Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[C:12]1=[O:27])[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[C:12]1=[O:27])[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccc(C(F)(F)F)cc2)C1=O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccc(C(F)(F)F)cc2)C1=O
Yield: 75.9 %

Procedure:
A solution of Example 139B (0.262 g) in dichloromethane (3 mL) was treated with trifluoroacetic acid (3 mL) at 25° C. for 16 h. The solvents were evaporated, and the crude residue was purified using reverse phase chromatography eluting with 95%water (0.1% trifluoroacetic acid)/5% acetonitrile to 100% acetonitrile to give the title compound (0.172 g, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]Cl)=[N:6][CH:7]=1.Cl.[CH3:11][O:12][NH2:13].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:13][O:12][CH3:11])=[N:6][CH:7]=1
Reactant: ClCc1ccc(Br)cn1
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CONCc1ccc(Br)cn1
Temperature: 60 °C
Yield: 28.5 %

Procedure:
To a stirred solution of 5-Bromo-2-chloromethyl-pyridine (2 g, 9.709 mmol) in dimethylformamide (30 mL) is added methoxy amine hydrochloride salt (0.973 g, 11.65 mmol) and K2CO3 (3.35 g, 24.27 mmol) at room temperature then heated to 60° C. for 16 hours. Reaction mixture diluted with water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combiflash using 30% ethyl acetate in hexane as an eluent to afford the title compound (0.6 g). 1HNMR (400 MHz, DMSO-d6) δ: 3.36 (s, 3H), 3.99 (d, J=5.88 HZ, 2H), 7.10 (t, 1H), 7.44-7.46 (dd, J1=8.32 Hz, J2=0.32 Hz, 1H), 7.99-8.02 (dd, J1=2.44 Hz, J2=8.4 Hz, 1H), 8.60-8.61 (dd, J1=2.4 Hz, J2=0.4 Hz, 1H). LC-MS (m/z): [M+H]=217.1.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]1[C:17]2[O:16][CH2:15][CH2:14][C:13]=2[C:12]([CH2:18][CH2:19][CH2:20][NH2:21])=[CH:11][CH:10]=1.C1COCC1>N1C=CC=CC=1>[F:8][C:9]1[C:17]2[O:16][CH2:15][CH2:14][C:13]=2[C:12]([CH2:18][CH2:19][CH2:20][NH:21][C:1](=[O:3])[CH3:2])=[CH:11][CH:10]=1
Reactant: NCCCc1ccc(F)c2c1CCO2
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)NCCCc1ccc(F)c2c1CCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (0.18 ml) was added dropwise to a solution of 3-(7-fluoro-2,3-dihydro-benzofuran-4-yl)-propylamine (256 mg) in, dry THF (10 ml) containing pyridine (0.21 ml) at 0° under nitrogen and the solution stirred overnight at room temperature. The solution was evaporated and the residue purified by column chromatography. Eluting with dichloromethane:methanol: (50:1) gave the title compound as a colouriess oil (133 mg)
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[H-].[Na+].Cl[C:12]1[C:21]2[C:16](=[C:17]([C:22]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH:34]([CH3:36])[CH3:35])=[C:29]([Cl:37])[CH:28]=4)[O:24][N:23]=3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1>CS(C)=O.C(Cl)Cl>[Cl:37][C:29]1[CH:28]=[C:27]([C:25]2[O:24][N:23]=[C:22]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:16]=3[CH:15]=[CH:14][N:13]=[C:12]4[NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])[N:26]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Cl)nccc34)no2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(N[C@H](C(=O)O)C(C)C)nccc34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
A mixture of L-valine (36.6 mg, 0.312 mmol) and sodium hydride (60%; 9.99 mg, 0.250 mmol) in dimethyl sulfoxide (DMSO) (2 ml) were stirred at room temp for 30 min. 1-Chloro-5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)isoquinoline (D7; 50 mg, 0.125 mmol) was added and the reaction mixture was stirred at 120° C. under nitrogen for 48 hr. The cooled reaction mixture was loaded onto an SCX column. The column was flushed with acetonitrile and then the desired product was eluted with 20% ammonia in acetonitrile. The solvent was removed in vacuo from the appropriate fractions to give an orange solid which was dissolved in DCM and washed with water. The organics were passed through a hydrophobic frit and the solvent was removed in vacuo to give the title compound as an orange solid (22 mg). MS (ES) C25H2535ClN4O4 requires 480. found 481 [M+H]+.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[F:11][C:12]([F:41])([F:40])[CH2:13][NH:14][C:15]([C:17]1([CH2:30][CH2:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16]>ClCCl.C(O)C>[F:40][C:12]([F:11])([F:41])[CH2:13][NH:14][C:15]([C:17]1([CH2:30][CH2:31][CH2:32][CH2:33][N:34]2[CH2:35][CH2:36][N:37]([C:2]3[NH:6][C:5]4[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=4[N:3]=3)[CH2:38][CH2:39]2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=2[C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:16]
Reactant: O=C(NCC(F)(F)F)C1(CCCCN2CCNCC2)c2ccccc2-c2ccccc21
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CCO
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3nc4ccccc4[nH]3)CC2)c2ccccc2-c2ccccc21
Temperature: 150 °C

