Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]3[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=3[N:12]=2)[CH3:10])[N:5]=[C:4]([NH2:27])[N:3]=1.[NH3:28]>O1CCOCC1>[F:26][C:23]1[CH:24]=[CH:25][C:13]2[N:12]=[C:11]([C@@H:9]([NH:8][C:6]3[N:5]=[C:4]([NH2:27])[N:3]=[C:2]([NH2:28])[N:7]=3)[CH3:10])[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]=2[CH:22]=1
Reactant: C[C@H](Nc1nc(N)nc(Cl)n1)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: N
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(N)nc(N)n1)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 100 °C
Yield: 77 %

Procedure:
To a solution of 6-chloro-N—[(S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]-[1,3,5]triazine-2,4-diamine (100 mg, 0.26 mmol) in dioxane (1 mL) was added 880 NH3 (4 mL). The reaction mixture was heated at 100° C. for 1 h using microwave irradiation. After cooling to RT, the reaction mixture was evaporated and purified by column chromatography (Si—PCC, gradient 2-12% 2M NH3/MeOH in DCM) affording 286 as a pink foam (72.9 mg, 77%). LCMS (Method K): RT 2.89 min [M+H]+ 365.0. 1H NMR (DMSO-d6, 400 MHz, 80° C.): δ 7.67-7.60 (3H, m), 7.57-7.51 (3H, m), 7.05 (1H, ddd, J=10.1, 8.8, 2.6 Hz), 6.78 (1H, dd, J=9.0, 2.5 Hz), 6.31 (1H, bd, J=7.5 Hz), 5.61 (4H, bs), 5.22 (1H, quintet, J=7.1 Hz), 1.40 (3H, d, J=6.9 Hz)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25](I)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O.[C:37]([O-])([O-])=[O:38].[K+].[K+]>[Pd].CCO.COCCOC>[Cl:2][C:3]1[CH:4]=[C:5]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:33]4[O:29][C:30]([CH:37]=[O:38])=[CH:31][CH:32]=4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: OB(O)c1ccco1
Reactant: O=C([O-])[O-]
Reactant: Clc1cc(Nc2ncnc3ccc(I)cc23)ccc1OCc1ccccn1
Agent: [Pd]
Agent: Cl
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c3c2)o1
Temperature: 75 °C

Procedure:
A mixture of compound 8.3 (489 mg, 1.0 mmol), 2-furylboronic acid (185 mg, 1.2 mmol) and palladium catalyst (73.0 mg, 0.10 mmol) in 1.0 mL of K2CO3 (2.0M), 1.0 mL of EtOH and 4.0 mL of DME was heated at 75° C. under nitrogen atmosphere for 4 hr. LS-MS showed the reaction completed. Concentrated the mixture under reduced pressure and washed the residue with water (2×5.0 mL) then with cool ether (10.0 mL) to get a gray solid (400 mg), which was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][N:17]([C:27]([C:28]5[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=5)=[O:34])[CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccncc1)N1CCc2[nH]c3c(cnc4cc(Cl)ccc43)c2C1
Reaction time: 8 h

Procedure:
To a mixture of 0.45 g (1.75 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline, 0.707 g (6.99 mmol) of triethylamine and 5 ml of dimethylformamide at ice-water bath temperature is added dropwise a solution of 0.247 g (1.75 mmol) of isonicotinoyl chloride hydrochloride and 1 ml of dimethylformamide. The reaction mixture is allowed to stir overnight while slowly reaching room temperature. A white precipitate is formed which is collected by filtration, washed with water and dried to yield 0.320 (50%) of the title compound as a white solid: m.p.>250° C.; m/e 362.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].[CH:14]1([CH2:17]Br)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:14]1([CH2:17][N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[C:6]2[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:16][CH2:15]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1nc([N+](=O)[O-])c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc([N+](=O)[O-])cn1CC1CC1

