Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@@H:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].CS(O[CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:15]([O:14][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[CH:11][CH:12]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH3:16]
Reactant: CS(=O)(=O)OCCCCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@H](Cc1ccc(OCCCCc2ccc([N+](=O)[O-])cc2)cc1)OCC
Yield: 92.9 %

Procedure:
(S)-2-Ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (1.0 g, 4.197 mmol) and 4-(4-nitrophenyl)butyl methanesulfonate (1.204 g, 4.406 mmol) were mixed in acetonitrile (20 ml). Potassium carbonate (anhydrous, 870 mg, 6.295 mmol) was added. The mixture was heated to reflux overnight. It was then evaporated in vacuum. Water and ethyl acetate were added into the residue. The two phases were separated. The organic phase was washed with water and brine and dried with magnesium sulfate. The solvent was removed by evaporation in vacuum. Column chromatography of the residue on silica gel using ethyl acetate/heptane (25:75) as eluant gave the desired product (1.62 g), yield 93%.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:15]=[C:14]([NH2:16])[CH:13]=[C:12]([Cl:17])[N:11]=1>CO.O>[NH2:9][C:10]1[N:15]=[C:14]([NH2:16])[C:13]([Cl:1])=[C:12]([Cl:17])[N:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cc(Cl)nc(N)n1
Solvent: CO
Solvent: O
Product: Nc1nc(N)c(Cl)c(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
50 g of N-chlorosuccinimide are added in portions at 23° C. to a solution of 45 g of 2,4-diamino-6-chloropyrimidine in methanol (1030 ml). On completion of addition, the reaction mixture is stirred at room temperature for 3 hours. The methanol is evaporated under reduced pressure and the crude product obtained is taken up under reflux in 850 ml of water for 1 hour. After filtering, the crude product is recrystallized two times from an EtOH:H2O (80:20) mixture to give 44.5 g of 2,4-diamino-5,6-dichloropyrimidine.
Reaction SMILES: [C:1]([CH2:3][C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7]1)=O)#[N:2].[CH3:21][NH:22][NH2:23]>C(O)C>[NH2:2][C:1]1[N:22]([CH3:21])[N:23]=[C:4]([CH:6]2[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:7]2)[CH:3]=1
Reactant: N#CCC(=O)C1CCN(C(=O)OCc2ccccc2)C1
Reactant: CNN
Solvent: CCO
Product: Cn1nc(C2CCN(C(=O)OCc3ccccc3)C2)cc1N
Yield: 84.7 %

Procedure:
A solution of EXAMPLE 24B (1.9 g, 7 mmol) and methylhydrazine (367 μL, 7 mmol) in ethanol (15 mL) was heated at reflux for 4 hours. After cooling, the mixture was concentrated and the residue purified by flash chromatography on silica gel using 0-15% methanol in dichloromethane to give the title compound (1.78 g, 85%). MS(DCI): m/z 301 (M+1)+.
Reaction SMILES: N(OC(C)(C)C)=O.[F:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]2[N:13]=[C:14](N)[S:15][C:11]=2[CH:10]=1.[ClH:21]>C(#N)C.[Cl-].[Na+].O.[Cu](Cl)Cl>[Cl:21][C:14]1[S:15][C:11]2[CH:10]=[C:9]([F:8])[C:18]([O:19][CH3:20])=[CH:17][C:12]=2[N:13]=1
Reactant: Cl
Reactant: COc1cc2nc(N)sc2cc1F
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Agent: [Cl-]
Solvent: CC#N
Solvent: O
Product: COc1cc2nc(Cl)sc2cc1F
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
A suspension of copper(II) chloride (546 mg) and tert-butyl nitrite (0.600 mL) in acetonitrile (10 mL) was stirred at 50° C. for 20 min. To the reaction mixture was added a solution of 6-fluoro-5-methoxy-1,3-benzothiazol-2-amine (670 mg) in acetonitrile (10 mL), and the mixture was further stirred at 50° C. for 30 min. 1M Hydrochloric acid and saturated brine were added to the reaction mixture, and the insoluble material was filtered. The filtrate was extracted with ethyl acetate, the filtered insoluble material was dissolved in THF, and the solution was combined with the organic layer. The mixture was applied to silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure and the obtained solid was washed with ethyl acetate/hexane to give the title compound (350 mg).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:9]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([OH:2])[CH2:4]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCc1ccccc1
Reactant: OC1CCCNC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: OC1CCCN(Cc2ccccc2)C1
Yield: 56.6 %

