Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2=[O:23])[C@H:15]2[C@H:6]1[C@@H:7]1[C:12]([CH2:13][C@H:14]2[CH3:24])=[CH:11][C:10](=[O:25])[CH2:9][CH2:8]1)(=O)C.[OH-].[K+]>O>[OH:4][C@@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2=[O:23])[C@H:15]2[C@H:6]1[C@@H:7]1[C:12]([CH2:13][C@H:14]2[CH3:24])=[CH:11][C:10](=[O:25])[CH2:9][CH2:8]1
Reactant: CC(=O)O[C@@H]1C[C@]2(C)C(=O)CC[C@H]2[C@H]2[C@H]1[C@H]1CCC(=O)C=C1C[C@H]2C
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@H]2O
Yield: 100 %

Procedure:
A solution of 1 g of 11α-acetoxy-7α-methyl-estr-4-ene-3,17-dione (E) in 20 ml of a 0.2 molar methanolic potassium hydroxide solution was stirred at room temperature for 3 hours. Then, it was added to water, extracted three times with ethyl acetate, washed neutral, dried on sodium sulfate, concentrated by evaporation in a vacuum and recrystallized from diethyl ether/acetone. 878 mg of pure 11α-hydroxy-7α-methyl-estr-4-ene-3,17-dione (F) with a melting point of 202.3° C. was obtained ([α]D20=+44.8° (c=0.5% in chloroform)).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([CH3:12])([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:5].[ClH:14]>CO.O.[Pt](=O)=O>[ClH:14].[CH3:1][O:2][C:3](=[O:13])[C:4]([CH3:5])([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)[CH3:12]
Reactant: COC(=O)C(C)(C)c1cccnc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)C(C)(C)C1CCCNC1
Reaction time: 5.5 h

Procedure:
A mixture of 0.823 g of 2-methyl-2-pyridin-3-yl-propionic acid methyl ester [476429-23-9] and 0.062 g of platinum(IV) oxide hydrate in 8 ml of methanol and 1.7 ml of 1.2M HCl in methanol at room temperature is hydrogenated for 5.5 hours. The catalyst is removed by filtration over Hyflo and the filtrate is concentrated by evaporation to provide the crude title compound as a brown oil which is used in the next step without further purification.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][CH2:19][O:20][CH2:21][C:22](O)=[O:23])[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:55]1([N:58]2[CH2:63][CH2:62][N:61]([C:64]3([CH2:70][N:71]4[CH2:79][C:78]5[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=5)[C:72]4=[O:80])[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]3)[CH2:60][CH2:59]2)[CH2:57][CH2:56]1>ClCCl>[CH:1]1([N:4]([CH2:18][CH2:19][O:20][CH2:21][C:22]([N:67]2[CH2:66][CH2:65][C:64]([N:61]3[CH2:62][CH2:63][N:58]([CH:55]4[CH2:56][CH2:57]4)[CH2:59][CH2:60]3)([CH2:70][N:71]3[CH2:79][C:78]4[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=4)[C:72]3=[O:80])[CH2:69][CH2:68]2)=[O:23])[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: O=C1c2ccccc2CN1CC1(N2CCN(C3CC3)CC2)CCNCC1
Reactant: COc1cc(C)c(S(=O)(=O)N(CCOCC(=O)O)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(CCOCC(=O)N2CCC(CN3Cc4ccccc4C3=O)(N3CCN(C4CC4)CC3)CC2)C2CC2)c(C)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a solution of 2-(2-(N-cyclopropyl-4-methoxy-2,6-dimethylphenyl-sulfonamido)ethoxy)acetic acid AC7 (0.306 mmol) in dichloromethane (10 ml/mmol) was added diisopropyl ethylamine (4.0 equiv.) at 0° C. followed by the addition of HOBT (1.0 equiv.) and EDCI (1.5 equiv.). The resultant solution was stirred at 25° C. for 15 min. It was again cooled to 0° C. and a solution of 2-((4-(4-cyclopropylpiperazin-1-yl)piperidin-4-yl)methyl)isoindolin-1-one AM13 (1.2 equiv) in dichloromethane (2 ml) was added. The reaction mixture was stirred for 16 h at 25° C. The mixture was diluted with dichloromethane, washed with saturated ammonium chloride solution, brine, saturated sodium bicarbonate and finally again with brine. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give the crude product which was purified by column chromatography. Yield: 50%. MS, Rt=3.4 min, m/z=694.5 [MH]+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:9]O)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].P(Br)(Br)[Br:12]>C1COCC1>[Br:12][CH2:9][C:3]1[C:2]([F:1])=[C:7]([CH3:8])[CH:6]=[CH:5][N:4]=1
Reactant: Cc1ccnc(CO)c1F
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: Cc1ccnc(CBr)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.6 %

