Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[OH:2].Cl.Cl.[CH2:5]([NH:7][C:8]([NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[NH:12])=[NH:9])[CH3:6].[CH3:26][C:27]([CH3:29])=[O:28]>>[C:27]([OH:2])(=[O:28])[CH3:29].[CH2:5]([NH:7][C:8]1[NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[N:12][C:27]([CH3:29])([CH3:26])[N:9]=1)[CH3:6]
Reactant: CO
Reactant: CC(C)=O
Reactant: CCCCCCCCCCCCNC(=N)NC(=N)NCC
Agent: Cl
Product: CC(=O)O
Product: CCCCCCCCCCCCNC1=NC(C)(C)N=C(NCC)N1

Procedure:
100 ml of methanol, 80ml of acetone and 2.6 ml of concentrated hydrochloric acid were added to 8.0 g (24.0 mmol) of N1-ethyl-N5-dodecyl-biguanide hydrochloride, and the mixture was refluxed for 64 hours. The solvent was distilled off under reduced pressure. To the residue were added 100 ml of ethanol, 60 ml of water and 12.0 ml of 5N sodium hydroxide, and the mixture was refluxed for 1 hour, concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed successively with 10% aqueous sodium acetate and water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from methyl ethyl ketone to obtain 6.2 g of colorless crystals having a melting point of 79 to 82° C.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][S:16]([C:19]1[CH:31]=[CH:30][C:22]([C:23]([NH:25][CH2:26][C:27]([OH:29])=O)=[O:24])=[CH:21][CH:20]=1)(=[O:18])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:32]1([CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:36][CH2:35][CH2:34][CH2:33]1>>[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][S:16]([C:19]1[CH:31]=[CH:30][C:22]([C:23]([NH:25][CH2:26][C:27](=[O:29])[N:42]2[CH2:41][CH2:40][N:39]([CH2:38][CH2:37][N:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)[CH2:44][CH2:43]2)=[O:24])=[CH:21][CH:20]=1)(=[O:17])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCN(CCN2CCNCC2)C1
Reactant: O=C(O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccccc2)cc1
Product: O=C(NCC(=O)N1CCN(CCN2CCCC2)CC1)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared from [4-(2-benzoyl-phenylsulfamoyl)-benzoylamino]-acetic acid and 1-(2-pyrrolidin-1-yl-ethyl)-piperazine (EMKA-Chemie) according to the method described in Example 1.1/f. MS (EI) 604.2 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]3)[N:7]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])[C:6]=2[C:5](=[O:30])[NH:4][C:3]1=[O:31].Br[C:33]1[C:34]2[CH:46]=[CH:45][CH:44]=[CH:43][C:35]=2[N:36]([CH3:42])[S:37](=[O:41])(=[O:40])[C:38]=1C.[C:47](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:42][N:36]1[C:35]2[CH:43]=[CH:44][CH:45]=[CH:46][C:34]=2[C:33]([CH2:47][N:4]2[C:5](=[O:30])[C:6]3[N:7]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])[C:8]([N:11]4[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:12]4)=[N:9][C:10]=3[N:2]([CH3:1])[C:3]2=[O:31])=[CH:38][S:37]1(=[O:40])=[O:41]
Reactant: CC1=C(Br)c2ccccc2N(C)S1(=O)=O
Reactant: O=C([O-])[O-]
Reactant: CC(C)=CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)[nH]c(=O)n2C
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC1=CS(=O)(=O)N(C)c3ccccc31)c(=O)n2C
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 260 mg of 3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxy-carbonylamino)-piperidin-1-yl]-xanthine, 185 mg of 4-bromo-methyl-1-methyl-1H-benzo[c][1,2]thiazine-2,2-dioxide and 550 mg of potassium carbonate in 4 ml N,N-dimethylformamide is stirred for about 40 h at ambient temperature. As no reaction of any note can be detected by thin layer chromatography, the mixture is heated to 60° C. for 2 h and then stirred for another 15 h at 50° C. until the reaction is virtually complete. Then 30 ml of water are added, the precipitate formed is suction filtered and dried. The crude product is purified by chromatography over a silica gel column with petroleum ether/ethyl acetate (1:1) as eluant.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH:7]=[CH:8]C2C=C3C(C(O)OC3=O)=CC=2)=[CH:5][CH:4]=1.[NH2:22][NH2:23].[CH3:24][CH2:25][OH:26]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:8][N:22]2[N:23]=[CH:6][C:5]3[C:24](=[CH:20][CH:21]=[CH:3][CH:4]=3)[C:25]2=[O:26])=[CH:20][CH:21]=1
Reactant: CCO
Reactant: NN
Reactant: COc1ccc(C=Cc2ccc3c(c2)C(=O)OC3O)cc1
Product: COc1ccc(C=Cn2ncc3ccccc3c2=O)cc1
Temperature: 25 °C

