Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1.[CH3:33][N:34]=[C:35]=[O:36]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:35]([NH:34][CH3:33])=[O:36])[CH2:28][CH2:27]4)[CH2:22][CH2:23]3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C(CC1CCNCC1)N1CCN(C2c3ccc(Cl)cc3CCc3cc(Br)cnc32)CC1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 47 h
Yield: 84.8 %

Procedure:
1-(3-Bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-[(4-piperidinyl)acetyl]piperazine (Preparative Example 10) (500 mg, 0.9 mmoles) was dissolved in anhydrous dichloromethane (5 ml) and methyl isocyanate (220.3 mg, 3.6 mmoles) was added. The mixture was stirred under argon at 25° C. for 47 h. Additional methyl isocyanate (110.15 mg, 1.8 mmoles) was added and the reaction was stirred for a total of 144 h. The solution was heated at 74° C. for 5 h and the stirred at 25° C. for an additional 24 h. The solution was chromatographed on silica gel using 2% (10% conc. NH4OH in methanol)dichloromethane as the eluant to give 438.9 mg of the title compound (Yield: 79%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br>C(#N)C.O>[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: BrCc1cccc(Br)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Brc1cccc(CN2CCOCC2)c1
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 47.1 %

Procedure:
To a stirred solution of morpholine (0.5 g, 5.8 mmol) in acetonitrile (5 ml) was added K2CO3 (2.4 g, 17.44 mmol), followed by 3-bromobenzyl bromide (1.45 g, 5.8 mmol) at 0° C. and the reaction mixture was stirred at 20-35° C. for 16 h. The progress of the reaction was monitored by TLC. After 16 h of stirring, the mixture was diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (50 ml), followed by drying over anhydrous Na2SO4 and filtering. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 5% ethyl acetate/hexane as an eluent to get the desired compound as a white solid (700 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ 7.26 (d, J=8.3 Hz, 2H), 7.19-7.15 (m, 2H), 5.18 (s, 2H), 3.56 (t, J=4.6 Hz, 4H), 2.58 (t, J=4.4 Hz, 4H).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([O:4][C:5]([NH:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:6])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO.O>[CH2:24]([O:15][C:14]([CH:11]1[CH2:12][CH2:13][N:8]([NH:7][C:5]([O:4][C:2]([CH3:17])([CH3:1])[CH3:3])=[O:6])[CH2:9][CH2:10]1)=[O:16])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)NN1CCC(C(=O)O)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NN1CCC(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
1-[(1,1-Dimethylethoxycarbonyl)amino]-piperidine-4-carboxylic acid (6 g, 26.16 mmol, 1 eq.), from step 1, was dissolved in methanol (150 ml) and cesium carbonate (4.26 g, 13.08 mmol, 0.5 eq.) was added. The mixture was stirred at room temperature for 2 h, the solvent was removed under reduced pressure. The crude was dissolved in DMF (100 ml) and benzylbromide (5.37 g, 31.39 mmol, 1.2 eq.) was added dropwise. The mixture was stirred overnight at room temperature and poured in water (300 ml), extracted with Ethyl Acetate (900 ml) The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a white solid. Yield 95%, 7 g.
Reaction SMILES: [F:1][C:2]([F:14])([C:5]([F:13])([F:12])[C:6]([F:11])([F:10])[CH:7]([F:9])[F:8])[CH2:3][OH:4].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29](F)[N:28]=1>O>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:4][CH2:3][C:2]([F:14])([F:1])[C:5]([F:12])([F:13])[C:6]([F:10])([F:11])[CH:7]([F:8])[F:9])[N:28]=1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: Fc1cccc(F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
A reaction flask was loaded with 2,2,3,3,4,4,5,5-octafluoropentanol (16.1 g), DMF (42 ml), anhydrous potassium carbonate (9.6 g), followed by stirring at room temperature for one hour. To this mixture, 2,6-difluoropyridine (8.0 g) was dropwise added. The temperature was raised to 60° C., and the mixture was stirred for four hours. The heating was stopped, and water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was condensed by an evaporator to give 2-fluoro-6-(2,2,3,3,4,4,5,5-octafluoropentyloxy)-pyridine (20 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:29])[C:5]([C:21]1[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=1)([CH3:20])[C:6](=[O:19])[NH:7]2.B(Br)(Br)Br.CCCCCC>CCOC(C)=O>[Cl:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:29])[C:5]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([CH3:20])[C:6](=[O:19])[NH:7]2
Reactant: COc1ccc(C2(C)C(=O)Nc3cc(N4CCN(C)CC4)cc(Cl)c3C2=O)cc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN1CCN(c2cc(Cl)c3c(c2)NC(=O)C(C)(c2ccc(O)cc2)C3=O)CC1
Yield: 67.9 %