Procedure:
Intermediate 6 ((3-fluoro-4-methyl-2-pyridinyl)methanol, 246 mg, 1.743 mmol) was dissolved in 10 mL of anhydrous THF. Phosphorous tribromide (ALDRICH, 519 mg, 1.917 mmol) was added. Reaction mixture was stirred at room temperature overnight. Solvent was evaporated and residue was partitioned between Et2O and NaHCO3 (aqueous saturated solution). Organic layer was dried over MgSO4 (anh), filtered and concentrated to give the title compound (372 mg, quantitative yield). 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.23-8.24 (m, 1H), 7.34-7.37 (m, 1H), 4.66 (s, 2H), 2.28 (s, 3H). [ES+MS] m/z 204 (M).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:33][CH3:34]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)([CH2:33][CH3:34])[C:19]([O:21][CH3:22])=[O:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 2b (10.0 g, 24.1 mmol) in DMF (20 mL) was added via syringe pump (1.6 mL/min) to a stirred suspension of sodium hydride (964 mg of a 60% wt/wt dispersion in mineral oil, 24.1 mmol) in DMF (60 mL) at 0° C. After 15 min, iodoethane (2.34 mL, 28.9 mmol) was added rapidly dropwise, and the resulting mixture was stirred at 0° C. for 2 h. The reaction was quenched by addition of saturated aqueous ammonium chloride and extracted with ether. The combined organics were washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting crude oil was purified by flash chromatography on silica gel (gradient elution; 0%-20% EtOAc/hexanes as eluent) to afford the title compound 3a. m/z (ES) 465 (MNa)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[C:10]1([CH3:22])[CH:15]=[CH:14][C:13]([S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17])=[CH:12][CH:11]=1>C1C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH:5]([C:20](=[O:21])[NH:19][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:22])=[CH:11][CH:12]=2)(=[O:17])=[O:18])[C:4](=[O:9])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CC1CC(=O)CC(=O)C1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)C2C(=O)CC(C)CC2=O)cc1

Procedure:
Reaction of equimolar amounts of 5-methyl-1,3-cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-METHYL-2-(N-p-TOLUENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 121.5°-122.5° C. (corr.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]([C:17](=[O:19])[NH2:18])[N:14]([CH2:20][CH2:21][CH2:22][C:23](OC(C)(C)C)=[O:24])[C:13](=[O:30])[C@@H:12]1[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH2:34]1[C:36]2([CH2:41][CH2:40][NH:39][CH2:38][C@H:37]2[OH:42])[CH2:35]1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([C:17](=[O:19])[NH2:18])[N:14]([CH2:20][CH2:21][CH2:22][C:23]([N:39]2[CH2:40][CH2:41][C:36]3([CH2:34][CH2:35]3)[C@H:37]([OH:42])[CH2:38]2)=[O:24])[C:13](=[O:30])[C@@H:12]1[CH3:31])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1C(=O)N(CCCC(=O)OC(C)(C)C)C(C(N)=O)CN1C(=O)OCc1ccccc1
Reactant: O[C@@H]1CNCCC12CC2
Agent: Cl
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)[C@@H](C(N)=O)CN1C(=O)OCc1ccccc1
Yield: 22 %

Procedure:
In analogy to the procedure described in example 120 step D, (2S,5RS)-4-(3-tert-butoxycarbonyl-propyl)-5-carbamoyl-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester was first hydrolysed with HCl and then coupled with (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2). The two diasterioisomers could be separated by flash column chromatography (SiO2, EtOAc/MeOH 1:0-9:1) affording first (2S,5R)-5-carbamoyl-4-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester in 22% yield as an amorphous white solid, MS: 487.30 (MH+) and then (2S,5S)-5-carbamoyl-4-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester in 20% yield as a colorless foam MS: 487.30 (MH+).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:29][C:21]3=[N:22][CH:23]=[C:24](CC#N)[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]([OH:33])(=[O:32])[CH3:31]>Cl>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:29][C:21]3=[N:22][CH:23]=[C:24]([CH2:31][C:30]([OH:33])=[O:32])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CC#N)cnc3[nH]2)cc1
Reactant: CC(=O)O
Agent: Cl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CC(=O)O)cnc3[nH]2)cc1

