Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH2:6][CH:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:27](=O)([O-])[O-:28].[K+].[K+].CC(C)=O>CO>[CH2:19]([O:8][C:9]1[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][C:4]=1[CH:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][C:7]([O:28][CH3:27])=[O:12])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc2c(c1)C(c1ccccc1)CC(=O)O2
Reactant: BrCc1ccccc1
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)CC(c1ccccc1)c1cc(C)ccc1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
675 g of 6-methyl-4 phenyl-3,4-dihydrocoumarin, 372 ml of benzyl bromide, and 513 g of potassium carbonate were charged into a round bottom flask containing a mixture of 2025 ml of acetone and 2025 ml of methanol. The contents were heated to reflux temperature for about 2-3 hours. Distilled off the solvent from the reaction mass at atmospheric conditions below 75° C. then under vacuum (about 600 mm Hg) at below 85° C. 6750 ml of water was added to the residue and stirred for 15 minutes for dissolution. Extracted the solution twice with ethyl acetate (4000 ml). Combined organic layers were washed with water (2×3375 ml) and distilled the solvent under vacuum (about 600 mm Hg) at below 85° C. 2025 ml of methanol was added to the residue at 50-55° C., then stirred the solution at 0-5° C. for about 2 hours. Filtered the formed solid and washed with 675 ml of methanol. Dried the solid at 50-55° C. for about 2-3 hours under vacuum (about 600 mm/Hg) to get 850 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[NH:5][C:4](=[O:14])[C:3]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23].[CH3:24][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[N:5]([CH3:24])[C:4](=[O:14])[C:3]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23]
Reactant: CON1CCC2(CC1)NC(=O)C(c1c(C)cc(C)cc1C)=C2O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CON1CCC2(CC1)C(O)=C(c1c(C)cc(C)cc1C)C(=O)N2C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one [starting material (SM) prepared according to WO09/049,851] (500 mg, 1.58 mmol) in tetrahydrofuran (20 ml) at 0° C. was added a 1.0 M lithium bis(trimethylsilyl)amide solution in hexanes (3.32 ml, 3.32 mmol) dropwise over 15 minutes. The mixture was stirred one hour at 0° C., treated with methyl iodide (0.099 ml, 225 mg, 1.59 mmol) dropwise over 10 minutes, and further stirred at 0° C. for 30 minutes and at room temperature for one hour. The reaction mixture was quenched over cold saturated aqueous ammonium chloride and extracted with tert-butyl methyl ether (3×), the combined organic phases washed with brine, dried over sodium sulfate and concentrated. The residue (210 mg) was suspended in hexane, stirred at room temperature for 10 minutes, filtered and dried. Yield: 171 mg of a clean mixture of starting material (SM) and 4-hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (title compound P2.2) as a beige solid. 1H-NMR and LC-MS analysis of the crude material indicated a ˜1:2.5 ratio of this mixture SM/compound P2.2.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:7]([F:19])=[C:8]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:9]([NH2:11])=O.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>CCCCC>[Cl:5][C:6]1[C:7]([F:19])=[C:8]([CH:12]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:14]=1)[C:9]#[N:11]
Reactant: NC(=O)c1cc(C(F)(F)F)cc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCC
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(C(F)(F)F)cc(Cl)c1F
Reaction time: 1 h
Yield: 71 %

Procedure:
Thionyl chloride, 6.0 g (50 mmol) was added to a slurry of 4.0 g (16 mmol) 3-chloro-2-fluoro-5-(trifluoromethyl) benzamide and 15 mL dimethylformamide at 0° C. After stirring for one hour the reaction mixture was diluted with 25 mL pentane and neutralized by dropwise addition of a saturated potassium carbonate solution and filtered. The pentane solution was dried and distilled to yield 3-chloro-2-fluoro-5-(trifluoromethyl) benzonitrile in 71% yield, bp 75°-85° C./20 mm Hg.
Reaction SMILES: [C:1]([O:6]CCO)(=[O:5])[C:2]([CH3:4])=[CH2:3].C([C:14]1C=C(C)C=C(C(C)(C)C)[C:15]=1[OH:25])(C)(C)C.[O:26]=[C:27]=[N:28]C1CC(C)(C)CC(C)(CN=C=O)C1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>>[C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[NH2:28][C:27]([O:25][CH2:15][CH3:14])=[O:26]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=C(C)C(=O)OCCO
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Product: C=C(C)C(=O)O
Product: CCOC(N)=O

