Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Cl[CH2:3][C:4]([OH:6])=[O:5].[CH3:7][CH:8]([CH3:10])[O-:9].[Na+].[CH:12](O)(C)C>O>[CH:8]([O:9][CH2:3][C:4]([O:6][CH3:12])=[O:5])([CH3:10])[CH3:7]
Reactant: O=C(O)CCl
Reactant: CC(C)O
Reactant: CC(C)[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: COC(=O)COC(C)C

Procedure:
116.5 g of the sodium salt of chloracetic acid are slowly added at 80° C. to a sodium isopropoxide solution (freshly prepared from 23 g of sodium and 250 ml of isopropylalcohol). The reaction mixture is refluxed for 2 hours and then combined with 500 ml of water. The mixture is evaporated down to a total volume of 200 ml and adjusted to pH1 with conc. sulphuric acid. The precipitate formed is filtered off, the two phases of the filtrate are and the organic phase is fractionally distilled in vacuo (101–103° C./10 Torr; 83 g; 70%). The 2-isopropoxy-acetic acid thus obtained is heated together with 0.2 ml of conc. sulphuric acid in 57 ml of methanol and 200 ml benzene for 7 hours using a water separator. After the excess methanol has been distilled off the residue is fractionally distilled in vacuo (50–55° C./10 Torr; 81.6 g; 88%).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([CH:8]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH:23]([C:28](=O)[CH2:29][CH3:30])[C:24](=O)[CH2:25][CH3:26])=[CH:15][CH:14]=1)(=[O:7])[CH2:5][CH3:6]>C(O)C>[C:4]([CH:8]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][C:23]2[C:28]([CH2:29][CH3:30])=[N:2][NH:3][C:24]=2[CH2:25][CH3:26])=[CH:15][CH:14]=1)(=[O:7])[CH2:5][CH3:6]
Reactant: CCC(=O)C(CCCOc1ccc(OCCCC(C(=O)CC)C(=O)CC)cc1)C(=O)CC
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCC(=O)C(CCCOc1ccc(OCCCc2c(CC)n[nH]c2CC)cc1)C(=O)CC
Reaction time: 8 h

Procedure:
A solution of 0.36 ml (0.00815 m) of hydrazine hydrate in 350 ml of ethanol was added dropwise during a 90 minute period to a solution of 3.3 g (0.0074 m) of 1,4-bis(4,4-dipropionylbutyloxy)benzene in 700 ml of ethanol held at 0°-5° C. and with vigorous stirring. The reaction mixture was then heated at reflux for 2.5 hours and allowed to stand at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was treated with ethereal hydrogen chloride. The solid product which formed was collected and stirred for two hours with 250 ml boiling isopropyl acetate, then filtered and concentrated. The solid residue was recrystallized from isopropyl acetate to give 1.6 g of 4-{3-[4-(4,4-dipropionylbutyloxy)phenoxy]propyl}-3,5-diethyl-1H-pyrazole, m.p. 135°-136° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:17]O>>[F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH3:17])=[O:7]
Reactant: CO
Reactant: O=C(O)c1ccc(F)cc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(F)cc1O
Yield: 92 %

Procedure:
4-Fluorosalicylic acid (10.0 g, 64 mmol) was dissolved in methanol (300 ml), and concentrated sulfuric acid (6.3 g, 64 mmol) was added thereto. The reaction mixture was refluxed for 48 hrs. The solvent was evaporated, and the residue was neutralized with 2 N aqueous sodium hydroxide solution. Ethyl acetate was added to the mixture. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give methyl 4-fluorosalicylate (10.0 g, 92%) as white crystals. Methyl 4-fluorosalicylate (10.0 g, 58 mmol) and N,N-dimethylthiocarbamoyl chloride (9.6 g, 77 mmol) were dissolved in DMF (100 ml), and 1,4-diazabicyclo[2.2.2]octane (8.5 g, 75 mmol) was added thereto. The reaction mixture was stirred at room temperature for 7 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:5, v/v) were collected, concentrated and recrystallized from ethyl acetate-hexane to give the titled compound (12.1 g, 80%) as white crystals.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.Cl.[CH3:22][N:23]([CH3:28])[CH2:24][C:25](O)=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C.CN(C)C=O>[CH2:1]([O:13][C:25](=[O:26])[CH2:24][N:23]([CH3:28])[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CN(C)CC(=O)O
Reactant: CCCCCCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOC(=O)CN(C)C
Temperature: 0 °C
Reaction time: 24 h
Yield: 48.4 %