Procedure:
To 260 mg (0.92 mmol) 6-p-methoxystyryl-3-hydroxyphthalide dissolved in 25 ml of 95% EtOH was added 0.2 ml (4.1 mmol) of hydrazine and the yellow solution was heated at reflux for 11/4 hours. The solution was allowed to cool to RT, finally in ice, and the solid which had formed was collected, washed well with cold 95% EtOH and air dried; yield of pale yellow crystals 0.13 g (50.8%): m.p. 267°-269°.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:24])=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1.[ClH:26].[S:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])[CH2:29][CH2:28]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:26].[CH3:25][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:24][C:36](=[O:37])[CH2:35][CH2:34][CH2:33][N:30]3[CH2:29][CH2:28][S:27][CH2:32][CH2:31]3)=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Reactant: O=C(O)CCCN1CCSCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCSCC2)c2c(c1)OC(C)(C)C1=C2CCC1
Yield: 35 %

Procedure:
A mixture of 1.5 g. (4.4 mmole) of 4,4-dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-tetrahydrocyclopenta[ c][1]benzopyran, 0.99 g. (4.4 mmole) of γ-thiomorpholinobutyric acid hydrochloride, and 0.99 g. (4.8 mmole) of dicyclohexylcarbodiimide in 125 ml. of methylene chloride was stirred and heated at reflux for 16 hours. The reaction mixture was cooled and the byproduct of dicyclohexylurea was removed by suction filtration. The solvents were evaporated to give a residue which crystallized from a mixture of 10 ml. chloroform/40 ml. diethyl ether to give 0.85 g. (35%) of the desired product as a beige solid, m.p. 167°-171°C. The material was pure by thin layer chromatography, and the infrared and nuclear magnetic resonance spectra were in agreement with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:20][C:21]3[C:22]([F:32])=[C:23]([CH:29]=[CH:30][CH:31]=3)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7][N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH3:19])[CH:16]=2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:40])C(=O)C1>C(Cl)Cl.O>[Cl:40][C:7]1[N:8]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH3:19])[CH:16]=2)[C:9]2[C:5]([C:6]=1[S:20][C:21]1[C:22]([F:32])=[C:23]([CH:29]=[CH:30][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[F:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCn1cc(-n2cc(Sc3cccc(C(=O)OCC)c3F)c3ccc(Cl)c(F)c32)cn1
Solvent: ClCCl
Solvent: O
Product: CCCn1cc(-n2c(Cl)c(Sc3cccc(C(=O)OCC)c3F)c3ccc(Cl)c(F)c32)cn1
Reaction time: 8 h
Yield: 46.7 %

Procedure:
To a stirred solution of ethyl 3-((6-chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate 1 (Example 7, Step 1; 100 mg, 0.21 mmol) in CH2Cl2 (3 mL) was added NCS (33.7 mg, 0.25 mmol) at RT under inert atmosphere. After 8 h stirring, additional NCS (33.7 mg, 0.25 mmol) was added at RT and stirred again for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 9-11% EtOAc/Hexanes to afford compound 2 (50 mg, 47%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.71-7.67 (m, 1H), 7.66 (s, 1H), 7.64 (s, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.18 (dd, J=8.4, 6.0 Hz, 1H), 7.04-6.97 (m, 2H), 4.40 (q, J=7.2 Hz, 2H), 4.18 (t, J=7.2 Hz, 2H), 2.04-1.93 (m, 2H), 1.40 (t, J=7.2 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H); LC-MS (ESI): 98.8%; m/z 510.4 (M+H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.94 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[C:11]([OH:13])=O.[NH2:18][C:19]1[CH:31]=[C:30]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[Cl:17][C:15]1[CH:14]=[C:10]([CH:9]=[C:8]([Cl:7])[CH:16]=1)[C:11]([NH:18][C:19]1[CH:31]=[C:30]([CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:13]
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1NC(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 1 h

