Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[S:2]([C:4]1[CH:5]=[C:6]([C:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:12])[CH:7]=[C:8]([F:10])[CH:9]=1)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>ClC(Cl)C>[F:10][C:8]1[CH:7]=[C:6]([C:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:12])[CH:5]=[C:4]([SH:2])[CH:9]=1
Reactant: CS(=O)c1cc(F)cc(C(=O)c2nccs2)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(Cl)Cl
Product: O=C(c1cc(F)cc(S)c1)c1nccs1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of the sulfoxide from Step 2 (0.35 g, 1.29 mmol) in dichloroethane (2.6 mL) was added TFAA (2.6 mL). The mixture was stirred at 80° C. for 0.5 h, cooled and evaporated. The residue was dissolved in MeOH: Et3N (1:1, 5 mL). The solvent was evaporated and taken up again in MeOH/Et3N. After evaporation of the solvent and chromatography using hexane:EtOAc (70:30) 0.28 g of the title compound was obtained.
Reaction SMILES: O.NN.[F:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][N:22]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:16][CH2:15]1.O>C(O)C>[F:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[N:14]1[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][NH2:22])[CH2:18][CH2:19]1
Reactant: O=C1c2ccccc2C(=O)N1CCC1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCC1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
Hydrazine monohydrate (0.272 ml, 5.61 mmol) was added to a solution of 2-{2-[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]ethyl}isoindoline-1,3-dione (compound of Reference Example 66; 0.745 g, 1.87 mmol) in ethanol (5 ml), and the mixture was stirred at 80° C. for 1 hour. Water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.170 g, 34%) as a yellow solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(COc1ccccc1)OC

Procedure:
A mixture of 31.3 g of phenol, 60.0 g of bromoacetaldehyde dimethyl acetal and 80 g of potassium carbonate was heated at 150° C. in 300 ml of dimethylformamide. After 4.5 hours the reaction mixture was cooled, added to water, and extracted with diethyl ether. Separation, drying and evaporation of the organic phase gave the crude product. Vacuum distillation, bp 88°-98° C./1 mm yielded the title compound as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]([OH:15])=O)[CH:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH:22]([N:25]([CH3:36])[C:26]1[S:27][C:28]2[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=2[N:30]=1)([CH3:24])[CH3:23]>>[CH:22]([N:25]([CH3:36])[C:26]1[S:27][C:28]2[CH:34]=[C:33]([NH:35][C:13]([C:10]3[CH:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[O:12][N:11]=3)=[O:15])[CH:32]=[CH:31][C:29]=2[N:30]=1)([CH3:24])[CH3:23]
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)on1
Reactant: CC(C)N(C)c1nc2ccc(N)cc2s1
Agent: O=C(Cl)C(=O)Cl
Product: CC(C)N(C)c1nc2ccc(NC(=O)c3cc(-c4ccc(Cl)cc4)on3)cc2s1
Yield: 36.2 %

Procedure:
Prepare according to Method C (Example 9), using 5-(4-chlorophenyl)isoxazole-3-carboxylic acid (39 mg, 0.174 mmol), oxalyl chloride (300 μL, 3.44 mmol), and N2-isopropyl-N2-methyl-benzothiazole-2,6-diamine (33 mg, 0.149 mmol) to afford the title compound (23 mg, 36%). mass spectrum (m/e): 427.0 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.24 (d, 1H, J=2.2 Hz), 8.01 (d, 2H, J=8.8 Hz), 7.66 (d, 2H, J=8.4 Hz), 7.60 (dd, 1H, J=8.8, 2.2 Hz), 7.54 (s, 1H), 7.41 (d, 1H, J=8.4 Hz), 4.34 (m, 1H), 2.98 (s, 3H), 1.23 (d, 6H, J=6.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=O)[CH3:28])[O:22][C:21]2=[O:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:19][CH2:18][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]2)[CH2:10][CH2:9]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1.O>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[S:40])[CH3:28])[O:22][C:21]2=[O:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:19][CH2:18][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]2)[CH2:10][CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)NC(=O)NC4=O)c(F)c2)C(=O)O1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=S)NC[C@H]1CN(c2ccc(N3CCC4(CC3)NC(=O)NC4=O)c(F)c2)C(=O)O1

