Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]([CH3:13])[C:6]([C:14]([O:16]C)=O)=[C:5]([OH:18])[C:4]=2[CH:3]=1.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:11])(=[O:12])[N:7]([CH3:13])[C:6]([C:14](=[O:16])[NH:19][C:20]3[S:21][CH:22]=[CH:23][N:24]=3)=[C:5]([OH:18])[C:4]=2[CH:3]=1
Reactant: Nc1nccs1
Reactant: COC(=O)C1=C(O)c2cc(Cl)sc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2cc(Cl)sc2S1(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.4 g. of 6-chloro-4-hydroxy-2-methyl-3-methoxycarbonyl-2H-thieno[3,2-e]1,2-thiazine-1,1-dioxide is heated under reflux for 16 hours with 0.19 g. of 2-aminothiazole in 45 ml. of absolute xylene, while passing a stream of nitrogen through the mixture. The reaction mixture is cooled to room temperature, and the product is crystallized out by scratching and then kept overnight in the cold. The precipitate crystals are removed by filtration under suction, recrystallized from ethanol, and 6-chloro-4-hydroxy-2-methyl-3-(2-thiazolecarbamoyl)-2H-thieno[3,2-e]1,2-thiazine-1,1-dioxide having a melting point of 136°-138° (with decomposition) is obtained.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[OH-].[Na+].[C:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)(=[O:12])[CH3:11]>CC(O)C.O>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:10](=[O:12])[CH3:11])=[CH:19][CH:18]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: OC(CCl)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)Nc1ccc(OCC(O)CCCl)cc1
Reaction time: 16 h
Yield: 53.5 %

Procedure:
To a solution of 500 g (3.5 mole) of 1,4-dichloro-2-butanol was added, dropwise, 500 ml (6.25 mole) of a 50% sodium hydroxide solution. The mixture was stirred for 16 hr and then 500 ml of water was added, dropwise, with the temperature maintained below 35° C. The mixture was extracted with 500 ml of isopropyl ether, dried over sodium sulfate and concentrated to give an oil which was purified by distillation. To 14.3 g (0.1 mole) of the purified epoxide was added a solution of 15.1 g (0.1 mole) of 4-acetamidophenol in 150 ml of 2-propanol and 4 g of (0.1 mole) of sodium hydroxide in 10.0 ml of water. The mixture was stirred for 15 hr and then poured into 400 ml of water at 0° C. The crude, collected solid was washed with water and allowed to air dry. The solid was suspended in 350 ml of acetone, collected by filtration, and washed with additional portions of acetone. The filtrate was concentrated under reduced pressure to give 13.8 g (53% yield) of solid. A portion of this solid was recrystallized from tetrahydrofuran to give cream-colored solid, m.p. 124°-127° C.
Reaction SMILES: C([O:5][C:6](=[O:24])/[CH:7]=[CH:8]/[C:9]1[CH:10]=[N:11][C:12]2[NH:21][C:20](=[O:22])[C@H:19]3[N:15]([CH2:16][CH2:17][CH2:18]3)[CH2:14][C:13]=2[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:33]>CCOCC>[ClH:33].[O:22]=[C:20]1[C@H:19]2[N:15]([CH2:16][CH2:17][CH2:18]2)[CH2:14][C:13]2[CH:23]=[C:9](/[CH:8]=[CH:7]/[C:6]([OH:24])=[O:5])[CH:10]=[N:11][C:12]=2[NH:21]1
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CN1CCC[C@H]1C(=O)N2
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cl
Product: O=C(O)/C=C/c1cnc2c(c1)CN1CCC[C@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A solution of (S)-(E)-3-(10-oxo-2,3,4,9,10,10a-hexahydro-1H-3a,8,9-triaza-benzo[f]azulen-6-yl)acrylic acid tert-butyl ester (0.65 g, 1.97 mmol) in CH2Cl2 (7 mL) was treated with TFA (7 mL). After stirring at room temperature for 30 min, the clear tan solution was concentrated in vacuo. The resulting oil was treated with anhydrous dioxane (20 mL of a 4.0 M solution in dioxane, 80 mmol). The resulting mixture was sonicated for 5 min, stirred under N2 for 5 min and diluted with Et2O. The solid was isolated by filtration, suspended in Et2O, concentrated to dryness, and dried under vacuum overnight to give the title compound (0.60 g, 88%) as an off-white solid: MS (ESI) m/e 274 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:17][CH2:16][C:8]2(OCC(C)(C)C[O:9]2)[CH2:7][C:6]1([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)O)[CH3:3].[ClH:27].O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[ClH:27].[CH3:3][N:2]([CH2:4][CH:5]1[CH2:17][CH2:16][C:8](=[O:9])[CH:7]=[C:6]1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)[CH3:1]
Reactant: COc1cccc(C2(O)CC3(CCC2CN(C)C)OCC(C)(C)CO3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(C2=CC(=O)CCC2CN(C)C)c1
Temperature: 5 °C
Reaction time: 72 h
Yield: 78.9 %

