Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.C[C@@:5]12[C@H:14]3[CH2:15][CH2:16][C@:17]4(C)[C:21]([C:22]5[CH:23]=[CH:24]C=NC=5)=C[CH2:19][C@H:18]4[C@@H:13]3[CH2:12][CH:11]=[C:10]1[CH2:9][C@@H:8]([OH:29])[CH2:7][CH2:6]2.C[OH:31]>>[CH3:9][C@@:10]12[C:8](=[O:29])[CH2:7][CH2:6][C@H:5]1[C@@H:14]1[CH2:15][CH:16]=[C:17]3[CH2:21][C@@H:22]([OH:31])[CH2:23][CH2:24][C@:18]3([CH3:19])[C@H:13]1[CH2:12][CH2:11]2
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Reactant: CO
Solvent: ClCCl
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 42.5 °C

Procedure:
34.8 ml of CH2Cl2 and 26.1 ml of methanol were added to 8.7 g (24.9 mmol) of crude stage 3 (abiraterone). The mixture was heated to 40-45° C. (reflux), to have a solution. The CH2Cl2 was then removed by distillation at atmospheric pressure. The mixture was cooled to 0-5° C., and then maintained 1 hour at 0-5° C. The suspension was filtered (fast filtration) and the cake was washed twice with 4.4 ml of methanol cooled to 0-5° C. The wet solid was dried at 40-45° C. under vacuum for 5 hours to give 7.2 g (yield of purification 82.8%) of pure stage 3 (abiraterone). The overall yield from DHEA was around 50%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[K].[CH:16](=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19]>O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[O:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[CH:16]=[O:24])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: O=Cc1ccccc1O
Agent: [K]
Solvent: O
Product: O=Cc1ccccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
200 parts of 4-chloro-3-nitrobenzotrifluoride was heated to 160° C. and stirred and 160 parts of the potassium salt of salicylaldehyde was added over a period of 30 minutes. After the addition was complete, an exothermic reaction took place and the temperature rose to about 195° C. Heating was then discontinued until the reaction subsided, and the mixture was then heated for 1 hour at 150° C. The mixture was cooled, ice and water were added, and it was then extracted with ether. The ether layer was filtered to remove insoluble material, and the resultant solution was dried over sodium sulfate. The ether solvent was then evaporated and the residual oil was recrystallized from a mixture of hexane and benzene to give 2-(2-nitro-4-trifluoromethylphenoxy)benzaldehyde melting at about 79°-81° C.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1(=[C:14]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]C(C)(C)C)=[O:24])=[C:17]([CH3:30])[CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[C:8]1(=[C:14]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[C:17]([CH3:30])[CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Cc1cc(C(=C2CCCCC2)c2ccc(O)cc2)ccc1/C=C/C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=C2CCCCC2)c2ccc(O)cc2)ccc1/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
Trifluoroacetic acid (2.0 mL) was added dropwise to 68 (210 mg, 0.519 mmol) dissolved in CH2Cl2 (2 mL) at 0° C. The reaction mixture was stirred at RT for 3 h and the volatiles were removed under reduced pressure. The residue was chromatographed on silica gel (20:1 CH2Cl2:MeOH) and recrystallized (EtOAc:hexanes) to afford 138 mg (76%) of 69 as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.51 (br s, 6H), 2.13 (m, 4H), 2.30 (s, 3H), 6.35 (d, J=16.0 Hz, 1H), 6.66 (d, J=8.2 Hz, 2H), 6.82-6.91 (m, 4H), 7.59 (d, J=7.9 Hz, 1H), 7.75 (d, J=16.0 Hz, 1H), 9.31 (s, 1H), 12.36 (br s, 1H). LRMS (ESI): m/z 349 (M+H)+.
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.[CH2:6]([O:13][CH2:14][CH2:15][CH2:16]CO)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:2][Br:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCCCCOCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCOCc1ccccc1
Temperature: -15 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
239 g of tetrabromomethane are added in portions to the solution of 105 g of 4-benzyloxybutan-1-ol and 191 g of triphenylphosphine in 1 l of methylene chloride cooled to −15° C. and the mixture is stirred at 0° C. for 1 h after addition is complete. After the reaction mixture has been concentrated in vacuo, purification is carried out by chromatography on silica gel using a hexane-ethyl acetate gradient. 133 g of 4-benzyloxy-1-bromobutane are obtained as an oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([F:17])([F:16])[F:15])[CH2:9]1)C1C=CC=CC=1>C(O)(=O)C.O.[Pd]>[F:15][C:14]([F:17])([F:16])[CH:10]1[CH2:9][NH:8][CH2:13][CH2:12][NH:11]1
Reactant: FC(F)(F)C1CN(Cc2ccccc2)CCN1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)C1CNCCN1

