Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Br)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([N:26]4[CH:27]=[CH:28][N:29]=[C:25]4[CH3:24])[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Br)ncc3O2)CC1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1cc2c(cn1)OC(C1CCN(C(=O)OC(C)(C)C)CC1)C2

Procedure:
The title compound is prepared from 4-(5-bromo-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 2-methyl-1H-imidazole following a procedure analogous to that described in Example 69. LC (method 7): tR=1.22 min; Mass spectrum (ESI+): m/z=385 [M+H]+.
Reaction SMILES: C(O)C.C(O)(=O)C.[Cl:8][C:9]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([C:35]3[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=3[CH3:42])[CH2:31][CH2:30]2)[C:26]([N+:43]([O-])=O)=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:16]=1)=[O:12]>[Fe]>[NH2:43][C:26]1[C:27]([N:29]2[CH2:30][CH2:31][N:32]([C:35]3[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=3[CH3:42])[CH2:33][CH2:34]2)=[CH:28][C:9]([Cl:8])=[C:10]([CH:25]=1)[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:16]=1)=[O:12]
Reactant: Cc1ccc(C)c(N2CCN(c3cc(Cl)c(C(=O)NCc4cccc(CN(C)C)c4)cc3[N+](=O)[O-])CC2)c1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(C)c(N2CCN(c3cc(Cl)c(C(=O)NCc4cccc(CN(C)C)c4)cc3N)CC2)c1
Temperature: 75 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stir bar and a septum with a nitrogen inlet, the iron powder (557.40 mg, 9.98 mmol) was suspended in clean, dry, reagent-grade ethanol (50.00 ml, 856.34 mmol) and the mixture was stirred together vigorously under nitrogen at room temperature as the acetic acid (5.00 ml, 87.34 mmol) was added. The reaction continued to stir at room temperature as the 2-chloro-N-(3-dimethylaminomethyl-benzyl)-4-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-5-nitro-benzamide 13a (214.40 mg, 0.40 mmol) was added in one portion. The reaction mixture was then warmed to 75° C. and the reaction stirred for 4 h. After 4 h, the reaction was cooled to room temperature and filtered through Celite, washing with methanol. The solvent was then removed from the filtrate under reduced pressure. The ruby red oil was then taken back up in 100 ml of ethyl acetate; an equivalent amount of saturated aqueous NaHCO3 solution was added to the organic solution. The layers were then separated and the aqueous layer was extracted with ethyl acetate (2×75 ml). The organic phases were combined and dried over Na2SO4. The product solution was then decanted and the solvent was removed under reduced pressure. The crude product, 5-amino-2-chloro-N-(3-dimethylaminomethyl-benzyl)-4-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-benzamide 13b (142.50 mg, 0.28 mmol), was isolated as a brown solid and was carried on without further purification. LCMS (m/e)=507 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Br:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[NH:11]C(=O)C.C(O)C.[OH-].[Na+]>O>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Br:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[NH2:11]
Reactant: CC(=O)Nc1c(Cl)cc(Br)c(C)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(Br)cc(Cl)c(N)c1Cl
Yield: 90 %