Procedure:
A mixture of {2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-acetonitrile (as prepared in Example 38, 140 mg, 0.34 mmol) in 36% hydrochloric acid (1 mL) and acetic acid (5 mL) was refluxed for 2 h. The mixture was concentrated in vacuo, extracted with ethyl acetate (250 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford {2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-acetic acid (150 mg, quant.) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C23H2N2O4S [M+H]+ 427.54, observed 427.0.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][C:7](O)=[O:8])[C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2.[Li].C(O)C>O1CCCC1>[S:1]1[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2
Reactant: O=C(O)Cc1csc2ccccc12
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCO
Product: OCCc1csc2ccccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of benzo[b]thiophen-3-yl-acetic acid (6.0 g, 31.2 mmol) in 40 ml of tetrahydrofuran was added dropwise at RT to a suspension of lithium alanate (1.54 g, 41 mmol) in 35 ml of tetrahydrofuran. The mixture was stirred for 60 minutes at 60° C., and then excess alanate was hydrolysed with ethanol. The mixture was suction-filtered over Kieselguhr and the solvent was removed in vacuo. The product was obtained in the form of a yellowish oil in a yield of 5.1 g (92%).
Reaction SMILES: C(OP(=O)(OCC)O[CH2:6]/[CH:7]=[CH:8]/[C:9](=[O:16])[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)C.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:24]=1[CH:25]=O.CC(C)([O-])C.[K+]>C1COCC1>[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:24]=1/[CH:25]=[CH:6]/[CH:7]=[CH:8]/[C:9]([N:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)=[O:16]
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: CCOP(=O)(OCC)OC/C=C/C(=O)N1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(OC)c(/C=C/C=C/C(=O)N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.4 %

Procedure:
(E)-diethyl 4-oxo-4-(piperidin-1-yl)but-2-enylphosphoric acid (50 mg, 0.17 mmol) and 2,5-dimethoxybenzaldehyde (28.4 mg, 0.17 mmol) were dissolved in THF (1.5 mL) at −10° C., and then potassium tert-butoxide (0.51 mL, 0.51 mmol) was added thereto, followed by stirring at the same temperature for 20 minutes under anhydrous reaction conditions. The temperature of the mixture was raised to room temperature, and the reaction was terminated by the addition of distilled water. After EtOAc was added, the oil layer was separated, followed by washing with distilled water and a saturated solution of NaCl, drying over anhydrous Na2SO4, and then filtering. The filtrate was distilled under reduced pressure, and the thus obtained residue was purified by column chromatography (hexane:EtOAc (2:1)) to give a target compound (40.7 mg, yield: 78.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([CH2:12][NH2:13])[O:8][C:7]=2[CH:14]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([CH2:12][NH:13][C:15](=[O:17])[CH3:16])[O:8][C:7]=2[CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)OC(CN)=CO2
Solvent: c1ccncc1
Product: COc1ccc2c(c1)OC(CNC(C)=O)=CO2
Temperature: 0 °C

Procedure:
The crude amine obtained in Step C is dissolved in 10 ml of anhydrous pyridine; the mixture is then cooled to 0° C. 0.41 g (4 mmol) of acetic anhydride is added to that solution; stirring is then maintained for 30 minutes. The solvent is then evaporated in vacuo; the residue is then taken up in dichloromethane. The organic phase is then acidified with a hydrochloric acid solution (1N); the aqueous phase is then extracted with dichloromethane. After during over magnesium sulphate and evaporation of the solvent in vacuo, the title amide is obtained pure in the form of a white solid after passage over a silica column (eluant: MeOH/CH2Cl2: 10/90).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[CH2:10]([N:17]([CH2:21][Si](C)(C)C)[CH2:18]OC)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:10]([N:17]1[CH2:18][CH2:7][C:3]([C:2]([F:9])([F:8])[F:1])([C:4]([OH:6])=[O:5])[CH2:21]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1(C(F)(F)F)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
2-(Trifluoromethyl)acrylic acid (2.48 g, 20 mmol) was dissolved in 30 mL of dry methylene chloride, a solution of 4.75 g (20 mmol) of N-benzyl-N-(methoxymethyl)-trimethylsilylmethylamine in 20 mL of dry methylene chloride was added dropwise under N2 at 0° C. To this solution was added 2 mL of TFA, and the solution was stirred for 2 hours at room temperature. The white precipitate was collected, washed and dried to give 3.22 g of the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[C:4]([CH:6]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:15][C:14]=2[F:27])[CH2:9][CH2:8]1)=[O:5])[CH3:2].[H-].[Na+].[CH3:38]I>CN(C=O)C.O>[CH2:34]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[N:7]1[CH2:8][CH2:9][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:38])[C:20](=[O:26])[CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:15][C:14]=2[F:27])[CH2:11][CH2:12]1)=[O:5])[CH3:35]
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)C(=O)N(C)c1ccc(N2CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(F)c1
Reaction time: 0.17 h
Yield: 50.3 %

