Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]5[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:22][CH:21]=4)[CH3:19])=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]4[N:37]=[CH:38][N:39]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>O1CCCC1>[O:17]=[C:16]1[C:15]([CH:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:22][CH:21]=2)[CH3:19])=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]2[N:37]=[CH:38][N:39]=[C:12]2[N:11]1[CH:8]1[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]1
Reactant: CCCc1c(C(C)c2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1c(C(C)c2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Yield: 100.5 %

Procedure:
A mixture of 4′-{1-[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]ethyl}biphenyl-2-carbonitrile (1.50 g), 3N hydrochloric acid (30 mL) and tetrahydrofuran (20 mL) was stirred under refluxing for 15 hr. The reaction mixture was neutralized with 1 M aqueous sodium hydroxide solution (90 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (1.38 g, quantitative).
Reaction SMILES: [F:1][C:2]([CH3:10])([CH3:9])[CH:3]([OH:8])[C:4]([O:6][CH3:7])=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15](S(C)(=O)=O)[N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([O:8][CH:3]([C:2]([F:1])([CH3:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5])[N:14]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(=O)C(O)C(C)(C)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(C)F
Temperature: 20 °C
Reaction time: 5 h

Procedure:
4 g (26.6 mmol) Methyl 3-fluoro-2-hydroxy-3-methylbutanoate and 5.81 g (26.6 mmol) 4,6-dimethoxy-2-methylsulphonylpyrimidine were dissolved in 75 ml dimethylformamide at 20° C. and treated with 1.84 g (13.3 mmol) potassium carbonate. The suspension was stirred for 5 hours at 20° C. and heated for one hour at 60° C. The reaction mixture was then poured into 150 ml ice-water and extracted with three lots of 75 ml ethyl acetate. The combined ethyl acetate phase was washed with water, dried over magnesium sulphate, filtered and evaporated. The solid residue was purified by silica gel column chromatography using hexane/ethyl acetate as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[N:19]=[C:18]([CH2:20]Cl)[O:17][N:16]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[N:19]=[C:18]([CH2:20][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])[O:17][N:16]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(Cl)cc2C1=O
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2cc(Cl)ccc2-3)no1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.3 %

Procedure:
A solution of 200 mg (0.54 mmol) of 8-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 4 ml of N,N-dimethylformamide was treated with 0.17 ml (1.65 mmol) of diethylamine and stirred at room temperature under argon for 1.5 hrs. The solution was evaporated and the residue was triturated in 10 ml of water. The crystals were filtered off under suction, the filtrate was extracted once with ethyl acetate and the extract was evaporated. The combined crude products were chromatographed on 20 g of silica gel (methylene chloride/acetone 4:1, 2:1). There were obtained 124 mg of 8-chloro-3-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted in acetone with ethereal hydrochloric acid into the hydrochloride. By crystallization from acetonitrile there were obtained 108 mg (42%) of 8-chloro-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one hydrochloride (1:1.9) of m.p. 191°-205° (dec.).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:34])[C:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:9][CH2:8][C:7](=[CH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[O:12])[CH2:6][CH2:5]1>[Pd].CO>[CH3:34][N:3]([CH3:2])[C:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:9][CH2:8][CH:7]([CH2:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[O:12])[CH2:6][CH2:5]1
Reactant: CN(C)C1(c2ccccc2)CCC(=CC(=O)NCCCCCc2c[nH]c3ccccc23)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(CC(=O)NCCCCCc2c[nH]c3ccccc23)CC1
Reaction time: 6 h
Yield: 46 %

Procedure:
Palladium-on-charcoal (5%, 15 mg) was added to a solution of 2-(4-dimethylamino-4-phenylcyclohexylidene)-N-[5-(1H-indol-3-yl)pentyl]acetamide (base of Example 17; 246 mg, 0.55 mmol) in abs. methanol (30 ml). The reaction mixture was hydrogenated at RT under a pressure of 2 bar for 6 h. The catalyst was separated off over Celite and the filtrate was concentrated. After separation of the residue (234 mg) by chromatography on silica gel (30 g) with EA/methanol (1:1), the product was isolated as a beige-coloured oil in a yield of 46% (112 mg).
Reaction SMILES: I[C:2]1[C:3]([CH3:11])=[N:4][NH:5][C:6]=1[NH:7][C:8](=[O:10])[CH3:9].[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.CN(C=O)C>C(OCC)(=O)C.O.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][C:3]1[C:2]([C:19]#[C:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([NH:7][C:8](=[O:10])[CH3:9])[NH:5][N:4]=1
Reactant: C#Cc1ccccc1
Reactant: CC(=O)Nc1[nH]nc(C)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1[nH]nc(C)c1C#Cc1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 51.4 %