Procedure:
A solution consisting of 2.07 g of N-(2,6-dichloro-4-bromo-3-methylphenyl)acetamide, 50 mL of ethanol, 25 mL of water and 25 mL of 50 percent NaOH were refluxed until hydrolysis was complete. The reaction mixture was cooled and extracted with ethyl ether. The extract was washed with water, dried over MgS04 and filtered. Removal of the solvent under reduced pressure gave 1.6 g of white solid. The product was purified by elution with pentane from a silica gel column and recrystallization from heptane (m.p. 67-69° C). 1H NMR (CCl4) δ7.33 (s, 1H), 4.40 (s, 2H, NH2), 2 40 (s, 3H, CH3).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:20]([O:19][C:12]1[CH:11]=[C:10]([CH2:9][CH2:8][NH2:7])[CH:15]=[CH:14][C:13]=1[O:16][CH2:17][CH3:18])[CH3:21]
Reactant: CCOc1ccc(CCNC(=O)OC(C)(C)C)cc1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(CCN)cc1OCC
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To a solution of 6.5 g of [2-(3,4-diethoxy-phenyl)-ethyl]-carbamic acid tert.-butyl ester in 20 mL DCM were added 5 mL of TFA at 0° C. The reaction mixture was stirred at rt for 30 min when another 5 mL of TFA were added. After stirring for further 2 h, 1M NaOH solution was dropwise added. The mixture was extracted twice with DCM, washed with water and brine. The organic phase was dried over MgSO4 and concentrated in vacuo to yield 4.3 g of 2-(3,4-diethoxy-phenyl)-ethylamine as yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([N:22]([CH3:24])[CH3:23])[C:15]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:6](O)CS(C)(=O)=O.C[O-].[Na+].[NH:29]([CH2:36][CH2:37][C:38]#[N:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CS(C)=O>[NH:29]([CH:36]=[C:37]([CH2:6][C:5]1[CH:13]=[C:14]([N:22]([CH3:23])[CH3:24])[C:15]([N:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:3]([N:2]([CH3:1])[CH3:25])[CH:4]=1)[C:38]#[N:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CN(C)c1cc(C(O)CS(C)(=O)=O)cc(N(C)C)c1N1CCCCC1
Reactant: N#CCCNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)c1cc(CC(C#N)=CNc2ccccc2)cc(N(C)C)c1N1CCCCC1

Procedure:
A mixture of 7.4 g. of 3,5-bis(dimethylamino)-α-[(methylsulfonyl)methyl]4-piperidinobenzyl alcohol, 1.64 g. of sodium methylate and 4.4 g. of β-anilinopropionitrile in 40 ml. of dimethylsulfoxide was stirred for 2 hours at 50° C. under nitrogen. The mixture was poured into 250 ml. of water, the precipitated product extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated. By purification of the residue over aluminum oxide with benzene and recrystallization from ethyl acetate/petroleum ether, there was obtained α-(anilinomethylene)-3,5-bis(dimethylamino)-4-piperidinohydrocinnamonitrile having a melting point of 200°-202° C.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][C:17]([OH:19])=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:22])=O>C1C=CC=CC=1>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][C:17]([Cl:22])=[O:19])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC1c2ccccc2CCc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)CC1c2ccccc2CCc2ccccc21

Procedure:
A mixture of 160 g of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetic acid and 230 ml of thionyl chloride is heated to boiling under reflux for 2.5 hours. After concentration of the mixture in vacuo, the residue is treated twice with 300 ml of dry benzene each time and in each case evaporated to dryness. 10,11-Dihydro-5H-dibenzo[a,d]cycloheptene-5-acetic acid chloride is obtained as a red-brown oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH2:16])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[C:23](Cl)(=[O:25])[CH3:24]>O.ClCCl>[CH3:24][C:23]([NH:16][CH2:15][CH2:14][C:11]1[C:12]2[CH:13]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1)=[O:25]
Reactant: CC(=O)Cl
Reactant: COc1ccc2cccc(CCN)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc2cccc(CCNC(C)=O)c2c1
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
The compound V (6.0 g, 0.03 mol) produced as described above and potassium carbonate (5 g) were added to 20 ml of water and 40 ml of dichloromethane, and stirred for 30 minutes. The aqueous layer was removed. The organic layer was cooled to the temperature of 0° C., and acetyl chloride (7.8 g, 0.1 mol) was added dropwise. A reaction was allowed to proceed at room temperature for 1 hour. 100 ml water was then added, and the reaction solution was extracted with dichloromethane (50 ml*3). The organic phases were combined, dried with anhydrous magnesium sulfate, and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure, to give a solid. The solid was recrystallized in a 2:1 toluene/n-hexane mixture, to produce 4.8 g of agomelatine. The yield was 78.5%. The melting point was 107-108° C. (in Literature [2], 109° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:20]1C(O)=CC=CC=1C.[OH-].[K+].CC(O)=O>C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:4]([CH3:20])[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(N=Nc2ccc(O)cc2)cc1
Reactant: Cc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(O)ccc1N=Nc1ccc(S(C)(=O)=O)cc1
Reaction time: 0.5 h
Yield: 58 %

