Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.Cl[S:42]([C:45]1[CH:46]=[C:47]([CH:58]=[CH:59][CH:60]=1)[C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])(=[O:44])=[O:43]>O1CCCC1.O>[C:20]([O:19][C:18]([N:17]([CH2:16][C:5]1[C:4]([F:3])=[C:8]([C:9]2[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=2)[N:7]([S:42]([C:45]2[CH:46]=[C:47]([CH:58]=[CH:59][CH:60]=2)[C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[O:49])(=[O:44])=[O:43])[CH:6]=1)[CH3:25])=[O:24])([CH3:21])([CH3:22])[CH3:23]
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=C(OCc1ccccc1)c1cccc(S(=O)(=O)Cl)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2cccc(C(=O)OCc3ccccc3)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of 3-(chlorosulfonyl)benzoyl chloride (1.5 g) in tetrahydrofuran (12 mL) were added benzyl alcohol (712 mg) and pyridine (370 mg) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:16:1) to give benzyl 3-(chlorosulfonyl)benzoate as a colorless oil (yield 1.70 g, 87%). To a suspension of sodium hydride (60% in oil, 120 mg) in tetrahydrofuran (8 mL) were added dropwise a solution (12 mL) of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (646 mg) in tetrahydrofuran, 15-crown-5 (660 mg) and benzyl 3-(chlorosulfonyl)benzoate (684 mg) under ice-cooling and the mixture was stirred for 1 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→3:2) to give the title compound as a pale-yellow oil (yield 1.09 g, 91%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([SH:17])[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].Cl[C:19](OC(Cl)(Cl)Cl)=[O:20].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([S:17][C:19]([N:37]3[CH2:38][CH2:39][N:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH3:26])[CH2:35][CH2:36]3)=[O:20])[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)c1cnc2c(S)cccn2c1=O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cnc2c(SC(=O)N3CCN(c4ccccc4OC)CC3)cccn2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.0 g (4 mmol) of 3-ethoxycarbonyl-9-mercapto-4-oxo-4H-pyrido[1,2-a]pyrimidine (II-1) in 40 ml of dry methylene chloride is added 0.24 ml (2 mmol) of trichloromethyl chloroformate, and the resultant mixture is stirred for 10 min. and concentrated at room temperature under atmospheric pressure. To the residue are added 60 ml of dry methylene chloride and 0.77 ml (44 mmol) of 4-(2-methoxyphenyl)piperazine under ice-cooling, and the reaction mixture is stirred for 1 hour at room temperature. The reaction mixture is washed with N--HCl, saturated aqueous NaHCO3 and water in order, and the organic layer is dried and concentrated under reduced pressure. The oily residue in 1.94 g is chromatographed on a column of silica gel eluting with ethyl acetate to give 45 mg of Ia-2 (m.p. 154°-156° C. recrystallized from chloroform-n-hexane) and 516 mg of IV-2 (m.p. 151°-153° C. recrystallized from ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Cl:13][CH2:14][CH2:15][O:16][C:17](Cl)=[O:18].O.O.O.O.O.O.O.O.O.O.O.O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].Cl.Cl[CH2:42]Cl>>[Cl:13][CH2:14][CH2:15][O:16][C:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)=[O:18].[CH:15]([O:16][CH:8]([CH3:9])[CH3:12])([CH3:42])[CH3:14]
Reactant: CC(C(=O)O)c1ccc(N)cc1
Reactant: ClCCl
Reactant: O=C(Cl)OCCCl
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C(=O)O)c1ccc(NC(=O)OCCCl)cc1
Product: CC(C)OC(C)C
Reaction time: 4 h