Procedure:
The objective compound was prepared by the same procedure for the example 13, using a 5-chloro-3-(4-methoxy-phenyl)-3-methyl-7-(4-methyl-piperazine-1-yl)-1H-quinoline-2,4-dione (0.03 g, 0.07 mmol) and BBr3(0.22 mL, 1.0 M dichloromethane solution). After normal workup, the pure objective compound (19 mg, 65%) was obtained as slightly yellow solid by recrytalization (n-hexane:EtOAc=1:3): 1H NMR (200 MHz, CDCl3) δ 1.75 (s, 3H, CH3), 2.38 (s, 3H, NCH3), 2.59-2.65 (m, 4H, 2×NCH2), 2.89-2.92 (m, 4H, 2×NCH2), 3.33 (s, 3H, OCH3), 6.52-6.55 (m, 2H, ArH), 6.69-6.74 (m, 2H, ArH), 7.04-7.08 (m, 2H, ArH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[O:5][CH2:6][CH:7]([OH:27])[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:18][C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])=[O:17])[CH2:11][CH2:10]1.[C:32](OC(=O)C)(=[O:34])[CH3:33].O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[O:5][CH2:6][CH:7]([O:27][C:32](=[O:34])[CH3:33])[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:18][C:19]2[C:20]([CH3:26])=[CH:21][CH:22]=[CH:23][C:24]=2[CH3:25])=[O:17])[CH2:11][CH2:10]1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1OCC(O)CN1CCN(CC(=O)Nc2c(C)cccc2C)CC1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccccc1OCC(CN1CCN(CC(=O)Nc2c(C)cccc2C)CC1)OC(C)=O
Reaction time: 2 h

Procedure:
One g of 1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine is dissolved in 25 ml of pyridine and cooled in an ice bath to 0°-5° C. Acetic anhydride (0.6 g) is slowly added and the reaction is stirred for 2 hours. After the addition of 100 ml of water, the reaction mixture is extracted twice with 100 ml portions of diethylether. After combining, the ether extract is washed twice with 100 ml of water and evaporated to dryness to produce 1-[3-(2-methoxyphenoxy)-2-acetoxypropyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7]2)([O-])=O.[H][H]>[Ni].CN(C)C=O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7]2
Reactant: [H][H]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]c1=O
Agent: [Ni]
Solvent: CN(C)C=O
Product: Nc1ccc2[nH]c(=O)c(C(=O)O)cc2c1

Procedure:
A solution of 3.63 g (14.9 mmol) of 1,2-dihydro-6-nitro-2-oxo-3-quinolinecarboxylic acid and 200 ml of dimethylformamide is hydrogenated using 1 g of Raney nickel catalyst at 52 psi and 23° until the required amount of hydrogen uptake is obtained. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue is treated with ethanol and 3.0 g of the desired product is filtered.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([CH:14]=1)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1>[Pd].C(O)C>[NH2:15][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:14][C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Cc1ccc([N+](=O)[O-])c(Nc2ccccn2)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(N)c(Nc2ccccn2)c1
Reaction time: 3 h

Procedure:
A mixture of 5-methyl-2-nitro-N-(2-pyridyl)aniline (3.8 g, 16.6 mmol), 5% palladium on carbon (500 mg) in ethanol (100 ml) was stirred under a hydrogen atmosphere for 3 h. The mixture was filtered through a pad of celite and the filtrate was concentrated to dryness to give 3.3 g (quant.) of the titled compound as gray solids.
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CC>C1(C)C=CC=CC=1.ClCCl>[CH2:2]([O:3][CH2:4][C@H:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOC[C@@H](O)CO
Temperature: 25 °C
Yield: 709.4 %