Procedure:
A stirred suspension of 32 (0.210 g, 0.500 mmol) in dioxane (5.0 mL), under nitrogen was treated with Lawesson's Reagent (0.202 g, 0.500 mmol), refluxed for 4 h and concentrated in vacuo. The residue was chromatographed on silica gel with mixctures of MeOH—NH4OH—CHCl3 containing 1-10% MeOH and 0.1-0.5% NH4OH and the resulting product was crystallized from MeOH—CHCl3—EtOAc to give 0.0491 g of 3: mip 218.5° C.; HR FAB MS theory for C19H22FN5O4S (M+): 435.1376; found 435.1370. Anal. calcd for C19H22FN5O4S. 0.5 H2O: C, 51.34; H, 5.21; N. 15.76. Found: C, 51.69; H, 5.00; N, 15.25.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=2)[O:10][CH:11]([CH2:15][CH2:16][CH3:17])[C:12](Cl)=[O:13])[N:3]=1.[N:21]1([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN(C)C1C=CN=CC=1.ClCCl>[N:21]1([C:27]2[CH:28]=[CH:29][C:30]([NH:31][C:12](=[O:13])[CH:11]([O:10][C:9]3[CH:18]=[CH:19][CH:20]=[C:7]([C:4]4[N:3]=[C:2]([CH3:1])[O:6][N:5]=4)[CH:8]=3)[CH2:15][CH2:16][CH3:17])=[CH:32][CH:33]=2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CCCC(Oc1cccc(-c2noc(C)n2)c1)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCC(Oc1cccc(-c2noc(C)n2)c1)C(=O)Nc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
200 mg of 4-dimethylaminopyridine on polystyrene are added to a solution of 100 mg (0.339 mmol) of 2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]pentanoyl chloride and 60.4 mg (0.339 mmol) of 4-morpholin-4-ylaniline in 6 ml of dichloromethane, and the mixture is stirred at room temperature for 18 hours. The reaction mixture is filtered, and the filtrate is evaporated, giving N-(4-morpholin-4-ylphenyl)-2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]pentanoamide as a colourless solid, ESI 437.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[N:27]=[CH:26][C:25]([Br:28])=[CH:24][N:23]=1>ClCCl.N1C=CC=CC=1>[Br:28][C:25]1[CH:24]=[N:23][C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[N:27]=[CH:26][C:25]([Br:28])=[CH:24][N:23]=2)=[O:13])=[N:27][CH:26]=1
Reactant: Nc1ncc(Br)cn1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ncc(Br)cn1)c1ccccc1SSc1ccccc1C(=O)Nc1ncc(Br)cn1
Yield: 11.1 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 2-amino-5-bromopyrimidine (2.03 g, 11.7 mmol) in 16 mL of pyridine. The crude product was triturated with a hot mixture of ethyl acetate and ethanol, filtered, and recrystallized first from DMF, then from acetonitrile-DMF to yield 0.40 g of the title compound, mp 249°-253° C.
Reaction SMILES: [OH-].[Na+].C(O)C.[CH2:6]([O:13][C:14]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C>[CH2:6]([O:13][C:14]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A 4 mol/L aqueous solution of sodium hydroxide (0.3 mL) was added to an ethanol (2.1 mL) solution of the obtained methyl 2-(benzyloxy)-5-(morpholin-4-yl)benzoate (0.26 g), followed by stirring at 50° C. for 1 hour. The reaction mixture was cooled to room temperature, and then a 10% aqueous solution of citric acid and ethyl acetate were sequentially added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.17 g of 2-(benzyloxy)-5-(morpholin-4-yl)benzoic acid as a white solid.
Reaction SMILES: ClCCO[CH:5]([O:13][CH2:14][CH2:15][Cl:16])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.C[Si]([C:21]#[N:22])(C)C.C(C(C#N)=C(C#N)C#N)#N>C(#N)C>[Cl:16][CH2:15][CH2:14][O:13][CH:5]([C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1)[C:21]#[N:22]
Reactant: Fc1ccc(C(OCCCl)OCCCl)cc1
Reactant: C[Si](C)(C)C#N
Agent: N#CC(C#N)=C(C#N)C#N
Solvent: CC#N
Product: N#CC(OCCCl)c1ccc(F)cc1