Procedure:
182 g 9-dimethylaminomethyl-8-(3-methoxy-phenyl)-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-8-ol were dissolved in 1,200 ml tetrahydrofuran and the reaction mixture was cooled to 5° C. A mixture of 600 ml 32% hydrochloric acid solution and 600 ml water was added at this temperature. The mixture was stirred at room temperature for 72 hours. When the reaction had ended 500 ml ethyl acetate were added at 5° C. and the reaction mixture was then brought to pH 12 with 32% sodium hydroxide solution. The phases were separated and the aqueous phase was washed three times with 300 ml ethyl acetate each time. The combined organic phases were then washed twice with 100 ml saturated sodium chloride solution each time, dried over magnesium sulfate and then freed from the solvent. Purification was carried out via hydrochloride formation. For this, 4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enone base was dissolved in 500 ml acetone and an equimolar amount of water and trimethylchlorosilane was added. The hydrochloride which had precipitated out was filtered off with suction and dried in vacuo. 63.6 g (78.9% of theory) 4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enone hydrochloride were obtained in this way. b) rac-cis-[4-Dimethylaminomethyl-3-hydroxy-3-(3-methoxy-phenyl)-cyclohexanone]hydrochloride (compound 1)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.CN(C)C=O.[CH2:14]([O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1Cl)[CH3:15]>O>[CH2:14]([O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[O:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:15]
Reactant: OCc1cccnc1
Reactant: CCOC(=O)c1cccnc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccnc1OCc1cccnc1
Reaction time: 0.5 h

Procedure:
To a solution of Pyridin-3-yl-methanol (0.59 grams, 5.4 mmole) in dimethylformamide (20 ml) sodium hydride (0.259 grams, 6.5 mmole) was added and stirred for 30 minutes. 2-Chloro-nicotinic acid ethyl ester (1.0 grams, 5.4 mmole) was added via syringe and stirred at room temperature over night. The mixture was diluted with water (150 ml) and extracted by diethyl ether and ethyl acetate. The combined extracts were washed with 1N NaOH, water and brine, dried over Na2SO4, filtered, and concentrated to an oil (1.3 g). MW 258.28; MS (m/e) 259 (M++1).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=4)[N:18]([CH:26]4[CH2:29][O:28][CH2:27]4)[N:17]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=4)[N:18]([CH:26]4[CH2:27][O:28][CH2:29]4)[N:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C4COC4)c4cc(F)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C4COC4)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.3 %

