Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35]>>[CH3:35][CH:34]([CH3:36])[CH2:33][CH2:32][CH2:31][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCCBr
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: CC(C)CCCOc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromo-4-methyl-pentane following the procedure of Example 478: MS (ES) m/z 478.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](O)([CH3:19])[CH3:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:21]([OH:24])(=O)[CH3:22].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].C(#[N:37])C>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][C:14]([C:17]([NH:37][C:21](=[O:24])[CH3:22])([CH3:19])[CH3:18])=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(C(C)(C)O)cn2)c1=O
Reactant: CC(=O)O
Reactant: CC#N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)NC(C)(C)c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
5-Bromo-3-[5-(1-hydroxy-1-methyl-ethyl)-pyridin-2-ylamino]-1-methyl-1H-pyridin-2-one (180 mg, 0.532 mmol) was dissolved in acetonitrile (10 ml). Acetic acid (0.5 ml) was added at room temperature, and then cooled to 0° C. Sulfuric acid, concentrated solution (0.5 ml) was added slowly to the cooled solution. The reaction mixture was allowed to warm up to room temperature after the addition and stirred overnight. The reaction mixture was poured into ice and ethyl acetate was added. Sodium bicarbonate was added slowly to neutralize the acidic mixture and the it was extracted with ethyl acetate, washed with brine and dried over sodium sulfate. The mixture was filtered and concentrated. Crude material was purified by 24 g column with 0-10% MeOH in EtOAc 1:1 Hex to give N-(2-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-3-yl)propan-2-yl)acetamide (69 mg, 34%) as a yellow solid. MS (H+)=379.0.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.Cl[C:24]1[N:25]=[CH:26][C:27]([C:30]([O:32]C)=O)=[N:28][CH:29]=1.[C:34]1([CH3:40])[CH:39]=[CH:38][CH:37]=[CH:36]C=1>>[CH2:40]1[CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][N:28]2[CH2:29][CH2:24][N:25]1[C:24]1[N:25]=[CH:26][C:27]([C:30]([NH:22][C:19]2[NH:20][N:21]=[C:17]([CH2:16][CH2:15][C:9]3[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=3)[CH:18]=2)=[O:32])=[N:28][CH:29]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Cc1ccccc1
Agent: C[Al](C)C
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN5CCCCC5C4)cn3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63 %

Procedure:
Trimethylaluminium (2M in toluene, 9.64 ml, 19.28 mmol) was added dropwise to a stirred suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (1.91 g, 7.71 mmol) and methyl 5-chloropyrazine-2-carboxylate (1.33 g, 7.71 mmol) in anhydrous toluene (38.6 ml) at ambient temperature. The resulting solution was then stirred under nitrogen at ambient temperature for 18 h. The reaction was incomplete so the temperature was increased to 60° C. and the reaction mixture was stirred for a further 3 h. The reaction mixture was quenched with methanol (10 mL) and HCl (2M aqueous solution). The mixture was diluted with EtOAc (100 mL) and water (250 mL) and then acidified with HCl (2N aqueous solution). The organic layer was removed and the aqueous further extracted with EtOAc (2×100 mL). The combined organics were washed with water (200 mL), brine (200 mL) dried over MgSO4 and concentrated under reduced pressure. Upon concentration a precipitate formed. The precipitate was collected by filtration, washed with MeOH (10 mL) and air dried to afford the desired compound (1.88 g, 63%) as a yellow solid, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:12]3[C:17]([NH:18][C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.N1C2C(=CC=CC=2)C(=O)C1=O.[NH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.Cl>C(OCCO)C.C(OCC)(=O)C.CO>[ClH:1].[CH:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10]1[NH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=1[C:2]([NH:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[N:3]2
Reactant: NCCN1CCNCC1
Reactant: Clc1nc2ccccc2c2[nH]c3ccccc3c12
Agent: Cl
Agent: O=C1Nc2ccccc2C1=O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCOCCO
Product: c1ccc2c(c1)nc(NCCN1CCNCC1)c1c3ccccc3[nH]c21

