Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+]>O>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(CO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(CO)cc1
Temperature: 20 °C

Procedure:
A mixture of Me pHMB (50.0 g., 0.30 mole) and 200 ml. of water containing sodium hydroxide (13.3 g., 0.33 mole) was refluxed for 3 hours. The colorless solution was filtered from a small amount (0.5 g.) of a gummy solid and extracted with methylene chloride (2 × 50 ml.). The aqueous portion was acidified with concentrated hydrochloric acid to give 37.0 g. of pHMBA: m.p. 180°-181° C. The filtrates were concentrated to 100 ml. at 100° C., cooled to 20° C., and filtered to give 6.7 g. of pHMBA (m.p. 181° C.). The combined yield of pHMBA was 43.7 g. (96%): silylation gc, 99.7% pHMBA.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C:12]2[C:16](=[CH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14][C:13]=2[C:26]([O:28]C)=[O:27])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C:12]2[C:16](=[CH:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:14][C:13]=2[C:26]([OH:28])=[O:27])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)C1=C(Sc2ccc(OC)c(OC)c2)C(=CCCc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(SC2=C(C(=O)O)CCC2=CCCc2ccccc2)cc1OC
Yield: 84.1 %

Procedure:
A mixture of methyl 2-[(3,4-dimethoxyphenyl)thio]-3-(3-phenylpropyl-1-yl)-1-cyclopentenecarboxylate (0.5 g, 1.2 mmol) and 10% sodium hydroxide (5 mL) in ethanol (10 mL) is heated under reflux for 4 hours. The mixture is cooled and is poured into aqueous HCl. The mixture is extracted with ether. The organic layer is washed with water and is dried over MgSO4. The solvent is removed in vacuo to provide 2-[(3,4-dimethoxyphenyl)thio]-3-(3-phenylpropyl-1-yl)-1-cyclopentenecarboxylic acid (0.4 g, 85%): m.p. 146-8° C. Anal. (C23H26O4S) C,H,N: 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.10-1.70 (m, 5H), 1.83-2.02 (m, 1H), 2.32-2.41 (t, 2H), 2.60-2.72 (m, 3H), 3.84 (s, 3H), 3.90 (s, 3H), 6.69-6.75 (d, 1H), 6.94-7.00 (m, 2H), 7.00-7.10 (d, 2H), 7.18-7.32 (m, 3H); MS (EI) m/e 398 (M+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[O:37])=[CH:31][CH:30]=2)O1>>[CH:13]1([C:9]2[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6](=[O:20])[N:5]3[C:10]=2[C:11]([CH3:12])=[C:2]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[O:37])=[CH:31][CH:30]=2)[CH:3]=[CH:4]3)[CH2:15][CH2:14]1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC1(C)OB(c2ccc(NC(N)=O)cc2)OC1(C)C
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(NC(N)=O)cc3)ccn2c1=O
Yield: 28.5 %

Procedure:
Methyl 1-cyclopropyl-9-methyl-4-oxo-8-(4-ureido-phenyl)-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (75 mg, 0.26 mmol) and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)-urea (84 mg, 0.32 mmol). Compound precipitated from solution and was filtered off and dried in vacuo to afford the title compound as a yellow solid (29 mg, 26%). ESI-MS m/z: 392 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH:20]([OH:25])[C:21]([O:23][CH3:24])=[O:22])[CH:15]=2)[N:10]=1.[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:28]=1[C:29](Cl)=[O:30].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:28]=1[C:29]([O:25][CH:20]([CH2:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH:18]=[CH:17]2)[C:21]([O:23][CH3:24])=[O:22])=[O:30]
Reactant: COC(=O)C(O)Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)OC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of methyl 3-[2-(2,6-dichlorophenyl)-6-quinolinyl]-2-hydroxypropanoate 55 (0.104 g) in pyridine (1 ml) is added 2,6-dichlorobenzoyl chloride (0.2 ml). The solution is stirred for 6 h at room temperature. A saturated solution of NaHCO3 (10 ml) is added. The aqueous phase is extracted with AcOEt (3×10 ml). The organic phases are washed with brine, dried over MgSO4 and evaporated. The residue is purified twice over silica gel using AcOEt/petroleum ether (10/90 to 20/80) as eluent.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH3:29]>C(Cl)Cl.CO>[NH:1]1[C:5]2[CH:4]=[CH:9][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[C:25]([C:26]([NH2:29])=[O:28])=[CH:24][CH:23]=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:7][C:6]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1cccc2c1[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Reactant: N
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1cccc2c1[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Yield: 58 %