Procedure:
19.4 grams of (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol, 49 grams of powdered KOH and 4.8 grams of hexadecyl bromide were stirred in 500 ml toluene (500 ml) were stirred and refluxed for 6 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 100 ml and the reaction mixture was cooled to room temperature. The cooled reaction mixture was dissolved in 500 ml dichloromethane, washed twice with 200 ml water, and the solvent was removed under reduced pressure. The obtained residue was dissolved in 500 ml of a 90:10:5 (v/v) mixture of methanol:water:concentrated H2SO4, and the resulting solution was refluxed for 30 minutes, cooled to room temperature, and extracted with 500 ml dichloromethane. The extract was washed twice with 100 ml water, 100 ml aqueous 5% sodium carbonate, and again with 100 ml water, until neutral. The solvent was removed under reduced pressure and the crude product was recrystallized from hexane at 4° C., yielding 35.3 grams of pure 1-hexadecyl-sn-glycerol. The yield was 76%.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([NH:6][C:7]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:8])=[CH:4][CH:3]=1.C1(=O)O[CH2:20][CH2:19][O:18]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[OH:18][CH2:19][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: O=C1OCCO1
Reactant: O=C(Nc1ccc(O)cc1)C1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Product: O=C(Nc1ccc(OCCO)cc1)C1CCOCC1
Temperature: 166 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
4′-Hydroxy-3,4,5,6-tetrahydro-2H-pyran-4-carboxanilide (13.5 g), ethylene carbonate (5.96 g) and tetrabutylammonium iodide (2.26 g) were combined and stirred for 2 hours at 166° C. After being cooled, the mixture was added with water (100 ml) and further mixed. Crystals formed were collected by filtration, washed with water and then dried under vacuum at 60° C. to obtain 4′-(2-hydroxyethoxy)-3,4,5,6-tetrahydro-2H-pyran-4-carboxanilide (14.5 g) as white crystal.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[OH-].[K+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:14]1([S:20]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:10]=[O:11])=[CH:2]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Yield: 33 %

Procedure:
To a solution of indole 3-carboxaldehyde (8y) (100 mmol) in ethanol (500 mL) at RT was added potassium hydroxide (1.1 equiv). The mixture was stirred until total solubilization. The ethanol was completely removed in vacuum and the residual was dissolved in acetone (250 mL) followed by adding benzenesulfonyl chloride (1.1 equiv, 110 mmol). The reaction mixture was stirred for half hour. The precipitate was filtered off and the filtrate was concentrated and recrystallized from methanol to give a white solid. Yield: 33%. 1H NMR (500 MHz, CDCl3) δ 10.17 (s, 1H), 8.25-8.39 (m, 2H), 7.97-8.09 (m, 3H), 7.69 (t, J=7.33 Hz, 1H), 7.59 (t, J=7.5 Hz, 2H), 7.39-7.54 (m, 2H). MS (ESI) calcd for C15H11NO3S 285.1. found 286.0 [M+H]+.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[N:14]=2)[N:11]=1.C1C(=O)N([I:26])C(=O)C1>O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([I:26])=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[N:14]=2)[N:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(=O)Nc1cn2nc(Cl)ccc2n1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc2ccc(Cl)nn2c1I
Temperature: 25 °C
Yield: 83.4 %