Procedure:
To a solution of 2-(6-fluoro-1-oxetan-3-yl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (98 mg, 0.18 mmol) in CH2Cl2 (1.5 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in 10:90:0.5 MeOH/CH2Cl2/NH4OH (3 mL) and stirred at room temperature for 3 h then concentrated. The residue was portioned between water and 10% MeOH/CH2Cl2. The aqueous layer was extracted with 10% MeOH/CH2Cl2 (3×). The combined organics were concentrated and the residue was purified by silica gel chromatography with 0% to 5% MeOH/CH2Cl2 (0.5% NH4OH) to afford 30 mg (41%) of 2-(6-fluoro-1-oxetan-3-yl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as a white solid. MS (M+Na)+=417; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.87 (br. s., 1H), 9.20 (s, 1H), 8.45-8.51 (m, 1H), 8.44 (s, 1H), 8.04 (d, J=7.6 Hz, 1H), 7.73 (dd, J=9.8, 1.9 Hz, 1H), 7.22 (td, J=9.1, 1.9 Hz, 1H), 6.13 (quin, J=7.0 Hz, 1H), 5.11-5.20 (m, 2H), 4.99-5.10 (m, 2H), 4.21 (dq, J=13.5, 6.4 Hz, 1H), 1.30 (d, J=6.4 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH2:7][N:8]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl.O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH2:7][N:8]2[CH2:12][CH2:11][C@H:10]([O:13][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O[C@H]1CCN(CCc2ccc(Cl)cc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CCN(CCc2ccc(Cl)cc2)C1

Procedure:
(S)-1-(4-Chlorophenethyl)-3-hydroxypyrrolidine (190 mg, 0.84 mmol) was dissolved in dichloromethane (6 ml). Triethylamine (110 mg, 1.09 mmol) and methanesulfonyl chloride (125 mg, 1.09 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred at 0° C. for 1 hour. The reaction liquid was distributed in dichloromethane and water. The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and then with a solvent mixture of dichloromethane and methanol (50:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (S)-1-(4-chlorophenethyl)-3-methanesulfonyloxypyrrolidine in the form of a light yellow oil (252 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:6]([N:10]2C(=O)C3=CC=CC=C3C2=O)=[C:7]([F:9])[CH:8]=1)[NH2:5].NN.[OH2:25].CS(C)=[O:28]>>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([NH2:10])=[C:4]([N+:5]([O-:28])=[O:25])[C:3]=1[O:21][CH3:22]
Reactant: CS(C)=O
Reactant: COc1c(Cl)cc(F)c(N2C(=O)c3ccccc3C2=O)c1N
Reactant: O
Agent: NN
Product: COc1c(Cl)cc(F)c(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-Chloro-5-fluoro-2-methoxy-6-(phthalimido)aniline (0.6 g, 1.7 mmol) was dissolved in dimethylsulfoxide (3 ml) and anhydrous hydrazine (0.22 g, 6.8 mmol) was added. The solution was stirred at ambient temperature for 12 hr under a stream of nitrogen. Water was added and the product extracted with ether. The organic layer was washed with water, dried (anhydrous sodium sulfate), and evaporated to furnish the title compound (0.22 g). 1H NMR (CDCl3, 300 MHz) 3.98 (3H, s), 5.09 (2H, br s), 7.2 (1H, d, J=10.5 Hz) ppm.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([CH:8]([CH2:21][CH2:22][CH2:23][CH3:24])[C:9]([NH:11][C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][NH:18]2)=[CH:14][CH:13]=1)=[O:10])[CH3:7].[OH-].[Na+].CN(C)[C:29](=[O:31])[CH3:30]>>[C:29]([C:16]1[C:15]2[C:19](=[CH:20][C:12]([NH:11][C:9](=[O:10])[CH:8]([CH2:6][CH3:7])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:14]=2)[NH:18][CH:17]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)N(C)C
Reactant: CCCCC(CC)C(=O)Nc1ccc2cc[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCC(CC)C(=O)Nc1ccc2c(C(C)=O)c[nH]c2c1
Yield: 80 %