Procedure:
The title compound is prepared from cis-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-10-carboxylic acid and ammonia (7 mol/L in methanol) following a procedure analogous to that described in Example 1. Yield: 58% of theory; TLC: rf=0.24 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=375 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][C@H:12]([CH3:17])[C:13]([O:15]C)=O)[CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][C@@H:20]([OH:31])[CH2:21][N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>CCO>[OH:31][C@@H:20]([CH2:21][N:22]1[CH2:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30]1)[CH2:19][NH:18][C:13](=[O:15])[C@H:12]([O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2)[CH3:17]
Reactant: NC[C@@H](O)CN1Cc2ccccc2C1
Reactant: COC(=O)[C@@H](C)Oc1cccc2cccnc12
Solvent: CCO
Product: C[C@@H](Oc1cccc2cccnc12)C(=O)NC[C@@H](O)CN1Cc2ccccc2C1
Temperature: 120 °C
Yield: 11 %

Procedure:
To a solution of (R)-methyl 2-(quinolin-8-yloxy)propanoate (100 mg, 0.433 mmol) in EtOH (1 mL) was added (R)-1-amino-3-(isoindolin-2-yl)propan-2-ol (83 mg, 0.433 mmol). The reaction mixture was heated under microwave conditions at 120° C. for 0.5 h, concentrated, and purified by preparative TLC first and then by preparative HPLC purification. (19 mg, yield 11%) MS (ESI+) e/z: 392.1 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 8.90 (d, J=2.76 Hz, 1H), 8.34 (d, J=8.28 Hz, 1H), 7.64-7.48 (m, 3H), 7.34-7.24 (m, 1H), 7.23-7.08 (m, 4H), 5.07 (q, J=6.53 Hz, 1H), 3.97-3.71 (m, 5H), 3.49 (dd, J=13.55, 5.27 Hz, 1H), 3.29 (d, J=6.27 Hz, 1H), 2.71 (d, J=6.02 Hz, 2H), 1.72 (d, J=6.53 Hz, 3H).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](OC(=O)C)(=[O:7])[CH3:6].[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[NH:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>ClCCCl>[C:5]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH:13]([NH:21][C:22](=[O:30])[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[CH2:12]2)(=[O:7])[CH3:6]
Reactant: O=C(NC1Cc2ccccc2C1)c1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc2c(c1)CC(NC(=O)c1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.87 g (21.6 mmol) aluminum trichloride were suspended in 10 ml 1,2-dichloroethane, 500 mg (4.9 mmol) acetic anhydride and 1.0 g N-(indan-2-yl)-4-fluoro-benzamide added, and the whole was stirred for 2 h at RT. The resulting mixture was poured onto ice water/HCl, extracted with dichloromethane, the organic phase was dried with Na2SO4 and evaporated.
Reaction SMILES: [H-].[Na+].[C:3]1([S:9]([NH2:12])(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[C:30]3[CH:38]=[CH:39][C:40]([C:42](O)=[O:43])=[CH:41][C:29]=3[N:28]=2)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O.ClCCl>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:31]([CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)[C:30]3[CH:38]=[CH:39][C:40]([C:42]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[S:9]([NH2:12])(=[O:11])=[O:10])=[O:43])=[CH:41][C:29]=3[N:28]=2)=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Reactant: NS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NS(=O)(=O)c1ccccc1C(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A suspension of compound 49 (0.060 g, 0.14 mmol) and thionyl chloride (0.051 mL) in benzene (2 mL) was refluxed for 2 h under an argon atmosphere. The reaction mixture was cooled to rt and concentrated on a rotary evaporator. The residue was coevaporated with benzene (2×) to afford the acid chloride as a white solid (0.062 g, 100%). Sodium hydride (0.0101 g, 0.252 mmol, 60% dispersion in oil was added to a solution of phenylsulfonamide (0.0425 g, 0.270 mmol) in dimethylformamide (1 mL) at rt under an argon atmosphere. After 1 h, dichloromethane was added (1 mL), followed by the acid chloride of 49 at 0° C. The reaction was warmed to rt. After 1 h, the reaction was diluted with dichloromethane and quenched with 1 N hydrochloric acid. The aqueous layer was washed with dichloromethane (3×). The combined organic layers were dried (MgSO4) and concentrated on a rotary evaporator. The residue was purified by column chromatography (silica gel, 25% acetone/toluene (v/v)). This material was further purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.05% trifluoroacetic acid) to afford 55 as a white solid (0.0219 g, 54%). 1H NMR (CDCl3) δ 8.71 (d, 1H, J=1.1 Hz), 8.05 (m, 3H), 7.82 (d, 1H, J=8.8 Hz), 7.69 (d, 2H, J=9.1 Hz), 7.58 (m, 1H), 7.51-7.36 (m, 7H), 7.21 (d, 2H, 8.8 Hz), 5.16 (s, 2H), 4.52 (m, 1H), 2.32 (br m, 2H), 2.01 (br m, 4H), 1.80 (br m, 1H), 1.35 (br m, 3H); ESI-MS m/e 566.4 (M+1); HPLC purity (ELSD)>95%.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH2:11][CH3:12])(=[O:9])[C:4]([O:6]CC)=O.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27](=[O:29])[CH3:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:11]([O:10][C:3](=[O:9])[C:4](=[O:6])[CH2:28][C:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:29])[CH3:12]
Reactant: CC(=O)c1ccccc1OCc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(=O)c1ccccc1OCc1ccccc1
Temperature: 0 °C
Yield: 70.9 %