Procedure:
Under argon, 15 g (81 mmol) of ethyl 4-nitro-1H-imidazole-2-carboxylate are stirred with 13.13 g (97.2 mmol) of cyclopropylmethyl bromide and 22.4 g (162 mmol) of potassium carbonate in 165 ml of DMF at 80° C. for 1 h. After cooling, the reaction mixture is diluted with water and extracted four times with ethyl acetate. The combined organic phases are washed once with water and three times with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated in vacuo. The crystalline residue is directly used further for the next reaction.
Reaction SMILES: C(O[C:4](=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.CC([O-])(C)C.[K+].[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](=[O:24])[CH3:23].Cl>C1COCC1.C(OCC)(=O)C.O>[CH2:8]([O:7][C:5](=[O:6])[C:4](=[O:10])[CH2:23][C:22]([C:18]1[O:17][CH:21]=[CH:20][CH:19]=1)=[O:24])[CH3:9]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccco1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(=O)c1ccco1

Procedure:
To a solution of 16 g oxalic acid diethyl ester in 350 ml THF, 10.1 g KOt-Bu were added at 0° C. Then 10 g 1-furan-2-yl-ethanone in 50 ml THF were added dropwise. After 1 h the reaction mixture was diluted with 300 ml ethyl acetate and 200 ml water. This solution was acidified with diluted hydrochloric acid to pH 5. The organic layer was separated, washed with 150 ml water, dried over MgSO4, filtered and concentrated under reduced pressure to yield a white solid.
Reaction SMILES: C[O:2][C:3]1[C:11]2[O:10][CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>C(Cl)Cl>[OH:2][C:3]1[C:11]2[O:10][CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2ccoc12
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Oc1cccc2ccoc12
Temperature: 220 °C
Yield: 50 %

Procedure:
A mixture of 7methoxybenzofuran (1.8 g.) and pyridine hydrochloride (4.6 g.) was heated at 220° C. for 21/2 hours. The reaction was cooled and diluted with methylene chloride. The solution was washed with 5% aqueous hydrochloric acid (six times); dried (MgSO4) and concentrated to an oil, 0.8 g. (50% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:45]([OH:48])(=[S:47])[CH3:46]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([S:47][C:45](=[O:48])[CH3:46])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)=S
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)S[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 18 h
Yield: 89.2 %

Procedure:
3 g (16 mmol) (R)-3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester and 4.63 g Triphenylphosphine were dissolved in 70 ml THF. Over a period of 10 min 2.8 ml (17.6 mmol) Diethylazodicarboxylate were added at 0° C. After 10 min 1.26 ml (17.6 mmol) Thioacetic acid was added and the mixture was allowed to come to RT and stirring was continued for 18 h. After evaporation the residue was purified over silica gel (heptane to 20% ethyl acetate in heptane) to give 3.5 g of the expected compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[C:12]#[N:13])(=[O:3])[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(OCC)C>[C:1]([O:4][C:5]1[CH:10]=[C:9]([CH2:11][Br:14])[CH:8]=[CH:7][C:6]=1[C:12]#[N:13])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1cc(C)ccc1C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1cc(CBr)ccc1C#N
Temperature: 25 °C
Yield: 29.7 %