Procedure:
2.0 mL of methylene chloride, 2.7 μL of N,N-dimethylformamide and 0.061 mL of oxalyl chloride were sequentially added to 0.13 g of 3,5-dichlorobenzoic acid at room temperature and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 3.0 mL of methylene chloride and 0.45 mL of triethylamine containing 60 mg of tert-butyl 2-amino-4-phenethylbenzoate at room temperature and stirred at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(3,5-dichlorobenzamido)-4-phenethylbenzoate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:13](OCC)C.S(=O)(=O)(O)O>C(O)C>[CH3:13][C:4]([C:3]1[C:2]([F:1])=[CH:10][C:9]([F:11])=[C:8]([F:12])[CH:7]=1)=[O:5]
Reactant: CCOCC
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CC(=O)c1cc(F)c(F)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
194.5 g (1 mol) of 2,4,5-trifluorobenzoyl chloride were initially introduced into 100 ml of diethyl ether and heated to boiling under reflux. 1.1 mol of ethoxymagnesium malonic ester dissolved in 100 ml of ethanol and 125 ml of diethyl ether were then allowed to drop in in the course of 30 minutes and the mixture was stirred for 1 hour under reflux. After cooling, the reaction mixture was stirred into 500 ml of ice water and adjusted to a pH of 1 with concentrated sulphuric acid, and the organic material (345 g) was separated off. This organic material was dissolved in 300 ml of acetic acid and, after adding 37.5 ml of concentrated sulphuric acid, heated to reflux until evolution of CO2 had ended, which took 6 hours. The reaction mixture was then cooled and poured into water, and the organic phase was separated off and distilled. 83 g of product having a boiling point at 10 mbar of 63° to 64° C. were obtained. This corresponds to a yield of 47% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11]N=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:26][C:27](=O)[CH2:28][CH2:29][CH2:30][CH3:31].CC1C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(O)=O.[Na+]>C1COCC1.CCOCC>[CH3:10][O:9][C:8]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[NH:11][C:27]([CH3:26])=[C:28]2[CH2:29][CH2:30][CH3:31]
Reactant: COc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1OC
Reactant: CCCCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1c(C)[nH]c2cc(OC)c(OC)cc12
Temperature: 25 °C
Yield: 81.2 %

Procedure:
N-(3,4-Dimethoxyphenyl)-benzophenone hydrazone (1.0 equiv., 0.32 mmol, 105 mg), 2-hexanone (5 equiv., 1.58 mmol, 0.19 mL), and TsOH.H2O (10 equiv., 3.2 mmol, 609 mg) were dissolved in THF (10 mL) and heated to reflux for 67 hours. The reaction mixture was then cooled to room temperature, diluted with Et2O (5 mL), neutralized with a saturated NaHCO3 solution, and extracted with Et2O (3×10 mL). The organic extracts were then dried over K2CO3, filtered and concentrated under vacuum. Purification by flash column chromatography (20% EtOAc/Hex) gave the title product as a yellow oil (60 mg, 0.26 mmol, 80% yield).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]=[O:9])(=[O:5])[CH2:2][CH2:3][CH3:4].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[SH:25][CH2:26][C:27](O)=[O:28]>C(Cl)Cl>[C:1]([O:6][CH2:7][CH:8]1[S:25][CH2:26][C:27](=[O:28])[O:9]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCC=O
Reactant: O=C(O)CS
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: CCCC(=O)OCC1OC(=O)CS1
Reaction time: 16 h
Yield: 44 %