Procedure:
A mixture of compound 4a as obtained from the above Synthesis Ex. 1 (1.26 g, 5 mmol) and 1-(2-aminoethyl)piperazine (1.94 g, 15 mmol) in 2-ethoxyethanol (50 mL) was heated at 140-150° C. for 48 hrs (by TLC monitoring). After cooling, the reaction mixture was evaporated in vacuo to give a residue, which was dissolved in ethyl acetate (EA) (50 mL). The EA layer was washed with H2O and brine, and then dried on MgSO4. Concentration of the EA layer gave a residue, which was dissolved in MeOH (10 mL), followed by addition of a solution of 6N HCl at 0° C. The resultant mixture was stirred at room temperature for 8 hrs to result in precipitation, followed by filtration. The precipitate thus collected was washed with MeOH and then dried at 90° C. under reduced pressure for 24 hrs to give N-(11H-indolo[3,2-c]quinolin-6-yl)-2-(piperazin-1-yl)ethanamine hydrochloride, which was purified by flash column chromatography (FCC) (silica gel; MeOH/CH2Cl2=1/10 to 1/3) to give the title compound 5 as an orange color powder (0.51 g, 29% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:15]1[CH:16]=[N:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[N:19][CH:20]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Cl[CH2:29][CH:30]([OH:43])[CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][CH2:41][CH3:42]>CN(C)C=O.O>[CH2:7]([C:15]1[CH:20]=[N:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:29][C@@H:30]([OH:43])[CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:23][CH:22]=2)=[N:17][CH:16]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCOCCOCCOCC(O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCc1cnc(-c2ccc(OC[C@@H](O)COCCOCCOCCCC)cc2)nc1
Temperature: 25 °C

Procedure:
Potassium carbonate (2.1 g, 15.7 mmol) was added to a solution of 5-octyl-2-(4-hydroxyphenyl)pyrimidine (3.0 g, 10.5 mmol) and 1-chloro-3-(2-(2-butoxyethoxy)ethoxy)-2-propanol (2.7 g, 10.5 mmol) in N,N-dimethylformamide (100 ml). The resulting mixture was stirred at reflux temperature for 18 hours and then cooled to ambient temperature. The mixture was diluted with water (100 ml) and was extracted with three 100 ml aliquots of diethyl ether. The extracts were dried (over MgSO4), filtered, and concentrated to give crude product as an oil. 5-octyl-2-[4-((S)-2-hydroxy-3-(2-(2-(butoxy)ethoxy)ethoxy)propoxy)phenyl]pyrimidine was then isolated by chromatography. The chiral (S)-hydroxy compound (3.5 g, 7.5 mmol) was treated with diethylaminosulfur trifluoride (5.3 g, 15 mmol) to produce Comparative Example 1.
Reaction SMILES: C1N2CN3[CH2:10][N:4](C2)CN1C3.[CH2:11]([O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](=[O:23])CBr)=[CH:18][CH:17]=1)[CH2:12][CH2:13][CH3:14].[ClH:26]>C(O)C>[Cl-:26].[CH2:11]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C:20](=[O:23])[CH2:10][NH3+:4])=[CH:24][CH:25]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCOc1ccc(C(=O)CBr)cc1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: Cl
Solvent: CCO
Product: CCCCOc1ccc(C(=O)C[NH3+])cc1
Product: [Cl-]
Reaction time: 8 h
Yield: 85 %