Procedure:
For these studies, half of the diazonium salt from example 1 was added to a solution of m-cresol (0.285 g, 2.34 mmol) and KOH (0.13 g, 2 mmol) in THF. The resulting red mixture was stirred for 0.5 h and then neutralized with HOAc to give a orange solid. This solid was filtered and recrystallized from THF/Hexanes to give 0.35 g (58%) of Compound 2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.O1[CH2:20][CH2:19]OCC1>>[CH3:4][N:3]1[CH2:20][CH:19]=[C:6]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=2)[CH2:7][CH2:2]1
Reactant: CC(C)Oc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: C1COCCO1
Product: CC(C)Oc1cc(C2=CCN(C)CC2)ncc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
800 mg of 2-chloro-5-nitro-4-(propan-2-yloxy)pyridine are introduced into 62 ml of 1,4-dioxane. After sparging for 10 min with argon in the reaction mixture, 1.25 g of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride, 6.02 g of caesium carbonate, 6.2 ml of water and 467 mg of bis(triphenylphosphine)palladium(II) dichloride are added. The reaction mixture is heated at 100° C. for 16 h. After cooling, the mixture is run into water and extracted with ethyl acetate. The organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification is carried out by flash chromatography on silica gel (40-63 microns), elution being carried out with a mixture of dichloromethane and methanol (90/10 to 80/20). 401 mg of 1′-methyl-5-nitro-4-(propan-2-yloxy)-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine are obtained in the form of a yellow gum.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13]C#N)=[O:11])[CH:2]=1.C(N(CC)CC)C>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:2]=1
Reactant: N#CCOC(=O)CCCc1cccnc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CCCc1cccnc1
Yield: 91.3 %

Procedure:
A mixture of cyanomethyl 4-(pyridin-3-yl)butanoate (0.57 g, 2.81 mmol) and triethylamine (57 mg, 0.56 mmol) in dry methanol (10 ml) was heated under reflux overnight, and evaporated to give a residue. The resultant residue was subjected to purification using column chromatography on silica gel to afford a target product, methyl 4-(pyridin-3-yl)butanoate (0.46 g, 92%).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)CCCCC(Cl)=[O:15].[OH-].[Na+:20]>>[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O-:8])=[O:15].[Na+:20]
Reactant: O=C1CCCCCN1
Reactant: O=C(Cl)CCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: NCCCCCC(=O)[O-]
Yield: 70 %