Procedure:
A solution containing 1-[bis-(2-chloroethoxy)methyl]-4-fluorobenzene (5.43 g), trimethylsilyl cyanide (4.06 mL) and tetracyanoethylene (520 mg) in acetonitrile (100 mL) was heated under reflux for four hours. The reaction solution was returned to room temperature and the solvent was evaporated under reduced pressure. Ethyl acetate and brine were added to the residue, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex, elution solvent: heptane/ethyl acetate) to obtain the title compound (4.3 g). The property values of the compound are as follows.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.C(Cl)(=O)[C:10]([Cl:12])=O.[N+](=C)=[N-].Cl>ClCCl.CCOCC>[Cl:12][CH2:10][C:6]([CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CCOC1
Agent: C=[N+]=[N-]
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(CCl)C1CCOC1
Yield: 88.1 %

Procedure:
(RS)-3-Tetrahydrofuroic acid (3.48 g) in dichloromethane (40 ml) was treated with oxalyl chloride (11.43 g) as described in Example 1 (a). The resultant acid chloride in dichloromethane (40 ml) was then treated with excess diazomethane (60 mM) in ether (100 ml), followed by hydrogen chloride. The solution was washed once with brine, dried and concentrated. Flash chromatography on silica gel, eluting with 40% ethyl acetate/hexane afforded the title compound as a pale yellow oil, (3.924 g, 88%); νmax (CH2Cl2) 1735 and 1716 cm-1 ; 2.17 (2 H, dt, J 7.0, 7.5 Hz), 3.47-3.58 (1 H, m), 3.77-4.04 (4 H, m) and 4.18 (2 H, s); [mass spectrum: +ve ion (ammonia) MNH4+ (166)].
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH2:17][CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:14][CH2:13][CH2:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([CH2:16][CH2:17][CH3:18])[CH:10]=2)[CH2:28][CH2:27]1
Reactant: CCCc1cc(CCC=O)n(-c2ccccc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccccc2)n1

Procedure:
151 mg (82%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.413 mmol), 1-(2-fluorophenyl)piperazine (74 mg, 0.413 mmol), DIPEA (0.110 mL, 0.620 mmol) and NaBH(OAc)3 (263 mg, 1.239 mmol).
Reaction SMILES: Br[C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[C:3]=1[O:17][CH2:18][O:19][CH3:20].[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=3)[C:3]=2[O:17][CH2:18][O:19][CH3:20])=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCCc1cc2cc(OC)ccc2c(OCOC)c1Br
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCc1cc2cc(OC)ccc2c(OCOC)c1-c1ccc(F)cc1
Yield: 95.8 %

Procedure:
2-Bromo-6-methoxy-1-methoxymethoxy-3-propyl-naphthalene (95) (1.26 g, 3.71 mmol), 4-fluorobenzeneboronic acid (1.04 g, 7.43 mmol), tetrakis(triphenylphosphino)palladium (0) (0.43 g, 0.371 mmol), 2 M sodium carbonate (20 mL) and ethylene glycol dimethyl ether (20 mL) were added in a sealed tube and reacted as described above to give 1.26 g (95%) of the title compound (225) as oil. 1H NMR (400 MHz, d-CDCl3): δ 0.80 (t, J=7.3 Hz, 3H), 1.43-1.45 (m, 2H), 2.50 (t, J=7.8 Hz, 2H), 3.11 (s, 3H), 3.93 (s, 3H), 4.73 (s, 2H), 7.10-7.15 (m, 4H), 7.29-7.32 (m, 2H), 7.43 (s, 1H), 8.00 (d, J=8.9 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].C([O-])(=O)C.[Na+].[Br:17]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:17][C:7]1[C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[C:4](=[O:8])[NH:5][CH:6]=1
Reactant: Cc1cc[nH]c(=O)c1[N+](=O)[O-]
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1c(Br)c[nH]c(=O)c1[N+](=O)[O-]
Reaction time: 5.5 h
Yield: 90 %

Procedure:
To a stirred solution of 4-methyl-3-nitro-2-pyridone (0.45 g, 2.9 mmol) in glacial acetic acid (3 mL) was added sodium acetate (0.24 g) followed by bromine (0.15 mL) dropwise. After 5.5 hours, the mixture was diluted with ethyl acetate, washed with water, dried, filtered and concentrated to give 5-bromo-4-methyl-3-nitro-2-pyridone (0.62 g, 2.6 mmol, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:19]([O:31][CH3:32])[CH:18]=1)=[O:15].[C:33](O)(=O)[CH3:34]>>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:14](=[O:15])[N:16]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]5[CH2:30][CH2:29][CH2:28][CH2:27]5)=[C:19]([O:31][CH3:32])[CH:18]=4)[C:33]([CH3:34])=[N:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: CC(=O)O
Reactant: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)cc2N)ccc1OCCN1CCCC1
Product: COc1cc(-n2c(C)nc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCN1CCCC1

