Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:19])([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([O-:18])(=[O:17])=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:20]([O-:23])(=[O:22])=[O:21])[CH:8]=2)[N:3]=1.[Na+].[Na+].C([O-])(=O)C.[Na+].S1(CCCC1)(=O)=O.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(OCC)(=O)C.CO>[CH2:38]([N+:3]1[C:4]2[C:9](=[CH:8][C:7]([S:20]([O-:23])(=[O:21])=[O:22])=[CH:6][CH:5]=2)[C:10]([CH3:19])([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:16])=[O:17])[C:2]=1[CH3:1])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC1=Nc2ccc(S(=O)(=O)[O-])cc2C1(C)CCCCS(=O)(=O)[O-]
Reactant: BrCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1=[N+](Cc2ccccc2)c2ccc(S(=O)(=O)[O-])cc2C1(C)CCCCS(=O)(=O)O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Disodium 2,3-dimethyl-3-(4-sulphonatobutyl)-3H-indole-5-sulphonate (5 g, 13.9 mmol) and sodium acetate (3.11 g) were stirred with methanol (100 ml) for 1 hour. Solvent removed by rotary evaporation and a further portion of methanol (100 ml) added. This was removed by rotary evaporation to yield an orange sticky solid. To this was added sulfolan (25 ml) and benzyl bromide (9.51 g, 55.6 mmol, 4 eq). The mixture was stirred overnight at 110° C. under a blanket of nitrogen. The cooled red solution was poured into stirring ethyl acetate (1 l) and the precipitate filtered off. The precipitate washed with copious ethyl acetate and diethyl ether and then dried under vacuum. A sample was dissolved in water and analysed by reverse Phase TLC using acetonitrile modified with 0.1% TFA: water modified with 0.1% TFA (30:70). Separation yielded the product (Rf 0.6) and starting material (Rf 0.95). The product spot turned red on standing indicating quaternisation had taken place. Yield: 8 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[F:23][C:24]([F:33])([F:32])[C:25]1[CH:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[F:33][C:24]([F:23])([F:32])[C:25]1[CH:29]=[C:28]([CH2:30][NH:31][C:20]([C:10]2[N:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:9]=2)=[O:22])[O:27][N:26]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Reactant: NCc1cc(C(F)(F)F)no1
Product: O=C(NCc1cc(C(F)(F)F)no1)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid (example M) and 3-trifluoromethyl-isoxazol-5-methanamine (example BA) as starting materials; MS: 480.0 (M)+.
Reaction SMILES: C([BH3-])#N.[Na+].C(N[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14](COC3C=CC=C(C=O)C=3)=[CH:13][C:11]=2[N:12]=1)C.N1CCCCC1.C(O)(=O)C>CO>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[CH:8]1
Reactant: CCNc1nc2cc(COc3cccc(C=O)c3)ccc2o1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: c1ccc2ocnc2c1
Yield: 108.8 %

Procedure:
Sodium cyanoborohydride (0.17 g) was added portionwise to a solution of 2-ethylamino-5-(3-formylphenoxymethyl)benzoxazole (0.80 g), piperidine (0.23 g) and acetic acid (0.76 ml) in methanol (10 ml) at 0° C. with stirring. The mixture was stirred at the same temperature for 2 hours and for further 6 hours at ambient temperature. The solvent was evaporated in vacuo. The residue was mixed with a saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel by eluting with a mixture of chloroform-methanol (20:1, V/V). The pure base was converted to the hydrochloride in a usual manner. The salt was dissolved in ethanol and reprecipitated with diethyl ether to give 2-ethylamino-5-3-piperidinomethylphenoxymethyl)benzoxazole (0.35 g) dihydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[H][H].Cl[C:20]1[CH:29]=[N:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1>CN(C)C=O.O>[N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:28]=[CH:29][C:20]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: Clc1cnc2ccccc2n1
Reactant: COC(=O)C(C)Oc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccc(Oc2cnc3ccccc3n2)cc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