Procedure:
First, 1-dodecyl alcohol (2.98 g, 0.016 mol), triethylamine (1.62 g, 0.016 mol) and 4-(N,N-dimethylamino)pyridine (DMAP; 0.195 g, 0.0016 mol) were added to a solution of N,N-dimethylglycine hydrochloride (2.23 g, 0.016 mol) in dry N,N-dimethylformamide (DMF; 100 mL) under nitrogen atmosphere, and cooled to 0° C. Then, dicyclohexylcarbodiimide (DCC; 3.63 g, 0.0176 mol) in dry DMF (60 ml) was added thereto at 0° C. The reaction mixture was returned to room temperature and stirred for about one day, then DMF was evaporated under reduced pressure with a pump. The residue was dissolved using ether and aqueous saturated sodium bicarbonate solution, and the ether layer was collected and washed once with water and once with saturated saline, after which it was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The resultant residue was separated by column chromatography (hexane:ethyl acetate:triethylamine=50:50:1) to give N,N-dimethylamino-acetate-1-dodecyl ester (C12-tertiary amine) (yield 48%, 2.10 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)(O)[O-].[Na+].[C:21](Cl)(Cl)=[S:22]>C(Cl)(Cl)Cl.O>[N:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:10][CH:11]=1)=[C:21]=[S:22]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(OCCn2ccnc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: S=C=Nc1ccc(OCCn2ccnc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 116.8 %

Procedure:
To an ice-cooled stirred biphasic solution of 4-[2-(1H-imidazol-1-yl)ethoxy]benzenamine (1.00 g; 4.92 mmol) and sodium bicarbonate (2.07 g; 24.6 mmol) in chloroform (100 mL) and water (50 mL) was added a solution of thiophosgene (452 μL; 5.90 mmol) in chloroform (10 mL) over 5 min. The mixture was stirred at ice-bath temperature for 20 min, and then the aqueous and organic phases were separated and the aqueous phase extracted with chloroform (50 mL). The combined chloroform layers were washed with brine, then dried over magnesium sulfate and concentrated under reduced pressure to give 1-[2-(4-isothiocyanatophenoxy)ethyl]-1H-imidazole (1.41 g) as a yellow oil.
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:15]([O:17]N1C(=O)CCC1=O)=O)[CH2:3][CH2:4][C:5](=[O:14])[O:6]CC1C=CC=CC=1.[NH2:32][C@H:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:34].Cl.C(N(CC)CC)C>CN(C=O)C>[NH:1]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C@H:2]([C:15]([NH:32][C@H:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:34])=[O:17])[CH2:3][CH2:4][C:5](=[O:14])[OH:6]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Boc-L-Glu(OBzl)OSu (Bachem), 434 mg (1 mmol) is reacted with L-Ala-OtBu.HCl, 182 mg (1 mmol) in 10 mL DMF containing triethylamine (202 mg). After stirring for 16 hours at room temperature, the reaction mixture is rotary evaporated to dryness and the residue is redissolved in methylene chloride, washed with water, dried over sodium sulfate and evaporated to dryness. The residue is redissolved in methanol, 50 mL, and transferred to a Parr flask. 10% Pd/C catalyst (Aldrich), 50 mg, is added and the flask is charged with 40 psi hydrogen gas on a Parr shaker. The mixture is shaken for 2 hours at room temperature or until no further consumption of hydrogen is noted. The Parr flask is evacuated and charged with argon gas. The mixture is filtered through Celite, and the filtrate is rotary evaporated to give crude Boc-L-Glu-L-Ala-OtBu.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]1=[O:26])(C)(C)C.C(C(O)=O)(F)(F)F>C(Cl)Cl>[NH2:7][CH:8]1[CH2:12][CH2:11][N:10]([CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]1=[O:26]
Reactant: CC(C)(C)OC(=O)NC1CCN(C(c2ccccc2)c2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(C(c2ccccc2)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To the solution of (1-benzhydryl-2-oxo-pyrrollidin-3-yl)-carbamic acid tert-butyl ester (41) (1.2 g, 3.26 mmol) in CH2Cl2 (20 ml) was added CF3CO2H (8 ml). The resulting mixture was stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium hydrogen carbonate (20 ml). The organic was dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2: MeOH (10:1) to give the desired product in 97% yield.
Reaction SMILES: N[CH2:2][CH2:3][C:4]1C=C[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1>C1COCC1>[C:8]([O:10][CH2:11][CH3:12])(=[O:9])[CH3:7].[CH3:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCOC(=O)c1ccc(CCN)cc1
Solvent: C1CCOC1
Product: CCCCCC
Product: CCOC(C)=O
Temperature: 50 °C
Reaction time: 20 h
Yield: 69 %