Procedure:
To a solution of (2-cyano-5-methyl-phenyl) acetate (0.72 g, 4.11 mmol) in CCl4 (10 mL) was added recrystallized N-bromosuccinimide (0.767 g, 4.31 mmol) followed by benzoyl peroxide (56 mg, 0.23 mmol). The resultant mixture was heated to reflux for 2.5 hours then cooled to room temperature. The mixture was diluted with diethyl ether (50 mL), filtered through filter paper, and the filtrate was concentrated. Purification of the crude material by column chromatography (6:1 hexanes-EtOAc) provided 0.31 g (30%) of (5-bromomethyl-2-cyano-phenyl) acetate as a colorless oil. 1H NMR (CDCl3) δ 2.40 (s, 3H), 4.45 (s, 2H), 7.33 (s, 1H), 7.35 (d, 1H, J=9 Hz), 7.65 (d, 1H, J=9 Hz).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:9][O:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([Br:25])=[CH:22][CH:23]=3)[CH:18]=[CH:17][C:16]=2[O:26][CH3:27])[C:4]1=[O:28].[C:29]([O:33][C:34]([NH:36][C@@H:37]([CH2:41][CH3:42])[C:38](O)=[O:39])=[O:35])([CH3:32])([CH3:31])[CH3:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Br:25][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[C:15]([CH2:14][N:5]1[C:4](=[O:28])[C@@H:3]([NH:2][C:38](=[O:39])[C@@H:37]([NH:36][C:34](=[O:35])[O:33][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:41][CH3:42])[CH2:9][O:8][C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]1=3)=[C:16]([O:26][CH3:27])[CH:17]=[CH:18]2
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](N)COc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1COc2ccccc2N(Cc2c(OC)ccc3cc(Br)ccc23)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
A mixture of (S)-3-amino-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride (348 mg, 750 μmol), (S)-2-(tert-butoxycarbonylamino)butanoic acid (168 mg, 825 μmol), DIEA (519 μL, 3.00 mmol), and HBTU (313 mg, 825 μmol) in DMF (2.5 mL) was stirred at RT for 30 min. The mixture was diluted with EtOAc, washed with sat. NaHCO3, H2O, and brine brine, then dried over Na2SO4, and filtered. The filtrate was concentrated to give a residue that was purified by silica gel chromatography to provide tert-butyl (S)-1-((S)-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxobutan-2-ylcarbamate (431 mg, 94%) as a white solid. MS m/z 634/636 (MNa)+
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:12])([CH3:11])[CH2:4][C@H:5]([NH2:10])[CH2:6][N:7]([CH3:9])[CH3:8].C(N(CC)CC)C.[CH3:20][C@@H:21]1[C@@H:26]([NH:27][C:28]([CH:30]2[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[N:31]2[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH:44]=O)[CH:39]=2)=[O:29])[CH2:25][C@H:24]2[CH2:46][C@@H:22]1[C:23]2([CH3:48])[CH3:47].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:20][C@@H:21]1[C@@H:26]([NH:27][C:28]([CH:30]2[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[N:31]2[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][NH:10][C@H:5]([CH2:6][N:7]([CH3:9])[CH3:8])[CH2:4][C:3]([CH3:12])([CH3:11])[CH3:2])[CH:39]=2)=[O:29])[CH2:25][C@H:24]2[CH2:46][C@@H:22]1[C:23]2([CH3:47])[CH3:48]
Reactant: CN(C)C[C@@H](N)CC(C)(C)C
Reactant: C[C@@H]1[C@@H](NC(=O)C2CCS(=O)(=O)N2Cc2cccc(C=O)c2)C[C@H]2C[C@@H]1C2(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1[C@@H](NC(=O)C2CCS(=O)(=O)N2Cc2cccc(CN[C@H](CN(C)C)CC(C)(C)C)c2)C[C@H]2C[C@@H]1C2(C)C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
To a stirred solution of (S)-4,4,N1,N1-tetramethyl-pentane-1,2-diamine hydrochloride salt (Intermediate 2, 0.100 g, 0.43 mmol) in methanol (5 mL) at 0° C. was added triethylamine (0.12 g, 0.16 ml, 1.2 mmol). After 10 min of stirring at the same temperature, a solution of 2-(3-formyl-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amide (0.181 g, 0.43 mmol) in methanol (1 mL) was added and stirring was continued for an additional 15 min at room temperature. The reaction mixture was again brought into 0° C. and sodium cyanoborohydride (0.022 g, 0.35 mmol) and acetic acid (0.2 mL) were added simultaneously into the reaction mixture. After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate (5 mL), washed with water (3 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide crude 2-{3-[((S)-1-dimethylaminomethyl-3,3-dimethyl-butylamino)methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amide (0.216 g, 89%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](O)=[C:4]([CH:9]2[CH2:11][CH2:10]2)[C:3]=1Br.C1(C)C=CC=CC=1.C[O:21]CCO[AlH2-]OCCOC.[Na+]>C1C=CC=CC=1>[CH:9]1([C:4]2[CH:5]=[CH:6][C:7]([OH:21])=[CH:2][CH:3]=2)[CH2:11][CH2:10]1
Reactant: COCCO[AlH2-]OCCOC
Reactant: Oc1ccc(Br)c(Br)c1C1CC1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: Oc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 500 ml flask equipped with a reflux condenser, and magnetic stirring bar under a nitrogen atmosphere were placed 11 g (37.6 moles) of dibromocyclopropylphenol, 100 ml of toluene, and 50 g of 70% solution of "Red-Al" [sodium bis(2-methoxyethoxy aluminum hydride)] in benzene. The solution was then heated to reflux for 6 hours and allowed to stir overnight at room temperature. The reaction was then quenched with water and acidified with concentrated hydrochloric acid. The layers were separated and the aqueous layer extracted with 100 ml of ether. The organic layers were combined and washed with dilute base. The water layer was then acidified with concentrated hydrochloric acid and extracted with methylene dichloride. The methylene dichloride extract was dried over anhydrous magnesium sulfate and the solvent evaporated. A yield of 3 g of 4-cyclopropylphenol, an amber oil, was obtained.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH:18]([CH3:20])[CH3:19].O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:18]([C:6]1[N:5]([CH2:4][CH:3]=[O:2])[C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=1)([CH3:20])[CH3:19]
Reactant: COC(=O)c1cccc2nc(C(C)C)n(CC(OC)OC)c12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cccc2nc(C(C)C)n(CC=O)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of methyl 1-(2,2-dimethoxyethyl)-2-isopropyl-1H-benzo[d]imidazole-7-carboxylate from Step A above in methylene chloride and water was added trifluoroacetic acid and the reaction was stirred at room temperature for 1.5 h and then heated at reflux for 2 h. The reaction mixture was concentrated under reduced pressure to remove the excess trifluoroacetic acid, diluted with methylene chloride, washed with saturated aqueous sodium bicarbonate, re-extracted with methylene chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 2-isopropyl-1-(2-oxoethyl)-1H-benzo[d]imidazole-7-carboxylate: 1H NMR (300 MHz, DMSO-d6) δ 9.69 (s, 1H), 7.87 (dd, J=8.1, 0.9 Hz, 7.68 (dd, J=7.5, 0.9 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 5.44 (s, 2H), 3.84 (s, 3H), 3.22-3.17 (m, 1H), 1.34-1.27 (m, 6H); MS (ESI+) m/z 261 (M+H).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[CH3:15][C:16]1[CH2:20][CH:19]=[C:18]([CH3:21])[C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].Cl>>[CH3:21][C:18]1[CH2:19][CH:20]=[C:16]([CH3:15])[C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC1=CCC(C)=C1c1ccccc1N
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: CC1=CCC(C)=C1c1ccccc1NC(=O)C(C)(C)C
Yield: 102.2 %