In a nitrogen atmosphere, a solution of 5.9 g (0.03 mole) methyl 2-(4-hydroxyphenoxy)propanoate in 20 cc of dimethylformamide was added dropwise at about 15° C. to 1.5 g (0.03 mole) 57% sodium hydride in 20 cc dimethylformamide. When the evolution of hydrogen ceased, 4.9 g (0.03 mole) 2-chloroquinoxaline was added and the reaction mixture was heated at 130° C. for 4 hours. After standing overnight at room temperature, the reaction mixture was poured into about 100 cc of cold water. The precipitated solid was filtered and crystallized from methanol to give 4.2 g of product, m.p. 110°-115°.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([O:14][CH2:15][C@H:16]([NH:34][C:35](=[O:38])[CH2:36]Cl)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C=O)C>C(OCC)(=O)C>[CH2:7]([O:14][CH2:15][C@H:16]([NH:34][C:35](=[O:38])[CH2:36][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CCl)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: Cc1ncc[nH]1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nccn1CC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
2-Methylimidazole (64 mg, 0.786 mmol) was added to a flask charged with (S)-3-(benzyloxy)-2-(2-chloroacetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (150 mg, 0.393 mmol), prepared as in Example 15, and DMF (3 mL). The mixture was stirred at 40° C. for 30 minutes then diluted with ethyl acetate (20 mL). The dilution was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. Product was purified from the residue by reverse phase HPLC to provide Compound 160, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(2-methyl-1H-imidazol-1-yl)acetamido)propanamide (100.8 mg, 0.201 mmol, 51% yield) as an off-white solid. 1H-NMR (400 MHz, CDCl3): 8.38 (s, 1H), 7.38-7.21 (m, 7H), 7.05-6.89 (m, 7H), 6.45 (d, 1H), 4.66 (d, 1H), 4.61 (s, 2H), 4.55 (d, 1H), 3.91 (dd, 1H), 3.55 (t, 1H), 2.38 (s, 3H). MS (EI) for C28H27FN4O4. found 502.9 (MH+).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:30]2[CH2:42][CH2:41][N:33]3[C:34]4[CH2:35][CH2:36][CH2:37][CH2:38][C:39]=4[CH:40]=[C:32]3[C:31]2=[O:43])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[N:24]=[C:23]3[N:25]=[CH:26][NH:27][C:22]3=[CH:21][CH:20]=2)[C:15](=[O:28])[N:14]([CH3:29])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:30]2[CH2:42][CH2:41][N:33]3[C:34]4[CH2:35][CH2:36][CH2:37][CH2:38][C:39]=4[CH:40]=[C:32]3[C:31]2=[O:43])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[N:24]=[C:23]3[N:25]=[CH:26][NH:27][C:22]3=[CH:21][CH:20]=2)[C:15](=[O:28])[N:14]([CH3:29])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc4[nH]cnc4n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc3[nH]cnc3n2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
A mixture of 217b (40 mg, 0.070 mmol) and lithium hydroxide (26 mg, 0.70 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at room temperature for 1 h. The mixture was evaporated in vacuo and the residue was diluted with water and ethyl acetate. The water phase was separated and extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 217 (15 mg, 40%) as a white solid. MS-ESI: [M+H]+ 537.3. 1H NMR (500 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.91-8.64 (m, 2H), 8.52 (d, J=4.5 Hz, 1H), 8.19-8.06 (m, 1H), 7.89-7.79 (m, 1H), 7.57-7.53 (m, 1H), 7.43-7.40 (m, 1H), 7.22 (d, J=8.5 Hz, 1H), 6.59 (s, 1H), 5.06-4.96 (m, 1H), 4.5-4.40 (m, 2H), 4.26-4.11 (m, 3H), 3.88-3.85 (m, 1H), 3.62 (s, 3H), 2.62-2.54 (m, 2H), 2.50-2.48 (m, 2H), 1.81-1.79 (m, 2H), 1.71-1.67 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[CH:23]=[CH:24][CH:25]=2)=[CH:14][CH:13]=1)[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.C(Cl)CCl.[CH3:51][NH:52][CH3:53]>ClCCl>[C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[CH:23]=[CH:24][CH:25]=2)=[CH:14][CH:13]=1)[C:9]([N:52]([CH3:53])[CH3:51])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC(C(=O)O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Reactant: CNC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C)C(=O)C(CC(=O)OC(C)(C)C)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Yield: 91 %

Procedure:
A solution of compound 50.3 (50 mg, 0.1 mmol) in dichloromethane (2 mL) was treated with 1-hydroxybenzotriazole (15 mg, 0.1 mmol) and EDC (21 mg, 0.11 mmol) sequentially. The resulting mixture was stirred for 1 h. before dimethylamine (9 mg, 0.2 mmol) was added dropwise. The reaction was quenched 30 min. later with water (5 mL). The reaction mixture was extracted with dichloromethane (2 mL×3). The organic extracts were combined, dried over MgSO4 and concentrated under reduced pressure to yield amide 50.4 (48 mg). The product was used in the next step without further purification. MS ESI (pos.) m/e: 527 (M+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])OC(C)(C)C)[CH2:4][CH2:3]1.[C:16](OC(=O)C(C)C)(=O)[CH:17](C)[CH3:18].[ClH:27].O1CCOCC1>C(Cl)Cl>[ClH:27].[NH2:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:15])[CH:17]([CH3:18])[CH3:16])[CH2:6][CH2:7]1
Reactant: CC(C)C(=O)OC(=O)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)C(=O)N[C@H]1CC[C@@H](N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl cis-4-aminocyclohexylcarbamate (500 mg, 2.333 mmol) in DCM (20 mL) was added isobutyric anhydride (0.407 mL, 2.450 mmol). The solution was stirred overnight at RT. After 16 hours, 4 M HCl in dioxane (2.333 mL, 9.33 mmol) was added, and the reaction was stirred at RT overnight. The resulting white precipitate was collected by vacuum filtration and dried in vacuo to generate N-(cis-4-aminocyclohexyl)isobutyramide hydrochloride as an off-white powder (508 mg, 99% yield).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.C(N(CC)C(C)C)(C)C.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:24]([Si:21]([O:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=1[O:10][CH3:11])([CH3:23])[CH3:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1cc(F)c(F)cc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(F)c(F)cc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
To a solution of 4,5-difluoro-2-methoxy-phenol (3.75 g, 23.42 mmol, Example 264) in methylene chloride (60 mL) cooled to 0° C. were added N,N-diisopropylethylamine (4.895 mL, 28.10 mmol), tert-butyldimethylsilyl chloride (4.367 g, 28.10 mmol, Aldrich), and dimethylaminopyridine (286 mg, 2.342 mmol, Aldrich). At the end of addition, the ice bath was removed and the reaction mixture was stirred at room temperature for 90 minutes. Water (30 mL) was added and the layers were separated. The aqueous layer was extracted with methylene chloride (20 mL). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, 60 Å silica gel, eluting with 3% ethyl acetate in hexanes) yielded tert-butyl-(4,5-difluoro-2-methoxy-phenoxy)-dimethyl-silane as a clear oil (5.22 g, 81%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[N:16]([CH3:17])[CH:10]([CH2:11][C:12](=O)[CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[CH2:1]([N:8]1[CH2:15][CH:14]2[N:16]([CH3:17])[CH:10]([CH2:11][C:12](=[N:20][OH:21])[CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1C2CC(=O)CC1CN(Cc1ccccc1)C2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: c1ccncc1
Solvent: O
Product: CN1C2CC(=NO)CC1CN(Cc1ccccc1)C2
Temperature: 25 °C
Yield: 878.5 %

Procedure:
A mixture of 3-benzyl-9-methyl-7-oxo-3,9-diazabicyclo[3.3.1]nonane (9.33 g ), hydroxylamine hydrochloride (3.98 g ), pyridine (12.5 ml ) and ethanol was heated at reflux for 2 hrs. The reaction solution was cooled down to room temperature, potassium carbonate (15 g) and water (8 ml ) were added and the stirring was continued for a while. The resultant suspension was filtered through celite and the solvent was distilled off under reduced pressure. The resulting residue was mixed with chloroform (200 ml ) and filtered through Celite. The solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography and crystallized to afford the title compound (3. 87 g ).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:33])(=[N:29][CH2:30][CH2:31]Br)=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:33])(=[N:29][CH2:30][CH2:31][N:36]([CH2:37][CH3:38])[CH2:34][CH3:35])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CCNCC
Reactant: CS(=O)(=NCCBr)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCN=S(C)(=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reaction time: 2 h