Procedure:
A solution of N-{4-[4-(diethylcarbamoyl-phenyl-methyl)-piperazin-1-yl]-3-fluoro-phenyl}-2-ethyl-butyramide (48 mg, 0.10 mmol) in DMF (2 mL) was treated with NaH (60% in mineral oil; 5 mg, 0.12 mmol). After 10 min, MeI (7 μL, 0.12 mmol) was added. After 3 h, the mixture was diluted with water and extracted with DCM. The organic layer was concentrated to give an oil, which was purified by PTLC to give an off white solid (25 mg, 50%). MS (ESI): mass calcd. for C29H41FN4O2, 496.96. m/z found, 497.5 [M+H]+. 1H NMR (CDCl3): 7.49-7.46 (m, 2H), 7.40-7.32 (m, 3H), 6.93-6.89 (m, 1H), 6.87-6.81 (m, 2H), 4.37 (s, 1H), 3.51-3.47 (m, 1H), 3.45-3.40 (m, 1H), 3.33-3.25 (m, 1H), 3.24 (s, 3H), 3.19-3.16 (m, 5H), 2.75-2.70 (m, 4H), 2.23-2.19 (m, 1H), 1.63-1.56 (m, 2H), 1.41-1.33 (m, 2H), 1.12-1.05 (m, 6H), 0.81 (t, J=7.4, 6H).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:44])[O:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][N:16]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[S:17]([NH:20][C:21](=[O:36])[C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)(=[O:19])=[O:18])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH3:4].[CH3:45]C(N)CCC.C(N)CCC>>[CH3:45][CH:1]([NH:5][C:6](=[O:44])[O:7][CH2:8][CH:9]1[CH2:10][CH2:11][CH:12]([CH2:15][N:16]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[S:17]([NH:20][C:21](=[O:36])[C:22]2[CH:23]=[C:24]([C:32]([F:35])([F:33])[F:34])[CH:25]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:27]=2)(=[O:18])=[O:19])[CH2:13][CH2:14]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)OCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reactant: CCCC(C)N
Solvent: CCCCN
Product: CCCC(C)NC(=O)OCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1