Procedure:
1 g (6 mmol) of 2-(4-aminophenyl)propanoic acid was suspended in 30 ml of dichloromethane and 1.24 ml (12 mmol) of 2-chloroethylchloroformate were added at 0° C. under stirring. After 30 minutes at the same temperature 2.27 g (6 mmol) of sodium phosphate dodecahydrate were added portionwise. After 4 hours the reaction was complete (HPLC-MS). The mixture was made acidic by using hydrochloric acid 0.5N and the product extracted with dichloromethane. The organic layer was dried over sodium sulphate and evaporated under vacuum. 1.4 g (100%yield) of the title compound were obtained by crystallization from diisopropylether.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:19]3[C:20]4[C:15]([CH2:16][CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[C:10]=2[CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=3)[CH2:25][CH2:24]2)=[CH:5][CH:4]=1.Br.[OH-].[Na+]>C(O)(=O)C.O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:19]3[C:20]4[C:15]([CH2:16][CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[C:10]=2[CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=3)[CH2:27][CH2:28]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2c(CCN3CCN(c4cc(C)ccn4)CC3)c3cccc4c3n2CCC4)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccnc(N2CCN(CCc3c(-c4ccc(O)cc4)n4c5c(cccc35)CCC4)CC2)c1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
7.5 g of 2-(4-methoxyphenyl)-1-{2-[4-(4-methylpyridin-2-yl)piperazin-1-yl]ethyl}-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (preparation see Example 7) were dissolved in 110 ml of acetic acid. 110 ml of 41% strength aqueous hydrobromic acid were added to the solution, and the reaction mixture was heated under reflux for 16 hours. To work up the reaction mixture it was cooled to room temperature, then diluted with 100 ml of water and neutralized by addition of 10% strength aqueous sodium hydroxide solution (pH=6). It was then extracted with dichloromethane, and the organic phase was separated, dried and concentrated. The oily residue which remained was crystallized from ethanol/ether. 5.2 g of 2-(4-hydroxyphenyl)-1-{2-[4-(4-methylpyridin-2-yl)piperazin-1-yl]ethyl}-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline having a melting point of 220° C. were obtained.
Reaction SMILES: [NH2:1][NH2:2].[CH2:3]([NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](Cl)=[N:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([NH:1][NH2:2])=[N:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NN
Reactant: O=C(NCc1ccccc1)c1ccc(Cl)nc1
Solvent: CCO
Product: NNc1ccc(C(=O)NCc2ccccc2)cn1
Yield: 61.4 %

Procedure:
Combined hydrazine (1.67 mL, 53.3 mmol) and a solution of N-benzyl-6-chloronicotinamide (2.19 g, 8.88 mmol) in ethanol (70 mL) and heated overnight at 100° C. The reaction mixture was then cooled and evaporated to give a solid. The solid was collected by filtration, washed with 70 mL water, and recrystallized from hot ethanol to give the title compound (1.32 g, 61%) as an off-white solid. MS m/z [M+H]+ 243.2.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@H:22]([O:34][CH2:35][CH2:36][O:37][CH3:38])[C@@H:21]1[CH2:39]I)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.F.F.F.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[CH3:38][O:37][CH2:36][CH2:35][O:34][C@@H:22]1[C@H:21]([CH3:39])[C@@H:20]([CH2:19][OH:18])[O:24][C@H:23]1[N:25]1[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[NH:28][C:26]1=[O:27]
Reactant: COCCO[C@@H]1[C@H](CI)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Agent: F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCO[C@@H]1[C@H](C)[C@@H](CO)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Yield: 97.2 %

Procedure:
A solution of 5′-O-(tert-butyldiphenylsilyl)-3′-deoxy-3′-(iodomethyl)-2′-O-(2-methoxyethyl)-5-methyluridine (1.12 g, 1.65 mmol) and triethylamine trihydrofluoride (1.1 mL, 1.1 g, 6.7 mmol) in 20 mL of THF was stirred at rt for 24 h. The reaction mixture was diluted with 50 mL of ethyl acetate and washed with water and brine. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on a silica gel column. Gradient elution with 2:1, 1:2 and then 1:3 hexanes-EtOAc provided 504 mg of the title compound as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH:4]([NH2:7])[CH:5]=O.COC(=O)C(C([CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O)N.[S-:30][C:31]#[N:32].[K+].Cl>O.O1CCCC1>[CH:16]([N:7]1[C:4]([C:3]([O:2][CH3:1])=[O:8])=[CH:5][N:32]=[C:31]1[SH:30])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N#C[S-]
Reactant: COC(=O)C(N)C(=O)C(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(N)C=O
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cnc(S)n1C(c1ccccc1)c1ccccc1