Procedure:
A mixture of 15.0 g of 3-hydroxypiperidine hydrochloride, 13.8 g of benzyl chloride, 22.1 g of triethylamine and 120 ml of toluene was stirred at reflux for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated and distilled under reduced pressure to obtain 11.8 g of 1-benzyl-3-hydroxypiperidine (yield: 56.9%). b.p.: 125°-126° C./3.5 mmHg
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][CH2:12][C:13]([O:15]C)=[O:14].[OH-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(=O)CCn1cnc2c(Cl)ncnc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCn1cnc2c(Cl)ncnc21

Procedure:
A solution of 10.4 g (0.0432 mol) of 6-chloro-9-(2-carbomethoxyethyl)purine in 400 mL dioxane, 20 mL H2O and 50 mL N NaOH was stirred 2 h at room temperature. Nearly all the solvent was removed by roto-evaporation and 50 mL of N HCl was added. The mixture was chilled and the precipitate collected; 9.00 g (92%); recrystallized from methanol-petroleum ether; mp 163°-165°; 1H NMR (200 MHz, DMSO-d6) δ8.80 (1H, s, 7 or 8-H), 4.52(2H, t), 2.97 (2H, t, CH2CO).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10]2.[N+:16]([O-])([OH:18])=[O:17]>>[N+:16]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][C:2]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10]1)[CH2:3]2)([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: O=C1NC(=O)C2(Cc3ccccc3C2)N1
Product: O=C1NC(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)N1

Procedure:
A solution of (±)-spiro[imidazolidine-4,2′-indane]-2,5-dione (3.0 g, 14.8 mmol, described in Intermediate 40) in conc. nitric acid (33 mL) was stirred at ambient temperature for 1 h. The reaction was then poured onto crushed ice and the resultant solid was isolated by filtration. The crude material was recrystallized from ethanol to give the title compound as a yellow solid. MS: m/z=248 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][C:11]([NH2:13])=[O:12])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[CH2:10][C:11]([NH2:13])=[O:12])=[CH:6][CH:7]=2)=[CH:18][CH:17]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: NC(=O)CC(=O)Nc1ccc(O)cc1
Product: NC(=O)CC(=O)Nc1ccc(OCc2ccc(Cl)cc2)cc1
Yield: 18 %

Procedure:
Prepared in analogy to example 8 from N-(4-hydroxy-phenyl)-malonamide and 4-chloro-benzylbromide. Colorless solid. Yield=18%. MS: m/e=319.1 (M++H).
Reaction SMILES: [NH2:1][C@H:2]([C:13]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17](=[O:25])[C:16]2=[CH:26][CH:27]=[CH:28][N:15]2[N:14]=1)[CH2:3][CH2:4][S:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[C:34](Cl)[N:33]=[CH:32][N:31]=1.C(N(CC)C(C)C)(C)C>>[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[C:34]([NH:1][C@H:2]([C:13]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:17](=[O:25])[C:16]3=[CH:26][CH:27]=[CH:28][N:15]3[N:14]=2)[CH2:3][CH2:4][S:5][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:33]=[CH:32][N:31]=1
Reactant: N[C@@H](CCSCc1ccccc1)c1nn2cccc2c(=O)n1-c1ccccc1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(N)ncnc1N[C@@H](CCSCc1ccccc1)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 78.6 %