Procedure:
0.2 mol of ®Voranol CP 6055 (DOW), 0.4 mol of hydroxyethyl methacrylate (HEMA), 500 ppm of 2,6-di-tert-butyl-4-methyl-phenol, based on the predicted amount of the final product, 0.46 mol of IPDI (isophorone diisocyanate) and 2*10−3 mol of dibutyltin dilaurate (DBTDL) are used as initial charge in a round-bottomed flask with reflux condenser, thermometer, stirrer, and dropping funnel, and are stirred at room temperature for one hour. The temperature of the mixture is then raised continuously to 80° C. within one hour. The temperature is then kept at 80° C. for about 5 hours until the content of isocyanate groups has fallen below 0.1%, with, above the mixture, a nitrogen-oxygen mixture using about 7% by volume of oxygen. If, despite prolonged continued reaction time, the isocyanate content fails to decrease below 0.1%, residual amounts of isocyanate groups are reacted with a stoichiometric amount of HEMA. 500 ppm of 2-tert-butyl-4,6-dimethylphenol, based on the total mass of the final product, are then added to the mixture. This reaction gives a mixture of urethane methacrylates, and this mixture can be used in further reactions without further work-up.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.CO>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][CH2:19][OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1c[nH]c2c(OCc3ccccc3)cccc12
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: OCCc1c[nH]c2c(OCc3ccccc3)cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of (7-(benzyloxy)-1H-indol-3-yl)acetic acid (7.21 g, 27.4 mmol) in tetrahydrofuran (150 mL) is added a 1M solution of borane.tetrahydrofuran complex in tetrahydrofuran (55 ml, 55 mmol) under nitrogen atmosphere, and the mixture is stirred at room temperature for 17 hours. To the reaction solution is added methanol (100 mL), and the mixture is stirred at room temperature for one hour. The solvent is evaporated, and the resulting crude product is purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1) to give 2-(7-(benzyloxy)-1H-indol-3-yl)ethanol (6.37 g, 23.8 mmol, yield: 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br.CS[C:17](=[NH:19])[NH2:18].[CH2:20](O)[CH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:17]3[N:19]=[C:21]4[CH:20]=[CH:4][CH:3]=[CH:2][CH:7]=[C:6]4[N:18]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CSC(=N)N
Reactant: CCO
Agent: Br
Product: Clc1cccc(N2CCN(c3nc4cccccc-4n3)CC2)c1

Procedure:
A mixture of 1-(3-chlorophenyl)piperazine (13 g, described in Example 11) and methylthiomethanimidamide hydrobromide (12.2 g) in ethanol (50 ml) was refluxed for 14 hr and evaporated. To the residue, 1N sodium ethoxide in ethanol (66 ml) and 2-methoxy-2,4,6-cycloheptatrien-1-one(9 g) were added. The mixture was refluxed for 2 hr and evaporated. The residue was chromatographed through a column of silica gel using ethyl acetate and the eluates were evaporated. The residue was crystallized from ethyl acetate to obtain the title compound (5.9 g): mp 217°-219° C; ir(mull)1615, 1590, 1575 and 1530 cm-1 ; uv max (MeOH) 289(ε9.870), 261(ε43,230) and 240 nm(ε29,040); nmr(CDCl3) δ 3.33(4H,t), 4.18(4H,t) and 7.5(9H,m) and Anal. Calcd for C18H17N4Cl: C, 66.56% H, 5.27% N, 17.25% and Found: C, 66.11% H, 5.10% N, 16.99%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]3[N:12]=[C:13](O)[C:14]4[C:19]([CH:20]=3)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=4)[CH:9]=[CH:10][C:2]1=2.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:13]1[C:14]2[C:19](=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2)[CH:20]=[C:11]([C:8]2[CH:9]=[CH:10][C:2]3[O:1][CH2:6][CH2:5][O:4][C:3]=3[CH:7]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)nc(-c3ccc4c(c3)OCCO4)cc2c1
Product: COc1ccc2c(Cl)nc(-c3ccc4c(c3)OCCO4)cc2c1
Yield: 75.5 %

Procedure:
A solution of 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-methoxyisoquinolin-1-ol (250 mg, 0.808 mmol) in POCl3 (5 mL, 53.6 mmol) was refluxed for 14 h. Concentrated the solvent. The residue was taken into a mixture of DCM and 4N NaOH solution. Adjust pH to 7. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 10% EtOAc/Hexanes as eluent to give 200 mg of the desired product 1-chloro-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-methoxyisoquinoline as a solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.18 (d, J=9.3 Hz, 1H), 7.77 (s, 1H), 7.65-7.55 (m, 2H), 7.21 (dd, J=9.2, 2.4 Hz, 1H), 7.08 (d, J=2.3 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 4.30 (s, 4H), 3.95 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[CH2:18][CH2:17][CH2:16]2.C(N(CC)CC)C>S(Cl)(Cl)=O.C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:19](=[O:23])[CH2:18][CH2:17][CH2:16][C:15]=2[CH:14]=1)=[O:6]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: Nc1ccc2c(c1)CCCC2=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc2c(c1)CCCC2=O)c1cc(Cl)ccc1Cl
Yield: 96 %