Procedure:
1.9 g. of phosphorus oxychloride was slowly added to 1.48 g. of N,N-dimethylacetamide at 0° C. The mixture was allowed to attain room temperature and a solution of 1.0 g. 6-(2-ethylhexanamido)indole in 2 ml. N,N-dimethylacetamide was added. After 15 minutes the reaction solution was basified to pH 14 with 20% w/v sodium hydroxide solution, briefly heated under reflux, then cooled and extracted with ethyl acetate. The combined extracts were washed with water, then with brine, dried (MgSO4) and evaporated to give 0.93 g (80%) of 3-acetyl-6-(2-ethylhexanamido)indole (DD) as an orange powder; partial NMR: 2.5 (s, 3H), COCH3), 7.7 (d, 1H, H2 -indole), 9.8 (br, s, 1H, NH).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13](=[O:17])[C:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O1CCOCC1.C(O)C>O>[CH2:1]([C:8]1[S:12][C:11]([C:13](=[O:17])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])C(=O)c1ccc(Cc2ccccc2)s1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: O=C(O)C(=O)c1ccc(Cc2ccccc2)s1
Reaction time: 3 h

Procedure:
A mixture of the 5-benzylthien-2-ylglyoxylate (1.37 g, 0.005 mole), potassium hydroxide (0.66 g, 0.01 mole), dioxane (3.3 ml), ethanol (33 ml) and H2O (6.6 ml) was stirred 3 hrs. at 27° C. The reaction mixture was concentrated and chilled to induce crystallization of 0.9 g of the potassium salt of 5-benzylthien-2-ylglyoxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:11]([CH:13]=[CH2:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH:16]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=1)[C:17]([F:20])([F:19])[F:18].N1C=CC=CC=1C1C=CC=CN=1>ClC1C=CC=CC=1Cl.[Cu]Cl>[Cl:27][C:25]1[CH:26]=[C:21]([CH:16]([C:17]([F:20])([F:18])[F:19])/[CH:14]=[CH:13]/[C:11]2[CH:10]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([CH3:1])[CH:12]=2)[CH:22]=[C:23]([Cl:28])[CH:24]=1
Reactant: FC(F)(F)C(Br)c1cc(Cl)cc(Cl)c1
Reactant: C=Cc1ccc(C(=O)OCC)c(C)c1
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1C
Temperature: 180 °C
Reaction time: 24 h
Yield: 38.8 %

Procedure:
To a stirred solution of ethyl 2-methyl-4-vinylbenzoate (2.0 g, 10.5 mmol) in 1,2-dichlorobenzene (25 mL) were added 1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (6.44 g, 21.0 mmol), copper(I) chloride (CuCl; 208 mg, 21 mmol) and 2,2bipyridyl (0.65 g, 4.1 mmol). The reaction mixture was degassed with argon for 30 min and then stirred at 180° C. for 24 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to 25° C. and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; eluting with 25-30% EtOAc in petroleum ether) afforded the title compound as a solid (1.7 g, 40%): 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J=8.0 Hz, 1H), 7.37 (m, 1H), 7.27-7.24 (m, 4H), 6.59 (d, J=16.0 Hz, 1H), 6.59 (dd, J=16.0, 8.0 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.08 (m, 1H), 2.62 (s, 3H), 1.42 (t, J=7.2 Hz, 3H); ESIMS m/z 415.06 ([M−H]−); IR (thin film) 1717, 1255, 1114 cm−1.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.[N:12]1C2C(=CC=CC=2)[CH:15]=[CH:14][CH:13]=1>P(Cl)(Cl)(Cl)=O.N1C=CC=CC=1>[NH2:12][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:13]([NH2:12])[CH2:14][CH3:15]
Reactant: c1ccc2ncccc2c1
Reactant: Oc1ccnc2cccnc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCCN
Product: Nc1ccnc2cccnc12

