M+H−Me2C═CH2]+, 100%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[C:14]=2[CH:28]=1)(O)=[O:8].[NH3:29]>CN(C)C=O.C(Cl)Cl>[C:7]([C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[C:14]=2[CH:28]=1)(=[O:8])[NH2:29]
Reactant: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccc(Cl)cc1Cl
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc2ccc(C(N)=O)cc2n1Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Oxalyl chloride (0.437 g) was added to a solution of 0.490 g of 6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole and 1 drop of N,N-dimethylformamide in 8 ml of methylene chloride while being cooled with ice, and the mixture was stirred at room temperature for 1.5 hours. Four milliliters of 28% aqueous ammonia were added thereto, and the solution was stirred at room temperature for 12 hours. The reaction solution was extracted with the addition of water and methylene chloride. The organic layer was concentrated, and the crystals precipitated were then collected, and were dried to give 0.240 g of 6-carbamoyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (223).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[CH:22]=O)=[O:14].C([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13](=[O:14])[NH:15][C:16]2[C:17]([CH:22]=1)=[CH:18][N:19]=[CH:20][CH:21]=2
Reactant: O=Cc1cnccc1NC(=O)Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c2ccncc2cc1-c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 79 %

Procedure:
A solution of 2-(2,6-dichloro-3-nitro-phenyl)-N-(3-formyl-pyridin-4-yl)-acetamide (5.0 g, 14.12 mmol) and Na2CO3 (2.5 g) in MeOH (300 mL) is heated for 15 minutes at 70° C. After filtration of the reaction mixture, the solvent is removed by concentration to give crude product, which is purified by flash silica gel column elute with CH2Cl2 (100%) gradient to CH2Cl2/MeOH (2N NH3) (93/7%) to give the titled intermediate as a solid (3.75 g, 77.7%).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]=1[CH3:16])C.[H-].[Na+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl>CS(C)=O.O>[F:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[C:7]([CH3:16])=[C:6]2[CH2:5][C:4]([OH:3])=[O:17]
Reactant: O=S(=O)(c1ccc(CBr)cc1)N1CCOCC1
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(F)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(CC(=O)O)c2cc(F)ccc2n1Cc1ccc(S(=O)(=O)N2CCOCC2)cc1

Procedure:
To a stirring suspension of (5-fluoro-2-methyl-1H-indol-3-yl)-acetic acid ethyl ester (100 mg, 0.43 mmol) in dry DMSO (1 ml), is added NaH (29 mg, 0.73 mmol). The reaction mixture is stirred at room temperature for 15 min after which time 4-(4-bromomethyl-benzenesulfonyl)-morpholine (136 mg, 0.43 mmol) is added. The reaction mixture is diluted with water (2 ml) and treated with 1N HCl aq to acidic pH. The crude reaction mixture is purified by reverse phase chromatography on a C18 Isolute™ cartridge (70 g) eluting in 0-100% MeCN in water using a FlashMaster Personal™ and GradMaster™; [M+H]+ 448.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][NH:13][CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][N:13]([C:26](=[O:27])[C:25]4[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=4)[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccc(F)cc21
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccc(F)cc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 by using ethyl 9-fluoro-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and 4-fluorobenzoyl chloride; 1H-NMR (CDCl3): δ 10.57 (1H, br s), 8.04 (1H, s), 7.62 (2H, dd), 7.29 (1H, m), 7.16 (3H, m), 6.95 (1H, m), 4.24 (4H, m), 3.20 (2H, m), 1.22 (3H, t); MS (ES): 397 (MH+).
Reaction SMILES: [BH4-].[Na+].[I-].[CH3:4][O:5][C:6]1[CH:7]=[N+:8]([CH3:25])[CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([O:21][CH:22]([CH3:24])[CH3:23])[CH:13]=1.O.C(OCC)(=O)C>C(O)C>[CH3:4][O:5][C:6]1[CH2:7][N:8]([CH3:25])[CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([O:21][CH:22]([CH3:24])[CH3:23])[CH:13]=1
Reactant: COc1c[n+](C)ccc1-c1ccc([N+](=O)[O-])c(OC(C)C)c1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COC1=C(c2ccc([N+](=O)[O-])c(OC(C)C)c2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
672 mg of NaBH4 are added, in portions, to a suspension of 5.09 g of 3-methoxy-1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridinium iodide in 90 ml of ethanol brought to 5° C. the reaction medium is stirred for 30 minutes at ambient temperature. 50 ml of water and 100 ml of ethyl acetate are added. The two phases are separated, and the aqueous phase is washed with twice 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated. Purification is carried out by flash chromatography on silica gel (40-63 μm), elution being carried out with a mixture of dichloromethane and acetone (95/5 to 80/20). 2.78 g of 5-methoxy-1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]-1,2,3,6-tetrahydropyridine are obtained in the form of a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].C[Al](C)C.C[O:20][C:21](=O)/[CH:22]=[C:23](\[NH:25][C:26](=O)[CH2:27][S:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)/[CH3:24]>C(Cl)Cl>[F:35][C:31]1[CH:30]=[C:29]([S:28][CH2:27][C:26]2[N:5]([C:4]3[CH:6]=[CH:7][C:8]([N:9]4[CH2:14][CH2:13][O:12][CH2:11][CH2:10]4)=[C:2]([F:1])[CH:3]=3)[C:21](=[O:20])[CH:22]=[C:23]([CH3:24])[N:25]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(=O)CSc1cccc(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(F)c2)c(CSc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
To a solution of 3-fluoro-4-morpholinoaniline (0.54 g, 2.75 mmol) in DCM (15 mL) was added trimethylaluminium (4.8 mL, 9.60 mmol, 2 M in toluene) and the mixture was stirred at rt for 0.5 h. A solution of (Z)-methyl-3-(2-((3-fluorophenyl)thio)acetamido)but-2-enoate (0.78 g, 2.75 mmol) in DCM (5 mL) was added slowly and the resulting mixture was stirred at rt for 12 h. The mixture was quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a pale brown solid (0.79 g, 67%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C[CH:2]([C@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5]([OH:7])=[O:6])C.C(N1CCC[C@H]1C(O)=O)(OCC1C=CC=CC=1)=O>CCO.[Pd]>[CH3:2][C@H:4]([NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[C:5]([OH:7])=[O:6]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [Pd]
Agent: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CCO
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 8 h