Procedure:
To a well-stirred suspension of 24 (1.3 g, 10 mmol) and CSA (116 mg, 0.50 mmol) in dry DCM (10 ml) was slowly added a solution of mercaptoacetic acid (2.76 g, 2.08 ml, 30 mmol) in dry DCM (5 ml). The reaction was left at room temperature for 16 hours with stirring. The reaction mixture was diluted with DCM (20 ml) and successively washed with: concentrated NaHCO3 (3×30 ml) and brine (2×30 ml), dried, filtered and evaporated to afford 25 (0.9 g, 4.4 mmol, 44%) as a colorless syrup.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[C:25](B(O)O)[C:24]([O:30][CH3:31])=[CH:23][C:22]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([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)=CC=1.O>[CH2:1]([S:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:25]3[C:24]([O:30][CH3:31])=[CH:23][C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=4)=[C:21]([Cl:20])[CH:26]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2cc(SCc3ccccc3)ccc12
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1ncnc2cc(SCc3ccccc3)ccc12

Procedure:
A microwave vial was charged with 7-(benzylthio)-4-chloroquinazoline (0.372 g, 1.298 mmol), (2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)boronic acid (0.364 g, 1.298 mmol), tetrakis(triphenylphosphine)palladium(0) (0.150 g, 0.130 mmol), and potassium carbonate (0.897 g, 6.49 mmol). Dioxane (3.24 ml) and Water (1.081 ml) were added; the vial was flushed with argon and sealed, and microwaved at 90° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-75% EtOAc:Heptane) to afford 7-(benzylthio)-4-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)quinazoline as a yellow solid. (ESI) 487.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][N:17]3[CH2:25][C:24]4[C:19](=[CH:20][C:21]([O:28][CH3:29])=[C:22]([O:26][CH3:27])[CH:23]=4)[C:18]3=[O:30])[CH2:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>C(Cl)Cl>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][N:17]3[CH2:25][C:24]4[C:19](=[CH:20][C:21]([O:28][CH3:29])=[C:22]([O:26][CH3:27])[CH:23]=4)[C:18]3=[O:30])[CH2:11]2)=[CH:6][CH:7]=1)[C:38]([CH3:39])=[O:40]
Reactant: COc1cc2c(cc1OC)C(=O)N(CC1CCCN(CCc3ccc(N)cc3)C1)C2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(=O)N(CC1CCCN(CCc3ccc(NC(C)=O)cc3)C1)C2
Temperature: 25 °C

Procedure:
819 mg (2 mmol) of 2-[(N-(2-(4-amino-phenyl)-ethyl)-piperidin-3-yl)-methyl]-5,6-dimethoxy-1-oxo-1,3-dihydro-isoindole are mixed with 10 ml of methylene chloride and after the addition of 0.3 ml (2.2 mmol) of triethylamine, 0.16 ml (2.2 mmol) of acetyl chloride are added dropwise. The reaction temperature rises to 30° C. The mixture is stirred for half an hour at ambient temperature, extracted twice with water, the organic phase is dried over magnesium sulphate and evaporated down in vacuo. The residue is crystallised from acetone.
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH2:6].N1C=CC=CC=1.Cl[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15].O>O1CCCC1>[S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][C:14](=[O:15])[O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1nncs1
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1nncs1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of 1,3,4-thiadiazole-2-amine (1.00 g, 9.89 mmol) and pyridine (0.968 ml, 11.9 mmol) in tetrahydrofuran (33 ml) was added 2,2,2-trichloroethyl chloroformate (1.64 ml, 11.9 mmol) with ice-cooling and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Hexane was poured to the residue and a solid was collected by filtration to obtain the desired product (2.16 g, 79.1%).
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][C:11]([CH3:15])=[C:12]([CH3:14])[CH3:13])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl>[O:24]1[C:12]([CH3:14])([CH3:13])[C:11]1([CH3:15])[CH2:10][CH2:9][C:2]([CH3:1])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)CCC=C(C)CCC(C)=C(C)C
Solvent: ClCCl
Product: CC(=O)CCC=C(C)CCC1(C)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 100 g. of 6,9,10-trimethyl-undeca-5,9-dien-2-one in 2,000 ml. of methylene chloride, there was added, while cooling with ice, 100 g. of m-chloro perbenzoic acid. The resulting mixture was allowed to stand while constantly stirring at room temperature for 1 hour. The resulting mixture was diluted with 1,000 ml. of methylene chloride. The resulting solution was washed with ice-cold 1-N sodium hydroxide solution and with a saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue was fractionally distilled under high vacuum. There was obtained 9,10-epoxy-6,9,10-trimethyl-undec-5-en-2-one. B.p. 89°-91°C./0.07 mm Hg; nD20 = 1.4656.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[CH2:13]([NH2:16])[CH2:14][CH3:15]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH2:13][CH2:14][CH3:15])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Reactant: CCCN
Solvent: ClCCl
Product: CCCNS(=O)(=O)c1ccc(Br)c(F)c1
Yield: 90.2 %