Procedure:
(S)-2-(1-Amino-3-(benzylthio)propyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (10 mg, 0.02 mmol) was treated with 4-amino-6-chloropyrimidine-5-carbonitrile (4 mg, 0.03 mmol) and N,N-diisopropylethylamine (24 μl, 0.14 mmol) according to the method described in Example 17. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 8 mg (66% yield) of the title compound as a yellow solid. Purity 90%.
Reaction SMILES: [CH3:1][N:2]([CH:9]=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:11](OCCCC)=[CH2:12].ClC(OC(=O)OC(Cl)(Cl)Cl)(Cl)Cl.[OH-].[Na+]>ClC1C=CC=CC=1.O>[CH3:1][N:2]([C:9]([CH:11]=[CH2:12])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C=O)c1ccccc1
Reactant: C=COCCCC
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: O
Product: C=CC(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of N-methylformanilide (30 g), butyl vinyl ether (22.2 g) in 25 ml of clorobenzene under stirring at 10° C., a solution of bis-trichloromethylcarbonate (24.3 g) in 50 ml of clorobenzene is added dropwise in 2 hours. The reaction mixture is kept under stirring at room temperature overnight. Water (50 ml) is added, the mixture is cooled at about 5–10° C. and the pH is corrected to about 7 by adding sodium hydroxide 30% aqueous solution (50 ml). After separation of the phases, the aqueous layer is extracted with chlorobenzene (50 ml) and the combined organic layers are washed with water (20 ml) and evaporated under reduced pressure. To the residue tert-butyl methyl ether (50 ml) is added and the mixture is cooled at −15° C. for 1 hour. The precipitate is filtered on Buchner, washed twice with tert-butyl methyl ether (25 ml×2) and dried at 30–35° C. under vacuum overnight. 24.66 g of pure compound are obtained (69% molar yield)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:22].[Mg+2]>CC(O)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N+:6]([O-:22])=[CH:7]2
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: Brc1cccc2cnccc12
Agent: [Mg+2]
Solvent: O
Solvent: CC(C)O
Product: [O-][n+]1ccc2c(Br)cccc2c1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
3.1 A suspension of 6.24 g (30.0 mmol) of 5-bromoisoquinoline and 17.5 g (30 mmol) of magnesium monoperoxyphthalate hexahydrate (85%) in 120 ml of 2-propanol is stirred at room temperature for 50 hours. The reaction mixture is evaporated in vacuo, and saturated sodium chloride solution, saturated sodium hydrogencarbonate solution and dichloromethane are added. The organic phase is separated off and washed a number of times with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated. The residue is stirred with tert-butyl methyl ether, giving 5-bromoisoquinoline 2-oxide as colourless crystals; HPLC/MS: 1.51 min, [M+H] 224/226.
Reaction SMILES: [CH3:1][C:2]([SH:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:23]=[C:22]([N+]([O-])=O)[CH:21]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>CC(C)=O>[Cl:12][C:13]1[CH:23]=[C:22]([S:5][C:2]([CH3:4])([CH3:3])[CH3:1])[CH:21]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: CC(C)(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(SC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
2-Methyl-2-propanethiol (7.47 g) was added to a suspension of potassium carbonate (9.52 g) in acetone. Ethyl 2-chloro-4-nitrobenzoate (10 g) was added and the mixture was stirred at room temperature overnight. Further 2-methyl-2-propanethiol (1.0 g) was added and the mixture was stirred and heated to 30° C. for 1 hour. Further 2-methyl-2-propanethiol (1.0 g) was added and the mixture was stirred and heated at reflux for 0.5 hours. Potassium carbonate (9.52 g) and 2-methyl-2-propanethiol was added and the mixture was stirred and heated at reflux overnight. Water was added and it was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give ethyl 2-chloro-4-(1,1-dimethylethylsulphenyl)benzoate (12.1 g) as a red oil NMR (CDCl3) 1.3 (s,9H) 1.35(t,3H) 4.3(q,2H) 7.1-7.7 (m,3H).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[Cl:23])=[O:12])[CH2:10][C:5]2=[N:4][CH:3]=1.C1C(=O)N([Cl:31])C(=O)C1>CN(C)C=O>[Cl:31][C:3]1[N:4]=[C:5]2[CH2:10][N:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[C:14]=3[Cl:23])=[O:12])[CH2:8][CH2:7][N:6]2[C:2]=1[Cl:1]
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Cl)cnc2C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nc(Cl)c2Cl)C1

Procedure:
3-Chloro-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (E43) (300 mg, 0.824 mmol) and NCS (121 mg, 0.906 mmol) were stirred at RT for 16 h in N,N-dimethylformamide (DMF) (2 mL). Solvents were concentrated in vacuo and the residue purified by MDAP to afford desired product in 145 mg.
Reaction SMILES: ClC1C=C2C(=CC=1)C(=O)NN=C2C(OC)=O.ClC1C=C(C=CC=1Cl)CCl.ClC1C=C(C=CC=1Cl)CN1N=C(C(O)=O)C2C(=CC(F)=CC=2)C1=O.[Cl:51][C:52]1[CH:53]=[C:54]([CH:72]=[CH:73][C:74]=1[Cl:75])[CH2:55][N:56]1[N:65]=[C:64]([C:66]([OH:68])=[O:67])[C:63]2[C:58](=[CH:59][C:60](Cl)=[C:61]([Cl:69])[CH:62]=2)[C:57]1=[O:71]>>[Cl:51][C:52]1[CH:53]=[C:54]([CH:72]=[CH:73][C:74]=1[Cl:75])[CH2:55][N:56]1[N:65]=[C:64]([C:66]([OH:68])=[O:67])[C:63]2[C:58](=[CH:59][CH:60]=[C:61]([Cl:69])[CH:62]=2)[C:57]1=[O:71]
Reactant: O=C(O)c1nn(Cc2ccc(Cl)c(Cl)c2)c(=O)c2cc(Cl)c(Cl)cc12
Agent: COC(=O)c1n[nH]c(=O)c2ccc(Cl)cc12
Agent: ClCc1ccc(Cl)c(Cl)c1
Agent: O=C(O)c1nn(Cc2ccc(Cl)c(Cl)c2)c(=O)c2cc(F)ccc12
Product: O=C(O)c1nn(Cc2ccc(Cl)c(Cl)c2)c(=O)c2ccc(Cl)cc12

