Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:15])[O:10][C:8](=[O:9])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[Br:16][C:17]1[CH:23]=[CH:22][C:20]([OH:21])=[CH:19][C:18]=1[OH:24].C(O)(=O)C1C(=CC=CC=1)C(O)=O>ClCC(Cl)(Cl)Cl.C(OCC)(=O)C.ClCCl.[N+](C)([O-])=O>[Br:16][C:17]1[C:18]([OH:24])=[CH:19][C:20]([OH:21])=[C:22]([CH:23]=1)[C:8]([C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[C:5]([OH:10])=[O:15])=[O:9]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Oc1ccc(Br)c(O)c1
Agent: ClCC(Cl)(Cl)Cl
Agent: O=C(O)c1ccccc1C(=O)O
Agent: [Al+3]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C[N+](=O)[O-]
Product: O=C(O)c1ccccc1C(=O)c1cc(Br)c(O)cc1O
Reaction time: 2 h

Procedure:
Aluminum chloride (8.48 g, 64 mmol) was added to a stirring suspension of phthalic anhydride (2.36 g, 16 mmol) in tetrachloroethane (40 mL) under nitrogen. Nitromethane (6 mL) was added to dissolve the reactants. 4-Bromoresorcinol (3 g, 16 mmol) was added and the mixture continued to stir under nitrogen. The reaction was monitored by high performance liquid chromatography (HPLC) over a period of 2 hours. It was observed that the reaction had ceased within the first 30 minutes, with starting materials remaining. The solution was diluted with ethyl acetate (˜150 mL) and washed with 1M hydrochloric acid (2×100 mL). The product was extracted from the organic layer into a saturated solution of sodium bicarbonate in water (200 mL). The basic aqueous phase was acidified with 3M hydrochloric acid to a pH of 5. The product was extracted from the aqueous phase into ethyl acetate (150 mL), washed with brine (2×100 mL), dried over magnesium sulfate and concentrated to give an orange oil which solidified upon standing for about 10 minutes. The solid was slurried in dichloromethane (20 mL) and filtered to give a mixture of the desired product and phthalic acid. Slurrying in water (20 mL) followed by filtration gave the desired product as a beige powder (1.72 g, 5.1 mmol, 32% yield).
Reaction SMILES: C(=O)=O.CC(C)=O.N.[K].[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:19])=[C:15]([CH:18]=1)[C:16]#[N:17].[C:20]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)#[N:21].[NH4+].[Cl-]>C1COCC1.O.O.O.O.O.O.O.O.O.[N+]([O-])([O-])=O.[Fe+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[Cl:10][C:11]1[CH:18]=[C:15]2[C:14]([CH:19]=[C:20]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[N:21]=[C:16]2[NH2:17])=[CH:13][CH:12]=1
Reactant: N#Cc1cccc2ccccc12
Reactant: Cc1ccc(Cl)cc1C#N
Agent: [Fe+3]
Agent: N
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: O
Product: Nc1nc(-c2cccc3ccccc23)cc2ccc(Cl)cc12
Reaction time: 0.08 h
Yield: 14.3 %

Procedure:
A 500-mL, three-necked, round-bottomed flask equipped with a dry ice-acetone cooled reflux condenser, addition funnel, and a gas inlet was charged with liquid ammonia (150 mL). Iron (III) nitrate nonahydrate (spatula end) was added in one portion as a solid, and then potassium metal (5.16 g, 132.0 mmol) was added cautiously in small portions. A solution of 5-chloro-2-methylbenzonitrile (10.00 g, 65.96 mmol) in THF (30 mL) was added dropwise over 5 minutes, the reaction mixture was stirred for 5 minutes, a solution of 1-cyanonaphthalene (15.16 g, 98.97 mmol) in THF was added dropwise over 5 minutes, and the reaction mixture was allowed to stir overnight as the liquid ammonia gradually evaporated. The crude reaction mixture was cautiously poured into saturated aqueous NH4Cl, and the aqueous phase was extracted with methylene chloride. The combined organic extracts were dried and concentrated. The residue was purified by flash chromatography with 2:1 hexane-ethyl acetate, and the crude product was recrystallized from 2:1 hexane-ethyl acetate to afford the title compound (2.88 g, 9.45 mmol, 14% yield) as yellow crystals: mp 180°-181°; IR(CHCl3) 3513, 3409 cm-1 ; MS m/e 305 (M+ +H NMR(CDCl3) δ 8.00-8.17(m,1H), 7.83-8.00(m,2H), 7.80(s,1H), 7.33-7.79(m,6H), 7.25(s,1H), 5.35(s,2H). Anal. Calcd for C19H13ClN2 : C,74.88; H,4.30; Cl,11.83; N,9.19. Found: C,74.77; H,4.09; Cl,11.87; N,8.81.
Reaction SMILES: [C:1]1([CH:13]2[CH2:18][CH2:17][C:16](=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2.C1(C2CCC(=CC#N)CC2)N=NN2C=1C1C=CNC=1N=C2>>[C:1]1([CH:13]2[CH2:14][CH2:15][CH:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:17][CH2:18]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2
Reactant: CCOC(=O)C=C1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Agent: N#CC=C1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Product: CCOC(=O)CC1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Yield: 51 %