Procedure:
Substantially the same procedure as described above was repeated except that N-t-BOC-L-valine (→P8) was used in place of the L-phenylalanine derivative. When N-CBZ-L-proline was used as starting material the deprotection was done by overnight hydrogenation with H2, 10% Pd/C in EtOH (→P9). In case of N-t-BOC-L-alanine the free amine was obtained after evaporation of the solvents and stirring the residue with saturated NaHCO3 solution (→P10).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[N:8]([C:13](=O)[CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]>O1CCCC1>[N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[N:8]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(CN1CCCC1)N1CCCOc2cc([N+](=O)[O-])ccc21
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)OCCCN2CCN1CCCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
1.00 M of Borane-THF complex in Tetrahydrofuran (10.0 mL; Acros) was added to 1-(3-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-2-pyrrolidin-1-yl-ethanone (0.401 g, 1.31 mmol) in Tetrahydrofuran (10 mL). The mixture was heated at 60° C. under an atmosphere of Nitrogen. overnight. The mixture was quenched with 1N HCl (5 mL) and stirred for 1 h at 60° C. The solution was neutralized by pouring into satd. sodium bicarbonate and extracted with DCM (3×). The extract was dried and conc. in vacuo to give 3-Nitro-9-(2-pyrrolidin-1-yl-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene as an oil (270 mg, 70%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:27])[CH2:7][N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:10]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[C:9]1=[O:26])C>C1COCC1>[O:26]=[C:9]1[N:8]([CH2:7][C:6]([OH:27])=[O:5])[C:12](=[O:13])[C:11]2([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[N:10]1[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1
Reactant: CCOC(=O)CN1C(=O)N(c2ccc(C)cc2)C2(CCCCC2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(N2C(=O)N(CC(=O)O)C(=O)C23CCCCC3)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
172 ml (0.172 mol; 1.5 eq.) of 1N sodium hydroxide are added to a solution of 39.5 g (0.114 mol; 1 eq.) of (2,4-dioxo-1-p-tolyl-1,3-diazaspiro[4.5]dec-3-yl)acetic acid ethyl ester in 400 ml of THF. The reaction medium is stirred at room temperature for about 72 hours. The reaction medium is concentrated and 250 ml of ethyl acetate are added, followed by 400 ml of water. 100 ml of 1N NaOH are added and the aqueous solution is washed with 250 ml of ethyl acetate. The aqueous phase is concentrated and then acidified to pH 4 approximately with 170 ml of 1N acetic acid. The white precipitate is filtered off and then rinsed with water until the pH of the filtrates is approximately equal to 7, and dried in an oven under vacuum at 40° C. The product (2,4-dioxo-1-p-tolyl-1,3-diazaspiro[4.5]dec-3-yl)acetic acid is obtained in the form of a white solid.