Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]23[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[S:17](=[O:25])(=[O:24])[CH2:16][C:10]4([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]4)[CH:8]2[O:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[H][H]>[Pd].C(Cl)Cl>[OH:9][C@@H:8]1[C:10]2([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:16][S:17](=[O:25])(=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S1(=O)CC2(CCCCC2)C2OC2(c2ccccc2)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: O=S1(=O)CC2(CCCCC2)[C@@H](O)[C@H](c2ccccc2)c2ccccc21
Yield: 40.1 %

Procedure:
A mixture of 0.5 g (1.4 mmoles) of 58, 20 ml of ethanol,10 ml of methylene chloride and 0.4 g of 10% Pd/C catalyst was hydrogenated with 70 psi hydrogen for 3 h at room temperature. The crude reaction slurry was filtered through Celite and evaporated to dryness. The residue was purified by HPLC (10% EtOAc-Hexane, 25% EtOAc-Hexane). The first fraction was 300 mg (60%) as a white solid, mp99-100° C. Proton NMR showed this was a trans isomer. The second fraction gave 200 mg of solid which was impure cis isomer.
Reaction SMILES: [BrH:1].C(=O)=O.[CH3:5]COCC.N[C@H](C(N[C:22]1[CH:30]=[CH:29][C:25]([N+]([O-])=O)=[CH:24][CH:23]=1)=O)CCCNC(=N)N>C(O)(=O)C>[CH2:5]([Br:1])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:29][CH:30]=1.[BrH:1]
Reactant: CCOCC
Reactant: N=C(N)NCCC[C@H](N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: Br
Agent: O=C=O
Solvent: CC(=O)O
Product: BrCc1ccccc1

Procedure:
4.65 g (10 mM) of compound 1a were treated, while stirring, with 40 ml of 2 N HBr in glacial acetic acid for 45 min. at 20° in the absence of moisture. The amino acid derivative dissolved with CO2 evolution. The reaction solution was added dropwise with vigorous stirring to 250 ml of absolute ether which resulted in the precipitation of 2HBr.H-Arg-pNA. The ethereal phase was sucked off, whereupon the solid phase was washed 4 times with portions of 100 ml of abs. ether in order to substantially remove benzyl bromide which had formed as a by-product as well as excess HBr and AcOH. The residue was dissolved in 50 ml of MeOH, the pH was adjusted to 4.5 by the addition of Et3N, and the solution was concentrated to dryness in vacuo at 30°. The resulting product was dissolved in 75 ml of MeOH and passed through a column of "Sephadex" LH-20 (cross-linked dextran gel) equilibrated with MeOH. From a fraction of the eluate there were obtained 4.18 g (91.6% of the theory) of amorphous compound 1b which was homogeneous in the SS as shown by TLC. Elementary analysis and calculation from the empirical formula C12H20N6O3Br2 gave the following values: C=31.15% (31.60%), H=4.35% (4.42%), N=18.84% (18.43%) and Br=34.81% (35.03%).