Procedure:
Reaction of 2,5-dichlorobenzoic acid (300 mg, 1.50 mmol) in thionyl chloride (3.5 mL) then with 6-Amino-3,4-dihydro-2H-naphthalen-1-one (80 mg, 0.50 mmol) in presence of triethylamine (90 μL, 0.65 mmol) in THF (6 mL) according to method B gave 2,5-dichloro-N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzamide (150 mg, 0.48 mmol, 76% yield) as a grey powder after purification by crystallisation in DCM.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[CH:19][CH:18]=1)=[O:16].C(N(CC)CC)C>C(O)(C)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:25])=[O:26])=[CH:21][CH:22]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C(=O)CBr)cc2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C(=O)CN3CCN(c4ccncc4)CC3)cc2)cc1
Reaction time: 18 h

Procedure:
A mixture of 1-(4-pyridyl)piperazine (1.79 g), N-(4-bromoacetylphenyl)-4-methylphenylsulphonamide (3.68 g) and triethylamine (1.39 ml) in isopropanol (50 ml) was stirred for 18 hours. The precipitated solid was collected, triturated with dichloromethane, filtered and dried. This solid was further purified by flash chromatography on neutral alumina eluting successively with dichloromethane, 2.5% v/v methanol/dichloromethane then 5% v/v methanol/dichloromethane. Evaporation of the desired fractions to a small volume followed by addition of dichloromethane gave a crystalline solid. This solid was collected, washed with dichloromethane to give the title compound, 440 mg, as crystals: m.p. 168°-170° C.; NMR (d6DMSO) δ8.14(2H,d), 7.86(2H,d), 7.71(2H,d), 7.35(2H,d), 7.18(2H,d), 6.80(2H,d), 3.79(2H,s), 3.31(4H,t), 2.59(4H t), 2.33(3H,s); m/e 451 (M+H)+ ; calculated for C24H26N4O3S: C, 64.0; H, 5.8; N, 12.4. found C, 63.4; H, 5.7; N, 12.2%.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Br:15])=[C:11](OC)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][S:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Br:15])=[C:11]([C:23]2[CH:24]=[CH:25][C:20]([S:19][CH3:18])=[CH:21][CH:22]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: COc1cnn(Cc2ccccc2)c(=O)c1Br
Product: CSc1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Br)cc1

Procedure:
2-Benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996, 33, 1579-1582) was converted to the 5-hydroxy-analog according to the method of Example 7 and then to the 5-(trifluoromethyl)sulfonyloxy-analog according to the method of Example 8. Subsequent coupling to 4-(methylthio)phenylboronic acid, according to the method of Example 9, provided 2-benzyl-4-bromo-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone. This intermediate was coupled with 4-methylphenylboronic acid according to the method of Example 6. This product was N-debenzylated according to the method of Example 11 and N-alkylated with 2-iodo-1,1,1-trifluoroethane according to the method of Example 20. The resulting sulfide was oxidized to the title compound according to the method of Example 10 (yield: 210 mg, 98%). mp 154-156° C. 1H NMR (300 MHz, CDCl3) δ 2.33 (s, 3H), 3.07 (s, 3H), 4.89 (q, J=9 Hz, 2H), 7.08 (s, 4H), 7.37 (d, J=9 Hz, 2H), 7.88 (s, 1H), 7.89 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 423 (M+H)+. Anal. calc. for C20H17F3N2O3S: C, 56.86; H, 4.05; N, 6.63. Found: C, 56.59; H, 4.11; N, 6.53.
Reaction SMILES: CN1[C:10]2[C:9](=O)NC(=O)N[C:5]=2N=C1.N1C=[CH:17][C:16](=O)NC1=O.C[Si](C)(C)[CH2:23][CH2:24][O:25][CH2:26][Cl:27]>>[CH2:24]([O:25][CH2:26][Cl:27])[C:23]1[CH:17]=[CH:16][CH:9]=[CH:10][CH:5]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cn1cnc2[nH]c(=O)[nH]c(=O)c21
Reactant: O=c1cc[nH]c(=O)[nH]1
Product: ClCOCc1ccccc1