Procedure:
To a solution of 1-(2-hydroxy-phenyl)-ethanone (5 g, 0.03672 mole) in DMF (75 mL) was added NaH (60% w/w dispersion in oil) (1.66 g, 0.0416 mole) and the resulting mixture was stirred at ambient temperature for 15 minutes. Benzyl bromide (7.23 g, 0.0422 mole) was then added and the mixture as stirred for an additional 4 hours. The reaction mixture was then quenched with cold aqueous NH4Cl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 8.4 g (100%) of 1-(2-benzyloxy-phenyl)-ethanone. LCMS: 227.1 (M+1)+, 84.14%. To a mixture of THF (200 mL) and NaH (60% w/w dispersion in oil) (4.4 g, 0.11 mole) cooled to 0° C. was added diethyl oxalate (10.73 g, 0.07345 mole). The resulting mixture was heated to reflux for 15 minutes. After cooing to ambient temperature, 1-(2-benzyloxy-phenyl)-ethanone (8.3 g, 0.0376 mole) was added dropwise over a period of 45 minutes. The resulting mixture was heated to 55° C. for 30 minutes. The reaction mixture was then quenched with cold aqueous NH4Cl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (4% ethyl acetate in hexane) to afford 8.7 g (71%) of 4-(2-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester. LCMS: 327.12 (M+1)+, 78.6%. A solution of 4-(2-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester (3.75 g, 0.01149 mole), acetic acid (20 mL) and hydrazine hydrate (0.632 g, 0.01264 mole) was heated to reflux for 3 hours. The reaction mixture was then poured into iced water basified with saturated aqueous NaHCO3 solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 3.703 g (100%) of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 323.13 (M+1)+, 97.14%.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]([O:15][CH2:16]C)=[O:14])[CH:10]=[CH:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>OS(O)(=O)=O.CO>[C:1]1([C:7]2[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:8]=2[C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(C)cc2)c(-c2ccccc2)n1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc(C)cc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure E, ethyl 6-phenyl-5-p-tolyl-pyridine-2-carboxylate (Compound 22, 70 mg, 0.22 mmol) and conc. H2SO4 (3 drops) in MeOH (3 ml) were reacted to produce the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[CH2:20][O:21][CH2:22][O:23][CH3:24])CCC>C1(C)C=CC=CC=1>[CH3:20][O:21][CH2:22][O:23][CH2:24][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)n2ccnc12
Reactant: CCCC[Sn](CCCC)(CCCC)COCOC
Solvent: Cc1ccccc1
Product: COCOCc1ccc(C(=O)OC)c2nccn12
Reaction time: 1 h
Yield: 22.8 %