Procedure:
4-Hydroxy-1,5-naphthyridines can be prepared from 3-aminopyridine derivatives by reaction with diethyl ethoxymethylene malonate to produce the 4-hydroxy-3-carboxylic acid ester derivative with subsequent hydrolysis to the acid, followed by thermal decarboxylation in quinoline (as for example described for 4-Hydroxy-[1,5]naphthyridine-3-carboxylic acid, Joe T. Adams et al., J.Amer.Chem.Soc., 1946, 68, 1317). A 4-hydroxy-[1,5]naphthyridine can be converted to the 4-chloro derivative by heating in phosphorus oxychloride. A 4-amino 1,5-naphthyridine can be obtained from the 4-chloro derivative by reaction with n-propylamine in pyridine.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN1CCOCC1.[NH2:26][C@H:27]([C:31]([N:33]1[CH2:53][CH2:52][CH2:51][C@H:34]1[C:35]([NH:37][C@H:38]([C:42]([C:44]([C:47]([F:50])([F:49])[F:48])([F:46])[F:45])=[O:43])[CH:39]([CH3:41])[CH3:40])=[O:36])=[O:32])[CH:28]([CH3:30])[CH3:29]>C(Cl)Cl>[N:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:26][C@H:27]([C:31]([N:33]3[CH2:53][CH2:52][CH2:51][C@H:34]3[C:35]([NH:37][CH:38]([CH:39]([CH3:40])[CH3:41])[C:42](=[O:43])[C:44]([F:45])([F:46])[C:47]([F:48])([F:49])[F:50])=[O:36])=[O:32])[CH:28]([CH3:29])[CH3:30])=[O:16])=[CH:17][CH:18]=2)(=[O:8])=[O:9])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)F)C(C)C
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(S(=O)(=O)N2CCOCC2)cc1)C(C)C)C(=O)C(F)(F)C(F)(F)F
Temperature: -22 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
To a solution of the benzoic acid derivative prepared above (0.240 g, 0.885 mmol) and NMM (0.446 g, 4.43 mmol, 0.489 ml) in CH2Cl2 (8.9 ml) at -22° C. under N2 was added IBCF (0.121 g, 0.885 mmol, 0.115 ml), and the reaction stirred at -22° C. for 20 min. The HCL.Val-Pro-Val-C2F5 (0.400 g, 0.885 mmol) was added in several portions, and the reaction was stirred at -22° C. for 0.5 h, followed by 4 h at room temperature. The reaction was diluted with CH2Cl2 (30 ml) and then washed successively with 10% HCl (2×15 ml), sat. NaHCO3 (2×15 ml), brine (1×15 ml), and dried over MgSO4. Solvent removal under vacuum gave an off-white foam which was purified by flash chromatography (silica gel; 25/75, hexane/EtOAc) to give 0.295 g (50%) of the title compound as a white solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Br:26][C:27]1[N:32]2[CH:33]=[CH:34][N:35]=[C:31]2[C:30](Br)=[N:29][CH:28]=1>C(O)(C)C>[Br:26][C:27]1[N:32]2[CH:33]=[CH:34][N:35]=[C:31]2[C:30]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)=[N:29][CH:28]=1
Reactant: Nc1ccc(OCCN2CCOCC2)cc1
Reactant: Brc1ncc(Br)n2ccnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cnc(Nc2ccc(OCCN3CCOCC3)cc2)c2nccn12
Yield: 86.3 %