Procedure:
A mixture of 0.05 g (0.328 mmol) of 2-chloro-1H-benzimidazole and 0.21 g (0.487 mmol) of 9-(4-piperazin-1-yl-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide is heated to 150° C. for two hours. After cooling, the reaction mixture is dissolved in dichloromethane/ethanol. The product is purified by column chromatography on silica gel (eluant: dichloromethane/ethanol=20:1).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.[Cl:12][C:13]1[C:20]([Cl:21])=[C:19]([O:22][CH3:23])[C:18]([O:24][CH3:25])=[CH:17][C:14]=1[CH:15]=[O:16].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:6][N:7]1[C:11]([CH:15]([OH:16])[C:14]2[CH:17]=[C:18]([O:24][CH3:25])[C:19]([O:22][CH3:23])=[C:20]([Cl:21])[C:13]=2[Cl:12])=[CH:10][CH:9]=[N:8]1
Reactant: Cn1cccn1
Reactant: COc1cc(C=O)c(Cl)c(Cl)c1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccnn2C)c(Cl)c(Cl)c1OC
Reaction time: 1 h
Yield: 90.5 %

Procedure:
18 ml of 1.6M n-butyl lithium in n-hexane is added dropwise to a solution of 2.26 g of 1-methyl-pyrazole in tetrahydrofuran at -60° C. under argon gas atmosphere and the mixture is stirred at the same temperature for 1 hour. A solution of 5.88 g of 2,3-dichloro-4,5-dimethoxybenzaldehyde in tetrahydrofuran is added dropwise to the mixture at -60° to -50° C. and the mixture is stirred at -50° C. to room temperature for 1 hour. An aqueous ammonium chloride solution is added to the reaction mixture and the mixture is concentrated to remove organic solvent. The residue is extracted with ethyl acetate, and the extract is washed, dried and evaporated to remove solvent. The residue is crystallized from isopropyl ether to give 7.18 g of α-(1-methylpyrazol-5-yl)-2,3-dichloro-4,5-dimethoxybenzylalcohol.
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[C:13]3[C:14]([O:17][CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[N:15][O:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:25]([C:27]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=O.C(C1(C(OC)=O)CCC1)=O>>[CH:1]1([CH2:6][O:7][C:8]2[C:13]3[C:14]([O:17][CH2:18][CH:19]4[CH2:20][CH2:21][N:22]([CH2:25][C:27]5([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)[CH2:23][CH2:24]4)=[N:15][O:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1cc(OCC2CCCC2)c2c(OCC3CCNCC3)noc2c1
Reactant: COC(=O)C1(C=O)CCOCC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(OCC5CCCC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 4-(cyclopentylmethoxy)-3-(piperidin-4-ylmethoxy)-1,2-benzisoxazole (EXAMPLE 22, Step 2) and methyl 4-formyltetrahydro-2H-pyran-4-carboxylate (EXAMPLE 18, Step 1) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.C1(C)C=CC=CC=1[Mg]Cl.C([Mg]Cl)(C)C.[F:25][C:26]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[O:29].Cl>O1CCCC1>[F:25][C:26]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]([C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1)[OH:29]
Reactant: O=Cc1cccc([N+](=O)[O-])c1F
Reactant: Ic1c[nH]c2ncncc12
Agent: CC(C)[Mg]Cl
Agent: Cc1ccccc1[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(C(O)c2c[nH]c3ncncc23)c1F
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
To 5-iodo-7H-pyrrolo[2,3-d]pyrimidine (35, 1.911 g, 7.799 mmol) 9.75 mL of tetrahydrofuran was added, the suspension was cooled to −5° C., and o-tolylmagnesium chloride (8.19 mL, 1.00 M in tetrahydrofuran, 8.19 mmol) was added. The reaction solution was stirred and kept between −5° C. and 0° C. for 30 minutes, then isopropylmagnesium chloride (4.29 mL, 2.0 M in tetrahydrofuran, 8.58 mmol) was slowly added dropwise. The reaction mixture was stirred and kept at 0° C. for 30 minutes, then 2-fluoro-3-nitro-benzaldehyde (36, 1.58 g, 9.36 mmol) in 4 mL of tetrahydrofuran was added dropwise using a syringe. The reaction mixture was stirred at −5° C. for 30 minutes and quenched with 1 N hydrochloric acid (1 equivalent) and extracted with ethyl acetate and saturated sodium bicarbonate in water. The organic layer was dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with a gradient of 60-80% ethyl acetate in hexanes (with 4% acetic acid). Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (37, 699 mg). MS(ESI) [M+H+]+=289.4.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:30][CH2:31][CH3:32])[C:28]=1[F:29])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([OH:24])[CH:17]=2)[CH2:10][CH2:9]1)[CH3:2].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:31]([O:30][C:27]1[CH:26]=[C:6]([CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:28]=1[F:29])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:16]2[CH:17]=[C:18]([O:24][S:34]([CH3:33])(=[O:36])=[O:35])[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=2)=[O:25])[CH2:10][CH2:9]1)[CH3:32]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(O)cc(OC)c3)CC2)cc(OCC)c1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OS(C)(=O)=O)c3)CC2)cc(OCC)c1F