Procedure:
The hexamethylene tetramine quaternary salt of p-n-butoxyphenacyl bromide (40.0 g) was stirred vigorously in ethanol (320 ml) and concentrated hydrochloric acid (40 ml) was added. The reaction mixture was allowed to stand overnight and deposited a large quantity of solid. More ethanol (250 ml) was added. After 60 more hours the reaction mixture was warmed gently and filtered. The precipitate was washed with 50 ml of warm ethanol. p-n-Butoxyphenacylammonium chloride (20.1 g -- 85% yield) was precipitated as a white powder by slowly dropping the alcohol solution into 3.0 l of dry ether. The precipitate was filtered and dried. The nuclear magnetic resonance spectrum in deuterium oxide at 60°C on a Varian A-60 spectrometer showed triplets centered at 1.10 and 4.05 (--CH2CH3 and --O CH2CH2 --), an aromatic A2B2 system at 6.80, 6.95, 7.75 and 7.90, a singlet at 4.68 (--CO CH2N--) and a broad absorption around 1.70 (aliphatic --CH2 -- chain). Integrated intensities were in accord with the structure of p-n-butoxyphenacylammonium chloride. p-n-Butoxyphenacylammonium chloride (20.0 g) and terephthaloyl chloride (8.0 g) were refluxed in dry pyridine (150 ml) in the absense of moisture for one hour. The mixture was then cooled and poured, with stirring, into water (500 ml) and the solid was filtered, washed with water, dried and recrystallized from 500 ml of pyridine. A white crystalline solid (7.7 g -- 35% yield) was obtained. The solid, upon analysis, proved to be N,N'-di-p-n-butoxyphenacylterephthalimide. Calculated for for C32H36N2O6 : C 70.6; H 6.62; N 5.14%. Found: C 70.66, 70.41; H 6.68, 6.56; N 5.20, 5.14%. The nuclear magnetic resonance spectrum (A-60) in deuterodimethyl sulfoxide at 105°C clearly showed triplets centered at 0.87 and 3.94 (CH3CH2 and --O CH2CH2 --), a singlet at 4.55 (--COCH2NH--), an A2B2 aromatic quartet at 6.72, 6.86, 7.63 and 7.78 (terminal aromatic protons) and aromatic singlet at 7.69 (central aromatic ring).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][CH2:2]1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[CH:13]=1.[BH4-].[Na+]>C(O)(=O)C.CO>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[NH:5][CH2:4][CH2:3][CH2:2]2)[CH:13]=1
Reactant: O=Cc1cccnc1
Reactant: c1ccc2c(c1)NCCCN2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1cncc(CN2CCCNc3ccccc32)c1
Temperature: 25 °C

Procedure:
To solution of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine from Example 15A (0.50 g, 3.38 mmol) in 1% acetic acid/methanol (25 ml), at room temperature, was added pyridine-3-carboxaldehyde (0.35 ml, 03.72 mmol). The mixture was stirred at reflux for 18 h and then allowed to cool to room temperature. Sodium borohydride (0.050 g, 0.80 mmol) was added. The mixture was stirred for 2 h and then evaporated in vacuo. The residue was partitioned between EtOAc and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacua. The residue was purified by flash chromatography on silica (eluant EtOAc) to give a white solid; yield 0.386 g (40%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:19]([N:21]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)[CH2:22][C:23](O)=[O:24])=[O:20])[CH2:13][C:14]2[N:18]=[CH:17][NH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[N:84]1[CH:89]=[CH:88][CH:87]=[CH:86][C:85]=1[CH2:90][CH2:91][NH2:92]>C(Cl)Cl>[CH2:7]([O:8][C:9](=[O:10])[NH:11][CH:12]([C:19](=[O:20])[N:21]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:31][CH:32]=1)[CH2:22][C:23](=[O:24])[NH:92][CH2:91][CH2:90][C:85]1[CH:86]=[CH:87][CH:88]=[CH:89][N:84]=1)[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Reactant: NCCc1ccccn1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)C(Cc1c[nH]cn1)NC(=O)OCc1ccccc1)NCCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
To a solution of the acid from Step 3 (0.33 g, 0.61 mmol) in methylene chloride was added PyBOP (0.67 g, 1.3 mmol) and diisopropylethylamine (0.23 mL, 1.3 mmol) followed by 2-pyridineethaneamine hydrochloride (0.082 g, 0.67 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, the residue taken up in ethyl acetate, which was washed 3 times with saturated NaHCO3, brine, dried over MgSO4, and concentrated. Flash chromatography gave 0.156 g (37%) of the title compound as a white foam; ES-MS 647 (m+1).
Reaction SMILES: [CH:1]1([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.[CH:7]1([C:10]([Cl:12])=[O:11])[CH2:9][CH2:8]1.Cl.O[CH:15]([C:30]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34](=[O:41])[NH:35]2)[CH2:16][NH:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1.CO>C(OCC)C>[ClH:12].[CH:1]1([C:4]([O:6][CH:15]([C:30]2[CH:39]=[CH:38][C:37]([O:40][C:10]([CH:7]3[CH2:9][CH2:8]3)=[O:11])=[C:36]3[C:31]=2[CH:32]=[CH:33][C:34](=[O:41])[NH:35]3)[CH2:16][NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(CCNCC(O)c2ccc(O)c3[nH]c(=O)ccc23)cc1OC
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(CCNCC(OC(=O)C2CC2)c2ccc(OC(=O)C3CC3)c3[nH]c(=O)ccc23)cc1OC
Temperature: 0 °C

