Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([C:19]([OH:21])=O)=[CH:12]2)([CH3:4])([CH3:3])[CH3:2].Cl.[C:24]([N:28]1[CH:41]=[C:40]2[C:30]([C:31](=[O:42])[CH2:32][C:33]3([CH2:39]2)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[N:29]1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([N:28]1[CH:41]=[C:40]2[C:30]([C:31](=[O:42])[CH2:32][C:33]3([CH2:39]2)[CH2:38][CH2:37][N:36]([C:19]([C:13]2[CH:14]=[N:15][C:16]4[C:11]([CH:12]=2)=[CH:10][C:9]([O:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:22])=[CH:18][CH:17]=4)=[O:21])[CH2:35][CH2:34]3)=[N:29]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)n1cc2c(n1)C(=O)CC1(CCNCC1)C2
Reactant: CC(C)(C)OC(=O)COc1ccc2ncc(C(=O)O)cc2c1
Agent: Cl
Product: CC(C)(C)OC(=O)COc1ccc2ncc(C(=O)N3CCC4(CC3)CC(=O)c3nn(C(C)(C)C)cc3C4)cc2c1

Procedure:
The title compound was prepared by a method analogous to that described for Example 3, using 6-(2-tert-butoxy-2-oxoethoxy)quinoline-3-carboxylic acid and 2-tert-butyl-4,6-dihydrospiro[indazole-5,4′-piperidin]-7(2H)-one hydrochloride salt. +ESI (M+H) 547.3; 1H NMR (400 MHz, CDCl3, δ): 8.77 (d, J=2.0 Hz, 1 H), 8.10 (d, J=1.6 Hz, 1 H), 8.06 (d, J=9.2 Hz, 1 H), 7.50 (dd, J=9.3, 2.8 Hz, 1 H), 7.41 (s, 1 H), 7.02 (d, J=2.7 Hz, 1 H), 4.64 (s, 2 H),3.68-3.93 (m, 2 H), 3.41-3.51 (m, 2 H), 2.78 (s, 2 H), 2.65 (s, 2 H), 1.53-1.76 (m, 4 H), 1.61 (s, 9 H), 1.49 (s, 9 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6](I)[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1.[CH:13]([Sn](C=C)(C=C)C=C)=[CH2:14].C(OCC)(=O)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([CH:13]=[CH2:14])[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1
Reactant: C=C[Sn](C=C)(C=C)C=C
Reactant: CC(O)c1cc(I)c(O)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1cc(C(C)O)nc(Cl)c1O
Temperature: 50 °C
Yield: 70.1 %

Procedure:
A solution of 2-chloro-3-hydroxy-4-iodo-6-(1-hydroxyethyl)-pyridine (3.6 g, 12 mmol) in 36 mL of N,N-dimethylformamide is treated with bis(triphenylphosphine)-palladium dichloride (632 mg, 0.9 mmol) and tetravinyltin (2.7 mL, 15 mmol) and heated at 50° C. for 24 h and at room temperature for 40 h. The mixture is poured into 300 mL of ethyl acetate, filtered through a celite pad and the filtrate is washed with 4×50 mL of saturated sodium chloride. The organics are concentrated in vacuo and the crude material is chromatographed over 150 g of silica gel (230-400 mesh), eluting with 25% ethyl acetate/hexanes to provide 1.68 g (70%) of 2-chloro-3-hydroxy-4-vinyl-6-(1-hydroxyethyl)-pyridine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]2[NH:11][C:10]3[CH2:12][CH2:13][CH2:14][CH2:15][C:9]=3[N:8]=2)[CH2:2]1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([NH2:24])[N:18]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:16][C:17]1[CH:22]=[C:21]([N:1]2[CH2:6][CH2:5][O:4][CH:3]([C:7]3[NH:8][C:9]4[CH2:15][CH2:14][CH2:13][CH2:12][C:10]=4[N:11]=3)[CH2:2]2)[N:20]=[C:19]([NH2:24])[N:18]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C1CCc2[nH]c(C3CNCCO3)nc2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(Cl)cc(N2CCOC(c3nc4c([nH]3)CCCC4)C2)n1
Yield: 15.5 %