Procedure:
In a similar manner to the procedures described in Reference Example 3, reactions were carried out using 7-methylxanthine, instead of pyrimidine-2,4-dione, and using 2-(trimethylsilyl)ethoxymethyl chloride, instead of benzyloxymethyl chloride, to give the title compound (yield 69%) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]2[CH:9](O)[CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:7][C:6]=2[C:17]=1[Cl:18].B(F)(F)F.CCOCC>O.[OH-].[Na+]>[Cl:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:7][C:6]=2[C:17]=1[Cl:18]
Reactant: COc1cc2c(c(Cl)c1Cl)SC(c1ccccc1)C2O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COc1cc2cc(-c3ccccc3)sc2c(Cl)c1Cl
Yield: 30.7 %

Procedure:
A mixture of 5.0 g of 6,7-dichloro-2,3-dihydro-3-hydroxy-5-methoxy-2-phenylbenzo[b]thiophene, 10 ml of boron trifluoride etherate and 20 ml of glacial acid is refluxed for 1 hour. The mixture is cooled, diluted with water and basified with dil sodium hydroxide solution. Extraction with dichloromethane followed by column chromatography over silica (50% dichloromethane in hexane) gives 1.45 g of 6,7-dichloro-5-methoxy-2-phenylbenzo[b]thiophene, mp 144°-145°.
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:4])[CH2:2][CH3:3].[CH:10](OC)(OC)[O:11][CH3:12].C(OC(=O)C)(=O)C>>[C:1]([C:5](=[CH:10][O:11][CH3:12])[C:6]([O:8][CH3:9])=[O:7])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)CC(=O)OC
Reactant: COC(OC)OC
Solvent: CC(=O)OC(C)=O
Product: CCC(=O)C(=COC)C(=O)OC

Procedure:
A mixture of methyl propionylacetate (112.2 g, 0.86 mol), trimethyl orthoformate (188 ml, 1.72 mol) and acetic anhydride (81 ml, 0.86 mol) was heated at reflux for 17 hours, then the volatile material removed in vacuo, finally at 70°/0.3mm. The residue was predominantly methyl 2-propanoyl-3-methoxyacrylate, and was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([S:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:24].[OH-:30].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([S:17]([CH3:18])(=[O:24])=[O:30])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [OH-]
Reactant: CSc1ccc2nc(-c3ccc(Cl)cc3)sc2c1
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2nc(-c3ccc(Cl)cc3)sc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
To a solution of 2-(4-chlorophenyl)-6-(methylthio)benzo[d]thiazole (240 mg, 0.82 mmol) in dichloromethane (20 mL) was added 3-chloroperoxybenzoic acid (77% in water, 710 mg, 4.11 mmol) over 5 min. The resulting mixture was stirred at room temperature for 3 h. 1M aqueous sodium hydroxide solution was added carefully, and the mixture was then stirred for 5 min. The organic layer was then washed with 1M aqueous sodium hydroxide solution, dried over anhydrous MgSO4 and evaporated. The resulting solid was recrystallised from hot ethyl acetate to afford 125 mg (47%) of the title compound (LCMS RT=6.81 min, MH+ 324.0)
Reaction SMILES: C1(=O)[N:5]([CH:6]2[CH2:9][N:8]([CH:10]([C:17]([O:19][CH3:20])=[O:18])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]2=[O:21])C(=O)C2=CC=CC=C12.CN(C)CCCN.CO>C(Cl)(Cl)Cl>[NH2:5][CH:6]1[CH2:9][N:8]([CH:10]([C:17]([O:19][CH3:20])=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]1=[O:21]
Reactant: COC(=O)C(c1ccccc1)N1CC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: CN(C)CCCN
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)C(c1ccccc1)N1CC(N)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.2 %

Procedure:
3-Phthalimido-1-(α-methoxycarbonylbenzyl)-2-azetidinone (0.36 g.) and N,N-dimethyl-1,3-propanediamine (0.22 g.) were added to a mixture of methanol (5 ml.) and chloroform (5 ml.), whereafter the mixture was stirred at ambient temperature for 18 hours. The reaction mixture was evaporated to dryness under reduced pressure, and ethyl acetate (20 ml.) and water were poured into the residue obtained. The ethyl acetate layer was separated out from the mixture and the remaining aqueous layer was further extracted with ethyl acetate (10 ml.). The combined ethyl acetate solution was extracted with 1 N hydrochloric acid (3 ml.) and water (10 ml.) respectively. The combined aqueous extracts were adjusted to pH 8.6 with an aqueous sodium bicarbonate. The aqueous solution was extracted with two 10 ml. portions of ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by distillation from the solution under reduced pressure to give oily 3-amino-1-(α-methoxycarbonylbenzyl)-2-azetidinone (0.13 g.).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:8]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([CH3:15])[CH:9]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:14][C:13]1[CH:12]=[CH:11][C:10]([CH3:15])=[CH:9][CH:8]=1)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: Cc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)Oc1ccc(C)cc1