Procedure:
1-Benzyl-3-(trifluoromethyl)piperazine (0.74 g, 3.0 mmol; Intermediate 44) was dissolved in acetic acid (70 mL) and water (5 mL). Pd, 5% on carbon, (0.074 g) was added and =hydrogenation was performed at 3 bar and 70° C. overnight. The reaction mixture was filtered through Celite and the pad was rinsed with water (5 mL). Solvents were removed in vacuo, toluene (20 mL) added to the residue, followed by re-concentration in vacuo to remove residual water. The desired product sublimated on the evaporator and 0.15 g (32%) was collected as a white powder. 1H NMR (270 MHz, methanol-d4) δ ppm 2.67-2.87 (m, 3H) 2.91-3.05 (m, 2H) 3.12-3.21 (m, 1H). MS (ESI+) m/z 155. *Previously described in Rec. Trav. Chim. Pays-Bas 1995, 114, 97-102.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:16]=[C:15]([CH3:17])[NH:14][C:13]=1[CH:18]=O>N1CCCCC1.C(O)C>[CH3:17][C:15]1[NH:14][C:13]([CH:18]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[C:12]([CH3:11])[CH:16]=1
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C)c(C=C2C(=O)Nc3ccccc32)[nH]1
Temperature: 90 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
A reaction mixture of 134.0 mg of oxindole, 147.8 mg of the 3,5-dimethylpyrrole-2-carboxaldehyde, and 3 drops of piperidine in 2 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 136.7 mg (57%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[N+:18]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N

Procedure:
The title compound was prepared from (2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A4) (30.0 g, 98 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a light yellow solid (26.5 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH:27]=[CH2:28])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-:29].[Na+].OO>C1COCC1.C(OCC)C>[Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH2:27][CH2:28][OH:29])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:17])([CH3:18])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: OO
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Reaction time: 5 h
Yield: 72 %

Procedure:
A solution of (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (26 g, 63 mmol) in THF (200 mL) was cooled in an ice-bath, followed by dropwise addition of 10 M BH3SMe2 (6.3 mL). After stirring for 5 hr, 10% NaOH solution (32 mL) followed by 30% H2O2 (32 mL) were added carefully. The reaction mixture was stirred at rt for 16 hr. The reaction mixture was diluted with diethyl ether (500 mL) and the aqueous layer was extracted with diethyl ether (3×250 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by column chromatography to afford (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxypentyl)-2,2-dimethyloxazolidine-3-carboxylate (19.6 g, 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]([C:14]#[N:15])=[C:6]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N>C(O)C.CO.[Ni]>[NH2:15][CH2:14][C:7]1[NH:8][C:9](=[O:13])[C:10]2[C:5]([C:6]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: COc1ccc2c(=O)[nH]c(C#N)c(-c3ccccc3)c2c1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: CCO
Product: COc1ccc2c(=O)[nH]c(CN)c(-c3ccccc3)c2c1
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a solution of 6-methoxy-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile (200 mg) in 40 mL ethanol were added Raney Ni and 4 mL of 2 M ammonia in methanol. The reaction was shaken under 50 psi H2 pressure overnight. The reaction was filtered and concentrated to give 178 mg of 3-(aminomethyl)-6-methoxy-4-phenylisoquinolin-1(2H)-one.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.CN(C)C=O>CCCCCC>[Si:14]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(O[Si](C)(C)C(C)(C)C)c1