Procedure:
The reactions in Synthetic Examplea 435 were carried out in substantially the same manners except that ethyl 2-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexylidene]acetate obtained in Synthetic Examplea 436 was used instead of 2-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexylidene]acetonitrile to give the title compound as a colorless solid (cis/trans mixture; 29.0 mg, yield 51%).
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:22][O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17]([OH:19])=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:30][C:31]([NH2:33])=[S:32].C([O-])(=O)C.[Na+].Cl>O>[NH2:33][C:31]1[S:32][CH:2]=[C:3]([C:4](=[N:22][O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:5]([NH:7][CH:8]2[C:20](=[O:21])[N:10]3[C:11]([C:17]([OH:19])=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]23)=[O:6])[N:30]=1
Reactant: NC(N)=S
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC)C(=O)CCl)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC)c3csc(N)n3)[C@H]2SC1
Yield: 90.6 %

Procedure:
To a suspension of 7-(4-chloro-2-methoxycarbonylmethoxyimino-3-oxobutyramido)-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (2.0 g) in water (20 ml) were added thiourea (0.683 g) and sodium acetate (1.84 g) at 40° C. with stirring. The reaction mixture was stirred at the same temperature for 1.5 hours. The resultant solution was adjusted to pH 2.8 with 10% hydrochloric acid and stirred under ice-cooling for 20 minutes. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-(2-aminothiazol-4-yl)-2-methoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.9 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:23])[CH:19]=3)[N:14]=1)[CH2:9][CH2:8]2.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:23][C:31](=[O:32])[CH2:30][C:27]4[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=4)[CH:19]=3)[N:14]=1)[CH2:9][CH2:8]2
Reactant: O=C(O)Cc1ccncc1
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)Cc4ccncc4)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method described in example 6 from rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine and 4-pyridine-acetic acid; MS: m/e=425.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([S:11]([CH3:13])=O)[N:3]=1.SC[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C1CCN2C(=NCCC2)CC1.O>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([S:11][CH2:13][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(Cl)c1C#N
Reactant: SCCc1ccccn1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(Cl)nc(N)nc1SCCc1ccccn1
Reaction time: 1 h
Yield: 22.3 %

Procedure:
To a stirred suspension of 1.00 g (4.62 mmol) 2-amino-4-chloro-6-methanesulfinyl-pyrimidine-5-carbonitrile in 10 ml DME were added 642 mg (4.62 mmol) 2-mercapto-ethylpyridine and 1.05 ml (6.92 mmol) DBU and stirring continued for 1 hour at room temperature. 50 ml water was then added and the resulting crystals collected by filtration and washed with ether. Chromatography (ethyl acetate/hexane 111 then ethyl acetate) followed by trituration in ether afforded 300 mg (22%) 2-amino-4-chloro-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 294 (M{37Cl}+H+, 30), 292 (M{35Cl}+H+, 100).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]([OH:22])[CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21].Cl[CH2:24][CH2:25][O:26][CH3:27]>>[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]([O:22][CH2:24][CH2:25][O:26][CH3:27])[CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21]
Reactant: COCCOCCOCC(O)COCCOCCOC
Reactant: COCCCl
Agent: [Na+]
Agent: [OH-]
Product: COCCOCCOCC(COCCOCCOC)OCCOC
Temperature: 60 °C
Yield: 84.6 %