Procedure:
31.3 g (0.1 mol) of 2-benzhydrylformyl)-amino-3-oxopropionic acid methyl ester (prepared by formylation of (benzhydrylformyl)-aminoacetic acid methyl ester according to J. Am. Chem. Soc. 71, (1949), page 644, and 18 g of potassium thiocyanate were introduced into a mixture of 200 cc of tetrahydrofurane, 200 cc of water and 16.5 cc of 36% aqueous hydrochloric acid while stirring. Stirring was continued for 31/2 hours at 40° C.; then the organic phase was separated and the solvent removed under reduced pressure. The residue was taken up in methylene chloride and freed from acid residues by shaking twice with water. After washing with methanol, 29.8 g (92% of the theory) of 1-benzhydryl-2-mercapto-5-methoxy-imidazole melting at 194° C. were obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([OH:14])=[C:8]([O:15][CH3:16])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:24][CH3:25].Cl>CN(C=O)C.O.CCOC(C)=O>[CH2:24]([O:14][C:9]1[C:8]([O:15][CH3:16])=[CH:7][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:11][C:10]=1[O:12][CH3:13])[CH3:25]
Reactant: CCI
Reactant: COc1cc(-c2ccco2)cc(OC)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1c(OC)cc(-c2ccco2)cc1OC
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 92.2 %

Procedure:
To a suspension of 4-(furan-2-yl)-2,6-dimethoxyphenol (0.493 g, 2.24 mmol) in anhydr DMF (10 mL) under argon was added Cs2CO3 (1.2 g, 3.7 mmol) and iodoethane (0.22 mL, 2.7 mmol). The mixture was stirred for 20 min then heated at 80° C. for 2 hrs. After cooling to room temperature, the reaction was diluted with H2O and EtOAc then it was acidified with the addition of 6 M HCl. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were diluted with hexanes and washed with H2O and brine, dried over Na2SO4 and filtered through a pad of silica gel on Celite. The filtrate was concentrated in vacuo to give 2-(4-ethoxy-3,5-dimethoxyphenyl)furan as a beige solid (0.513 g, 92% yield). The product was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[C:13]3[C:18]4=[C:19]([CH2:21][CH2:22][N:17]4[C:16](=[O:23])[CH2:15][CH2:14]3)[CH:20]=2)=[O:10])[CH2:3][CH2:2]1.CS(O[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)(=O)=O>>[ClH:37].[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][N:1]2[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][C:9]([C:11]3[CH:12]=[C:13]4[C:18]5=[C:19]([CH2:21][CH2:22][N:17]5[C:16](=[O:23])[CH2:15][CH2:14]4)[CH:20]=3)=[O:10])[CH2:5][CH2:6]2)=[CH:32][CH:33]=1
Reactant: O=C(CCC1CCNCC1)c1cc2c3c(c1)CCN3C(=O)CC2
Reactant: CS(=O)(=O)OCCc1ccc(Cl)cc1
Product: Cl
Product: O=C(CCC1CCN(CCc2ccc(Cl)cc2)CC1)c1cc2c3c(c1)CCN3C(=O)CC2

Procedure:
Using 8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one and 2-(4-chlorophenyl)ethyl methanesulfonate according to the same method as that of Example 81, the title compound was obtained as colorless crystals having a melting point of 204 to. 206° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])O.[Na+].O.[C:16](Cl)(=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1.C(OCC)(=O)C>[OH:8][C:6]1[CH:7]=[C:2]([NH:1][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=[CH:4][C:5]=1[CH3:9]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1ccc(N)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5-amino-2-methylphenol (39.6 g, 321 mmol) and sodium hydrogen carbonate (40.5 g, 482 mmol) in tetrahydrofuran (300 mL)/water (150 mL) was added dropwise benzyl chlorocarbonate (48.1 mL, 321 mmol) at 0° C. over 30 min, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL), and the obtained aqueous layer was extracted with ethyl acetate (2×100 ml). The combined organic layer was washed with saturated brine (100 mL), and purified by silica gel (ethyl acetate). The obtained solution was concentrated under reduced pressure to give the title compound (83.1 g, quantitatively) as a pale-brown solid. The obtained compound was used for the next reaction without purification.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11](F)[CH:10]=1.[C:19]([NH:26][CH2:27][CH2:28][NH2:29])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CS(C)=O>[C:22]([O:21][C:19](=[O:20])[NH:26][CH2:27][CH2:28][NH:29][C:11]1[CH:10]=[C:9]([O:8][CH3:7])[CH:14]=[CH:13][C:12]=1[N+:15]([O-:17])=[O:16])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc([N+](=O)[O-])c(NCCNC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 104 %