Procedure:
Nitrogen was bubbled through a mixture of N-(4-iodo-3-methyl-1H-pyrazol-5-yl)acetamide (32.5 g, 0.122 mol), phenyl acetylene (25.0 g, 0.245 mol), triethylamine (300 mL) and DMF (100 mL) for 15 min. Copper iodide (2.3 g, 12 mmol) and bis(triphenylphosphine)palladium(II) dichloride (4.2 g, 6.0 mmol) were added and the reaction mixture stirred at 90° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and water. The organic phase was washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, isohexane/ethyl acetate 5:1 to 1:1) yielding the title compound as a solid (15 g).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[O:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:20][C:21]1[CH:30]=[CH:29][C:24]2[N:25]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[C:26](=[O:28])[O:27][C:23]=2[CH:22]=1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: O=c1[nH]c2ccc(Cl)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(Cl)ccc43)CC2)ccc1Cl

Procedure:
In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), 6-chloro-3H-benzooxazol-2-one (105 mg, 0.69 mmol, 1.05 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.5 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 6-chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (3): HPLC retention time, 2.62 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 436.3, found, 436.4.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([N+:16]([O-])=O)=[CH:8][N:7]=1.C(Cl)Cl.CO>CO.[Pd]>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[N:7]=[CH:8][C:9]([NH2:16])=[CH:10][C:11]=1[C:12]([F:15])([F:13])[F:14]
Reactant: CN(C)CCOc1ncc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCOc1ncc(N)cc1C(F)(F)F
Yield: 80.6 %

Procedure:
A solution of N,N-dimethyl-2-((5-nitro-3-(trifluoromethyl)pyridin-2-yl)oxy)ethanamine (500 mg, 1.791 mmol) and Pd/C (191 mg, 1.791 mmol) in MeOH (30 mL) was stirred at 20° C. under H2. After TLC analysis (DCM/MeOH=20/1) showed the starting material had disappeared, the mixture was filtered. The filtrate was concentrated to yield a oil of 6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-amine (360 mg, 1.444 mmol, 81.1% yield): 1H NMR (400 MHz, CD3OD) δ 7.77 (d, J=2.4 Hz, 1H), 7.37 (d, J=3.2 Hz, 1H), 4.43 (t, J=5.6 Hz, 2H), 2.78 (t, J=6.4 Hz, 2H), 2.35 (s, 6H); ES-LCMS m/z 250.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:14]([F:17])([F:16])[F:15].Cl.Cl[Sn](Cl)(Cl)Cl.[OH-].[Na+]>O>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:14]([F:16])([F:15])[F:17]
Reactant: Cn1c(C(F)(F)F)nc2ccc([N+](=O)[O-])cc21
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: Cn1c(C(F)(F)F)nc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A 250 ml round bottomed flask was charged with 1-methyl-6-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole (6 g, 24 mmol) and concentrated HCl (40 ml). Once the solution has become clear, water (˜15 ml) was added until the solution just started to become cloudy. SnCl4 (27 g, 120 mmol) was added in portions over 5 minutes (caution exotherm!). Initial exotherm caused the temperature to rise to 60° C. The reaction mixture was stirred and allowed to cool down to room temperature. After 1 hour, the reaction mixture was diluted with water (100 ml), basified with 1M NaOH and extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a dark coloured solid. (5 g, 100% yield). 1H NMR (DMSO D6, 400 MHz) 3.75 (3H, s), 4.6 (2H, br s), 6.65 (1H, s), 6.7 (1H, d), 7.75 (1H, d); MS (ES+) 215.
Reaction SMILES: [CH2:1]([SH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([NH:21][C:22](=[O:25])[O:23][CH3:24])([CH3:20])[CH3:19])=[CH:14][CH:13]=1>CN(C=O)C>[CH2:1]([S:7][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([NH:21][C:22](=[O:25])[O:23][CH3:24])([CH3:20])[CH3:19])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COC(=O)NC(C)(C)c1ccc(CBr)cc1
Reactant: CCCCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCSCc1ccc(C(C)(C)NC(=O)OC)cc1
Reaction time: 0.17 h