Procedure:
1.98 g (9.59 mmol) (S)—O-Benzyl-dihydro-5-hydroxymethyl-2(3H)furanone and 3.14 g (16.25 mmol) ethyl p-aminoethylbenzoate were dissolved in 50 mL THF and stirred at 50° C. for 20 hours. Reaction was concentrated and crude residue purified via chromatography, eluting with 50% ethyl acetate/hexane yielding 2.24 g (5.61 mmol, 58% yield) N′-[2-(4-carboethoxyphenyl)ethyl]-5-benzyloxy-4-hydroxypentanamide as a white solid. Step 3
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CS(O[CH2:15][C:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:18])[CH3:17])(=O)=O>CN(C=O)C>[CH3:18][C:16]([NH:19][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:15])[CH2:17][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(COc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 9 %

Procedure:
To a solution of phenol (2.1 g, 22.4 mmol, 3 equiv) in DMF (10 ml) at room temperature were added NaH (60% dispersion in mineral oil, 360 mg, 9.0 mmol, 1.2 equiv) and after 10 min 2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylpropyl methanesulfonate (D273) (2 g, 7.5 mmol, 1 equiv) and the resulting solution was stirred at 50° C. for 2 h then cooled to room temperature and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 9/1 to 6/1) gave 1,1-dimethylethyl [1,1-dimethyl-2-(phenyloxy)ethyl]carbamate (D274) (180 mg, 9%) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl>[O:19]1[CH2:20][CH2:21][N:16]([C:7]([C:6]2[CH:10]=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:8])[CH2:17][CH2:18]1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)N1CCOCC1
Reaction time: 2 h

Procedure:
A solution of 17.4 g. (0.075 mol.) of 3,4 dinitrobenzoylchloride in 250 ml of methylene chloride is treated at 0°-20° C. with a solution of 13 g. (0.15 mol.) of morpholine in 100 ml. of methylene chloride. The solution is kept at 20°-25° C. for 2 hrs., the solvent is evaporated and the residue triturated with water. Recrystallization from methanol affords 4-morpholinocarbonyl-1,2-dinitrobenzene (m.p. 136°-137° C.). 17.0 G. of 4-morpholinocarbonyl-1,2-dinitrobenzene in 340 ml. of methanol is hydrogenated for 3 hrs. at 45-50 psi in the presence of 1.7 g. of 5% palladized charcoal. The resulting solution of 1,2-diamino-4-morpholinocarbonylbenzene is filtered and concentrated to ~170 ml. 14.0 G. of 1,3-bis-methoxycarbonyl-S-methyl isothiourea, 170 ml. of water and 4 ml. of acetic acid are added to the diamine solution and the mixture is refluxed for 3 hrs. The solution is concentrated and cooled. Filtration and recrystallization from methanol-chloroform affords 5(6)-morpholinocarbonyl-2-carbomethoxyaminobenzimidazole (m.p. 224° C. dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C([N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23](Cl)=[O:24])=[CH:20][CH:21]=2)[C:16]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[N:15]1)(=O)C.O>N1C=CC=CC=1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[C:19]([C:23]([NH:7][C:6]4[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)=[O:24])[CH:18]=3)[NH:14][N:15]=2)=[CH:31][CH:30]=1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution containing 3-nitroaniline (96 mg, 0.694 mmol) in pyridine (5 mL) was added 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (200 mg, 0.631 mmol). The reaction mixture was allowed to stir for 18 hours at ambient temperature. Water (30 mL) was then added and the resulting precipitate was filtered and dried to afford the title compound. This precipitate was taken on directly to the next step for deprotection.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:27](O)=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].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.C([O:67][C:68](=[O:71])[CH2:69][NH2:70])(C)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:16]1[C:17]2[CH:5]([CH2:4][O:3][C:1]([NH:18][C@H:19]([C:27]([NH:70][CH2:69][C:68]([OH:67])=[O:71])=[O:28])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:2])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of Fmoc-phenylalanine (1.0 g, 2.58 mmol) in DMF (13 mL) at 0° C. was added DIEA (899 μL, 5.16 mmol) and HBTU (979 mg, 2.58 mmol). After stirring for 10 min at 0° C., glycine t-butyl ester (353 μL, 2.58 mmol) was added and stirring was pursued for 1 h at 0° C. The reaction mixture was diluted with ethyl acetate, washed with H2O, 1N HCl solution, saturated NaHCO3 solution and saturated NaCl solution. The organic layer was dried over MgSO4, filtered and concentrated to dryness. The crude product was purified by silica gel chromatography on a Biotage™ flash chromatography system using 50% ethyl acetate in hexanes. Dipeptide 72 was obtained as a white solid (1.05 g, 81%). 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 3.08-3.13 (m, 2H), 3.78-3.95 (m, 2H), 4.18 (t, J=6.9 Hz, 1H), 4.31-4.37 (m, 2H), 4.40-4.47 (m, 1H), 5.27 (bs, 1H), 6.21 (bs, 1H), 7.17-7.22 (m, 2H), 7.24-7.32 (m, 5H), 7.40 (t, J=7.5 Hz, 2H), 7.53 (t, J=7.9 Hz, 2H), 7.76 (d, J=7.5 Hz, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:10][C:11](=[O:34])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]3[N:24]([CH:25]=2)[N:23]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=2)[S:21]3)=[CH:14][CH:13]=1)C.O>ClCCl>[OH:32][C:29]1[CH:30]=[CH:31][C:26]([C:22]2[S:21][C:20]3=[N:19][C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:11]([OH:34])=[O:10])=[CH:13][CH:14]=4)=[CH:25][N:24]3[N:23]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1ccc(-c2cn3nc(-c4ccc(OC)cc4)sc3n2)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2cn3nc(-c4ccc(O)cc4)sc3n2)cc1
Temperature: 25 °C
Yield: 130.6 %