Procedure:
2 ml of cyclopropanecarboxylic acid and 1 ml of cyclopropanecarboxylic acid chloride were added to 500 mg of 5-[1-hydroxy-2-(3,4-dimethoxyphenethylamino)ethyl]-8-hydroxycarbostyril hydrochloride, and the mixture was allowed to react for 1 hour at a temperature of 80° C. After completion of the reaction, 10 ml of methanol was added to the reaction mixture while cooling with ice-water followed by addition of diethyl ether to crystallize the product. The crystals thus obtained were separated by filtration, washed with diethyl ether and recrystallized from a mixture of ethanol and acetone to obtain 210 mg of 5-[1-cyclopropylcarbonyloxy-2-(3,4-dimethoxyphenethylamino)ethyl]-8-cyclopropylcarbonyloxycarbostyril hydrochloride having a melting point of 167°-168° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]#[N:6].[ClH:7].[CH2:8]([OH:10])[CH3:9]>>[ClH:7].[CH3:1][O:2][CH2:3][CH2:4][C:5](=[NH:6])[O:10][CH2:8][CH3:9]
Reactant: COCCC#N
Reactant: CCO
Agent: Cl
Product: CCOC(=N)CCOC
Temperature: 25 °C
Reaction time: 6 h
Yield: 63 %

Procedure:
3-Methoxypropanenitrile (5.0 g, 58.8 mmol) was dissolved in anhydrous ethanol (50 mL) under an atmosphere of Ar. The solution was cooled to 0° C., saturated with HCl gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo. The residue was slurried with hexanes (50 mL) and sonicated for 10 min. The solids were allowed to settle and the solvent was removed by decantation. This was repeated (3×). The solid was collected and dried under high vacuum for 5 h to afford ethyl 3-methoxypropanimidate hydrochloride (6.2 g, 63%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.03 (br s, 1H), 11.22 (br s, 1H), 4.42 (q, J=7.0 Hz, 2H), 3.60 (t, J=5.9 Hz, 2H), 3.23 (s, 3H), 2.87 (t, J=5.9 Hz, 2H), 1.33 (t, J=7.0 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[N:31]1([C:23]([C:22]2[CH:21]=[CH:20][C:19]([N:16]3[CH2:15][CH2:14][N:13]([CH2:12][C:9]4[CH:10]=[N:11][C:5]5[N:4]6[CH2:28][CH2:29][CH2:30][C@H:3]6[C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:18][CH2:17]3)=[CH:27][CH:26]=2)=[O:25])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C1Nc2cc(CN3CCN(c4ccc(C(=O)N5CCCC5)cc4)CC3)cnc2N2CCC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
In a 1 dram vial, (S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (100 mg, 0.245 mmol) was suspended in DMF (Volume: 1.227 mL) then added pyrrolidine (0.024 mL, 0.295 mmol), HATU (140 mg, 0.368 mmol) and N-methylmorpholine (0.108 mL, 0.982 mmol). The r×n was stirred at RT overnight. The mixture was purified by prep HPLC-MS (acidic mode, 15-35%). The pH of the combined fractions was adjusted to pH=8-9 and extracted with EtOAc (3×30 ml), washed with brine, dried with MgSO4, filtered and concentrated to dryness. The residue was taken up with water/ACN (1:1), and concentrated in vacuo to provide the title compound as a fluffy white solid (29 mg, 26% yield). m.p.=121.3° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.73-1.87 (m, 4H) 1.87-2.01 (m, 3H) 2.14-2.21 (m, 1H) 2.43-2.49 (m, 4H) 3.15-3.23 (m, 4H) 3.35 (br. s., 2H) 3.37-3.49 (m, 5H) 3.54-3.65 (m, 1H) 3.95-4.04 (m, 1H) 6.91 (d, J=9.09 Hz, 2H) 6.99 (d, J=2.02 Hz, 1H) 7.42 (d, J=8.84 Hz, 2H) 7.62 (d, J=1.77 Hz, 1H) 10.44 (s, 1H). [M+H] calc'd for C26H32N6O2, 461; found, 461.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)=[C:6]([NH:21][C@@H:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23]2)[N:5]=[CH:4][N:3]=1.O.NN>C(O)C>[NH2:10][CH2:9][CH2:8][C:7]1[C:6]([NH:21][C@@H:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23]2)=[N:5][CH:4]=[N:3][C:2]=1[Cl:1]
Reactant: O=C1c2ccccc2C(=O)N1CCc1c(Cl)ncnc1N[C@H]1CCc2ccccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCc1c(Cl)ncnc1N[C@H]1CCc2ccccc21
Temperature: 23 °C
Yield: 49.9 %