Procedure:
0.130 g (1.29 mmol) of triethylamine and 0.155 g (1.29 mmol) of pivaloyl chloride were added to 0.263 g (1.42 mmol) of 2-(2,5-dimethylcyclopenta-1,4-dienyl)phenylamine dissolved in 10 mL of an MC solvent and then reacted at room temperature for one hour. 5 mL of 2N HCl was added to the reaction solution and then strongly stirred for a few minutes. The organic layer was collected and then neutralized by 5 mL of NaHCO3 saturated aqueous solution. The resultant product was purified through a column chromatography using a solvent of hexane/ethyl acetate (v/v, 10:1), and then dried in vacuum to remove the solvent therein, thereby obtaining white solid (0.355 g, 93%).
Reaction SMILES: [Br-].[CH2:2]([S:18][CH2:19][CH:20]([O:28][CH3:29])[CH2:21][N+:22]([CH3:27])([CH3:26])[CH2:23][CH2:24]O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(SC[CH:48]([O:51]CC)C[Br:50])CCCCCCCCCCCCCCC.[CH3:54]N(C(O)CC)C>>[Br-:50].[CH2:2]([S:18][CH2:19][CH:20]([O:28][CH2:29][CH3:54])[CH2:21][N+:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][CH2:48][OH:51])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCSCC(C[N+](C)(C)CCO)OC
Reactant: CCC(O)N(C)C
Reactant: CCCCCCCCCCCCCCCCSCC(CBr)OCC
Agent: [Br-]
Product: CCCCCCCCCCCCCCCCSCC(C[N+](C)(C)CCCO)OCC
Yield: 22 %