Procedure:
A solution of 1-hexanethiol (4.89 g) in DMF (15 ml) was added to a suspension of sodium hydride (1.66 g, 60% dispersion in mineral oil) in DMF (35 ml) over 15 minutes with stirring under nitrogen. The mixture was stirred at ambient temperature for 3 hours and then heated on a steam bath for 15 minutes. A solution of methyl N-[1-(4-bromomethylphenyl)-1-methylethyl]-carbamate (11.85 g) in DMF (50 ml) was added to this mixture, dropwise, over 10 minutes, at 20° C., with stirring. The mixture was stirred at ambient temperature for 18 hours and then quenched with saturated potassium carbonate solution (100 ml). The mixture was diluted with water and extracted with ether to give methyl N-[1-(4-hexylthiomethylphenyl)-1-methylethyl]carbamate as an oil.
Reaction SMILES: [CH2:1](C(C)=O)[CH:2](C)C.[CH2:8]([N:10]([CH2:18][CH3:19])[C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)[CH3:9].C(=O)([O-])[O-].[K+].[K+].C(Br)C>O>[CH2:18]([N:10]([CH2:8][CH3:9])[C:11]1[CH:12]=[C:13]([O:17][CH2:1][CH3:2])[CH:14]=[CH:15][CH:16]=1)[CH3:19]
Reactant: CC(=O)CC(C)C
Reactant: CCN(CC)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCBr
Product: CCOc1cccc(N(CC)CC)c1
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A 1 liter reactor is charged with 150 ml of methyl isobutyl ketone, 73.1 g of 3-diethylaminophenol and 153.3 g of ground potassium carbonate. The mixture is stirred for 30 minutes, then 72.7 g of ethyl bromide are added and the autoclave is closed. The reaction mixture is heated first for 3 hours to 115°-129° C. and then for a further 5 hours at 140°-142° C. (pressure: 4 bar). After cooling to c. 25° C. and addition of water, the product is isolated with the organic phase, which is washed with water and concentrated by evaporation, to give 80.67 g (97.2% yield) of 3-diethylaminophenetol with a titre of 94.8%.
Reaction SMILES: [CH3:1][C:2]1[C:13]([NH:14][CH:15]=[O:16])=[CH:12][C:5]2[N:6]3[CH2:11][CH2:10][N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1.[CH3:17]N(C)P(=O)(N(C)C)N(C)C.[H-].[Na+].S(OC)(OC)(=O)=O>O.CC(C)CC(=O)C>[CH3:1][C:2]1[C:13]([N:14]([CH3:17])[CH:15]=[O:16])=[CH:12][C:5]2[N:6]3[CH2:11][CH2:10][N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: Cc1cc2c(cc1NC=O)N1CCN=C1S2
Agent: [H-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Cc1cc2c(cc1N(C)C=O)N1CCN=C1S2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 5.5 parts of N-(2,3-dihydro-7-methylimidazo[2,1-b]benzothiazol-6-yl)formamide and 80 parts of hexamethylphosphoric triamide are added portionwise 1.24 parts of sodium hydride dispersion 75.8%. After stirring for 2 hours at room temperature, there are added dropwise 4.9 parts of dimethyl sulfate. Upon completion, stirring is continued for 3 hours at 50° C. and overnight at room temperature. 4-Methyl-2-pentanone and water are added and the layers are separated. The aqueous phase is extracted twice with 4-methyl-2-pentanone. The combined organic phases are washed with water, dried, filtered and evaporated. The residue is crystallized from methylbenzene. The product is filtered off and dried, yielding 1.5 parts of N-(2,3-dihydro-7-methylimidazo[2,1-b]benzothiazol-6-yl)-N-methylformamide; mp. 164.2° C.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:17])[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([O:14]C)[CH:10]=[CH:9][C:8]=2[CH3:16])([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].CO>ClC1C=CC=CC=1>[OH:14][C:11]1[CH:10]=[CH:9][C:8]([CH3:16])=[C:7]2[C:12]=1[CH:13]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:17])[NH:6]2
Reactant: COc1ccc(C)c2[nH]c(=O)c(C(C)C)cc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: Clc1ccccc1
Product: Cc1ccc(O)c2cc(C(C)C)c(=O)[nH]c12
Temperature: 110 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
3-Isopropyl-5-methoxy-8-methylcarbostyril (2.10 g, 9.90 mmol) was suspended in chlorobenzene (50 ml), to which aluminum chloride (4.20 g, 31.5 mmol) was added. The mixture was stirred at 110° C. for 1 hour. The reaction mixture was cooled on ice, and methanol (30 ml) was added thereto. After stirring for 10 minutes, the reaction mixture was condensed under reduced pressure. The resultant residue was recrystallized from water to obtain 1.60 g of the title compound as pale yellow powdery crystals (81.1%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]C(=O)N(C)C)=[CH:4][C:3]=1[CH3:15].C[O-].[Na+].Cl>CO.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([SH:9])=[CH:4][C:3]=1[CH3:15]
Reactant: Cc1cc(SC(=O)N(C)C)cc(C)c1Br
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(S)cc(C)c1Br
Temperature: 25 °C