Procedure:
In analogy to the procedure described in example 72a), N-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-3-hydroxy-5-methoxy-benzamide (example 257) was reacted with methanesulfonyl chloride, N-ethyl-diisopropylamine in CH2Cl2 at rt to yield the title compound as colorless solid. MS: 525.2 (MH+).
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:24]=[C:21]1[N:20]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:10]2=[N:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:25])=[CH:6][CH:5]=3)[N:8]=[C:9]2[CH2:23][CH2:22]1
Reactant: CCOC(=O)CCCCCCBr
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NC(=O)CC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCN1C(=O)CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21

Procedure:
A yellow solution of 2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one (step 1) (1.0 g, 3.04 mmol) and ethyl 7-bromoheptanoate (1.440 g, 6.07 mmol) in DMF (20 ml), under a nitrogen atmosphere, was treated with potassium carbonate (2.098 g, 15.18 mmol) and the resultant suspension was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with EtOAc (×2). The extracts were washed with water (×2) and brine, dried (MgSO4) and evaporated under vacuum to a brown oil. The crude material was purified by chromatography on silica eluting with 0-100% EtOAc/iso-hexane to afford the title compound as a pale solid;
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[OH:25])=[O:16].O>CN(C)C=O>[F:14][C:12]1[CH:13]=[CH:8][C:9]2[C:15](=[O:16])[C:17]3[C:18]([O:25][C:10]=2[CH:11]=1)=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3
Reactant: COc1ccc(C(=O)c2ccc(F)cc2F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(=O)c3ccc(F)cc3oc2c1
Temperature: 100 °C
Yield: 88.9 %

Procedure:
A mixture of potassium carbonate (2.13 g, 15.4 mmol) and (2,4-difluoro-phenyl)-(2-hydroxy-4-methoxy-phenyl)-methanone (3.4 g, 12.9 mmol) in N,N-dimethylformamide (50 mL) was heated at 100° C. for 2 h. The mixture was cooled and poured into water (˜150 mL). A solid was collected by filtration, washed with water, and dried in vacuo to give the title compound (2.8 g), which was used without purification in the subsequent step. MS: m/z 244.9 (MH+). 1H NMR (CDCl3): δ 3.94 (s, 1H), 6.88 (d, 1H, J=2.4 Hz), 6.96 (d of d, 1H, J=2.4 & 8.9 Hz), 7.07 (m, 2H), 8.24 (d, 1H, 8.9 Hz) and 8.34 (d of d, 1H, J=6.5 & 8.8 Hz).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]1([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26]>O1CCCC1>[CH3:21][C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:18]([OH:20])=[O:19]
Reactant: CC(C(=O)O)c1ccccc1
Reactant: CC(C)CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CCC(C)(C(=O)O)c1ccccc1
Temperature: 42.5 °C

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (278.57 g, 1.66 mol) in tetrahydrofuran (700 mL) was added 2-phenyl propionic acid (100.0 g, 0.666 mol) over 40 minutes maintaining the temperature below 15° C. The solution was warmed 40-45° C. for 20 minutes, then cooled below 25° C. and 1-bromo-3-methylbutane (156.0 g, 1.03 mol) was added. The reaction mixture was heated to 50° C. for 10 h, then was cooled to RT, and concentrated to a thick sludge. Methyl tert-butyl ether (900 mL) and water (1100 mL) were added, and the layers were separated. The organic phase was extracted with H2O (200 mL). The combined aqueous phases were treated with 3 M HCl (520 mL) to adjust the pH to approximately 2. The product was extracted with ethyl acetate (1000 mL) and the organic layer was concentrated to a thick oil to give the title compound. The crude oil (assayed for 136.99 g of Example 39-1, 95.3% assay yield) was used directly.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:9]([O:17]CC)(=O)[CH2:10][C:11]([O:13]CC)=O>>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:11](=[O:13])[CH2:10][C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8])=[O:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccccc1N
Product: Cc1ccccc1NC(=O)CC(=O)Nc1ccccc1C
Temperature: 170 °C
Reaction time: 8 h