Procedure:
A mixture of methyl 3-hydroxy-4-methoxybenzoate (120 mg, 0.66 mmol, prepared in Step 1, above), tert-butyldimethylsilyl chloride: (109 mg, 0.72 mmol), imidazole (98 mg, 1.24 mmol) and dimethylformamide (DMF, 2 ml) was stirred at room temperature over night. Extractive workup with hexane gave 90 mg of methyl 3-tert-butyldimethylsilyloxy-4-methoxybenzoate. NMR(δ): 0.18 (s, 3H), 1.00 (s, 9H),3.88 (s, 3H), 3.89 (s, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]2[N:7]([CH:11]=[C:12]([CH3:14])[N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Br:15]N1C(=O)CCC1=O>C(O)C.C(OCC)(=O)C>[C:1]([O:4][C:5]1[C:6]2[N:7]([C:11]([Br:15])=[C:12]([CH3:14])[N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1cccn2cc(C)nc12
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cccn2c(Br)c(C)nc12
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of 8-acetoxy-2-methylimidazo[1,2-a]pyridine (100 mg) in ethanol (1 ml) was added N-bromosuccinimide (103 mg) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature. The mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (ethyl acetate) to give 8-acetoxy-3-bromo-2-methylimidazo[1,2-a]pyridine (123 mg) as oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc(NC2CCN(Cc3ccccc3)CC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/c1ccc(NC2CCN(Cc3ccccc3)CC2)nc1
Temperature: 67.5 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A mixture of ethyl (2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}acrylate (470 mg) and 1N NaOH solution (2.6 ml) in MeOH (15 ml) was stirred at 65-70° C. for 2 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved with AcOEt and H2O. The aqueous solution was adjusted to PH6.0 with aq.HCl and evaporated in vacuo. The residue was chromatographed on silicagel eluting with AcOEt-MeOH (85:15). The eluted fractions containing the desired product were collected and evaporated in vacuo to give (2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}acrylic acid (430 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][C:12]#[N:13])[C:9]=1[Cl:10])=[O:4].B.C1COCC1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][CH2:12][NH2:13])[C:9]=1[Cl:10])=[O:4]
Reactant: COC(=O)c1scc(CC#N)c1Cl
Agent: B
Solvent: C1CCOC1
Product: COC(=O)c1scc(CCN)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Methoxycarbonyl-3-chloro-4-cyanomethylthiophene (2 g, 9.27 mmol) was dissolved in THF (100 mL) and BH3-THF (18.6 mL of a 1 M solution in THF, 18.6 mmol) was added. After stirring for 16 hours at ambient temperature, the reaction was quenched with water followed by 1 M NaOH. Potassium carbonate was added to afford two layers. The organic layer was separated and concentrated in vacuo to afford 2-methoxycarbonyl-3-chloro-4-(2-aminoethyl)thiophene.
Reaction SMILES: C(Cl)Cl.[OH:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:16])/[C:11]([O:13][CH2:14][CH3:15])=[O:12].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O>[O:4]([CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:16])/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CCOC(=O)/C(C)=C/CCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)/C(C)=C/CCCCO[Si](C)(C)C(C)(C)C
Reaction time: 0.33 h
Yield: 98.8 %