Procedure:
2-(2-{4-chloro-6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-5-yl}ethyl)-1H-isoindole-1,3(2H)-dione (3.50 g, 8.32 mmol) was suspended in ethanol (102 mL) and hydrazine hydrate (1.62 mL, 33.3 mmol) was added. The mixture was heated to reflux for 1 hour. At that time, LCMS indicated complete conversion. The mixture was cooled to 23° C., crystals were filtered off, the residue was evaporated in vacuo and purified using chromatography on silica gel using gradient 0 to 20% MeOH in methylene chloride to afford the title compound (1.20 g, 50%). LC/MS: Rt=1.29 min, ES+ 289 (AA standard).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]4[CH2:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[C:29]1([CH2:35][C:36]([N:38]=[C:39]=[O:40])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O.CCCCCC.C(OCC)C>[C:29]1([CH2:35][C:36]([NH:38][C:39](=[O:40])[NH:1][C:2]2[CH:28]=[CH:27][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:17][CH2:18][CH:19]([CH2:22][N:23]5[CH2:26][CH2:25][CH2:24]5)[CH2:20][CH2:21]4)=[O:15])[CH:8]=3)=[CH:4][CH:3]=2)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCC4)CC3)c2)cc1
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCC4)CC3)c2)cc1
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a solution of 4-(azetidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (31 mg) in N,N-dimethylformamide (1 ml) was added a solution of 0.25 M 2-phenylacetyl isocyanate in hexane (0.982 ml) under a nitrogen atmosphere, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml), brine (50 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated to give a residue, which was then suspended in diethyl ether (1.5 ml) and hexane (3 ml). The solid was filtered off and dried under aeration to provide the titled compound (28.0 mg, 63.1%) as white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].C(Cl)CCl.C(N(CC)CC)C.Cl>ClCCl>[CH3:24][O:23][N:22]([CH3:21])[C:17]([CH:14]1[CH2:13][CH2:12][N:11]([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]1)=[O:19]
Reactant: CNOC
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
In a 1 L round-bottomed flask, a solution of 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (21.0 g, 80 mmol) in anhydrous dichloromethane (250 mL) was stirred at room temperature until completely dissolved. After becoming clear, the reaction mixture was cooled to 0° C. and sequentially treated with N,O-dimethylhydroxylamine hydrochloride (9.74 g, 100 mmol), EDC (19.2 g, 100 mmol), and triethylamine (30.4 g, 41.81 mL, 300 mmol). After the additions were complete, the reaction mixture was stirred at room temperature overnight. 1 N HCl (250 mL) was added and after 5 min of additional stirring, the organic phase was separated, washed with 1 N HCl (100 mL), saturated aqueous NaHCO3 (150 mL), dried over MgSO4, filtered and concentrated. Purification by MPLC (100 g column, 50-100% ethyl acetate in heptane) gave benzyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (22.23 g, 91%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.42-7.29 (m, 5H), 5.21 (s, 2H), 4.32-4.16 (m, 2H), 3.70 (s, 3H), 3.18 (s, 3H), 2.96-2.78 (m, 3H), 1.80-1.64 (m, 4H). ESI MS found for C16H22N2O4 m/z [307.1 (M+1), 329.2 (M+23)].
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Cl)=[CH:5][C:3]=1[NH2:4].[CH2:13]([SH:16])[CH2:14][CH3:15].[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([S:16][CH2:13][CH2:14][CH3:15])=[CH:5][C:3]=1[NH2:4].[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([S:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][C:3]=1[NH2:4]
Reactant: Sc1ccccc1
Reactant: CCCS
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1cc(N)c(Cl)cc1[N+](=O)[O-]
Product: Nc1cc(Sc2ccccc2)c([N+](=O)[O-])cc1Cl

Procedure:
Similarly, 2.5-dichloro-4-nitroaniline is allowed to react with n-propyl mercaptan and thiophenol in dimethylformamide at 100° C. in the presence of potassium carbonate to afford 2-chloro-4-nitro-5-n-propylthioaniline, m.p. 125°-127° C., and 2-chloro-4-nitro-5-phenylthioaniline, m.p. 163°-166° C.