Procedure:
This ester was then reacted with 3,4-dichlorobenzyl chloride in an analogous manner to that described in part (i) and (ii) above. There was then obtained methyl 2-(3,4-dichlorobenzyl)-6-chloro-1,2-dihydro-1-oxophthalazin-4-ylcarboxylate, m.p. 168°-170° C. (recrystallised from toluene) in 45% yield. This ester was then hydrolysed as described in part (i) above to give 2-(3,4-dichlorobenzyl)-6-chloro-1,2-dihydro-1-oxophthalazin-4-ylcarboxylic acid, m.p. 222°-223° C. (recrystallised from ethanol) in 60% yield.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[C:8]=2[C:7]([C:17]([OH:19])=[O:18])=[CH:6][CH:5]=1.[CH:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[C:23](O)[CH:22]=1.CCN=C=NCCCN(C)C.CC1(C)C=CN=C(N)C1>CN(C=O)C>[F:20][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[C:8]=2[C:7]([C:17]([O:19][C:23]2[CH:22]=[CH:21][C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=2)=[O:18])=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(OC(F)F)c2oc3ccncc3c12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CC1(C)C=CN=C(N)C1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC(F)F)c2oc3ccncc3c12
Temperature: 72.5 °C

Procedure:
A mixture of 6-Difluoromethyloxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylic acid (5.5 g, 0.0197 moles), p-nitro phenol (4.1 g, 0.0295 moles), EDCI (5.7 g, 0.295 moles), 4,4-dimethyl amino pyridine (250 mg, 0.00197 moles) in DMF (603.0 mL) was heated to 70-75° C. for 4-5 hours. The residue obtained after removal of solvent under vacuo was triturated with water (50.0 mL) to give intermediate-18 (6.0 mg) as yellow solid.
Reaction SMILES: [C:1]([OH:4])(=O)C.C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[N:12]2[CH:18]=[N:17][CH:16]=[C:13]2[S:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O.ClCCl>[CH:1]([N:9]([CH2:10][C:11]1[N:12]2[CH:18]=[N:17][CH:16]=[C:13]2[S:14][CH:15]=1)[CH3:8])=[O:4]
Reactant: CC(=O)O
Reactant: CNCc1csc2cncn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Solvent: O
Solvent: ClCCl
Product: CN(C=O)Cc1csc2cncn12
Reaction time: 0.5 h

Procedure:
A mixed solution of 0.25 ml of anhydrous acetic acid and 0.50 ml of formic acid which had been beforehand reacted with each other at 50° C. for 5 minutes was added to 6 ml of a dichloromethane solution containing 294 mg of 3-(N-methylamino)methylimidazo[5,1-b]thiazole under ice-cooling, followed by stirring at the same temperature for 30 minutes. Then, water was added to the reaction solution, and the solution was then alkalified with anhydrous potassium carbonate under stirring, followed by extraction three times with dichloromethane. The organic layer was dried over anhydrous potassium carbonate and then filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by a silica gel column chromatograph to obtain 174 mg of the title compound.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH:15]1[C:16]2[C:12](=[CH:11][C:10]([N:9]3[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]3)=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: c1cc2cc(N3CCNCC3)ccc2[nH]1
Yield: 18.5 %