Procedure:
The literature has described various syntheses for TOCAP and related compounds. German Patent 949,568 (Kruckenberg) describes the reaction of caprolactam with various acyl halides including adipoyl dichloride in the presence of sodium hydroxide. Once sodium 6-aminocaproate has formed, the reactor is charged with a first portion acyl halide, sodium hydroxide and then a final portion acyl halide. Example 1 best details this process. Synthesis of TOCAP is reported by Zinner et al in J. Prakt. Chem. 17, 147-153 (1962). The procedure requires the addition of all the sodium hydroxide to be charged to the reaction vessel at the beginning of the synthesis. The reported yield is 70% of theory. Plate-like crystals are recovered through recrystallization from dimethyl formamide/water (2:5).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][NH:6][C:5](=[O:8])[CH2:4]1.[H-].[Na+].Cl[C:12]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:24]([C:35]([F:38])([F:37])[F:36])[CH:23]=2)[CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2>CC(N(C)C)=O>[O:32]1[CH2:33][CH2:34][CH:29]([O:28][C:25]2[CH:26]=[CH:27][C:22]([C:20]3[CH:19]=[C:18]4[C:13]([CH:14]=[CH:15][CH:16]=[N:17]4)=[C:12]([O:1][CH2:2][C@H:3]4[CH2:7][NH:6][C:5](=[O:8])[CH2:4]4)[N:21]=3)=[CH:23][C:24]=2[C:35]([F:38])([F:37])[F:36])[CH2:30][CH2:31]1
Reactant: O=C1C[C@@H](CO)CN1
Reactant: FC(F)(F)c1cc(-c2cc3ncccc3c(Cl)n2)ccc1OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C1C[C@@H](COc2nc(-c3ccc(OC4CCOCC4)c(C(F)(F)F)c3)cc3ncccc23)CN1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
50.7 mg (R)-4-Hydroxymethyl-pyrrolidine-2-one (2.2) was placed in 1.5 mL of dimethylacetamide at ambient temperature under nitrogen before 20.5 mg sodium hydride (60% dispersion in oil) was added. The reaction was stirred for 10 min and then 150 mg 5-chloro-7-[4-(tetrahydro-pyran-4-yloxy)-3-trifluoromethyl-phenyl]-[1,6]naphthyridine (6.23) was introduced and the reaction was heated to 70° C. and stirred overnight. After this time the mixture was cooled to ambient temperature and partitioned between ethyl acetate, water and some saturated sodium chloride solution. The organic layer was separated, dried over sodium sulfate, filtered and the solvent was removed from the filtrate under reduced pressure. Purification by chromatography on silica provided the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([OH:26])=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Si](C=[N+]=[N-])(C)C>CO>[N:11]1([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([O:26][CH3:27])=[O:25]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)O)C1
Solvent: CO
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
1-(Benzyloxycarbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1-JJ, 1.07 g, 2.9 mmol, Small Molecules, Inc., Hoboken, N.J. USA) was dissolved in 10 mL of dry methanol and trimethylsilyl diazomethane (2.0 M in diethyl ether, Aldrich) was added dropwise with stirring at rt until a slight yellow color persisted. The solution was then concentrated under reduced pressure, and flash chromatography (0-50% EtOAc/hexanes elution) gave 1-benzyl 4-tert-butyl 2-methyl piperazine-1,2,4-tricarboxylate (compound II-JJ) as a colorless oil: [M+Na]+=401.2 (35%); [M-Boc+H]+=279.1 (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:6][C:3]=1[CH2:4][OH:5].[C:23](=O)([O-])[O-:24].[K+].[K+].C(Cl)(Cl)=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[C:17]1([S:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:2]3[NH:1][C:23](=[O:24])[O:5][CH2:4][C:3]=3[CH:6]=2)=[O:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(OCCCCS(=O)c2ccccc2)cc1CO
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1Nc2ccc(OCCCCS(=O)c3ccccc3)cc2CO1

Procedure:
An amount of 4.2 gm (0.0133 mol) of 2-amino-5-(4-phenylsulfinylbutoxy)-benzyl alcohol [prepared from 2-nitro-5-(4-phenylsulfinyl-butoxy)-benzyl alcohol by catalytic hydrogenation] is dissolved in 150 ml of chloroform and mixed with 6.9 gm (0.05 mol) of potassium carbonate. Ten milliliters of a 20% solution of phosgene in toluene is slowly added dropwise to this mixture under stirring. After further stirring for two hours, the solution is washed with water and dried with sodium sulfate, and the solvents are distilled off in vacuo. The residue is recrystallized from ethyl acetate/cyclohexane.
Reaction SMILES: [C:1]([C@@H:3]1[C@@H:10]2[C@@H:6]([O:7][C:8]([CH3:12])([CH3:11])[O:9]2)[C@H:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[O:4]1)#[CH:2].I[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36].C(N(CC)CC)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:11][C:8]1([CH3:12])[O:7][C@@H:6]2[C@@H:10]([C@@H:3]([C:1]#[C:2][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]([F:38])([F:37])[F:36])[O:4][C@H:5]2[N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[O:9]1
Reactant: FC(F)(F)c1ccccc1I
Reactant: C#C[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C#Cc1ccccc1C(F)(F)F)O[C@H]2n1cnc2c(NC3CCCC3)ncnc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of [9-((1R,2R,4R,5R)-4-ethynyl-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl)purin-6-yl]cyclopentylamine (40 mg, 0.12 mmol), a compound of formula (5), in tetrahydrofuran (4 ml) under nitrogen was added catalytic amounts (3 mg) of dichlorobis(triphenylphosphine)palladium(II) and copper(II)iodide, followed by 1-iodo-2-trifluoromethylbenzene (0.25 ml, 0.3 mmol). Triethylamine (0.4 ml) was then added, and the mixture stirred for 15 minutes at room temperature. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC, eluting with methanol:methylene chloride (6.5:1), to yield [9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-(trifluoromethyl)-phenyl]ethynyl}-3,6,8-trioxabicyclo[3.3.0]oct-2-yl)purin-6-yl]cyclopentylamine, a compound of formula (6).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[C:21]([Br:23])[CH:20]=[C:19]([Br:24])[C:18]=3[NH2:25])[CH2:12][CH2:11]2)=[O:8])[CH2:3][CH2:2]1.[C:26]([Cl:34])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.C(OC(C)C)(C)C>N1C=CC=CC=1>[ClH:34].[O:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[C:21]([Br:23])[CH:20]=[C:19]([Br:24])[C:18]=3[NH:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:12][CH2:11]2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1c(Br)cc(Br)cc1CN1CCN(CC(=O)N2CCOCC2)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)OC(C)C
Product: O=C(Nc1c(Br)cc(Br)cc1CN1CCN(CC(=O)N2CCOCC2)CC1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 0.423 part of N1 -(morpholinocarbonylmethyl)-N4 -(2-amino-3,5-dibromobenzyl)piperazine in 4 volume parts of pyridine is added 0.25 part of benzoylchloride, and the mixture is kept standing overnight at room temperature. The solvent is distilled off, and residue is chromatographed over alumina. Ethyl acetate eluates gives oily substance. The resultant oily substance is treated with ethanolic hydrochloric acid, and to the resultant is added isopropyl ether to give N1 -morpholinocarbonylmethyl-N4 -(2-monobenzoylamino-3,5-dibromobenzyl)piperazine hydrochloride melting at 162° to 164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH:25]([OH:29])[CH2:26][O:27][CH3:28])[CH2:19]4)[C:14]([F:30])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH:25]([OH:29])[CH2:26][O:27][CH3:28])[CH2:19]4)[C:14]([F:30])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCC(O)CN1CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCC(O)CN1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 120 °C