Procedure:
To a suspension of methyl 5-chloroimidazo[1,2-a]pyridine-8-carboxylate (1.115 g, 5.29 mmol) and tributyl({[(methyloxy)methyl]oxy}methyl)stannane (2.03 g, 5.56 mmol) in anhydrous toluene (10 mL) was added chloro(di-2-norbonylphosphino)(2′-dimethylamino-1,1′-biphenyl-2-yl)palladium (II) (300 mg, 0.535 mmol). The reaction vessel was sealed and heated in a Biotage Initiator microwave using initial absorption setting high to 170° C. for 1 hour. After cooling the reaction was poured onto a biphasic mixture of ethyl acetate (100 mL) and an aqueous potassium floride solution (2 g in 100 mL). The mixture was stirred rapidly and filtered through a pad of celite (10 g). The biphasic filtrate was separated and the aqueous layer back extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in DCM and purified on a silica cartridge (100 g) using a 0-15% methanol-DCM gradient over 60 min. The appropriate fractions were combined and evaporated in vacuo to give impure material which was subjected to a second chromatographic purification on silica (100 g) using a 0-100% ethyl acetate-DCM gradient over 40 min followed by a 0-15% methanol-DCM gradient over 40 min. The appropriate fractions were combined and evaporated in vacuo to give still impure methyl 5-({[(methyloxy)methyl]oxy}methyl)imidazo[1,2-a]pyridine-8-carboxylate (302 mg, purity by LCMS/UV ca 65%) which was used directly in the next step.
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:3]=1.[O-]Cl.[Na+].[OH-].[NH4+:19]>[OH-].[Na+].O>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[N:3]=[C:2]([S:1][NH2:19])[S:6][N:5]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(-c2nsc(S)n2)cc1
Reactant: [NH4+]
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: COc1ccc(-c2nsc(SN)n2)cc1
Reaction time: 0.25 h