Procedure:
A solution of 2-(2-morpholinyl)-4,5,6,7-tetrahydro-1H-benzimidazole (0.8 g, 3.86 mmol), 4,6-dichloro-2-pyrimidinamine (0.633 g, 3.86 mmol) and Hunig's base (1.681 mL, 9.65 mmol) in ethanol (19.3 mL) was heated at 85° C. overnight. The mixture was concentrated and chromatographed (eluent EtOAc+NH4OH) to afford the title compound (200 mg). LC-MS (ES) m/z=335 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[N:47]([CH3:48])[N:46]=[C:45]([CH3:49])[C:44]=1[S:50](Cl)(=[O:52])=[O:51]>C(#N)C>[CH3:48][N:47]1[C:43]([Cl:42])=[C:44]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:52])=[O:51])[C:45]([CH3:49])=[N:46]1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 29 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0292 g, 0.0633 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (0.0447 g, 0.195 mmol) to obtain 4-(1,3-dimethyl-5-chloro-1H-pyrazol-4-ylsulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0120 g, yield 29%).
Reaction SMILES: [F:1][CH2:2][C:3]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])([CH2:6][CH2:7][CH2:8]OS(C)(=O)=O)[C:4]#[N:5].[I-:25].[Na+]>CC(C)=O.CCOCC>[F:1][CH2:2][C:3]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])([CH2:6][CH2:7][CH2:8][I:25])[C:4]#[N:5]
Reactant: CS(=O)(=O)OCCCC(C#N)(CF)N1C(=O)c2ccccc2C1=O
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: N#CC(CF)(CCCI)N1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
A solution of 2-fluoromethyl-2-phthalimido-5-methanesulfonyloxy-valeronitrile (42 g) and sodium iodide (35.7 g) in acetone (600 ml) is stirred and heated under reflux. After about 1/2 hour, the mixture solidifies. Acetone (500 ml) is added, and refluxing and stirring is continued overnight. The salts are removed by filtration and washed several times with acetone. The acetone is evaporated to give a residue which is dissolved in ether (1.5 l). The ether solution is washed subsequently with water (2×), sodium sulfite solution, and water again (3×). After drying (MgSO4) and evaporating the ether, the title compound is obtained as an oil (34.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C(OC([N:50]1[CH2:54][CH2:53][C@H:52]([C@H:55](O)[CH2:56][O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH2:51]1)=O)(C)(C)C>C1(C)C=CC=CC=1>[CH2:58]([O:57][CH2:56][C@@H:55]([C@H:52]1[CH2:53][CH2:54][NH:50][CH2:51]1)[O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH3:9])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: Cc1cc(Cl)ccc1O
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)COCc2ccccc2)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)ccc1O[C@@H](COCc1ccccc1)[C@H]1CCNC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
4-Chloro-2-methylphenol (14.1 mg, 98.9 μmol) was combined with PPh3 (26.0 mg, 98.9 μmol) dissolved in toluene (87.8 μL), and the mixture heated at 100° C. DIAD (19.5 μL, 98.9 μmol) was combined with (S)-3-((S)-2-benzyloxy-1-hydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (19.1 mg, 59.3 mmol) dissolved in toluene (58.0 μL), and slowly added to the heated mixture and stirred for two hours. The mixture was cooled to room temperature and concentrated. The residue was treated with 1.25M HCl in EtOH (474.6 μL) overnight at room temperature. The mixture was concentrated, the residue was redissolved in a mixture of MeCN (0.4 mL), AcOH (0.6 mL) and water (0.6 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound as a mono-TFA salt (7.8 mg, 99% purity). MS m/z: [M+H]+ calcd for C20H24ClNO2, 346.15. found 346.2.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[C:6]([OH:14])(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>ClCCl>[CH3:5][O:4][N:3]([CH3:2])[C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccccc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
N,O-dimethyl hydroxyl amine hydrochloride (4.393 g, 45.037 mmol) was added to a stirred solution of benzoic acid (5.0 g, 40.943), EDC.HCl (9.418 g, 49.132) and N-methyl morpholine (4.141 g, 40.943 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at rt for 4 h. After completion of the reaction, the reaction mixture was concentrated. Diethyl ether was added and the mixture was extracted with water and brine. The organic layer was dried over Na2SO4 and filtrated. Concentration of the organic layer furnished the title compound as a colorless liquid (4.933 g, 73%). [1H-NMR (CDCl3, 300 MHz) δ 7.72-7.64 (m, 2H), 7.52-7.36 (m, 3H), 3.58 (s, 3H), 3.38 (s, 3H); HPLC RtA=6.281 min. (98%); LCMS RtA=0.38 min; [M+H]+=166.1]
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5](C)[CH2:4][CH2:3]1.Cl[C:10]([O:12][CH:13]([Cl:15])[CH3:14])=[O:11]>>[Cl:15][CH:13]([O:12][C:10]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:11])[CH3:14]
Reactant: CN1CCN(C)CC1
Reactant: CC(Cl)OC(=O)Cl
Product: CC(Cl)OC(=O)N1CCN(C)CC1