Procedure:
In the same way as described in the general procedure for amine displacement using 4-(2-morpholin-4-yl-ethoxy)-phenylamine (600 mg, 2.7 mmol), N,N-diisopropylethylamine (0.470 mL, 2.7 mmol) and a solution of 5,8-dibromo-imidazo[1,2-a]pyrazine (0.500 g, 1.80 mmol) in isopropanol (6 mL). Purification by silica gel column chromatography eluting with a mixture 97:3 DCM:MeOH affords the title compound as a pale yellow solid (650 mg, 86%). 1H-NMR (400 MHz, CDCl3) δ (ppm) 2.51-2.62 (4H, m), 2.75-2.83 (2H, t), 3.71-3.78 (4H, m), 4.09-4.18 (2H, m), 6.90 (2H, d), 7.51 (1H, s), 7.61 (1H, s), 7.64 (2H, d), 7.70 (1H, s), 7.90 (1H, s). LCMS: Rt 2.09 min (97%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]2[C:11]=1[O:12][C:13]1[C:14]([CH2:30][C:31]([OH:33])=[O:32])=[C:15]([O:28][CH3:29])[CH:16]=[CH:17][C:18]=1[C:19]2([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34](O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]2[C:11]=1[O:12][C:13]1[C:14]([CH2:30][C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[C:15]([O:28][CH3:29])[CH:16]=[CH:17][C:18]=1[C:19]2([CH3:26])[CH3:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: OCc1ccccc1
Reactant: COc1ccc2c(c1CNC(=O)OC(C)(C)C)Oc1c(ccc(OC)c1CC(=O)O)C2(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(c1CNC(=O)OC(C)(C)C)Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
A solution of 3 g (6.55 mmol) of 5-[(1-tert-butoxyformamido)methyl]-3,6-dimethoxy-9,9-dimethylxanthene-4-acetic acid in 65 ml of methylene chloride was cooled to 20° and treated with 1.1 ml (10.62 mmol) of benzyl alcohol. After the addition of 20 mg of 4-dimethylaminopyridine a solution of 1.5 g (7.27 mmol) of dicyclohexylcarbodiimide in 16 ml of methylene chloride was added dropwise, whereupon the mixture was warmed to room temperature and was stirred for 3 hours. The precipitated dicyclohexylurea was filtered off and washed with a small amount of methylene chloride. The filtrate was washed with sodium bicarbonate solution and water, dried over sodium sulphate and concentrated. The residue remaining was chromatographed on silica gel with hexane/ethyl acetate, whereby 2.9 g of benzyl 5-[(1-tert-butoxyformamido)methyl]-3,6-dimethoxy-9,9-dimethylxanthene-4-acetate were obtained as a colourless powder m.p. of 139°-141°; IR 3443, 2972, 2930, 1724, 1605, 1498 cm-1.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[NH2:8][CH2:9][C:10]1[N:11]2[CH:17]=[N:16][CH:15]=[C:12]2[S:13][CH:14]=1.P(=O)(O)(O)O.[C:23](=O)(O)[O-:24].[Na+]>ClCCl.C(N(CC)CC)C.CO>[CH3:23][O:24][C:6]([NH:5][S:2]([NH:8][CH2:9][C:10]1[N:11]2[CH:17]=[N:16][CH:15]=[C:12]2[S:13][CH:14]=1)(=[O:4])=[O:3])=[O:7]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: NCc1csc2cncn12
Reactant: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NS(=O)(=O)NCc1csc2cncn12

Procedure:
A 0.081 ml potion of dry methanol was added dropwise to 0.35 ml of a dry dichloromethane solution containing 0.175 ml of chlorosulfonyl isocyanate at a bath temperature of -55° C. under stirring, and the mixture was then stirred for 20 minutes. Then, the precipitate was dissolved in 2.0 ml of dry dichloromethane, and this mixed solution was added dropwise to 10 ml of a dry dichloromethane solution containing 153 mg of 3-aminomethylimidazo[5,1-b]thiazole and 0.28 ml of triethylamine at an internal temperature of -47° C. over 2 minutes, and the mixture was then stirred at -47 to -35° C. for 60 minutes. After the addition of 10 ml of a 1/15M phosphoric acid buffer, the solution was adjusted to pH 7.5 with 5% sodium bicarbonate, and after salting-out, extraction was carried out five times with 30 ml of dichloromethane. Further, the aqueous layer was adjusted to pH 6 with 1N hydrochloric acid, and extraction was then carried out five times with 30 ml of ethyl acetate. The extract was combined with the above dichloromethane extract. Afterward, the solution was dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The resulting residue was recrystallized from methanol to obtain 87.4 mg of the title compound as a light yellow crystal.