Procedure:
A mixture of 3-amino-5-(4-chlorophenyl)-N-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy) phenyl]thiophene-2-carboxamide and glacial acetic acid was refluxed overnight, concentrated to an amber viscous oil, triturated with water then filtered to give the title compound as its acetic acid salt as a tan solid (0.032 g, 64%). LCMS m/z 496 (MH+). 1H NMR (300 MHz, DMSO-d6) δ 8.35 (br, 1H), 8.00 (s, 1H), 7.95 (d, 2H), 7.55 (d, 2H), 7.20 (s, 1H), 7.10 (d, 1H), 6.95 (d, 1H), 4.20 (m, 2H), 3.75 (s, 3H), 2.75 (m, 2H), 2.55 (m, 4H), 2.20 (s, 3H), 2.00 (s, 3H), 1.65 (m, 4H) ppm.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH3:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[CH3:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:7]([C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[NH:8])=[CH:14][CH:13]=1
Reactant: CSc1ccc(C#N)cc1
Reactant: Cc1ccc(N)cc1
Product: CSc1ccc(C(=N)Nc2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from 4-methylthiobenzonitrile (2.50 g, 16.78 mmol) and 4-methylaniline (1.789 g, 16.78 mmol) by following the procedure described in preparation 1, (2.05 g, 47.6%, purity 79% by HPLC), mp 143-145° C. 1H-NMR (CDCl3):δ 2.33 (s, 3H), 2.52 (s, 3H), 4.75 (bs, 2H, D2O exchangeable), 6.87-6.89 (d, 2H), 7.14-7.16 (d, 2H), 7.27-7.29 (d, 2H), 7.7-7.79 (d, 2H). MS m/z: 257.1(M+).
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:10]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[N:11][C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.C[O:22]C1C=CC(CO)=CC=1>[Cl-].[NH4+].C(OCC)(=O)C>[NH2:15][C:12]1[N:11]=[C:10]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[C:9]([C:6]2[CH:5]=[CH:4][C:3](=[O:22])[NH:8][CH:7]=2)=[CH:14][N:13]=1
Reactant: Nc1ncc(-c2ccc(Cl)nc2)c(-c2ccco2)n1
Reactant: COc1ccc(CO)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCOC(C)=O
Product: Nc1ncc(-c2ccc(=O)[nH]c2)c(-c2ccco2)n1
Reaction time: 1.5 h

Procedure:
After sodium (455 mg, 19.8 mmol) was dissolved in 4-methoxybenzyl alcohol (15 ml) at 90° C. under an atmosphere of nitrogen gas, 5-(6-chloro-3-pyridyl)-4-(2-furyl)-2-pyrimidinylamine (1.80 g, 6.60 mmol) was added thereto and the mixture was stirred as it was. After 1.5 hours, the reaction mixture was cooled as it was and then diluted with an aqueous saturated ammonium chloride solution and ethyl acetate. The resulting organic layer was washed with an aqueous saturated ammonium chloride solution, dried over anhydrous sodium sulfate and concentrated. Trifluoroacetic acid (40 ml) was added to the residue, followed by stirring at 65° C. After 18 hours, the reaction mixture was cooled as it was and diluted with dichloromethane, water and 5N hydrochloride. The resulting aqueous layer was washed with ethyl acetate and adjusted to pH 6 with 5N sodium hydroxide. The resulting crystals were collected by filtration and washed with water, to give crude crystals of the title compound. The resulting crude crystals were suspended in ethyl acetate, collected by filtration and washed with ethyl acetate, to give the title compound (820 mg, 49%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[N:7][CH:8]=[CH:9][N:4]2[N:3]=1.[Cl-].[Na+].[OH:12][S:13](O)(=[O:15])=[O:14].O=S(=O)=O>>[Br:1][C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([S:13]([OH:15])(=[O:14])=[O:12])[N:4]2[N:3]=1
Reactant: O=S(=O)(O)O
Reactant: Brc1nn2ccnc2s1
Agent: O=S(=O)=O
Agent: [Cl-]
Agent: [Na+]
Product: O=S(=O)(O)c1cnc2sc(Br)nn12
Temperature: 80 °C