Yield: 60 %

Procedure:
To a stirring solution of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-methyl-N-[2-bromo-ethyl]sulfoximide (150 mg, 0.00026 mol) in DMF(0.7 mL) was added diethyl amine (1 mL) at 25° C. Reaction mixture was stirred at same temperature for 2 hr. Reaction mixture was diluted with water and filtered. Drying afforded 85 mg of titled compound in 60% yield.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1(N)[NH:12][C:11]([CH3:13])=[N:10][C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])=[CH:8]1)[CH2:4][CH3:5])[CH3:2].C([N:27]([CH2:30]C)CC)C.ClC(Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[N:12]=[C:11]([CH3:13])[N:10]=[C:9]2[C:8]=1[NH:27][C:30](=[O:35])[N:14]2[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])[CH2:4][CH3:5])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Reactant: CCC(CC)OC1(N)C=C(Nc2c(C)cc(C)cc2C)N=C(C)N1
Solvent: C1CCOC1
Product: CCC(CC)Oc1nc(C)nc2c1[nH]c(=O)n2-c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 254.8 %

Procedure:
A mixture of 6-(1-ethyl-propoxy)-2-methyl-N4-(2,4,6 trimethyl-phenyl)-pyrimidine-4,6-diamine (182 mg, 0.554 mmol), triethylamine (39 mg, 0.388 mmol) and triphosgene (58 mg, 0.196 mmol) in 6 ml of dry THF was stirred at room temperature for 30 min. The mixture was quenched with water and extracted with chloroform. The organic layer was dried and concentrated to give 177 mg (90%) of the title compound as a white solid, mp 159-160° C. 1H NMR(CDCl3) δ 8.50(s, 1H), 6.99(s, 2H), 5.30(m, 1H), 2.47(s, 3H), 2.32(s, 3H), 2.08(s, 6H), 1.73(m, 4H), 0.94(t, 6H) ppm.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=2[OH:12])[CH2:5][CH2:4]1.C(OC(=O)C)(=O)C.[N+:21]([O-])([OH:23])=[O:22]>C(O)(=O)C>[ClH:1].[NH2:2][CH:3]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[C:9]([N+:21]([O-:23])=[O:22])[C:10]=2[OH:12])[CH2:5][CH2:4]1
Reactant: Cc1ccc(O)c2c1CCC2N
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])c(O)c2c1CCC2N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5.75 Grams of 1-amino-7-hydroxy-4-methylindane hydrochloride was suspended in 40 ml of acetic acid, then 3.27 ml of acetic anhydride and a solution consisting of 2.59 ml of concentrated nitric acid and 10 ml of acetic acid were added thereto, and the whole mixture was stirred at a room temperature for 6 hours. The solvent was removed by evaporation, the residue was washed with acetone and recrystallized from ethanol to obtain 2 g of 1-amino-7-hydroxy-4-methyl-6-nitroindane hydrochloride in the form of yellow needle-like crystals. Melting point: 200°-230° C. (decomp.).
Reaction SMILES: [OH:1][C@@H:2]([C:7]1[C:36]([CH3:37])=[N:35][C:34]2=[CH:38][C:31]3=[N:32][N:33]2[C:8]=1[N:9]1[CH2:43][CH2:42][C:12]([CH3:44])([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([CH3:41])[O:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:40])=[CH:24][C:25]=2[C:26]2[CH:39]=[C:30]3[CH:29]=[CH:28][CH:27]=2)[CH2:11][CH2:10]1)[C:3]([O:5]C)=[O:4].C(O[C:49]1([CH3:53])[CH2:52][CH2:51][CH2:50]1)(=O)C.Cl(O)(=O)(=O)=O.[OH-].[Na+]>C(Cl)Cl.CO>[CH3:53][C:49]1([O:1][C@@H:2]([C:7]2[C:36]([CH3:37])=[N:35][C:34]3=[CH:38][C:31]4=[N:32][N:33]3[C:8]=2[N:9]2[CH2:43][CH2:42][C:12]([CH3:44])([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([CH3:41])[O:19][C:20]3[CH:21]=[CH:22][C:23]([CH3:40])=[CH:24][C:25]=3[C:26]3[CH:39]=[C:30]4[CH:29]=[CH:28][CH:27]=3)[CH2:11][CH2:10]2)[C:3]([OH:5])=[O:4])[CH2:52][CH2:51][CH2:50]1
Reactant: CC(=O)OC1(C)CCC1
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(C)cc1-c1cccc-3c1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc2c(c1)-c1cccc(c1)-c1cc3nc(C)c([C@H](OC4(C)CCC4)C(=O)O)c(n3n1)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Reaction time: 3 h
Yield: 35.8 %

Procedure:
To a stirred solution of methyl (2S)-2-hydroxy-2-[(22S)-4,17,22,28-tetramethyl-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (40 mg, 0.067 mmol) in DCM (2 mL) and 1-methylcyclobutyl acetate (599 mg, 4.68 mmol) at rt was added 70 wt % perchloric acid (0.017 mL, 0.200 mmol). After 3 h, the reaction mixture was diluted with DCM (25 mL), carefully quenched with sat. NaHCO3 (5 mL), organic layer separated and washed with brine (10 mL), dried (Na2SO4), filtered and concentrated to give yellow paste. The crude was then tretated with 1N NaOH (0.334 mL, 0.334 mmol) in MeOH (1 mL) at 75° C. for 3 h. Mixture was then cooled and purified by prep HPLC to afford (2S)-2-(1-methylcyclobutoxy)-2-[(22S)-4,17,22,28-tetramethyl-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid (15.8 mg, 0.024 mmol, 36.2% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.17-7.11 (m, 2H), 7.08 (s, 1H), 7.05 (d, J=8.2 Hz, 1H), 5.49 (s, 1H), 4.62 (d, J=5.5 Hz, 1H), 4.45 (t, J=12.2 Hz, 1H), 3.61-3.53 (m, 1H), 3.40-3.20 (m, 7H), 2.83 (d, J=10.4 Hz, 1H), 2.29 (s, 3H), 2.22 (q, J=10.0 Hz, 1H), 2.01-1.86 (m, 4H), 1.82 (br. s., 1H), 1.70-1.62 (m, 5H), 1.58-1.41 (m, 4H), 1.28 (s, 3H), 1.17 (s, 3H), 1.07 (d, J=5.8 Hz, 3H). LCMS (M+H)=653.6.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:11]([NH:14][NH:15][CH:16]=O)[CH2:12][CH3:13])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[OH:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][N:34]([C:37]3[CH:42]=[CH:41][C:40]([NH:43][C:44](=O)[O:45]C4C=CC=CC=4)=[CH:39][CH:38]=3)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C@H:9]([C@@H:11]([N:14]1[C:44](=[O:45])[N:43]([C:40]2[CH:39]=[CH:38][C:37]([N:34]3[CH2:33][CH2:32][N:31]([C:28]4[CH:29]=[CH:30][C:25]([OH:24])=[CH:26][CH:27]=4)[CH2:36][CH2:35]3)=[CH:42][CH:41]=2)[CH:16]=[N:15]1)[CH2:12][CH3:13])[CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(N2CCN(c3ccc(O)cc3)CC2)cc1)Oc1ccccc1
Reactant: CC[C@H](NNC=O)[C@H](C)OCc1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H]([C@H](C)OCc1ccccc1)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Temperature: 95 °C
Reaction time: 24 h

Procedure:
A mixture of N′-((2S,3S)-2-(benzyloxy)pentan-3-yl)formohydrazide compound of formula-17 (45.5 g) obtained in example-13, dioxane (500 ml) added phenyl 4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenylcarbamate compound of formula-19 (50 g) was heated to 90-100° C. Triethylamine (26 g) was added to the reaction mixture at 90-100° C. over a period of 1 hour and stirred for 24 hours at 90-100° C. After completion of the reaction, the reaction mixture was cooled to 25-30° C. and dichloromethane was added to the reaction mixture. Filtered the reaction mixture through hyflow bed and washed with dichloromethane. Water was added to the filtrate. Both organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Both organic layers were combined and washed with 2% sodium hydroxide solution followed by water, and then with 5% hydrochloric acid solution followed by water and 5% NaHCO3 solution washing. Distilled off the solvent from organic layer under reduced pressure to get the title compound. Isopropyl alcohol (75 ml) was added to the obtained compound and the reaction mixture was cooled to 25-30° C. The reaction mixture was stirred for 6 hours at 25-30° C. Filtered the solid, washed with isopropyl alcohol and then dried to get the title compound. Yield: 28 g; Purity by HPLC: 97.67%; Impurity-A: 0.37%
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7](C(O)=O)[N:8]=[CH:9][N:4]2[CH:3]=1.C1(O)C=CC=CC=1>ClC1C=CC(Cl)=CC=1Cl.CCCCCC>[Br:1][C:2]1[S:6][C:5]2=[CH:7][N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: O=C(O)c1ncn2cc(Br)sc12
Solvent: Oc1ccccc1
Solvent: CCCCCC
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: Brc1cn2cncc2s1
Temperature: 180 °C
Reaction time: 24 h
Yield: 53.4 %

Procedure:
A solution of 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid (31 mg, 0.12 mmol) and phenol (12 mg, 0.12 mmol) dissolved in 1,2,4-trichlorobenzene (1 ml) was stirred at 180° C. for 24 hr. The reaction solution was allowed to cool to room temperature, was diluted with hexane, and was extracted with 1 M hydrochloric acid (3 ml×3). The aqueous layer was neutralized with a 2 M aqueous solution of sodium hydroxide and was extracted with ethyl acetate (5 ml×3). The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 2-bromoimidazo[5,1-b]thiazole (13 mg, 50%) as a white solid.