Procedure:
Bis(2-chloroethyl)amine hydrochloride (3.60 g, 20.2 mmol) was added to a suspension of 5-aminoindole (2.53 g, 19.1 mmol) in ethanol (30 ml) and the mixture heated at reflux for 16 h. The mixture was allowed to cool, sodium carbonate (2.14 g, 20.2 mmol) was added and the reaction mixture heated at reflux for 8 h. The mixture was allowed to cool, filtered and the filtrate evaporated. The residue was dissolved in 1M hydrochloric acid (100 ml) and extracted with dichloromethane (2×50 ml). The aqueous phase was made basic with 4M sodium hydroxide (30 ml) and extracted with ethyl acetate (2×100 ml). The extracts were washed with brine (100 ml), combined and dried (MgSO4). The residue from evaporation of the extracts was purified by flash chromatography, eluting with dichloromethane/methanol/ammonia, to give 1-(5-indolyl)piperazine (0.71 g, 18%), as a cream solid; δH (DMSO-d6) 2.94 (4H, m, 2×piperazinyl CH2), 3.00 (4H, m, 2×piperazinyl CH2), 6.29 (1H, m, 3-H), 6.84 (1H, dd, J 9.0, 2.0 Hz, 6-H), 7.00 (1H, d, J 2.0 Hz, 2-H), 7.24 (2H, m, 4-H, 7-H), and 10.82 (1H, br s, NH).
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].S(C1C=CC(C)=CC=1)([O:13][CH2:14][CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=1)[CH3:17])(=O)=O>CN(C)C=O.O>[CH2:25]([O:24][C:20]1[CH:19]=[C:18]([CH:16]([CH3:17])[CH2:15][CH2:14][O:13][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)c2cccc(OCc3ccccc3)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CCOc1ccccc1)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of phenol (4.56 g., 48.6 mmole) in dimethylformamide (40 ml.) is added under a nitrogen atmosphere to a suspension of sodium hydride (2.32 g., 48.6 mmole) of 50% previously washed with pentane) in dimethylformamide (70 ml.) at 60° C. The reaction mixture is stirred for one hour at 60°-70° C., after which a solution of 3-(3-benzyloxyphenyl)butyl tosylate (18.9 g., 46 mmole) in dimethylformamide (80 ml.) is added. The reaction mixture is stirred at 80° C. for a half hour and is then cooled to room temperature, diluted with cold water (2500 ml.) and extracted with ether (4 × 400 ml.). The combined extracts are washed successively with cold 2N hydrochloric acid (2 × 300 ml.) and saturated sodium chloride solution (3 × 300 ml.) and then dried (Na2SO4). Removal of the solvent under reduced pressure affords the product as an oil. The oily residue is dissolved in benzene and filtered through silica gel (100 g.). Concentration of the filtrate under reduced pressure gives the product as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([OH:22])=[O:21])[CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23]1(O)[CH2:27][CH2:26][CH2:25][CH2:24]1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([O:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:21])[CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OC1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@H](CCO[Si](C)(C)C(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CCO[Si](C)(C)C(C)(C)C)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-O-[tert-butyl(dimethyl)silyl]-D-homoserine (2.53 g, 7.6 mmol) in DCM (50 ml) at 0° C. was added cyclopentanol (1.39 ml, 15.3 ml, 2 eq), EDC (1.61 g, 8.4 mmol, 1.1 eq) and DMAP (0.093 g, 0.76 mmol, 0.1 eq). The reaction mixture was stirred for 16 hours at room temperature before evaporation under reduced pressure. The crude residue was dissolved in ethyl acetate (100 ml) and washed with 1M HCl, 1M Na2CO3 and brine. The organic layer was then dried over magnesium sulphate and evaporated under reduced pressure. The product was purified by column chromatography using ethyl acetate/heptane (1:4) to give 2.24 g, 73% yield of title compound.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[CH3:27][O-:28].[Na+]>CO>[CH3:27][O:28][CH2:2][C:3]1([OH:1])[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:7][CH2:8]1
Reactant: C[O-]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Agent: [Na+]
Solvent: CO
Product: COCC1(O)CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Yield: 82 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.3 mmol) with sodium methoxide (1.6 mmol) in methanol (10 ml) at a temperature 65° C. for 6 hours and by purifying the compound by silica gel column chromatography in 82% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][C@H:23]([CH3:26])[CH2:24][OH:25].O>C(Cl)Cl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][C@H:23]([CH3:26])[CH2:24][OH:25])=[N:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: C[C@@H](N)CO
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](CO)Nc1c([N+](=O)[O-])cnc2cccnc12
Reaction time: 18 h
Yield: 95 %

Procedure:
A solution of 4-chloro-3-nitro[1,5]naphthyridine (6.30 g, 30.1 mmol) dissolved in 150 mL of CH2Cl2 was treated with triethylamine (8.35 mL, 60.0 mmol) and (R)-2-aminopropanol (2.76 mL, 35.5 mmol) and the mixture was stirred under N2. After 18 hours, the reaction mixture was concentrated to give a yellow solid. The yellow solid was combined with 150 mL of H2O and the suspension was heated to reflux, with stirring, for 20 minutes. The mixture was cooled in an ice bath and the resulting yellow solid was isolated by filtration. The solid washed with cold H2O and two 50 mL-portions of Et2O and then dried with suction to give (2R)-2-[(3-nitro[1,5]naphthyridin-4-yl)amino]propan-1-ol (7.10 g) as a yellow powder.