Procedure:
Following the procedure to make (13), 1-methylbutyl amine was substituted for butyl amine to give the title compound after purification. 1H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 2H), 8.12 (s, 1H), 7.37 (d, 2H), 7.24 (t, 2H), 7.17 (t, 1H), 6.79 (d, 1H), 4.35 (s, 2H), 3.60 (d, 2H), 3.41 (m, 1H), 3.30 (water), 2.89 (d, 2H), 2.48 (DMSO), 1.62 (m, 2H), 1.55 (m, 2H), 1.34-1.19 (m, 6H), 0.96 (d, 3H), 0.80 (t, 3H), 0.62 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:13]=2[CH:12]=1.II.[Br:43]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:40])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([Br:43])=[CH:18][CH:19]=3)[C:14]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:13]=2[CH:12]=1
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(-c3ccc(Br)cc3C(=O)OC)cc21
Reactant: BrBr
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc(-c3ccc(Br)cc3C(=O)OC)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
40 g (66 mmol) 15 is dissolved in 300 ml dichloromethane. The solution is cooled to 0° C., 1 g iodine is added and the mixture is stirred for 30 min. Then a solution of 11 g bromine in dichloromethane is slowly added by a dropping funnel. The solution is heated to reflux until the reaction is completed The reaction mixture is allowed to warm up to room temperature and of a 200 ml saturated Na2S2O3 solution is added. The organic layer is separated and the aqueous layer is extracted with dichloromethane. The unified organic layers are washed twice with 100 ml water dried over sodium sulfate, filtrated and the solvent is removed under vacuum. The residue is recystallisated from butanole to result white solid (38 g 55.6 mmol, yield: 84%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:34])[C@@H:5]1[CH2:12][N:11]2[C:13]3[CH:14]=[C:15]([C:26]([O:28][CH3:29])=[O:27])[CH:16]=[CH:17][C:18]=3[C:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:10]2[C:9]2[CH:30]=[CH:31][CH:32]=[CH:33][C:8]=2[O:7][CH2:6]1.[CH:35](OCC(F)(F)F)=O>C1COCC1>[CH:20]1([C:19]2[C:18]3[CH:17]=[CH:16][C:15]([C:26]([O:28][CH3:29])=[O:27])=[CH:14][C:13]=3[N:11]3[C:10]=2[C:9]2[CH:30]=[CH:31][CH:32]=[CH:33][C:8]=2[O:7][CH2:6][C@H:5]([N:4]([CH3:34])[CH2:3][CH2:2][NH:1][CH3:35])[CH2:12]3)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=COCC(F)(F)F
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCN)COc1ccccc1-3
Solvent: C1CCOC1
Product: CNCCN(C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A solution (0.1 M) of methyl(7R)-7-[(2-aminoethyl)(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate in THF was treated dropwise with 2,2,2-trifluoroethyl formate (1.5 eq.) and stirred overnight at RT. The volatiles were removed in vacuo and the residue dissolved (0.1 M) in THF and treated dropwise with BH3-DMS complex (2M in THF; 5 eq.). The resulting solution was stirred at RT for 3 h. The reaction was quenched by the careful addition of HCl/MeOH (1.25 M) and the resulting solution heated to dryness. The residue was then partitioned between sat. aq. NaHCO3 and EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified by FC (EtOAc/MeOH 99.5:0.5+1% NEt3) to afford the product (40%). (ES+) m/z 476 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCCC2)cc1
Solvent: CCO
Product: Nc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 42.5 %

Procedure:
In ethanol (100 ml) was dissolved 1—(4-nitrobenzyl)-pyrrolidine (23.5 g), and to the mixture was added dried 10% palladium on carbon (1.00 g). Under hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 20 hours. The palladium was filtered off, and the filtrate was concentrated. The residue was separated and purified with column chromatography (ethyl acetate/triethylamine=10/1) to give 1—(4-aminobenzyl)pyrrolidine (8.54 g) as orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].Br.[Br:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20]Br.C(=O)([O-])[O-].[Na+].[Na+]>CO>[BrH:15].[CH3:13][O:12][C:8]1[CH:7]=[C:5]([N:6]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11]
Reactant: BrCCNCCBr
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(N2CCNCC2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
18.3 Grams of 3,4,5-trimethoxyaniline and 31.2 g of bis(β-bromoethyl)amine monohydrobromide are mixed with 170 ml of methanol and refluxed by heating under a nitrogen gas stream for 10 hours. After cooling the reaction mixture, 5.3 g of anhydrous sodium carbonate are added to the mixture and refluxed by heating for and additional 10 hours. Under reduced pressure, about 70 ml of methanol are removed off by distillation, and the mixture is allowed to stand to cool at room temperature. The crystals thus precipitated are collected by filtration and washed with a small amount of ethanol. Recrystallization from ethanol obtains 38 g of 4-(3,4,5-trimethoxyphenyl)piperazine monohydrobromide in the form of colorless plate-like crystals with a melting point of 227°-228° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21](Br)([F:23])[F:22].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[F:22][C:21]([F:23])=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: FC(F)(Br)Br
Reactant: O=Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)=Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
5.25 g (0.02 mol) of triphenyl phosphine was dissolved in 20 ml of dichloromethane, and the mixture was cooled to 0° C. 2.1 g (0.01 mol) of dibromodifluoromethane was added to the mixture using an injector, and the reaction mixture was stirred for 30 minutes at room temperature. 1.06 g (0.01 mol) of benzaldehyde was added thereto and the mixture was refluxed for 4 hours. The resulting mixture was distilled under a reduced pressure at 40° C./1 mmHg using a distilling apparatus to obtain the title compound (0.81 g, 57.5%).