Procedure:
To a suspension of 4-[2-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt (1.0 g) in dichloromethane (10 ml) was added borone tribromide (1.0M solution in dichloromethane) (8.0 ml) at 0° C. and the mixture was stirred at ambient temperature for 1 week. The reaction mixture was pulverized with cold water. The precipitate was collected by filtration and dried to give 4-[2-(4-hydroxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid (893 mg).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[O:21]=[C:22]1[NH:26][C:25]2[CH:27]=[CH:28][C:29]([C:31]([OH:33])=[O:32])=[CH:30][C:24]=2[S:23]1>>[C:31]([OH:33])(=[O:32])[CH3:29].[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C@H:3]([OH:20])[CH2:2][NH:1][C:31]([C:29]2[CH:28]=[CH:27][C:25]3[NH:26][C:22](=[O:21])[S:23][C:24]=3[CH:30]=2)=[O:32])[CH2:6][CH2:7]1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: O=C(O)c1ccc2[nH]c(=O)sc2c1
Product: CC(=O)O
Product: O=C(NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1ccc2[nH]c(=O)sc2c1

Procedure:
Prepared as described in Example 1 from (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1 g) and 2-oxo-2,3-dihydro-1,3-benzothiazole-6-carboxylic acid (0.061 g). Title compound obtained as acetate salt, a white solid (0.10 g).
Reaction SMILES: [CH2:1]([C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][N:6]=1)[CH2:2][CH:3]=C.[O:14]1CCOCC1.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O.C(OCC)(=O)C>[O:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:5]([CH2:1][CH2:2][CH:3]=[O:14])=[N:6]1
Reactant: C1COCCO1
Reactant: C=CCCc1noc2ccccc12
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=CCCc1noc2ccccc12
Reaction time: 1 h