Procedure:
Dimethyl-thiocarbamic acid S-(4-bromo-3,5-dimethyl-phenyl) ester (5.78 g, 20.14 mmol) is diluted with methanol (50 mL) and sodium methoxide (4.75 mL of 4.25M in methanol, 20.14 mmol) is added. The reaction is heated to reflux under nitrogen and monitored by TLC. After complete conversion, 20 hours, the reaction is allowed to cool to room temperature. The reaction is neutralized with 1N hydrochloric acid (7.5 mL) and diluted with ethyl acetate (150 mL). The two phases are separated and the organic layer is washed with water (75 mL), then brine (75 mL). The organic layer is dried over anhydrous sodium sulfate, concentrated and loaded onto silica gel column. The title compound is purified using flash column chromatography, yielding 4.0 g, or 92%.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C:11]([NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])=[O:12].[CH2:39]([N:41]([CH2:80][CH3:81])[C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:49]([C:51]2[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=2)[C:54]([OH:56])=O)=[O:50])=[C:44]([C:60]2[CH:65]=[C:64]([C:66](=[O:79])[NH:67][CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[C:71]([C:75]([F:78])([F:77])[F:76])[CH:70]=3)[CH:63]=[CH:62][N:61]=2)[CH:43]=1)[CH3:40].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:38][O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][C:11]([C@@H:6]1[CH2:7][CH2:8][CH2:9][CH2:10][N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[C:54](=[O:56])[C:53]1[CH:57]=[CH:58][CH:59]=[C:51]([C:49]([NH:48][C:45]2[CH:46]=[CH:47][C:42]([N:41]([CH2:39][CH3:40])[CH2:80][CH3:81])=[CH:43][C:44]=2[C:60]2[CH:65]=[C:64]([C:66](=[O:79])[NH:67][CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[C:71]([C:75]([F:76])([F:77])[F:78])[CH:70]=3)[CH:63]=[CH:62][N:61]=2)=[O:50])[CH:52]=1)=[O:12]
Reactant: CNCCN1CCCC[C@H]1C(=O)NCCOCCOCCOCCOCCOCCOCCOCCOC
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCCC[C@H]3C(=O)NCCOCCOCCOCCOCCOCCOCCOCCOC)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a mixture of (S)-1-(2-(methylamino)ethyl)-N-(2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl)piperidine-2-carboxamide (0.145 mmol), 3-((4-(diethylamino)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzoic acid (0.12 mmol, 80 mg) and DIEA (0.6 mmol, 78 mg) in DMF (0.4 mL) was added HATU (0.145 mmol, 55 mg). The mixture was stirred at 60° C. for 1 h and purified by prep. HPLC to give a yellow solid (91 mg, 52%). MS (ES, m/z): 1124.38 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5](C(O)=O)=[N:6][C:7]=1[CH3:8]>ClC1C=CC=CC=1Cl>[CH3:8][C:7]1[N:6]=[CH:5][C:4]([C:12]([OH:14])=[O:13])=[N:3][C:2]=1[CH3:1]
Reactant: Cc1nc(C(=O)O)c(C(=O)O)nc1C
Solvent: Clc1ccccc1Cl
Product: Cc1ncc(C(=O)O)nc1C
Temperature: 170 °C
Yield: 77.8 %