Procedure:
According to general procedure C, 4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and propylamine (0.30 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-3-fluoro-N-propylbenzenesulfonamide (0.39 g, 90%) was provided after purification. HRMS: calcd for C9H11BrFNO2S, 294.96779; found (EI, M+.), 294.9684. HPLC purity 100.0% at 210-370 nm, 10.3 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:3]=1[NH2:4].SC1SC2C=C(OC(F)(F)F)C=CC=2N=1.[Cl:29][C:30]1[S:31]C2C=CC(Cl)=CC=2N=1>>[Cl:29][C:30]1[S:31][C:2]2[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: Clc1ccc2sc(Cl)nc2c1
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Agent: FC(F)(F)Oc1ccc2nc(S)sc2c1
Product: FC(F)(F)Oc1ccc2nc(Cl)sc2c1
Temperature: 150 °C

Procedure:
The title compound was prepared from 2-bromo-4-trifluoromethoxyaniline via 2-mercapto-6-trifluoromethoxy-1,3-benzothiazole as described for 2,5-dichloro-1,3-benzothiazole except that in the first step the reaction mixture was heated to 150° C. for 16 h.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[CH2:5][NH:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].C(N(CC)C(C)C)(C)C.[Br:22][CH2:23][CH2:24][CH2:25]Br>C1(C)C=CC=CC=1>[Br:22][CH2:23][CH2:24][CH2:25][N:6]([CH2:5][C:4]([O:3][CH3:2])=[O:12])[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: BrCCCBr
Reactant: COC(=O)CNCC(=O)OC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)CN(CCCBr)CC(=O)OC
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 1 mmol iminodiacetic acid dimethylester hydrochloride salt, 5 mmol N,N-diisopropyl-ethylamine and 3 mmol 1,3-dibromopropane in 2 mL toluene was stirred at 90° C. for 16 h and then chromatographed to provide the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.[Br:22][CH:23](C)[C:24](Cl)=O.CN([CH:31]=[O:32])C>>[Br:22][CH2:23][CH2:24][C:31]([NH:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1)=[O:32]
Reactant: CN(C)C=O
Reactant: Cc1nc(N)sc1-c1ccnc(Nc2ccc(F)cc2)n1
Reactant: CC(Br)C(=O)Cl
Product: Cc1nc(NC(=O)CCBr)sc1-c1ccnc(Nc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of [4-(2-amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine (0.3 g, 1.0 mmol) in DMF (2 mL) was cooled on an ice bath and was treated with 2-bromopropionyl chloride (0.17 g, 1.0 mmol). After completion of the addition, the reaction mixture was allowed to stir at room temperature for 18 h. It was poured into ice water and was extracted with CH2Cl2. The organics were combined, washed with brine, dried on MgSO4, and the solvent was evaporated to leave a brown residue. This was purified by SiO2 chromatography (1:1 EtOAc/PE) to afford the title compound as a light yellow solid. Anal. RP-HPLC: tR=17.1 min (0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity >93%). 1H-NMR (DMSO-d6) δ: 1.99 (m, 2H, CH2), 2.68 (s, 3H, CH3), 4.65 (m, 2H, CH2), 7.02 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 7.11 (m, 2H, Ph-H), 7.62 (m, 2H, Ph-H), 8.19 (d, 1H, J=5.5 Hz, pyrimidinyl-H).