Procedure:
20.4 g (0.51 mol) of NaOH pellets were added to 100 g (0.34 mol) of 1,3-bis[2-(2-methoxyethoxy)ethoxy]-2-propanol resulting from Step 1. 48.2 g (0.51 mol) of 2-chloroethylmethylether was dropwise added in small portions while stirring at 60° C. After the completion of dropwise addition, the mixture was stirred for about 2 hours and a precipitated salt was filtered off, the filtrate was condensed and purified by a vacuum distillation to give 102 g of 1,3-bis[2-(2-methoxyethoxy)ethoxy]-2-(2-methoxyethoxy)propane (E) (yield: 85%). The distillation temperature was from 155 to 161° C./0.2 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]2([CH2:27][F:28])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:9]2)[CH:7]=1.[CH3:30][O:31][C:32]1[N:33]=[CH:34][C:35]([C:38](O)=[O:39])=[N:36][CH:37]=1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C>CN(C=O)C.O.CCOC(C)=O>[C:19]([NH:18][C:10]1[O:11][C@H:12]([C:14]([F:15])([F:16])[F:17])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:38]([C:35]3[CH:34]=[N:33][C:32]([O:31][CH3:30])=[CH:37][N:36]=3)=[O:39])[CH:3]=[CH:4][C:5]=2[F:29])([CH2:27][F:28])[N:9]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(NC(=O)c3ccccc3)=N2)c1
Reactant: COc1cnc(C(=O)O)cn1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(NC(=O)c4ccccc4)=N3)c2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of crude N-((4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (1k, 0.25 g, 0.605 mmol, step 9) in DMF (3 ml) was added 5-methoxypyrazine-2-carboxylic acid (0.117 g, 0.756 mmol, Ark Pharm), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.345 g, 0.907 mmol, Oakwood Products) and di-isopropylethylamine (0.156 g, 1.210 mmol, Aldrich). The reaction was stirred at ambient temperature for 10 minutes. The reaction was diluted with water and EtOAc. The organic layer was separated and washed sequentially with aqueous saturated sodium bicarbonate solution, 1 M aqueous LiCl solution, and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude material was purified via silica gel flash chromatography using a gradient of 0-45% EtOAc in hexanes to afford the title compound as a white solid (0.110 g, 0.2 mmol, 33% overall yield for this step and steps 9 in Example 1). MS m/z=550.0 [M+H]+. Calculated for C25H20F5N5O4: 549.449
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[C:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:19]O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[C:7]([CH3:11])[C:8]([O:10][CH3:19])=[O:9])=[CH:12][CH:13]=1
Reactant: CO
Reactant: CC(=Cc1ccc(O)cc1)C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)=Cc1ccc(O)cc1

Procedure:
To 4-hydroxy-α-methylcinnamic acid (55 g), absolute methanol (400 ml) and conc. sulfuric acid (10 ml) were added and refluxed for 12 hours. After the reaction mixture was allowed to cool, it was concentrated under reduced pressure. To the residue was added water (300 ml), and the mixture was neutralized with sodium hydrogen carbonate, and the resulting precipitate was collected by filtration, washed with water, and recrystallized from ethyl acetate/nhexane to give methyl 4-hydroxy-α-methylcinnamate (53 g). mp. 103°-104° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[CH:15][C:14]([Cl:27])=[CH:13][CH:12]=2)=[O:8].[C:31](OC(=O)C)(=[O:33])[CH3:32]>O1CCCC1.O>[C:31]([NH:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])=[O:20])=[CH:15][C:14]([Cl:27])=[CH:13][CH:12]=2)=[O:8])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(CNC(=O)c2[nH]c3ccc(Cl)cc3c2S(=O)(=O)c2ccccc2)c1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cccc(CNC(=O)c2[nH]c3ccc(Cl)cc3c2S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N-(3-aminobenzyl) 3-phenylsulfonyl-5-chloroindole-2-carboxamide (Examplle 41) (176 mg, 0.4 mmol) in dry tetrahydrofuran (7 mL) containing acetic anhydride (0.05 mL, 0.5 mmol) was stirred at room temperature for 16 hours. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered through charcoal, and the solvents evaporated. The residue was triturated with methylene chloride and the solid collected by filtration to give the product, mp 249°-250° C.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH2:14][CH2:15][O:16][CH3:17])[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>CN(C=O)C>[CH3:17][O:16][CH2:15][CH2:14][N:4]1[C:5](=[O:13])[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:2]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[C:3]1=[O:18]
Reactant: COc1ccc(N)cc1
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)C1=O
Solvent: CN(C)C=O
Product: COCCN1C(=O)C(Nc2ccc(OC)cc2)=C(c2ccccc2)C1=O
Temperature: 150 °C
Yield: 21.3 %