Procedure:
In a similar manner, N,N'-di-methylpiperazine is reacted with α-chloroethyl chloroformate (ACE-Cl) to give the intermediate N-α-chloroethoxycarbonyl N'-methyl piperazine, which is then dehydrohalogenated as in Example 21b to give N-(vinyloxycarbonyl)N'-methylpiperazine.
Reaction SMILES: C(CC(O)=O)#N.[F-:7].[Cs+].[CH2:9]([Sn:13](C1SC=CC=1)([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].ClCCl>C1(C)C=CC=CC=1.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>[Sn:13]([F:7])([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: [F-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#CCC(=O)O
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCC[Sn](F)(CCCC)CCCC
Temperature: 120 °C
Reaction time: 12 h

Procedure:
1 is halogenated chromophore 2 is metalated conjugated system step a) Reaction of 1 and 2 by palladium mediated Stille coupling results in formation of compound 3; step b) The carboxylaldehyde moiety is introduced to compound 3 by Vilsmaier-Haak reaction; And step c) transformed by reaction of 4 with cyano-acetic acid to the targeted 5. Step a) Under inert atmosphere, to a mixture of chromophore 1, 1 mol % catalysator Pd(PPh3)4, 1 equivalent of CsF in toluene, 1.2 equivalent of tributylstannyl-thiophene were added. The reaction mixture was stirred at 120° C. for 12 h. After cooling to room temperature, dichloromethane was added. The white salt (Bu3SnF) formed during the reaction was filtered off and the solvent removed under reduced pressure. Purification of the crude product was performed by column chromatography on silica gel with (2/8) dichloromethane/ethylacetate to give the pure thiophene derived squarylium dye 3. Analytical Data for 3
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]([CH3:13])=[CH:11][C:10]2[N:9]=[C:8]3[C:14]4[C:19]([CH2:20][C:7]3([CH3:21])[C:6]=2[C:5]=1[CH3:22])=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH3:2].O1CCC[CH2:24]1>C[Li].CCOCC>[CH2:1]([O:3][C:4]1[C:12]([CH3:13])=[CH:11][C:10]2[NH:9][C@:8]3([CH3:24])[C:14]4[C:19]([CH2:20][C@:7]3([CH3:21])[C:6]=2[C:5]=1[CH3:22])=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH3:2]
Reactant: C1CCOC1
Reactant: CCOc1c(C)cc2c(c1C)C1(C)Cc3ccccc3C1=N2
Agent: [Li]C
Solvent: CCOCC
Product: CCOc1c(C)cc2c(c1C)[C@@]1(C)Cc3ccccc3[C@@]1(C)N2
Reaction time: 1 h
Yield: 96 %

Procedure:
To a cold (-78° C.) solution of 2.0 g (0.0063 mol) of 9b,10-dihydro-8-ethoxy-7,9,9b-trimethylindeno[1,2-b]indole in 20 ml of dry tetrahydrofuran, 10 ml of methyllithium (1.6N) in ether was added dropwise with stirring and under argon. After the addition was complete the stirring was continued for 1 hour at -20° C. and then for 1 hour at room temperature. The reaction mixture was quenched by addition of 20 ml of saturated ammonium chloride solution. After addition of 100 ml of ether the organic phase was separated and washed twice with ammonium chloride solution. Drying (Na2SO4) and evaporation gave 2.0 g (96%) of the product. 1H NMR (CDCl3): 1.35 (3H,t), 1.4 (6H,d), 2.1 (3H,s), 2.35 (3H,s), 2.95-3.05 (1H,d), 3.55-3.75 (3H,m), 6.1 (1H,s), 7.0-7.3 (4H,m).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7][CH2:6]1)=[O:4].CCN(CC)CC.[CH3:19][O:20][C:21](Cl)=[O:22]>C(Cl)Cl>[CH3:19][O:20][C:21]([NH:11][CH:8]1[CH2:9][CH2:10][CH:5]([C:3]([OH:2])=[O:4])[CH2:6][CH2:7]1)=[O:22]
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NC1CCC(C(=O)O)CC1
Reaction time: 8 h