Procedure:
A 2 L flask equipped with a stir bar was charged with DMSO (800 mL), K2CO3 (161 g, 1.6 mol) and 4-methoxy-2-fluoro-1-nitrobenzene (10 g, 0.58 mol). Mono-N-Boc-1,2-diaminoethane (94 g, 0.55 mol) was added to the reaction mixture and stirred for 12 h at 60° C. The reaction mixture was triturated with ice cold water (1.2 L) and the resulting yellow precipitate was collected by vacuum filtration. The precipitate washed several times with water (5×1 L) and dried on a high vacuum for 48 h to give the desired product as a bright yellow solid (178 g, 98%.)
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][Cl:11])=[CH:8][CH:7]=1>C(O)C>[ClH:11].[ClH:11].[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:2][NH2:3])=[CH:8][CH:7]=1
Reactant: NN
Reactant: COc1ccc(CCl)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc(CNN)cc1
Product: Cl
Temperature: 90 °C

Procedure:
A solution containing 7.9 ml of hydrazine hydrate in 80 ml of ethanol was treated with 3.7 ml of 4-methoxybenzylchloride and heated at 90° C. for 2.0 h. The solvent was reduced by evaporation under reduced pressure and then the resulting residue was dissolved in 30 ml of ethanol. The solution was acidified with 30 ml of 5N HCl at 0° C. and a white precipitate separated. The white solid was filtered off and dried to give 2.75 g of (4-methoxybenzyl)hydrazine dihydrochloride (PMBNHNH2.2HCl), which was used without further purification.
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.N1CCOCC1.[C:22]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)#[N:23]>C1(C)C=CC=CC=1>[C:22]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[N:15][C:13]2[C:12]3[C:7]([N:6]=[C:5]4[C:14]=2[CH2:1][CH2:2][CH2:3][CH2:4]4)=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:26][CH:25]=1)#[N:23]
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Reactant: N#Cc1ccc(C=O)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: N#Cc1ccc(C=Nc2c3c(nc4ccccc24)CCCC3)cc1
Yield: 45.8 %

Procedure:
1,2,3,4-Tetrahydro-9-acridinamine (3.2 g) was refluxed in 300 ml of toluene containing morpholine (2.8 g) and 4-cyanobenzaldehyde (2.60 g). After twenty-four (24) hours the reaction mixture was concentrated and purified by flash chromatography. Fractions containing the product were concentrated and recrytallized from CH2Cl2 /pentane to give 2.30 g of product, m.p. 204°-205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].C1C(=O)N([Br:18])C(=O)C1>>[Br:18][C:9]1[C:2]([Cl:1])=[C:3]([C:6]([F:10])=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: N#Cc1c(F)cccc1Cl
Reactant: O=C1CCC(=O)N1Br
Product: N#Cc1c(F)ccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-6-fluorobenzonitrile (15.6 g, 100 mmol) was dissolved in trific acid (75 mL) at 0° C., then NBS (17.8 g, 100 mmol) was added. The reaction was warmed up to room temperature and stirred overnight. The reaction mixture was poured into ice and extracted with DCM (2×). DCM layers were washed with NaHCO3 and brine. The DCM was dried over Na2SO4 then filtered and concentrated. The product was purified by chromatography through a 330 g ISCO Redi-Sep column with 10-20% ethyl acetate/hexane solvent system to yield 3-bromo-2-chloro-6-fluorobenzonitrile.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[CH2:3][OH:4].C([O-])(=O)C.[Na+].[N:26]#[C:27]Br.N>CO>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C@H:2]3[CH2:3][O:4][C:27]([NH2:26])=[N:1]3)=[CH:8][CH:9]=2)=[CH:19][CH:18]=1
Reactant: N[C@H](CO)CCc1ccc(Nc2ccc(Cl)cc2)cc1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: CO
Product: NC1=N[C@@H](CCc2ccc(Nc3ccc(Cl)cc3)cc2)CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.5 %