Procedure:
To a CHCl3 (20 mL) solution of N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide (320.4 mg, 1521 μmol) was added n-iodosuccinimide (167.4 μl, 1673 μmol) as a solid in a single portion. The solution was maintained at rt for 20 min, then poured into water. The resulting mixture was extracted with CH2Cl2 (1×50 mL). The layers were separated and the organic layer was washed with saturated aqueous Na2S2O3 (1×20 mL) and brine (1×10 mL). The organic layer was dried (Na2SO4) and concentrated for purification by MPLC (CombiFlash® Companion®, Teledyne Isco, Lincoln, Nebr.). The residue was taken up in minimal CH2Cl2/MeOH and absorbed onto a 25 g silica loading cartridge and passed through a Redi-Sep® pre-packed silica gel column (80 g) (Teledyne Isco, Lincoln, Nebr.) using a gradient of 1% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2 to afford N-(6-chloro-3-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (427.0 mg, 83.41% yield) as a grey solid. LCMS (ESI positive ionization) m/z: 337.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH2:23][CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(OCC)(=O)C>CN(C)C=O>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH:17]([CH2:23][CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: CCOC(=O)C(Br)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC)Oc1cccc(C=O)c1

Procedure:
3-Hydroxybenzaldehyde (18.3 g, 0.150 mol) was dissolved in N,N-dimethylformamide (150 mL). Subsequently, potassium carbonate (22.80 g, 0.165 mol), and then ethyl 2-bromobutyrate (29.26 g, 0.150 mol) were added thereto, and the resultant mixture was stirred overnight at 80° C. The temperature of the reaction mixture was returned to room temperature. Ethyl acetate was added. Washing was performed sequentially with water and brine, followed by drying over sodium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate=5/1), whereby a colorless oil was obtained (35.29 g, 0.149 mol, 99.6%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([NH2:24])[CH2:19]2)=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([NH:24][CH:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:11][C:9]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([Br:8])[N:4]=2)=[O:10])[CH2:19]1)(=[O:34])[CH3:33]
Reactant: Nc1ncc(Br)nc1C(=O)Nc1cnccc1N1CCCC(N)C1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1CCCN(c2ccncc2NC(=O)c2nc(Br)cnc2N)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To solution of 3-amino-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-bromopyrazine-2-carboxamide in CH2Cl2 at a concentration of 0.5 M at room temperature was added triethylamine (3 eq) followed by acetic anhydride (1.2 eq). The reaction was stirred at room temperature for 30 minutes, concentrated, purified by reverse phase HPLC and lyophilized to provide N-(4-(3-acetamidopiperidin-1-yl)pyridin-3-yl)-3-amino-6-bromopyrazine-2-carboxamide, as the TFA salt. LCMS (m/z): 434.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N([O-])=O.[Na+].[N-:12]=[N+:13]=[N-].[Na+]>O.Cl>[N:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N+:12]=[N-:13]
Reactant: Nc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.2 %

Procedure:
To a solution of aniline (300 mg, 3.22 mmol) in water (2 mL) and conc. HCl (1 mL) at 0° C. was slowly added a solution of sodium nitrite (289 mg, 4.19 mmol) in water (1 mL). The reaction mixture was stirred at 0° C. for 10 min then a solution of sodium azide (251 mg, 3.87 mmol) in water (1 mL) was slowly added. The reaction mixture was stirred at room temp for 1 h then extracted with Et2O (2×). The combined organics were washed with water, dried over MgSO4, and carefully concentrated at 300 torr and ambient temperature to afford 350 mg (91%) of azidobenzene as a light orange oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].CCN(CC)CC.[C:16](Cl)(=[O:20])[CH:17]([CH3:19])[CH3:18]>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)C(C)C