Procedure:
Compound 26 (549 mg, 3.2 mmol), water (5 mL), 1,4-dioxane (15 mL) and osmium tetroxide (15 mg, 0.06 mmol) were stirred for 5 min. in a small flask. Sodium metaperiodate (1.56 g, 7.3 mmol) was added over 30 min. and the suspension was then stirred for 1 hour. Ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate and dichloromethane. The combined organic phases were dried over magnesium sulphate and evaporated to dryness to produce 784 mg of crude 27, which was used directly without further purification in the synthesis compound 28.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.ClC1C=C2C(=CC=1)C(=O)CC2.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][CH2:23][C:24]2=[O:27])=[CH:20][CH:19]=1>O1CCCC1.C(OCC)C>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][CH2:23][C:24]2([CH:1]2[CH2:3][CH2:2]2)[OH:27])=[CH:20][CH:19]=1
Reactant: Br[Mg]C1CC1
Reactant: O=C1CCc2ccc(Cl)cc21
Agent: O=C1CCc2cc(Cl)ccc21
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(C2CC2)CCc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
45 ml (22.5 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran were added to 2.50 g (15.0 mmol) of a mixture of 5-chloro-2,3-dihydro-1H-inden-1-one and 6-chloro-2,3-dihydro-1H-inden-1-one in 56 ml of diethyl ether at RT, and the mixture was stirred at RT overnight. The reaction mixture was added to ice-water, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) and preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 152 mg (5% of theory) of the title compound.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][C:25]=1[Cl:26])[CH:22]([C:27](Cl)=[O:28])[CH2:21][C:20]2=[O:30].[OH-].[Na+]>>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][C:25]=1[Cl:26])[CH:22]([C:27]([N:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[CH2:9][N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:28])[CH2:21][C:20]2=[O:30]
Reactant: C1CCN(CC2CCCCN2)CC1
Reactant: O=C1CC(C(=O)Cl)c2cc(Cl)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CC(C(=O)N2CCCCC2CN2CCCCC2)c2cc(Cl)c(Cl)cc21
Yield: 52 %

Procedure:
From 1.5 g of 2-(piperidinomethyl)piperidine dihydrochloride, 2.5 g of 5,6-dichloro-3-oxoindan-1-carbonyl chloride and 45 ml of 1N aqueous sodium hydroxide solution. 1.1 g of the title compound was obtained, melting at 240°-245° C. (dec), using a procedure similar to that in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:13][S:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:21]([N:8]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:7]=2)[C:10]2([CH2:13][S:12][CH2:11]2)[CH2:9]1)(=[O:23])[CH3:22]
Reactant: Brc1ccc2c(c1)NCC21CSC1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC2(CSC2)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice cooled solution of 6-bromo-1,2-dihydrospiro[indole-3,3′-thietane] (0.25 g, 0.96 mmol), 4-dimethylaminopyridine (5.89 mg, 0.048 mmol), and triethylamine (0.269 mL, 1.928 mmol) in DCM (9.64 mL) was added acetyl chloride (0.137 mL, 1.928 mmol). The solution was stirred for 5 min at this temperature, the ice bath was removed and the solution was stirred at rt for 3 h. The reaction was poured into 2N HCl aqueous solution and extracted with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to give 1-acetyl-6-bromo-1,2-dihydrospiro[indole-3,3′-thietane] as a yellow solid. Mass Spectrum (ESI) m/e=297.9 [(M+1) (79Br)] and 300.0 [(M+1) (81Br)].
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][S:11]([C:14]2[C:22]3[C:17](=[C:18]([O:23][CH2:24][C:25]([O:27]CC)=O)[CH:19]=[CH:20][CH:21]=3)[N:16]([CH3:30])[CH:15]=2)(=[O:13])=[O:12])=[O:9])=[N:4][CH:3]=1.[NH3:31].CO>>[Br:1][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][S:11]([C:14]2[C:22]3[C:17](=[C:18]([O:23][CH2:24][C:25]([NH2:31])=[O:27])[CH:19]=[CH:20][CH:21]=3)[N:16]([CH3:30])[CH:15]=2)(=[O:12])=[O:13])=[O:9])=[N:4][CH:3]=1
Reactant: CCOC(=O)COc1cccc2c(S(=O)(=O)NC(=O)Nc3ncc(Br)s3)cn(C)c12
Reactant: N
Solvent: CO
Product: Cn1cc(S(=O)(=O)NC(=O)Nc2ncc(Br)s2)c2cccc(OCC(N)=O)c21

Procedure:
A solution of ethyl {[3-({[(5-bromo-1,3-thiazol-2-yl)carbamoyl]amino}sulfonyl)-1-methyl-1H-indol-7-yl]oxy}acetate (0.050 g, 0.09 mmol) in 7N ammonia/methanol, (5 mL) was heated at 40° C. for 5 h. The reaction mixture was concentrated to dryness and dried under high vacuum to obtain the title compound (0.040 g) as a grey amorphous solid. MS (ISN): m/e 486.4, 488.3 (M−H)−