Procedure:
The starting 2-bromo-imidazo[2,1-b][1,3,4]thiadiazole (2.0 g; 9.9 mmol) was dissolved in oleum (4.0 mL) and the resulting solution was heated at 80° C. for 8 hours. The reaction was allowed to cool to room temperature and then poured onto crushed ice. One spoon of sodium chloride was added and the resulting precipitate was isolated by vacuum filtration and washed with cold water. It was dried by azeotrope distillation with toluene. The title compound 2-bromo-imidazo[2,1-b][1,3,4]thiadiazole-5-sulfonic acid was isolated as a beige solid, (2.33 g; 83% yield).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15]CC)=O)=[CH:8][CH:7]=1>CO>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([NH:2][NH2:3])=[O:15])=[CH:8][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(OC)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: COc1ccc(CC(=O)NN)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydrazine hydrate (4.7 cm3) was added dropwise to ethyl (4-methoxyphenyl)acetate (3.73 g) and then methanol (20 cm3) was added to form a homogeneous reaction mixture. This mixture was stirred for 18 hours at ambient temperature during which time a white precipitate formed. The precipitate was isolated by filtration and washed with methanol and water, then air-dried to give (4-methoxyphenyl)acetic acid hydrazide (2 g). M+ =180; 1H NMR: δ 3.50(2H,s); 3.80(3H,s); 3.85(2H,br s); 6.70(1H,br s); 6.90(2H,d); 7.20(2H,d); (solid).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Li]CCCC>CN(C=O)C.CO>[C:13]1([S:19]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([CH3:3])=[CH:5]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reaction time: 0.25 h
Yield: 85 %

Procedure:
50% sodium hydride (1.1 g) was added to a solution of 3-methylindole (4 g) dissolved in anhydrous DMF (50 ml), keeping the temperature under 30° C. Stir for 15 minutes, then drip carefully the phenylsulphonyl chloride (4.7 ml) dissolved in anhydrous DMF (20 ml) and leave under stirring for 2 hours at 25° C. Then add methanol (5 ml) to decompose the possible present traces of BuLi; remove the solvent under reduced pressure, add water (20 ml) and extract exhaustively with methylenchloride. The organic phase is made anhydrous on sodium sulfate and the solvent is removed under reduced pressure. The residue (9.5 g) is ground in methylenchloride/hexane 1:1 to obtain N-(phenylsulphonyl)-3-methylindole (2 g) (m.p. 116-120° C.). The mother liquors are chromatographied to recover more product, eluting with methylenchloride/hexane 1:1. N-(phenylsulphonyl)-3-methylindole (7 g) is recovered from the intermediate fractions, removing the solvent under reduced pressure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[N:20]1([C:26]2[N:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CCCCCC.C(OCC)(=O)C>[O:23]1[CH2:24][CH2:25][N:20]([C:26]2[N:31]=[CH:30][C:29]([C:2]3[N:7]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:5]=[C:4]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[N:3]=3)=[CH:28][CH:27]=2)[CH2:21][CH2:22]1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1cc(N2CCOCC2)ncc1-c1nc(N2CCOCC2)nc(N2CCOCC2)n1

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 6-(morpholin-4-yl)pyridine-3-boronic acid pinacol ester acid pinacol ester with reaction time of 15 h. Chromatography (hexane/ethyl acetate 1:1) gave the title compound as a colorless solid.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][N:7]([C:9]2[C:18]([F:19])=[C:17]3[C:12]([C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15][N:16]3[CH2:20][CH3:21])=[CH:11][C:10]=2[F:26])[CH2:6][CH2:5][O:4]1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>>[CH2:27]([N:29]([CH2:2][CH:3]1[CH2:8][N:7]([C:9]2[C:18]([F:19])=[C:17]3[C:12]([C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15][N:16]3[CH2:20][CH3:21])=[CH:11][C:10]=2[F:26])[CH2:6][CH2:5][O:4]1)[CH2:30][CH3:31])[CH3:28]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CCl)C3)c(F)c21
Reactant: CCNCC
Product: CCN(CC)CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(CC)c3c2F)CCO1

Procedure:
By the use of 7-(2-chloromethylmorpholino)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and diethylamine, the reaction is similarly carried out as Example 4 to give 7-[2-(diethylaminomethyl)morpholino]-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.