Procedure:
To a stirred suspension of (S)-2-amino-4-[4-(4-chloro-phenylamino)-phenyl]-butan-1-ol (210 mg) and sodium acetate (121 mg) in methanol (5 ml) was added dropwise a solution of cyanogen bromide (68 mg) in methanol (0.3 ml). The resulting pale yellow solution was then stirred at room temperature for 16 h. Aqueous ammonia solution (0.4 ml, 25%) was added dropwise and stirring was continued for a further hour. The mixture was then concentrated in vacuo and the residue was purified by column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/EtOAc/MeOH) to give (S)-4-{2-[4-(4-chloro-phenylamino)-phenyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine (74 mg, 48%) as a yellow solid. MS (ISP): 318.1 ([{37Cl}M+H]+), 316.1 ([{35Cl}M+H]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C@@H:4]([CH:5]=O)[C@H:3]1[C:7]([O-:9])=[O:8].[Na+].[Cl-].[CH3:13][O:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.P(O)(O)([O-])=O.[Na+]>CN(C)C=O>[CH3:1][C:2]1([CH3:10])[CH:4]([CH:5]=[CH:13][O:14][CH3:15])[CH:3]1[C:7]([OH:9])=[O:8]
Reactant: CC1(C)[C@H](C(=O)[O-])[C@@H]1C=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC=CC1C(C(=O)O)C1(C)C
Reaction time: 1.5 h

Procedure:
A solution of 9 g of 96.5% potassium tert.-butylate in 90 ml of dimethylformamide was added at -60° C. to a solution of 12.58 g of sodium (1R,cis) 2,2-dimethyl-3-formyl-cyclopropane-carboxylate, 350 ml of dimethylformamide and 26.27 g of methoxymethyl triphenylphosphonium chloride and the temperature was allowed to rise to 20° C. with stirring over 90 minutes. The mixture was poured into aqueous monosodium phosphate solution and was extracted with diisopropyl oxide. The combined organic phases were extracted with 100 ml of aqueous N sodium hydroxide and the aqueous extract was stirred at 5° C. with a mixture of diisopropyl oxide and monosodium phosphate. The mixture was diluted with water and the decanted aqueous phase was extracted with diisopropyl oxide. The organic phase was evaporated to dryness under reduced pressure to obtain 5.22 g of (1R,cis)(E+Z) 2,2-dimethyl-3-(2-methoxy-1-ethenyl)-cyclopropane-carboxylic acid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[CH3:20][N:21]([CH3:39])[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:35]([F:38])([F:37])[F:36])[C:32]=1[O:33][CH3:34])[C:27](Cl)=[O:28])=[O:23]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:39][N:21]([CH3:20])[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:35]([F:36])([F:38])[F:37])[C:32]=1[O:33][CH3:34])[C:27]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:28])=[O:23]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(C(=O)N(C)C)cc(C(=O)Cl)cc1C(F)(F)F
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1c(C(=O)N(C)C)cc(C(=O)N2CSc3ccccc32)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (214 mg) and 37% formalin (0.14 mL) in the same manner as in Example 1 was dissolved in chloroform (4 mL), and triethylamine (0.47 mL) and 3-dimethylcarbamoyl-4-methoxy-5-trifluoromethylbenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (g).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C(OCC)(=O)C>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32](=[O:33])[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: c1ccc(CNCC(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(F)cc1F)N(Cc1ccccc1)CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.4 %

Procedure:
To a solution of N-benzyl-2,2-diphenyl ethyl amine (1.5 g, 0.005 mol) in 100 mL ethyl acetate was added 2,4-difluorophenyl isocyanate (0.8 g, 0.005 mol). The mixture was stirred for 20 hours at room temperature and then concentrated under vacuum. The residue was taken up in hexane. The solid suspension was filtered and oven-dried, affording 2.2 g of a fine white powder, mp 120-123° C.