Procedure:
329 mmol o-toluidine and 165 mmol diethyl malonate were put together and stirred overnight at 170° C. The formed ethanol was distilled off directly on a stream of nitrogen. N1,N3-di(2-methylphenyl)malonamide was formed as one solid block. The reaction was cooled and EtOAc was added. The product had to be crushed with a mortar, because it resembled very hard brick. The crushed material was stirred in EtOAc and filtered. EtOAc added was added twice and the mixture was stirred and filtered each time. 38.1 g N1,N3-di(2-methylphenyl) malonamide (yield 82%) was obtained.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]([O:10][C:11]([NH:13][CH2:14][C:15]1[C+:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]1[CH2:24][CH:25]=[C:26]([CH3:28])[CH:27]=[C:19]1[C:18]2([CH3:30])[CH3:29])=[O:12])([CH3:9])([CH3:8])[CH3:7].CO[CH:33](OC)[N:34]([CH3:36])[CH3:35].N12CCCN=C1CCCCC2>CN(C)C=O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]([O:10][C:11]([NH:13][CH2:14][C:15]1[C+:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]1[CH2:24][CH:25]=[C:26]([CH:28]=[CH:33][N:34]([CH3:36])[CH3:35])[CH:27]=[C:19]1[C:18]2([CH3:30])[CH3:29])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC1=CCN2C3=CC=C(CNC(=O)OC(C)(C)C)[C+]=C3C(C)(C)C2=C1
Reactant: COC(OC)N(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CN(C)C=CC1=CCN2C3=CC=C(CNC(=O)OC(C)(C)C)[C+]=C3C(C)(C)C2=C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(tert-Butoxycarbonylamino-methyl)-8,10,10-trimethyl-10H-pyrido[1,2-a]indolylium perchlorate (34 g, 0.077 mol; Sigma-Aldrich) was placed in 1-L round-bottom, one-necked flask equipped with magnetic stir bar and a reflux condenser. 75 mL of dimethylformamide and 38.5 mL of 1,1-Dimethoxy-N,N-dimethylmethanamine (38.5 mL, 0.290 mol; Aldrich) were added to the flask followed by 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.1 g, 0.0006 mol; Aldrich). The flask was immersed in oil bath with temperature set to 100° C. Stirring was started and continued for 30 min. The flask was cooled to room temperature, the solvent was evaporated in vacuum and the residue was recrystallized from methanol. The yield was 29 g (green crystals, 71% of theory).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:7][CH2:8]Cl)[CH2:4][CH2:5]Cl.[N+:10]([C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])([O-:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:2][N:3]1[CH2:7][CH2:8][N:16]([C:15]2[CH:14]=[C:13]([N+:10]([O-:12])=[O:11])[CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:4]1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A mixture of N-methylbis(2-chloroethyl)-amine hydrochloride (9.8 g) and 3-nitroaniline (7.0 g) in 1-butanol (100 ml) was heated at reflux for 60 h then cooled to room temperature. Sodium carbonate (2.8 g) was added and the mixture heated at reflux for a further 18 h. The mixture was cooled to 0° C. and filtered. The solid was collected, washed with anhydrous ether then partitioned between dichloromethane (200 ml) and sodium hydroxide solution (1M, 150 ml). The organic layer was separated and the aqueous phase washed once more with dichloromethane (200 ml). The combined organic layers were dried (K2CO3) and evaporated in vacuo. The resultant residue was chromatographed on silica gel, using dichloromethane:methanol (96:4) as the eluant, to afford an orange oil. The oil crystallized on standing and the resultant solid was triturated with petrol (60/80) to give the desired piperazine (5.64 g). 1H NMR (360 MHz, CDCl3) δ 2.37 (3H, s), 2.58 (4H, t, J=5 Hz), 3.30 (4H, t, J=5 Hz), 7.18 (1H, dd, J=9 and 3 Hz), 7.35 (1H, t, J=8 Hz), 7.64 (1H, dd, J=9 and 2 Hz), 7.71 (1H, d, J=2 Hz). MS (CI, NH3) 222 (M+1).