Procedure:
3-Chloro-1-(2-methoxyethyl)-4-phenyl-1H-pyrrole-2,5-dione (0.20 mmol, 53 mg) and 4-methoxyaniline (0.48 mmol, 59 mg) were dissolved in DMF (1 mL). The mixture was heated in a microwave reactor at 150° C. for five min.min. After cooling, the reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 15 mg (21%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 7.27 (bs, 1H), 7.13-7.04 (m, 3H), 7.00-6.96 (m, 2H), 6.61-6.50 (m, 4H), 3.80 (t, J=5.6 Hz, 2H), 3.67 (s, 3H), 3.62 (t, J=5.6 Hz, 2H), 3.36 (s, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:8][NH:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:11])=[O:5].[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[N:26]1([C:24]([CH:7]([NH:6][C:4](=[O:5])[CH2:3][NH:2][S:38]([C:35]2[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=2)(=[O:40])=[O:39])[CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[O:25])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCC(=O)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)NCC(=O)NC(CNC(=O)C2CCN(c3ccncc3)CC2)C(=O)N2CCCCC2)cc1
Yield: 50 %

Procedure:
Using an analogous procedure to that described in Example 2, 2-amino-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamide hydrochloride salt was reacted with 4-toluenesulphonyl chloride to give N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}-2-(4-toluenesulphonamido)aceta mide in 50% yield as a foam;
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1.[CH:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1>C1COCC1>[Cl:6][C:7]1[C:12]([CH:26]([C:23]2[CH:24]=[CH:25][C:20]([O:19][C:16]3[CH:15]=[CH:14][CH:13]=[CH:18][CH:17]=3)=[CH:21][CH:22]=2)[OH:27])=[N:11][CH:10]=[CH:9][N:8]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: Clc1cnccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.5 M of n-BuLi in hexanes (10 mL) in THF (50 mL) was added 2,2,66-tetramethyl-piperidine (5.3 mL, 0.031 mol) slowly at −78° C. The cooling bath was replaced by an ice-water bath for 30 min and the solution was re-cooled to −78° C. After 5 min a solution of 2-chloropyrazine (2.3 mL, 0.026 mol) in THF (10 mL) is added. The reaction mixture turned brown in color. After 10 min, 4-formyldiphenyl ether (6.2 g, 0.031 mol) was added slowly. The reaction mixture was stirred at −78° C. for 2.5 h. The reaction mixture was quenched using sat. aq. NH4Cl at −78° C. After warming up to rt, the reaction mixture was concentrated under vacuo and purified by flash column chromatography (eluting with 10% EtOAc in hexanes) to afford the title compound. 1H NMR (400 MHz, CDCl3): δ 6.02 (s, 1H), 6.93-6.98 (m, 2H), 7.00 (d, J=7.58 Hz, 2H), 7.12 (t, J=7.33 Hz, 1H), 7.29-7.37 (m, 4H), 8.39 (d, J=2.53 Hz, 1H), 8.58 (d, J=2.53 Hz, 1H). MS (ES+): m/z 295.08 (100)[M-18]. HPLC: tR=3.46 min (Open lynx, polar—5 min).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[CH:12][N:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[Cl:25][CH2:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28].[ClH:32]>CN(C=O)C.C(OCC)C>[ClH:25].[ClH:32].[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[CH:18][CH:17]=3)=[CH:12][N:11]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2cnc(-c3ccc(O)cc3)cn2)CC1
Reactant: CN(C)C(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)N1CCN(c2cnc(-c3ccc(OCC(=O)N(C)C)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
4-(4-Isopropyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl)phenol (0.15 g, 0.404 mmol) was dissolved in DMF (4 mL) in a 5 mL microwave vial. NaH (0.039 g, 1.62 mmol) was added slowly and the mixture was stirred at rt for 30 min. Chloro-N,N-dimethylacetamide (0.147 g, 1.21 mmol) was added and the reaction mixture was heated for 2.5 h at 130° C. in a microwave oven. The reaction mixture was evaporated in vacuo and the residue was redissolved in a mixture of DCM and water. The phases were separated and the aqueous phase was extracted with DCM (2×25 mL). The combined organic extracts were evaporated, redissolved in MeOH and purified by preparative HPLC Method B. This afforded an oil which was treated with HCl in diethyl ether to give a solid material. Recrystallization from acetone and MeOH afforded 75 mg (41%) of the title compound.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([OH:13])[C:9](=[CH:11][CH:12]=1)[OH:10])([O-:5])=[O:4].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>CN(C=O)C.O>[N+:3]([C:6]1[CH:12]=[CH:11][C:9]2[O:10][CH:16]([CH2:17][OH:18])[CH2:14][O:13][C:8]=2[CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)OCC(CO)O2
Yield: 32.8 %