Procedure:
This product was prepared in an analogous manner to that of (±)-3-hexadecylthio-2-methoxy-N,N-dimethyl-N-β-hydroxyethyl-1-propyl ammonium bromide from 2.2 grams (0.005 mole) of (±)-1-hexadecylthio-2-ethoxy-3-bromopropane and 0.6 milliliter (0.006 mole) of N,N-dimethylaminopropanol to give 0.575 milligram (22%) of product, (mp 96°-98° Centigrade). 1H-NMR (CDCl3): delta, 0.87(t, 3H, terminal methyl), 1.2-1.6[m, 31H, (CH2)14, CH3 --CH2 --O], 2.2(m, 2H, N--CH2 --CH2 --CH2), 2.58(m, 2H, S--CH2), 2.7-2.9(m, 2H, CH2 --S), 3.48[s, 6H, N(CH3)2 ], 3.9-4.3(m, 9H, CH3CH2OCH, CH2 --N--CH2 --CH2 --CH2 --OH). Anal. (C26H56NO2SBr) C,H,N.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)[N:31]2[CH2:34][CH:33]([CH2:35][S:36]([NH:39][C:40]3[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=3C(O)=O)(=[O:38])=[O:37])[CH2:32]2)=[CH:26][CH:25]=1.Cl.[NH2:57][C@@H:58]([C:60]([NH2:62])=[O:61])[CH3:59].[O:63]1CCC[CH2:64]1>ClCCl.C(N(CC)CC)C>[Cl:55][C:52]1[CH:51]=[CH:50][C:49]([CH:30]([C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=2)[N:31]2[CH2:32][CH:33]([CH2:35][S:36]([NH:39][C:40]3[CH:48]=[C:47]([CH:46]=[CH:45][CH:41]=3)[C:64]([NH:57][C@@H:58]([C:60](=[O:61])[NH2:62])[CH3:59])=[O:63])(=[O:38])=[O:37])[CH2:34]2)=[CH:54][CH:53]=1
Reactant: C[C@@H](N)C(N)=O
Reactant: C1CCOC1
Reactant: O=C(O)c1ccccc1NS(=O)(=O)CC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)c1cccc(NS(=O)(=O)CC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1)C(N)=O
Temperature: 20 °C
Reaction time: 8 h

Procedure:
67 mg of 1-hydroxybenzotriazole, 0.4 cm3 of triethylamine and 228 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added successively to a solution of 500 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylaminobenzoic acid and 150 mg of D-alaninamide hydrochloride in 20 cm3 of tetrahydrofuran. The reaction mixture is left stirring overnight at a temperature in the region of 20° C. After concentration of the reaction medium to dryness under reduced pressure, the yellowish-white powder obtained is dissolved with dichloromethane. The organic phase is washed with water. After separation by settling out, the aqueous phase is again extracted with dichloromethane. The reaction crude obtained after concentration of the organic phases to dryness under reduced pressure is purified by flash chromatography on a Merck 30 g silica cartridge (elution gradient: 100/0 to 95/5 dichloromethane/methanol). After concentration of the fractions under reduced pressure, a product is obtained which is washed with diethyl ether and oven-dried under vacuum. 220 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-N—((R)-1-carbamoylethyl)benzamide are thus obtained in the form of white crystals.
Reaction SMILES: O[CH:2]([CH2:11]C=CC)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.CO[C:28]1[CH:36]=CC(C([O-])=O)=C[CH:29]=1.[Na+]>C(OCC)(=O)C>[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]2[O:22][C:6]3[C:5]([C:3](=[O:4])[C:2]=2[CH3:11])=[CH:10][CH:9]=[CH:8][C:7]=3[CH:29]=[CH:28][CH3:36])=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)[O-])cc1
Reactant: CC=CCC(O)C(=O)c1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC=Cc1cccc2c(=O)c(C)c(-c3ccc(OC)cc3)oc12
Reaction time: 5 h
Yield: 75.4 %