Procedure:
To a stirred solution of trans-4-amino-cyclohexanecarboxylic acid methyl ester (commercially available) in CH2Cl2 was added Et3N (2 eq.) and methyl-chloroformate (1.05 eq.). Stirring was continued overnight at RT. The reaction was quenched by addition of H2O, the product was extracted with CH2Cl2 and the organic phase washed with aq. HCl 1M. The combined organic phases were dried over Na2SO4 and concentrated under vacuo. The residue was dissolved in MeOH and a 2M KOH aq. solution was added. The reaction was stirred at RT 4 hours, aq. HCl was added until ph=6, and then the product was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated under vacuo to afford the title product as a white foam which was used in the next step without further purification.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[I-].[Na+].C(N(CC)CC)C.Cl[CH2:47][CH2:48][CH2:49][OH:50]>CN(C)C=O>[OH:50][CH2:49][CH2:48][CH2:47][N:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:5])=[O:36])[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([OH:31])=[O:30])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Reactant: OCCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)CN1CCN(CCCO)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,4,7,10-Tetraazacyclododecane-4,7,10-triacetic acid tri-t-butyl ester (360 mg, 0.70 mmol) (Example 22(a)) was dissolved in dimethylformamide (2.1 ml) . Sodium iodide (15 mg, 1 mmol), triethylamine (142 mg, 1.4 mmol) and 3-chloro-1-propanol (132 mg, 1.4 mmol) were added to the stirred mixture at ambient temperature. The mixture was stirred for 3 hours at ambient temperature, the temperature was then raised to 100° C. and kept there for 2 hours. The solvent was evaporated and the residue was dissolved in dichloromethane (3 ml) and washed with water (1 ml). Trifluoroacetic acid (2 ml) was added to the dichloromethane solution and the mixture was stirred at ambient temperature for 1 hour. The solvents were evaporated and the residue dissolved in water (6 ml). The aqueous solution was washed with ether (6×3 ml). The aqueous solution was acidified, the water was evaporated, and the title compound was isolated as a hygroscopic white powder. Yield 192 mg (68%), FAB MS: 405(M+1). The structure was confirmed by 1HNMR and 13CNMR.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:10][C:11]1[C:19]2[CH:18]=[CH:17][S:16][C:15]=2[CH:14]=[CH:13][CH:12]=1>ClCCl>[Br:1][CH2:2][C:3]([C:17]1[S:16][C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:10])[C:19]=2[CH:18]=1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: Clc1cccc2sccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CBr)c1cc2c(Cl)cccc2s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Bromoacetyl bromide (16.14 g) was added dropwise at 0° C. under nitrogen to a stirred mixture of anhydrous aluminium chloride (21.36 g) and dichloromethane (200 ml), then the mixture was stirred at 0° C. for 30 minutes. A solution of 4-chloro-benzo[b]thiophene (13.46 g; prepared in a manner similar to that described above) in dichloromethane (100 ml) was added dropwise, and the mixture was stirred at 0° C. for 2 hours then it was poured onto ice-water (500 ml). The product was extracted into dichloromethane (2×250 ml) and the combined extracts were washed with water (200 ml), saturated aqueous sodium hydrogencarbonate solution (2×200 ml) and saturated aqueous sodium chloride solution (200 ml), then dried (Na2SO4). The solvent was removed in vacuo to leave a brown oil, which was purified by flash chromatography over silica using a 10:1 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 2-bromo-1-(4-chlorobenzo[b]thiophen-2-yl]ethan-1-one (2.8 g) as a colourless solid which was used without further purification.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[OH-].[Na+].Cl[C:12](=[CH:17][C:18]([F:21])([F:20])[F:19])[C:13]([F:16])([F:15])[F:14]>CN(C)C=O>[F:14][C:13]([F:16])([F:15])[CH2:12][C:17]1([C:18]([F:21])([F:20])[F:19])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: Oc1ccccc1O
Reactant: FC(F)(F)C=C(Cl)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: FC(F)(F)CC1(C(F)(F)F)Oc2ccccc2O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
11 g of pyrocatechol were dissolved in 200 ml of dimethylformamide and the solution was treated with 18 g of 45% strength by weight aqueous sodium hydroxide solution. The mixture was treated dropwise at 75° C. with 20 g of 2-chloro-1,1,1,4,4,4-hexafluoro-2-butene. Stirring was continued for 30 minutes at 75° C. The batch was subsequently poured into 500 ml of ice-water and extracted using diethyl ether. The organic phase was washed with water, dried with magnesium sulphate and concentrated. Finally, the product was distilled under a high vacuum. The yield was 15 g (=56%), and the boiling point 60° C. at 10 mbar. The NMR spectra showed the following characteristic absorptions: 19F-NMR: -59.0 and -84.6 ppm. 1H-NMR: 3.02 ppm.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8](Cl)=[O:9])[S:4][N:3]=1.[NH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.N1C=CC=CC=1>O1CCCC1>[N:12]1([NH:11][C:8]([C:5]2[S:4][N:3]=[C:2]([Cl:1])[C:6]=2[Cl:7])=[O:9])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: NN1CCOCC1
Reactant: O=C(Cl)c1snc(Cl)c1Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(NN1CCOCC1)c1snc(Cl)c1Cl
Temperature: 2.5 °C
Yield: 63.4 %