Procedure:
1.93 g of 60% sodium hydride was suspended in 90 mL DMF. At 0° C. a solution of 5.15 g of 4-nitrocatechol was added dropwise over 15 min. Subsequently, 3.9 g of epichlorohydrin in 10 mL DMF were added over 15 min. Stirring was continued at room temperature, then at 80° C. overnight. The mixture was diluted with water and extracted three times with ethyl acetate, dried (Na2SO4), filtered and concentrated under vacuum to give a yellow oil. The oil was purified by column chromatography on silica gel using a EtOAc-hexanes (0-100% gradient) to give the product (2.3 g) as a yellow solid.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:12])[CH2:8][CH2:9][CH2:10][NH2:11])([CH3:5])([CH3:4])[CH3:3].[Cl:13][C:14]1[CH:15]=[C:16]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH2:17][N:18]1[CH2:23][CH2:22][O:21][C@@H:20]([CH2:24][NH:25][C:26](=O)[O:27]C2C=CC([N+]([O-])=O)=CC=2)[CH2:19]1.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:13][C:14]1[CH:15]=[C:16]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH2:17][N:18]1[CH2:23][CH2:22][O:21][C@@H:20]([CH2:24][NH:25][C:26]([NH:11][CH2:10][CH2:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:12])=[O:27])[CH2:19]1
Reactant: CC(C)(C)OC(=O)CCCN
Reactant: O=C(NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCCNC(=O)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 22 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
4-Aminobutyric acid tert-butyl ester hydrochloride (0.235 g) was added to a stirred solution of Intermediate 13 (0.440 g) and N,N-diisopropylethylamine (0.42 ml) in dry dichloromethane (20 ml) under nitrogen, and the mixture was stirred at 22° C. for 18 h. The mixture was treated with saturated aqueous potassium carbonate (20 ml) and stirred for 5 min. The layers were separated and the organic layer applied to a silica gel cartridge (10 g Varian Bond Elut). Elution with dichloromethane, ether, ethyl acetate, and acetone gave the crude product (0.357 g). Further purification by chromatography on silica gel (10 g Varian Bond Elut cartridge), eluting with dichloromethane (1 column volume), ether (4 column volumes) and ethyl acetate (8 column volumes) gave the title compound as a gum (0.345 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.P(Br)(Br)[Br:20]>C(Cl)Cl>[Br:20][CH2:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(COc1ccc(CO)cc1)c1ccccc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: O=C(COc1ccc(CBr)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a 50 mL RB flask charged with 2-[4-(hydroxymethyl)phenoxy]-1-phenylethanone (10 g, 41.2 mmol) in DCM was added phosphorus tribromide (16.76 g, 61.9 mmol) in drops over period of 5 min at 0° C. Reaction mixture was stirred at RT for 1 h and then quenched with ice-water. Diluted it with excess DCM, washed with water, sat.NaHCO3 solution and brine solution successively. Organic phase was dried over anhydrous Na2SO4 and concentrated to afford product (9 g, Yield: 71.4%); 1H NMR (300 MHz, DMSO-d6): δ 7.90-7.93 (t, 2H), 7.53-7.58 (t, 1H), 7.41-7.46 (t, 2H), 7.23-7.26 (d, 2H), 6.81-6.84 (t, 2H), 5.20 (s, 2H), 4.40 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](CS(C)(=O)=O)[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.CC(C)([O-])C.[K+].CI>C1COCC1.[NH4+].[Cl-]>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cc1cc(Br)c2ncccc2c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: c1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-bromo-6-methanesulfonylmethyl-quinoline from Step 1 (1 eq.) in THF (0.2M) at 0° C., was added potassium t-butoxide (1.3 eq.) over 30 min. After 0.5 h at 0° C., MeI (1.6 eq.) was added and the reaction mixture was stirred at 0° C. for 2 h. A second portion of potassium t-butoxide (1.3 eq.) was added over 30 min, followed by MeI (1.6 eq.). The final mixture was stirred at rt for 2 h. The mixture was poured in saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was vigorously stirred in Et2O and the title compound was isolated by filtration as a pale yellow solid.