Procedure:
To 2.47 grams of 2-hydroxy-3-propenylpropiophenone are added 6.65 grams of p-methoxybenzoyl chloride and one half of 6.88 grams of anhydrous sodium p-methoxybenzoate, the mixture is heated in a nitrogen stream and, when 2-hydroxy-3-propenyl-propiopheone is dissolved, the residue of anhydrous sodium p-methoxybenzoate is added thereto, and the mixture is stirred at 180° to 190° C. for five hours. After cooled, the mixture is dissolved in ethyl acetate, the solution is washed with 10% sodium hydroxide solution and with water, and dried with anhydrous magnesium sulfate and finally the solvent is evaporated therefrom to give 3.0 grams of 4'-methoxy-3-methyl-8-propenylflavone, colorless needles, melting point 169° to 171° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=2)[C:17]([NH:19][CH2:20][C:21]([OH:23])=O)=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C([O:30][C:31](=[O:37])[CH2:32][C@@H:33]([C:35]#[CH:36])[NH2:34])C.[F:38][C:39]([F:44])([F:43])[C:40]([O-:42])=[O:41]>>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[N:11]1([C:14]2[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=2)[C:17]([NH:19][CH2:20][C:21]([NH:34][C@H:33]([C:35]#[CH:36])[CH2:32][C:31]([OH:37])=[O:30])=[O:23])=[O:18])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)NCC(=O)O)c2)CC1
Reactant: O=C([O-])C(F)(F)F
Reactant: C#C[C@@H](N)CC(=O)OCC
Agent: Cl
Product: C#C[C@H](CC(=O)O)NC(=O)CNC(=O)c1cccc(N2CCNCC2)c1
Product: O=C(O)C(F)(F)F

Procedure:
The acid 17-1 was coupled with 3(S)-ethynyl-β-alanine ethyl ester hydrochloride (Zablocki et al., J. Med. Chem., 1995, 38, 2378-2394) using standard peptide coupling conditions. The product was then fully deprotected using previously described methodology to give, after reverse phase chromatography, 17-4 as the trifluoroacetate salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH2:11]1[CH:15]2[CH2:16][NH:17][CH2:18][CH:14]2[CH2:13][N:12]1[C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][N:27]=2)[N:24]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:17]2[CH2:16][CH:15]3[CH2:11][N:12]([C:19]4[CH:20]=[CH:21][C:22]5=[N:27][N:26]=[C:25]([C:28]([F:31])([F:29])[F:30])[N:23]5[N:24]=4)[CH2:13][CH:14]3[CH2:18]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(F)cc1)N1CC2CN(c3ccc4nnc(C(F)(F)F)n4n3)CC2C1
Temperature: 70 °C
Yield: 41.7 %

Procedure:
1-Fluoro-4-isocyanatobenzene (0.026 g, 0.19 mmol) was added to a suspension of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.05 g, 0.17 mmol) in toluene (1.5 mL). The reaction mixture was heated at 70° C. for 1 hour and evaporated to give an involatile residue. The residue was purified by hplc using a Phenomenex Luna C18 100A column (10μ silica, 21 mm diameter, 150 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% trifluoroacetic acid) and acetonitrile as eluents to give N-(4-fluorophenyl)-2-[3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazin-6-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxamide (0.0309 g, 42%) as a white solid.