Procedure:
10.00 g of glycine ethyl ester hydrochloride (71.6 mmol) and 21.97 ml of NEt3 (2.2 eq.) were dissolved in 200 ml of CH2Cl2 and treated between 0° and 5° dropwise with 7.81 ml of isobutyryl chloride (1.05 eq.), dissolved in 50 ml of CH2Cl2. The reaction mixture was allowed to reach ambient temperature (2.5 h) and then quenched by carefully pouring onto crashed ice/HCl/AcOEt. Separation of the layers, additional extraction of the aqueous phase with AcOEt, washing with Na2CO3 and brine, drying of the combined organic phase over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=6/4) yielded 11.74 g of the title compound as colorless oil.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1>ClCCl>[C:4]([O:3][C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:19]1[CH2:20][CH2:21][CH2:22][C@H:18]1[CH3:17])=[O:12])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: C[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
Equimolar amounts of (S) BOC proline (CAS 15761-39-4) and 2-(R)-methyl-pyrrolidine hydrochloride (CAS 135324-85-5) are coupled in a manner substantially analogous to Procedure D in dichloromethane to give 2(S)-(2(R)-methyl-pyrrolidine-1-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. The material is deprotected by stirring in dichloromethane at 5-10° C. while trifluoroacetic acid (10 eq,) is added and then stirred at room temperature for 18 h. The reaction is concentrated, dissolved in H2O, and the pH is adjusted to 8-9 with K2CO3. The mixture is extracted several times with CH2Cl2. The extracts are combined, dried (Na2SO4), filtered, and concentrated in vacuo to give (2(R)-methyl-pyrrolidin-1-yl)-pyrrolidin-2-yl-methanone. A 1 M lithium aluminum hydride/THF solution (3 eq.) is diluted with an equal volume of THF and stirred under N2 as a THF solution of (2(R)-methyl-pyrrolidin-1-yl)-pyrrolidin-2-yl-methanone is added dropwise, allowing the reaction to mildly exotherm. The reaction mixture is stirred at 40° C. for 45 min, and then at room temperature 18 h. The mixture is cooled in an ice bath and quenched with H2O (3 eq.), 4 N NaOH (3 eq.), then H2O (9 eq.) while keeping the reaction temperature less than 15° C. The mixture is stirred overnight, filtered, and the precipitate is washed three times with THF. The filtrate and washes are combined and concentrated to give 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 169.3 (M+H)+. The title compound is used as such or is purified by SCX chromatography or distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH:18][C:19](=[O:29])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[N+:26]([O-])=O)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.O1CCCC1.[H][H].N>[Ni].CO>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][CH2:17][CH2:16][N:13]1[CH2:12][CH2:11][CH:10]([N:6]2[C:5]3[CH:30]=[CH:31][C:2]([Cl:1])=[CH:3][C:4]=3[NH:8][C:7]2=[O:9])[CH2:15][CH2:14]1)=[O:29]
Reactant: [H][H]
Reactant: O=C(NCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1)c1ccccc1[N+](=O)[O-]
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccccc1C(=O)NCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1

Procedure:
A mixture of 16 parts of N{2-[4-(5-chloro-2,3-dihydro-2-oxo- 1H-benzimidazol-1-yl)-1-piperidinyl] ethyl}-2-nitrobenzamide in 90 parts of tetrahydrofuran and 40 parts of methanol is hydrogenated at normal pressure and at room temperature with 3 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, there is added a solution of methanol, previously saturated with gaseous ammonia. The catalyst is filtered off and the filtrate is evaporated. The residue is taken up in acidified water and the whole is washed twice with trichloromethane. The aqueous phase is separated and alkalized with a diluted sodium hydroxide solution. The product is extracted twice with trichloromethane. The combined extracts are washed three times with water, dried, filtered and evaporated. The residue is triturated in 2,2'-oxybispropane. The product is filtered off and crystallized from a mixture of ethanol and a small amount of water, yielding 2 parts of 2-amino-N-{2-[4-(5-chloro-2,3-dihydro-2-oxo- 1H-benzimidazol-1-yl)-1-piperidinyl] ethyl} benzamide; mp. 226.8° C.
Reaction SMILES: [CH3:1][O:2]/[CH:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([OH:24])=O)[CH:17]=1)/[C:5]([O:7][CH3:8])=[O:6].C(Cl)(=O)C([Cl:28])=O>C1COCC1.CN(C=O)C>[CH3:1][O:2]/[CH:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([Cl:28])=[O:24])[CH:17]=1)/[C:5]([O:7][CH3:8])=[O:6]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cccc(C(=O)Cl)c1
Reaction time: 0.75 h

Procedure:
The carboxylic acid from the previous stage (0.33 g) stirred in dry THF (10 ml) was treated with oxalyl chloride (0.11 ml) and one drop of dry DMF. The reaction mixture was stirred for 45 minutes, stood overnight and then evaporated to give crude (E)-methyl 3-methoxy-2-(2-[3-chlorocarbonylphenoxy]phenyl)propenoate as an orange-yellow oil.