Procedure:
Pentanoyl chloride (39.8 g) in dichloromethane (50 ml) was added slowly to a solution of p-cresol (32.4 g) and triethylamine (36.4 g) in dichloromethane (250 ml) with ice cooling. After 1 hour the reaction mixture was washed with brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 4-methylphenyl pentanoate.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH:11]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1.[CH3:20]I>C(O)C>[CH3:20][NH:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH:11]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1
Reactant: CI
Reactant: Nc1ccc2c(c1)sc1nc(-c3ccccc3)cn12
Solvent: CCO
Product: CNc1ccc2c(c1)sc1nc(-c3ccccc3)cn12
Yield: 9.6 %

Procedure:
To 50 ml of ethanol were added 500 mg of 7-amino-2-phenylimidazo[2,1-b]benzothiazole, 265 mg of methyl iodide and 260 mg of potassium carbonate anhydride and while stirring vigorously, the mixture was refluxed for 2 days. The reaction mixture was cooled and then concentrated under reduced pressure. The residue was extracted with 50 ml of ethyl acetate and the extract was washed with water, dried with anhydrous magnesium sulfate, and then the extract was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluant: toluene:ethyl acetate=4:1) and the obtained crystals were recrystallized from toluene to provide 50 mg of 7-methylamino-2-phenylimidazo-[2,1-b]benzothiazole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH2:20][C@@H:21]([OH:24])[CH2:22][OH:23])[CH:15]=[N:14][C:13]=3[N:12]([CH3:25])[C:11](=[O:26])[CH:10]=2)=[C:4]([F:27])[CH:3]=1.C1C(=O)N([Cl:35])C(=O)C1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH2:20][C@@H:21]([OH:24])[CH2:22][OH:23])[CH:15]=[N:14][C:13]=3[N:12]([CH3:25])[C:11](=[O:26])[C:10]=2[Cl:35])=[C:4]([F:27])[CH:3]=1
Reactant: Cn1c(=O)cc(Nc2ccc(Br)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Cn1c(=O)c(Cl)c(Nc2ccc(Br)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 20C (60 mg, 0.136 mmol) was dissolved in 2 mL DCM. NCS (22 mg, 0.165 mmol) was added. The mixture was stirred at room temperature overnight. Example 29 (35.3 mg, 54%) was isolated by preparative HPLC separation. 1H NMR (400 MHz, MeOD) δ 8.50 (s, 1H) 7.45 (d, J=8.0 Hz, 1H) 7.38 (d, J=8.0 Hz, 1H) 7.10 (t, J=8.0 Hz, 1H) 4.51 (m, 1H) 4.03 (m, 1H) 3.88 (m, 1H), 3.82 (s, 3H) 3.68 (d, J=4 Hz, 2H). [M+H] calc'd for C17H15BrClFN4O4, 475. found, 475.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:28])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)=[N:4][CH:3]=1.[ClH:29]>C(Cl)(Cl)Cl.CO.O1CCOCC1>[ClH:29].[ClH:29].[NH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:6]=[CH:7][C:8]2=[O:28])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NC1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,1-dimethylethyl {1-[2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl]-4-piperidinyl}carbamate (1.591 g, 4.079 mmol) in chloroform (15 ml) and MeOH (15 ml) was added 4M HCl in 1,4-dioxane (15 ml). The reaction was stirred at rt for 0.5 h before evaporation to provide the desired compound as a slightly impure white solid which was used without further purification (1.633 g, 110%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=3)[NH2:24])[CH2:15][CH2:14]2)[CH:3]=1.[C:28]([Cl:31])(=[O:30])[CH3:29]>>[ClH:1].[ClH:31].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([NH:24][C:28](=[O:30])[CH3:29])[CH:25]=[CH:26][CH:27]=3)[CH2:17][CH2:18]2)[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cc(Cl)cc2n1
Product: CC(=O)Nc1cccc(CCN2CCN(c3cc(Cl)cc4nc(C)ccc34)CC2)c1
Product: Cl
Yield: 65 %

Procedure:
The title compound was prepared in 65% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(7-Chloro-2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D18) and acetyl chloride.