Procedure:
At 0 to 5° C. and with ice-cooling and stirring, 2.43 g (0.01 mol) of 3,4-dichloro-isothiazole-5-carbonyl chloride are added dropwise over a period of 5 minutes to a mixture of 1.21 g (0.011 mol) of 4-amino-morpholine and 22 ml of absolute pyridine. After the addition, the reaction mixture is admixed with 1.5 ml of absolute tetrahydrofuran, allowed to warm to room temperature and then stirred at room temperature for one hour. The reaction mixture is subsequently concentrated under reduced pressure. The residue that remains is admixed with 60 ml of water and 60 ml of ethyl acetate. The organic phase is separated off and the aqueous phase is extracted twice more with ethyl acetate. The combined organic phases are successively washed with 20 ml of saturated aqueous sodium bicarbonate solution and 50 ml of water, then dried over sodium sulphate and concentrated under reduced pressure. The residue is triturated in a mixture of 30 ml methylene chloride and 70 ml of petroleum ether. The resulting solid is filtered off with suction and dried. In this manner, 1.79 g (63% of theory) of N-morpholinyl-3,4-dichloro-isothiazole-5-carboxamide are obtained in the form of a solid of melting point 198 to 199° C.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:9]=[N:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[N:6][CH:5]=1)[CH3:3].C(N(CC)CC)C.[N+:30]([C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36])([O-:32])=[O:31]>ClCCl>[N+:30]([C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([NH:1][CH:2]([C:4]1[N:9]=[N:8][C:7]([NH:10][C:11]2[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=2)=[N:6][CH:5]=1)[CH3:3])=[O:36])([O-:32])=[O:31]
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3[N+](=O)[O-])nn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
To a stirred solution of 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (0.30 g, 1.0 mmol) in dichloromethane (10 mL) cooled to −78° C. was added triethylamine (0.42 mL, 3.0 mmol) and 2-nitrobenzoyl chloride (0.35 mL, 1.5 mmol). After stirring for one hour, the solution was quenched with water and allowed to warm to room temperature. The solution was diluted with dichloromethane (50 mL) and washed with 0.1N HCl (2×50 mL) and brine (50 mL). The solution was dried with magnesium sulfate and filtered, and silica gel (5 g) was added to the solution, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexane (20:80) to ethyl acetate:hexanes (100:0) using a RediSep silica gel cartridge (12 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 2-nitro-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (0.12 g) as a white solid. MS m/z455 (M+1).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:15][C:14](=S)[CH2:13][CH2:12][S:11](=[O:18])(=[O:17])[CH:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:9]=2[CH:26]=1>O1CCCC1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:15]=[C:14]([NH:2][NH2:3])[CH2:13][CH2:12][S:11](=[O:18])(=[O:17])[CH:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:9]=2[CH:26]=1
Reactant: NN
Reactant: O=S1(=O)CCC(=S)Nc2ccc(Cl)cc2C1c1ccccc1F
Solvent: C1CCOC1
Solvent: O
Product: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A solution of 0.9 ml of hydrazine hydrate in 134 ml of tetrahydrofuran is treated with 6.2 g of 8-chloro-6-(2-fluorophenyl)-1,3,4,6-tetrahydro-2-thiono-2H-5,1-benzothiazocine 5,5-dioxide. The solution is stirred at room temperature under a stream of argon for 1.25 hours and then evaporated in vacuo. The residue is crystallized from diisopropyl ether, there being obtained 8-chloro-6-(2-fluorophenyl)-2-hydrazino-3,6-dihydro-4H-5,1-benzothiazocine 5,5-dioxide of melting point 159°.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]#[CH:6])[CH3:3].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>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.CN(C=O)C.CCN(CC)CC>[CH3:1][N:2]([CH2:4][C:5]#[C:6][C:9]1[C:8]([F:7])=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:18]/[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24])/[C:12](=[O:17])[NH:13]2)[CH3:3]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCN(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN(C)C)c21

Procedure:
Using Method C above, N,N-dimethyl propargylamine (42.2 mg, 0.51 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (75 mg, 0.203 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (23.5 mg) and Cul (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give (Z)-1,3-dihydro-4-[3-(N,N-dimethylamino)-1-propynyl]-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 40 mg, 61%).