Reaction SMILES: COC([N:5]1[CH2:10][CH:9]([CH2:11][CH:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH2:13][CH3:14])[C:8](=[O:24])N(C)C1C(C)(C)C)=O.Cl.[O:31]1CCOCC1>>[NH2:5][CH2:10][C@@H:9]([CH2:11][C@H:12]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23])[CH2:13][CH3:14])[C:8]([OH:24])=[O:31]
Reactant: C1COCCO1
Reactant: CCC(Cc1ccc(F)cc1F)CC1CN(C(=O)OC)C(C(C)(C)C)N(C)C1=O
Agent: Cl
Product: CC[C@@H](Cc1ccc(F)cc1F)C[C@H](CN)C(=O)O
Temperature: 110 °C
Yield: 24 %

Procedure:
A flask was charged with 0.5 g (1.2 mmol) of 2-tert-butyl-5-[2-(2,4-difluoro-benzyl)-butyl]-3-methyl-4-oxo-tetrahydro-pyrimidine-1-carboxylic acid methyl ester, 20 mL of dioxane, and 20 mL of conc. HCl solution. The mixture was stirred and heated at 110° C. for 4 days. The solvents were removed under reduced pressure. The residue was taken up in 20 mL of water and 4 drops of conc. HCl solution. The aqueous layer was washed with dichloromethane. The aqueous layer was collected and the water was removed under reduced pressure. The residue was treated with 2 mL of triethylamine, and the excess triethylamine was removed under reduced pressure. The remaining solid was purified by column chromatography (1:8:27 NH4OH, MeOH, dichloromethane eluent). The resulting white solid was washed with acetonitrile and dried under vacuum. This gave 80 mg (24% yield) of the titled compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].S(Cl)([Cl:19])=O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([Cl:19])=[O:8])([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Product: O=C(Cl)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1

Procedure:
A solution of thionyl chloride (30 ml) and 3-nitro-5-(trifluoromethyl)benzoic acid (10 g) was heated to reflux for 2 h. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene (10 ml—removed under reduced pressure) to afford 3-nitro-5-(trifluoromethyl)benzoyl chloride. Step 2: To a solution of 3-nitro-5-(trifluoromethyl)benzoyl chloride (2.35 g, 9.3 mmol) in CH2Cl2 (40 ml) at room temperature was added N-methylpiperazine (1.26 ml, 9.3 mmol) and the mixture was allowed to stir for 30 min. The reaction was concentrated under reduced pressure, taken up in 1 M HCl (50 ml) and the aqueous layer was washed with Et2O (2×20 ml). The aqueous layer was basified to a pH of about 9 with 6N NaOH and extracted with Et2O (3×50 ml). The organic extracts were combined and washed with water (1×20 ml) followed by brine (1×20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (4-methylpiperazin-1-yl)(3-nitro-5-trifluoromethyl)phenyl)-methanone as a tan oil. MS m/z=318 [M+H]+; Calc'd for C13H14F3N3O3: 317.3.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[N:6]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:5]=1)(=[O:3])[CH3:2].Cl.Cl[CH2:21][C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:21][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:11]=2)[N:6]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)Cn1nc(C(C)=O)c2cc(O)ccc21
Reactant: ClCc1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)Cn1nc(C(C)=O)c2cc(OCc3ncccn3)ccc21
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To methyl 2-(3-acetyl-5-hydroxy-1H-indazol-1-yl)acetate (1.80 g, 7.25 mmol) in CH3CN (75 mL) was added 2-(chloromethyl)pyrimidine hydrochloride (1.32 g, 7.98 mmol) and Cs2CO3 (5.91 g, 18.13 mmol). The reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was filtered and washed with CH3CN. The solvent was removed under reduced pressure and the crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1 to 1:3). TLC, Rf (c-hexane/EtOAc 1:3)=0.35; MS (LC/MS): 340.9 [M+H]+, 363.0 [M+Na]+; tR (HPLC conditions e): 3.64 min.