Procedure:
To a methylene chloride solution (300 ml) of Ester 3 (13.91 g; 0.0748 mol), 43 ml of DMF (dimethylformamide) and imidazole (7.6 g; 0.112 mol) are added and the whole is stirred until imidazole is fully dissolved. Tert-butyldimethylsilyl chloride (13.5 g; 0.0897 mol) is then added thereto and the whole is stirred for 20 min. After stirring, the resultant solution is quenched using a buffer solution (100 ml) and the organic compound is extracted three times with ethyl acetate, followed by the wash of the organic layer in a saturated saline solution and drying over anhydrous magnesium sulfate. After anhydrous magnesium sulfate is filtered and the solvent is distilled off under reduced pressure, the residue is separated and purified by column chromatography (developing solution, ethyl acetate:hexane=1:1) to produce Ester 4 (22.16 g; 0.0739 mol) of 99% in yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:22])[S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15]3)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[N:23]1([CH2:28][CH2:29][O:30][C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35]([CH:40]=O)=[CH:34]3)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:22])[S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[C:15]3=[CH:40][C:35]2[NH:36][C:37]3[C:33]([CH:34]=2)=[CH:32][C:31]([O:30][CH2:29][CH2:28][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:39][CH:38]=3)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(c1cccc(Cl)c1)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Product: CN(c1cccc(Cl)c1)S(=O)(=O)c1ccc2c(c1)C(=Cc1cc3cc(OCCN4CCCC4)ccc3[nH]1)C(=O)N2

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chloro-phenyl)-methyl-amide was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:7][C:8]1[CH:9]=[CH:10][C:11]2[C:21](=[C:22]3[CH2:27][CH2:26][N:25](C)[CH2:24][CH2:23]3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]=2[CH:29]=1.C(N(CC)CC)C.C>C1(C)C=CC=CC=1>[F:7][C:8]1[CH:9]=[CH:10][C:11]2[C:21](=[C:22]3[CH2:23][CH2:24][N:25]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:26][CH2:27]3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]=2[CH:29]=1
Reactant: CN1CCC(=C2c3ccc(F)cc3CCc3cccnc32)CC1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(=C2c3ccc(F)cc3CCc3cccnc32)CC1
Temperature: 80 °C
Yield: 62.9 %

Procedure:
Ethyl chloroformate (8.5 mL, 9.65 g, 0.089 mole) is slowly added at 80° C. to a solution of 8-fluoro11-(1-methyl-4-piperidylidene)-6,ll-dihydro-5H-benzo[5,6)cyclohepta[1,2-b]pyridine (5.4 g, 0.0175 mole) and triethylamine (3.6 mL, 2.61 g, 0.026 mole) in 60 mL of toluene. Following complete addition, the temperature is maintained at 80° C. for 1 hour. The reaction mixture is treated with charcoal, filtered, and concentrated to a residue. Following purification by silica gel chromatography and crystallization from pentane, 4.10 g (0.011 mole) of 8-fluoro-6,11-dihydro-11-(1- ethoxycarbonyl-4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine is obtained in 63% yield. 8-bromo, 8,9-dichloro, 9-chloro, and 9-fluoro analogs of this 8-fluoro-11-(1-ethoxycarbonyl-4piperidylidene) compound can be prepared.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=2[CH3:27])[CH:14]=[CH:13][N:12]=1)=[O:9])[CH3:2].[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:28][CH3:29])[CH2:1][CH3:2])=[O:9])[CH:16]=2)=[C:19]([CH3:27])[CH:20]=1
Reactant: CCN(CC)CCCNC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2C)ccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCN(CC)CCCNC(=O)Nc1cc(Oc2ccc(N)cc2C)ccn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
To a solution of 1-(3-diethylaminopropyl)-3-[4-(2-methyl-4-nitrophenoxy)pyridin-2-yl]urea (794 mg) in ethanol (50 ml) were added electrolytic iron powder (442 mg), ammonium chloride (847 mg) and water (10 ml), followed by stirring at 90° C. for 1 hr. The reaction mixture was allowed to cool down to room temperature, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate (100 ml), washed with a saturated aqueous solution of sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. The solvent was removed and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=1:1 to 1:2, ethyl acetate, then ethyl acetate:methanol=20:1 to 10:1) to provide the titled compound (110 mg, 15%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-])=O)[CH:4]=[C:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C([O-])=O.[NH4+].[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:23][CH:24]=2)=[O:30])[CH:4]=[C:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cn1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cn1C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
304 mg (1.53 mmol) of ethyl 1-methyl-4-nitro-1H-pyrrole-2-carboxylate are initially charged in 6 ml of ethyl acetate/ethanol (1:1), 163 mg (0.15 mmol) of palladium (10% on activated carbon) and 580 mg (9.20 mmol) of ammonium formate are added, and the mixture is stirred at 80° C. for 1 h. After cooling, the mixture is filtered through kieselguhr, the filtercake is rinsed with ethanol and the filtrate is freed from the solvent under reduced pressure. The residue is dissolved in 6 ml of THF, 374 mg (1.84 mmol) of 4-trifluoromethoxyphenyl isocyanate are added and the mixture is stirred at RT for 1 h. The reaction solution is concentrated and the residue is purified by RP-HPLC (acetonitrile/water). This gives a solid.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].C[Si](C)(C)N[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[O:33]1[CH2:37][CH2:36][O:35][CH2:34]1>>[OH:35][CH2:36][CH2:37][O:33][CH2:34][N:6]1[CH:7]=[N:8][C:9]2[C:10](=[O:11])[NH:1][C:2]([NH2:3])=[N:4][C:5]1=2
Reactant: C1COCO1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Product: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Temperature: 70 °C
Yield: 78 %