Procedure:
A solution of 25 g of 5-mercapto-3-(4-methoxyphenyl)-1,2,4-thiadiazole in 350 ml of 5% sodium hydroxide and a solution prepared by diluting 220 ml of 5.25% NaOCl to 350 ml with water were added simultaneously to 950 ml of ammonium hydroxide solution while maintaining the mixture at 0°. The resulting mixture was stirred for 15 minutes and the precipitated solid was collected, washed with water and dried (P2O5 /high vacuum) to give 15.6 g of solid, m.p. 136°-139°.
Reaction SMILES: CN(C)[C:3](=[O:23])[CH2:4][C:5]1[N:12]2[C:8]([S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=32)=[N:7][C:6]=1[C:17]1[S:18][C:19]([CH3:22])=[CH:20][CH:21]=1.C[O:26]CCO.[OH-].[Na+]>O>[CH3:22][C:19]1[S:18][C:17]([C:6]2[N:7]=[C:8]3[N:12]([C:5]=2[CH2:4][C:3]([OH:23])=[O:26])[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[S:9]3)=[CH:21][CH:20]=1
Reactant: Cc1ccc(-c2nc3sc4ccccc4n3c2CC(=O)N(C)C)s1
Reactant: COCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(-c2nc3sc4ccccc4n3c2CC(=O)O)s1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
23.8 g (0.067 mole) of N,N-dimethyl-2-(5-methylthien-2-yl) imidazo[2,1-b]benzothiazole-3-acetamide and 450 ml of 2-methoxyethanol are introduced into a 1 liter round-bottomed flask, and the mixture is stirred and it is heated on an oil bath at around 130° C. until the solid dissolves. A solution of 13.4 g (0.335 mole) of sodium hydroxide pellets in 70 ml of water is added hot, with precaution, then after 30 minutes, a further 13.4 g (0.335 mole) of sodium hydroxide pellets in 70 ml of water, and the heating is maintained for 7 h 30 min, while monitoring the progress of the reaction by thin-layer chromatography. The mixture is cooled to around 20° C., the solvent is evaporated under reduced pressure, without exceeding 60° C. 1200 ml of water are added to the residue, an insoluble matter is removed by filtration, 150 ml of acetic acid are added to the filtrate up to a pH=4. A yellow-coloured precipitate is obtained which is stirred for 30 minutes while cooling to around 5° C. The solid is separated by filtration, it is washed with water and then with diethyl ether, and it is dried under vacuum at around 60° C. 17.5 g of compound are obtained of which 1.65 g (0.005 mole) are purified by recrystallization from 250 ml of boiling methanol. 1.1.g of a light yellow-coloured solid are isolated. Melting point: 255°-259° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:19][C:20]([OH:22])=[O:21])[CH:8]=[C:9](OS(C(F)(F)F)(=O)=O)[CH:10]=1.[CH3:36][Zn]C>O1CCOCC1.C1(C)C=CC=CC=1.[Pd].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:1][C:2]1[CH:26]=[C:25]([S:27]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)(=[O:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:19][C:20]([OH:22])=[O:21])[CH:8]=[C:9]([CH3:36])[CH:10]=1
Reactant: C[Zn]C
Reactant: O=C(O)Cc1cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2F)cc(OS(=O)(=O)C(F)(F)F)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(CC(=O)O)cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared by treating the product from step (ii) (0.25 g) in dry dioxane (10 ml) with bisdiphenylphosphinoferrocene palladium (0.02 g) and 2.0M dimethylzinc in toluene (0.40 ml). The mixture was heated to reflux for 3 h, partitioned between water and ethyl acetate, the organics separated, dried (MgSO4) and evaporated under reduced pressure to an oil. The oil was dissolved in methanol (10 ml), 2M NaOH (10 ml) added and stirred at RT overnight. The mixture was diluted with water, extracted with ether (discarded). The aqueous layer was acidified with 2M HCl, extracted with ethyl acetate, dried (MgSO4) and evaporated under reduced pressure to an oil, which was purified by RPHPLC to give a white solid (0.085 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[OH-].[K+].[F:13][C:14]([F:18])([F:17])[CH2:15][OH:16]>>[NH2:1][C:2]1[N:3]=[C:4]([NH:9][CH3:10])[N:5]=[C:6]([O:16][CH2:15][C:14]([F:18])([F:17])[F:13])[N:7]=1
Reactant: CNc1nc(N)nc(Cl)n1
Reactant: OCC(F)(F)F
Agent: [K+]
Agent: [OH-]
Product: CNc1nc(N)nc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Amino-4-chloro-6-methylamino-1,3,5-triazine (0.2 mole) was slurried in 80 ml of 2,2,2-trifluoroethanol at room temperature. Potassium hydroxide pellets (0.2 mole) were added portionwise and the mixture was stirred at room temperature overnight. The following day the reaction was heated at gentle reflux for 2 hours during which time the solids gradually dissolved. The solution was cooled and the solvent was removed under vacuum. The residue was washed with water and filtered to give 20.9 g shining off-white crystals of the product named above with the following characteristics: m.p. 204°-205° C. NMR (DMSO-d6): δ 2.75, d, (NHCH3); 4.8, q, (OCH2CF3); 6.5-7.3, m, (NH2 +NHCH3).
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:19]([CH3:20])[O:18][C:17](=[O:21])[CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1>[C:22]([O:1][CH:2]([C:15]1[CH:19]([CH3:20])[O:18][C:17](=[O:21])[CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCC(O)C1=CC(=O)OC1C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(OC(C)=O)C1=CC(=O)OC1C

Procedure:
4-(1-Hydroxytridecyl)-5-methyl-2(5H)-furanone (Compound 3, 329 mg, 1.11 mmol), acetic anhydride (453 mg, 4.45 mmol), triethylamine (227 mg, 2.22 mmol) and 4-dimethylaminopyridine (2 mg, 0.02 mmol ) were stirred at room temperature under argon for 3 hours in anhydrous THF (30 mL). The crude reaction mixture was concentrated and the residue was taken up in diethyl ether and washed with a 10% aqueous HCl solution, a saturated solution of sodium bicarbonate, H20 and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by flash chromatography on silica using 20% ethyl acetate/hexane to give the title compound.