Reaction SMILES: [C:1]([NH:20][CH:21]1[CH:28]2[CH2:29][CH:24]3[CH2:25][C:26]([OH:31])([CH2:30][CH:22]1[CH2:23]3)[CH2:27]2)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[C:41]1[CH:48]=[CH:47][C:44]([CH2:45]Br)=[CH:43][CH:42]=1.CO>C1COCC1>[C:1]([NH:20][CH:21]1[CH:22]2[CH2:23][CH:24]3[CH2:25][C:26]([O:31][CH2:45][C:44]4[CH:47]=[CH:48][C:41]([C:33]5[O:32][C:36]6[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=6[N:34]=5)=[CH:42][CH:43]=4)([CH2:27][CH:28]1[CH2:29]3)[CH2:30]2)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: OC12CC3CC(C1)C(NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C3)C2
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc(C(NC2C3CC4CC2CC(OCc2ccc(-c5nc6ccccc6o5)cc2)(C4)C3)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To KH (35%; (0.34 g; 0.0029 mole) in THF (8 ml) under N2 and cooled in an ice bath is added N-trityl-5-hydroxytricyclo-[3.3.1.13,7 ]decan-2-amine (1.0 g; 0.0025 mole) This forms a pale yellow solution and is stirred at room temperature for 1 hour. The reaction mixture is then cooled in ice and 4-(benzoxazol-2-yl)benzyl bromide (0.7 g; 0.0025 mole) is added all at once. The mixture is stirred for 1/2 hour with ice cooling and then 31/2 hours at room temperature then cooled in ice and MeOH is added to quench the KH. The mixture is evaporated to dryness. Purification is accomplished on HPLC eluting with a gradient system staring with 10% and ending with 20% ethyl acetate/hexane to obtain N-trityl-5-[4-(benzoxazol-2-yl)benzyloxy]tricyclo[3.3.1.13,7 ]decan-2-amine which is used directly in step F.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]3[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:7]=3[N:6]2[CH:23]=1.C(=O)([O-])[OH:25].[Na+]>O1CCOCC1.O>[Cl:22][C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[CH:23]=[C:3]([CH2:2][OH:25])[N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: O=C([O-])O
Reactant: ClCc1cn2c(n1)CN=C(c1ccccn1)c1cc(Cl)ccc1-2
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1cn2c(n1)CN=C(c1ccccn1)c1cc(Cl)ccc1-2
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 87.2 %

Procedure:
A solution of 2.0 g of 2-chloromethyl-8-chloro-6-(2-pyridyl)-4H-imidazo [1,2-a][1,4]benzodiazepine in 50 ml of dioxan was treated with a solution of 0.62 g of sodium hydrogen carbonate in 18 ml of water and the mixture was stirred at 80° C. for 1.5 h. The mixture was evaporated in a vacuum. The residue was partitioned between dichloromethane and aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted twice with dichloromethane. The dichloromethane extracts were dried over magnesium sulphate and chromatographed over 100 g of silica gel. 1.7 g of the desired product were eluted with dichloromethane/ethanol mixtures containing 8 to 12% ethanol. After recrystallization from ethyl acetate/diethyl (sic) ether there were obtained 1.65 g of 8-chloro-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 206-207° C., which was converted into the hydrochloride (dec. above 300° C.).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[C:17](O)(=[O:21])[C:18]([CH3:20])=[CH2:19].CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[CH3:1][C:2]1[S:3][C:4]2[C:17](=[O:21])[CH:18]([CH3:20])[CH2:19][C:5]=2[C:6]=1[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1sccc1-c1cccc2ccccc12
Reactant: C=C(C)C(=O)O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: Cc1sc2c(c1-c1cccc3ccccc13)CC(C)C2=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 77.7 %

Procedure:
A mixture of 5 g of 2-methyl-3-naphthalen-1-ylthiophene (0.022 mol) and 2.1 ml of methacrylic acid (0.025 mol) was added within 15 minutes at 80° C. to 125 ml of Eaton's reagent. After a further 5 minutes, the reaction mixture was poured into ice-water and the precipitated product was dissolved by adding 300 ml of dichloromethane. The organic phase was removed, washed with a saturated aqueous solution of sodium hydrogencarbonate and dried over magnesium sulfate. After removing the solvent, 5 g of product (2) were obtained which, according to GC analysis, was present as a single isomer in 99% purity.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:13][CH2:14][OH:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[Cl-:16].[S:17]([CH2:36][CH2:37][NH:38][C:39](=[O:52])[CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N+:43]([CH3:50])=[C:42]1[CH3:51])[S:18][CH2:19][CH2:20][NH:21][C:22](=[O:35])[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N+:26]([CH3:33])=[C:25]1[CH3:34].[Cl-]>C(O)C.N1CCCCC1>[Cl-:16].[S:17]([CH2:36][CH2:37][NH:38][C:39](=[O:52])[CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N+:43]([CH3:50])=[C:42]1[CH:51]=[CH:9][C:8]1[CH:7]=[CH:6][C:5]([N:4]([CH2:3][CH2:2][OH:1])[CH2:13][CH2:14][OH:15])=[CH:12][CH:11]=1)[S:18][CH2:19][CH2:20][NH:21][C:22](=[O:35])[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N+:26]([CH3:33])=[C:25]1[CH:34]=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:13][CH2:14][OH:15])[CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=1.[Cl-:16]
Reactant: O=Cc1ccc(N(CCO)CCO)cc1
Reactant: Cc1n(CC(=O)NCCSSCCNC(=O)Cn2c(C)[n+](C)c3ccccc32)c2ccccc2[n+]1C
Agent: [Cl-]
Solvent: C1CCNCC1
Solvent: CCO
Product: C[n+]1c(C=Cc2ccc(N(CCO)CCO)cc2)n(CC(=O)NCCSSCCNC(=O)Cn2c(C=Cc3ccc(N(CCO)CCO)cc3)[n+](C)c3ccccc32)c2ccccc21
Yield: 163.3 %

Procedure:
To a stirring solution of 4-[bis(2-hydroxyethyl)-amino]benzaldehyde (1.7 g, 8.1 mmol) and 1,1′-{disulfanediylbis[ethane-2,1-diylimino(2-oxoethane-2,1-diyl)]}bis(2,3-dimethyl-1H-benzimidazol-3-ium) chloride (1.2 g, 2 mmol) in 35 ml of ethanol, 0.5 ml of piperidine was added as a catalyst. The reaction mixture was heated to reflux for 7 h. After cooling, the resulting orange solids were collected by filtration and then washed with dichloromethane and methanol. The drying afforded 1.6 g of a orange solid. Analyses were in accordance with the expected structure.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([OH:15])[CH:9]=[CH:10][CH:11]=2)[N:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:28][C:29](=[O:31])[CH3:30]>C1COCC1>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([O:15][CH2:28][C:29](=[O:31])[CH3:30])[CH:9]=[CH:10][CH:11]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)CCl
Reactant: CC(=O)Oc1ccc2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)COc1cccc2ccc(OC(C)=O)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A mixture of 5b (1.02 g, 5 mmol), potassium carbonate (0.69 g, 5 mmol) and dry N,N-dimethylformamide (DMF) (40 ml) was stirred at room temperature for 30 min and then chloroacetone (0.46 g, 5 mmol) in dry THF (10 ml) was added in one portion. The resulting mixture was continued to stir at room temperature for 24 h (monitored by TLC). After this period, it was poured into ice water (100 ml) and the pale yellow solid thus obtained was crystallized from dichloromethane and ether to afford 2-Acetoxy-8-(2-oxopropoxy)quinoline (5c) (0.85 g, 66%). mp: 79°-80° C.; 1H-NMR (CDCl3): δ2.16 (s, 3H, OAc), 2.42 (s, 3H, 3'-CH3), 4.85 (s, 2H, OCH2), 7.06 (d, 3-H), 7.26-7.67 (m, 3H, Ar--H), 8.08 (d, 4-H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([S:29]([NH:32][C:33]4[CH:38]=[CH:37][N:36]=[CH:35][N:34]=4)(=[O:31])=[O:30])=[CH:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[C:15]([O:39][CH3:40])[CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>O.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([S:29]([NH:32][C:33]4[CH:38]=[CH:37][N:36]=[CH:35][N:34]=4)(=[O:30])=[O:31])=[CH:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[C:15]([O:39][CH3:40])[CH:14]=1