Procedure:
A mixture of guanine (25 g) , hexamethyldisilazane (HMDS, 125 ml), and trimethylsilyl trifluoromethanesulfonate (1 ml) was heated to reflux (130°-135° C.) for 24 hours. The resulting mixture was cooled to 70° C., 1,3-dioxolane (25 ml) added, and the resulting mixture refluxed for 16 hours. Excess HMDS and 1,3-dioxolane were removed by distillation under reduced pressure. The reaction mixture was cooled to 70° C., and poured into a mixture of 600 ml of 10% aqueous acetic acid. The mixture was heated to give a solution. The hot solution was treated with a small amount of activated carbon (1.25 g) to remove any color, filtered, and the filtrate slowly cooled to 5° C. The white crystalline solid thus produced was filtered off, to yield pure 9-(2-hydroxyethoxymethyl)guanine (29 g, 78%). 1H NMR: 3.38 (4H, singlet); 4.64 (1H, broad singlet); 5.26 (2H, singlet); 6.54 (2H, broad singlet); 7.68 (1H, singlet).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].O=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]>>[O:5]=[C:4]1[CH2:3][NH:2][CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[NH:6]1
Reactant: COC(=O)CCCCC=O
Reactant: NCC(N)=O
Agent: Cl
Product: COC(=O)CCCCC1NCC(=O)N1

Procedure:
Glycinamide hydrochloride (6.73 g, 0.061 mol) and methyl 6-oxohexanoate (8.8 ml, 0.061 mol) were reacted together according to the procedure of example 2, to give 0.93 (7.6%) of the title compound, m.p. 58°-60° C. (with decomposition). NMR (DMSO-d6): deltaH =8.10 (b.s., 1H, CONH); 4.50-4.15 (c.a., 1H, NHCHNH); 3.55 (s, 3H, COOCH3); 3.20 (b.s., 1H, CH2NHCH); 3.05 (s, 2H, NHCH2CO); 2.45-2.10 (c.a., 2H, CH2COO); 1.80-1.10 (c.a., 6H, CH2CH2CH2CH2COO). MS (E.I., 70 eV, 1.5 mA) m/z=200 (M+), 169 (M-OCH3)+, 85 (C3H5N2O)+.
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Br:20][C:21]1[CH:29]=[C:28]([Br:30])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Br:20][C:21]1[CH:29]=[C:28]([Br:30])[CH:27]=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C(Cl)c1ccc(Br)cc1Br
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1ccc(Br)cc1Br)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,4-Dibromobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,4-dibromobenzoyl)-3,4-dibromohexahydrophthalimide.