Procedure:
To a solution of 1-[(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-1-piperidyl]-3-methoxy-propan-2-ol, 1d, (0.15 g, 0.24 mmol) in THF was added 1N LiOH solution. The reaction mixture was heated in a microwave reactor at 120° C. for 5 minutes. The reaction mixture was diluted with water and the aqueous phase was extracted with EtOAc (twice). The combined organic phases were dried (MgSO4), filtered and concentrated under vacuo. The resulting solid was purified by silica gel chromatography (5-20% MeOH: CH2Cl2) to afford the desired product (537) as a white solid.
Reaction SMILES: CO[C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3([CH2:19][CH3:20])[O:18]CCO3)[CH:12]=2)[N:7]([CH2:21][CH3:22])[C:6]1=[O:23])=[O:4].[NH2:24][C:25]1[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=1)[C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>>[C:31]1([NH:30][C:28]([C:27]2[CH:26]=[C:25]([NH:24][C:3]([CH:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:18])[CH2:19][CH3:20])[CH:12]=4)[N:7]([CH2:21][CH3:22])[C:6]3=[O:23])=[O:4])[CH:39]=[CH:38][CH:37]=2)=[O:29])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCN1C(=O)C(C(=O)OC)c2cc(C3(CC)OCCO3)ccc21
Reactant: Nc1cccc(C(=O)Nc2ccccc2)c1
Product: CCC(=O)c1ccc2c(c1)C(C(=O)Nc1cccc(C(=O)Nc3ccccc3)c1)C(=O)N2CC

Procedure:
Prepared as in Example 1 from 1-ethyl-5-(2-ethyl-[1,3]dioxolan-2-yl)-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester and 3-amino-N-phenyl-benzamide. Purified by flash-chromatography (chloroform/methanol, 20:1) followed by trituration in hexanes/ethyl acetate. mp 179-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH2:18]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1)[CH2:19][CH3:20]>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1ccc(CCC)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.7 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g. 0.00045 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.20 g, 0.0036 mol) and allowed to stir for 10 min at RT. 2-propyl-5-vinyl-pyridine (0.2 g, 0.00136 mol) was added and stirred for further 24 h. at 100° C. After completion (TLC), reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was semi-purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.016 g, 9.6% yield). 8-Chloro-5-[2-(6-isopropyl-pyridin-3-yl)-ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.016 g, 0.0000435 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.005 g, 0.00007 mol) in THF (0.5 mL) was added and stirred for 30 min at RT. Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.010 g, 52% yield).