Reactant: COc1ccccc1B(O)O
Reactant: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1-c1ccc(-c2nccc3cc(S(=O)(=O)Nc4ccncn4)ccc23)c(OC)c1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 23.9 %

Procedure:
A microwave vial charged with Pd(Amphos)2Cl2 (0.008 g, 0.012 mmol), 2-methoxyphenylboronic acid (0.036 g, 0.234 mmol), 1-(4-chloro-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (From example 160; 0.050 g, 0.117 mmol), potassium phosphate (0.099 g, 0.469 mmol), 1.5 mL dioxane, and 0.25 mL water was heated to 150° C. in the microwave for 30 minutes. LC/MS showed mostly product, so the aqueous layer was removed and the reaction mixture was treated with HCl (4N in dioxane) (117 μl, 0.469 mmol). After stirring for 10 minutes, the reaction mixture was concentrated. The crude residue was purified by [PREP LC/MS-2 System Column: XBridge 19×100 mm 12230326114 03 Mobile phase: 0.1% NH4OH in water/acetonitrile Flow rate: 40 ml/min Inj: 2200 uL. Gradient: 10 min10-40%_LV_NH3] yielding 1-(2′,3-dimethoxy-[1,1′-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.014 g, 0.028 mmol, 24.0%). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.67 (s, 3H) 3.79-3.88 (m, 3H) 6.99-7.13 (m, 2H) 7.17 (d, J=8.12 Hz, 1H) 7.22-7.32 (m, 2H) 7.32-7.48 (m, 3H) 7.81 (d, J=8.76 Hz, 1H) 7.98 (d, J=9.03 Hz, 1H) 8.09 (d, J=5.61 Hz, 1H) 8.26 (br. s., 1H) 8.58 (s, 1H) 8.61-8.72 (m, 2H); (M+H)+=499.3.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:29])[C@@H:16]2[CH2:20][C@@H:19](O)[CH2:18][N:17]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49]([N:57]1[C:62](=[O:63])[C:61]([CH3:64])=[CH:60][NH:59][C:58]1=[O:65])(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]1([CH:7]([O:14][C:15](=[O:29])[C@@H:16]2[CH2:20][C@H:19]([N:59]3[CH:60]=[C:61]([CH3:64])[C:62](=[O:63])[N:57]([C:49](=[O:56])[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:58]3=[O:65])[CH2:18][N:17]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1c[nH]c(=O)n(C(=O)c2ccccc2)c1=O
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cn([C@H]2C[C@@H](C(=O)OC(c3ccccc3)c3ccccc3)N(C(=O)OC(C)(C)C)C2)c(=O)n(C(=O)c2ccccc2)c1=O
Temperature: -15 °C

Procedure:
N-Boc-trans-4-hydroxy-Lroline diphenylmethyl ester (2a) (0.425 g, 1.07 mmol), triphenylphosphine (0.290 g, 1.10 mmol) and N3-benzoylthymine (0.250 g, 1.09 mmol) were dissolved in dry THF (10 ml) and the solution was cooled to −15° C. DEAD (180 μL, 1.10 mmol) was then added dropwise with stirring. The reaction mixture was stirred under argon at room temperature overnight. The solvent was evaporated and the residue was chromatographed on silica gel using dichloromethane-acetone 20:1 as eluant to give N-tert-butoxycarbony-cis-4-(N3-benzoylthymin-1-yl)-L-proline diphenylmethyl ester (3a) (Rf 0.56), which was recrystallised from ethanol to give a white fluffy solid (0.310 g, 51%), m.p. 183-185° C., (Found C, 68.9; H, 5.5; N, 6.7%; C35H35N3O7 requires C, 69.0; H, 5.8; N, 6.9%), δH (200 MHz; CDCl3) 1.30 and 1.49 (9H, 2xbr s, Boc rotamers), 1.82 (3H, br s, thymine CH3), 2.05 and 2.85 [2H, br m, CH2(3′)], 3.65 (1H, br m) and 4.02 (1H, dd, J=12.0, 8.0 Hz)[CH2(5′)], 4.54 [1H, br m, CH(2′)], 5.26 [1H, br m, CH(4′)], 6.94 (1H, s, CHPh2), 7.12 and 7.18 [1H, 2xbr s, CH(6) rotamers], 7.30-7.42 (10H, br m, phenyl CH), 7.50 (2H, t, J=7.9 Hz, benzoyl m-CH), 7.67 (1H, t, J=7.0 Hz, benzoyl p-CH), 7.92 (2H, d, J=7.0 Hz, benzoyl o-CH); δC (50.28 MHz; CDCl3) 12.3 (thymine CH3), 27.9 and 28.2 (Boc CH3 rotamers), 34.9 and 35.3 [CH2(3′) rotamers], 49.3 and 49.4 [CH2(5′) rotamers], 52.1 and 52.5 [CH(4′) rotamers], 57.5 [CH2(2′)], 78.1 and 78.4 (CHPh2 rotamers), 81.3 (Boc C), 111.7 [C(5)], 126.9-130.6 (aromatic CH), 131.6 (benzoyl C), 135.3 (benzoyl p-CH), 136.0 and 136.2 [CH(6) rotamers], 139.4 (phenyl C), 150.1 [C(2)], 153.6 (Boc CO), 162.6 [C(4)], 169.1 (benzoyl CO), 171.6 (ester CO); m/z (FAB+) 632 (M+Na+, 10%), 610 (M+H+, 39), 554 ([M−C4H8+H]+, 27), 506 ([M−PhCO+H]+, 18), 338 ([M-PhCO-Ph2CH+, 20), 266 (31), 231 (BzT+H+, 52), 167 (Ph2CH+, 100), 105 (PhCO+, 24), 57 (C4H9+, 28); νmax (KBr)/cm31 1 1751, 1694 and 1659 (C═O); [α]D≅−17.2 (c=1.0, DMF).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[OH-].[K+].[CH3:20][C:21]1[CH:26]=[N:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1>CN1CCCC1=O.O>[CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([CH3:20])=[CH:26][N:25]=3)[C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cnc(C)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cnc(CCn2c3c(c4cc(C(C)C)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.5 %

Procedure:
To a solution of 8-Isopropyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g. 0.87 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.5 g, 8.7 mmol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrazine (0.25 g, 2.1 mmol) was added and stirred for further 5 h. at 60 deg C. After completion (TLC), reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (6% MeOH:DCM in silica 100-200 mesh, Diameter of column 2.5 cm, Height of silica—approx. 5 inch) then further purified through preparative TLC to provide the desired compound as yellow solid (0.05 g, 16% yield). 8-Isopropyl-2-methyl-5-[2-(5-methyl-pyrazin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.05 g, 0.143 mmol) was dissolved in THF (2.0 mL). A solution of oxalic acid dihydrate (0.018 g, 0.143 mmol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.02 g, 32% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:29])[C:16]([NH:18][C:19]([CH3:28])([CH3:27])[CH2:20][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:17])[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1.[CH:30]1([CH:36]=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(O)(=O)C.ClCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:30]1([CH2:36][N:24]2[CH2:23][CH2:22][N:21]([CH2:20][C:19]([NH:18][C:16](=[O:17])[C:15]([NH:14][C:5]3[CH:6]=[CH:7][C:8]([C:9]4[O:13][CH:12]=[N:11][CH:10]=4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:29])([CH3:27])[CH3:28])[CH2:26][CH2:25]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1cc(NC(=O)C(=O)NC(C)(C)CN2CCNCC2)ccc1-c1cnco1
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(NC(=O)C(=O)NC(C)(C)CN2CCN(CC3CCCCC3)CC2)ccc1-c1cnco1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 48 mg of N-[3-methoxy-4-(5-oxazolyl)phenyl]-N′-[1,1-dimethyl-2-(1-piperazinyl)ethyl]oxalamide (1.2 mmol) and 13 mg of cyclohexanecarboxaldehyde (1.2 mmol) in 1 ml of a 5% acetic acid/dichloromethane mixture was treated with a solution of 38 mg of sodium triacetoxyborohydride (1.8 mmol) in 1 ml of a 5% acetic acid/dichloromethane mixture. After stirring overnight at room temperature the reaction mixture was diluted with 10 ml of dichloromethane and washed with 8 ml of a sodium bicarbonate solution followed by 8 ml of water. The organic layer was then evaporated and purified using flash chromatography on a silica gel column eluting with 5% methanol/dichloromethane to give after evaporation of the fractions 14.3 mg (0.3 mmol, 25%) of N-[2-[4-(cyclohexylmethyl)-1-piperazinyl-1,1-dimethylethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide in the form of a white solid. MS: m/e 498.2 [M+H]+.