Procedure:
A suspension of 5,6-dimethylpyrazine-2,3-dicarboxylic acid (110 g.) in 1,2-dichlorobenzene (330 cc.) is heated at a temperature of about 170° C. until the evolution of gas ceases. The reaction mixture is then cooled to a temperature of about 20° C., after which the insoluble product is filtered off and washed with diisopropyl ether (6 × 25 cc.). After drying, 5,6-dimethylpyrazine-2-carboxylic acid (66.4 g.), melting at 187° C., is obtained.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14]>COCCOCCOC>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:3]2[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CSc1nccc(=O)[nH]1
Reactant: Nc1cccc(Cl)c1
Solvent: COCCOCCOC
Product: O=c1ccnc(Nc2cccc(Cl)c2)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
To 2-(methylthio)pyrimidine-4(3H)-one, 1, (4.88 g, 34.37 mmol) in diglyme (20 mL) is added 3-chloroaniline (4.3 mL, 68.74 mmol). The resulting mixture is heated to reflux and stirred for 18 hours. A solid forms upon cooling the mixture to room temperature. The solid is washed with hexanes to afford 5.0 g (66% yield) of the desired compound. 1H NMR (DMSO-d6, 300 MHz): δ 5.91 (d, J=5.7 Hz, 2H), 7.05 (d, J=7.5 Hz, 1H), 7.11 (br s, 1H), 7.32 (t, J=7.8, 15.9 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.86 (d, J=4.5 Hz, 1H), 7.94 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:18][C:17]2[N:19]3[C:10](=[CH:11][N:12]=[C:13]3[CH:14]=[CH:15][CH:16]=2)[C:9]1=[O:20])=O)(C)(C)C.[ClH:21]>C(O)C>[ClH:21].[N:12]1[CH:11]=[C:10]2[N:19]3[C:17](=[CH:16][CH:15]=[CH:14][C:13]=13)[CH2:18][NH:8][C:9]2=[O:20]
Reactant: CC(C)(C)OC(=O)N1Cc2cccc3ncc(n23)C1=O
Agent: Cl
Solvent: CCO
Product: O=C1NCc2cccc3ncc1n23
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of 95.7 mg (0.35 mmol) of 4,5-dihydro-4-(tert-butoxycarbonyl)-3H-1,4,8b-triazaacenaphthylen-3-one in 100 ml of ethanol was added 0.09 ml (1.05 mmol) of 12N HCl. The mixture was stirred for one hour at room temperature. The resulting crystalline precipitates were collected by filtration, washed with a small volume of ethanol and ether and dried to give 56.1 mg of the desired compound (76.4%, white solid).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)=[C:11]([CH3:12])[C:6]=2[O:5][C:4](=[O:20])[C:3]=1[CH:21]=O.Cl.[CH3:24][O:25][NH2:26].C([O-])(=O)C.[K+].C(O)C>ClCCl.O>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)=[C:11]([CH3:12])[C:6]=2[O:5][C:4](=[O:20])[C:3]=1[CH:21]=[N:26][O:25][CH3:24]
Reactant: Cc1c(OC2CCCCO2)ccc2c(O)c(C=O)c(=O)oc12
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CON=Cc1c(O)c2ccc(OC3CCCCO3)c(C)c2oc1=O
Yield: 86.7 %

Procedure:
A mixture containing 2.0 g of the product prepared in Stage A, 1.08 g of methoxyamine hydrochloride, 1.93 g of potassium acetate and 20 ml of ethanol is heated under reflux for 1 hour. After evaporating to dryness, the product obtained is dissolved in a mixture of dichloromethane and water (100 ml-100 ml), washed with a dilute solution of sodium acid phosphate and dried. After evaporation, the residue is triturated under ultrasound in the presence of ethyl ether, separated and dried. 1.90 g of product is obtained.