Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:24]2[C:32]3[C:31]([CH:33]4[CH2:35][CH2:34]4)=[N:30][CH:29]=[N:28][C:27]=3[N:26]([S:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:38])=[O:37])[CH:25]=2)O)=[C:18]([F:45])[N:17]=1)[C:8]1[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[C:39]1([S:36]([N:26]2[C:27]3[N:28]=[CH:29][N:30]=[C:31]([CH:33]4[CH2:34][CH2:35]4)[C:32]=3[C:24]([CH2:22][C:19]3[CH:20]=[CH:21][C:16]([NH:7][C:8]4[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=4)=[N:17][C:18]=3[F:45])=[CH:25]2)(=[O:38])=[O:37])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn(S(=O)(=O)c4ccccc4)c4ncnc(C5CC5)c34)c(F)n2)cn1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COc1ccc(Nc2ccc(Cc3cn(S(=O)(=O)c4ccccc4)c4ncnc(C5CC5)c34)c(F)n2)cn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 71.5 %

Procedure:
To {5-[(7-benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl}-(6-methoxy-pyridin-3-yl)-carbamic acid tert-butyl ester (75, 0.290 g, 0.448 mmol) in 9.93 mL of 1,2-dichloroethane, triethylsilane (0.31 mL, 2.0 mmol) and trifluoroacetic acid (0.16 mL, 2.0 mmol) are added and the reaction stirred at 80° C. for 4 hours. The reaction is poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer is dried with sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (76, 170 mg). MS (ESI) [M+H+]+=530.9.
Reaction SMILES: [CH2:1](N1CCC(=O)CC1)C1C=CC=CC=1.[F:15][C:16]([F:48])([F:47])[C:17]1[CH:18]=[C:19]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:20]([N:22]1[CH2:39][CH2:38][C:25]2([N:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]([CH3:36])[NH:27][C:26]2=[O:37])[CH2:24][CH2:23]1)=[O:21].CI>>[F:48][C:16]([F:15])([F:47])[C:17]1[CH:18]=[C:19]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:20]([N:22]1[CH2:23][CH2:24][C:25]2([N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:28]([CH3:36])[N:27]([CH3:1])[C:26]2=[O:37])[CH2:38][CH2:39]1)=[O:21]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1c1ccccc1
Solvent: CI
Product: CC1N(C)C(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1c1ccccc1

Procedure:
The title compound, MS: m/e=500.2 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one 1-benzyl-piperidin-4-one and methyl iodide.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Br[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1.C(N(CC)CC)C>C(O)(C)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[O:18][CH2:17][CH2:16][N:15]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH2:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CC(C)(C)c1cc(NC(=O)C2CNCCO2)no1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: CC(C)(C)c1cc(NC(=O)C2CN(c3ccc(C(F)(F)F)cn3)CCO2)no1
Temperature: 175 °C
Reaction time: 18 h

Procedure:
A microwave vial is charged with morpholine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (75 mg; 0.259 mmol), 2-bromo-5-trifluoromethylpyridine (58.8 mg; 0.26 mmol), triethylamine (0.072 mL; 0.52 mmol) and t-butanol (0.5 mL). The vial is heated in microwave at 175° C. for 1 hour then left standing at room temperature for 18 hours. After this time, the reaction mixture is concentrated in vacuo. Purification by flash chromatography using methanol/methylene chloride provides the title compound, m/z 399 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][OH:9])=[O:5].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].Cl>C(Cl)Cl.C(OCC)(=O)C>[CH3:22][S:23]([O:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:2]=1[F:1])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCCO)c1ccc(F)cc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCNC(=O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a solution of 2,4-difluoro-N-(2-hydroxyethyl)benzamide (299 mg, 1.49 mmol) and triethylamine (302 mg, 2.98 mmol) in CH2Cl2 under nitrogen at 0° C. was added methanesulfonyl chloride (335 mg, 2.98 mmol) The reaction mixture was stirred for 1 h at 0° C. 1 N HCl (5 mL) was added to quench the reaction and the solution was diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 (100 mL) and saturated NaCl (100 mL), dried over MgSO4, filtered and concentrated in vacuo. Purification by column chromatography (hexanes:EtOAc 4:1) yielded 2-[(2,4-difluorobenzoyl)amino]ethyl methanesulfonate (300 mg, 72%) as a clear liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@@H:20]3[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@H:19]3[C@@H:18]([C:26]([NH:28][NH2:29])=[O:27])[O:17]2)=[C:4]([F:32])[CH:3]=1.C(N(C(C)C)CC)(C)C.[C:42](Cl)(=[O:44])[CH3:43]>CN(C=O)C>[C:42]([NH:29][NH:28][C:26]([C@@H:18]1[C@H:19]2[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]2)[C@H:16]([N:11]2[CH:10]=[N:9][C:8]3[C:12]2=[N:13][CH:14]=[N:15][C:7]=3[NH:6][C:5]2[CH:30]=[CH:31][C:2]([Cl:1])=[CH:3][C:4]=2[F:32])[O:17]1)=[O:27])(=[O:44])[CH3:43]
Reactant: CC(=O)Cl
Reactant: CC1(C)O[C@@H]2[C@@H](O1)[C@H](n1cnc3c(Nc4ccc(Cl)cc4F)ncnc31)O[C@@H]2C(=O)NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)[C@H]1O[C@@H](n2cnc3c(Nc4ccc(Cl)cc4F)ncnc32)[C@@H]2OC(C)(C)O[C@H]21
Temperature: 0 °C
Reaction time: 5 h
Yield: 45.8 %

Procedure:
To a stirred solution of (3aR,4S,6R,6aR)-6-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole4-carbohydrazide (50 mg) in N,N′-dimethylformamide (2 ml) at 0° C. was added diisopropylethylamine (28 μl) and acetyl chloride (9 mg). The reaction mixture was stirred at 0 ° C. for 5 h. The mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was washed with brine (20 ml), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by automated preparative HPLC (gradient profile 5-95% (ii) over 18.5 min) to give the title compound (25 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:31]=2)[CH:29]=[O:30])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O>[CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:31]=[C:28]([CH2:29][OH:30])[CH:27]=[N:26][CH:25]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.7 %

Procedure:
To a solution of 5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinaldehyde (30.0 mg, 0.0740 mmol) in methanol (25 mL) was added NaBH4 (8.40 mg, 0.220 mmol). Reaction mixture was stirred at room temperature for 3 h and diluted with cold water (50 mL). The aqueous solution was extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with saturated brain solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a residue which was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 12 g, 40% EtOAc/hexanes) to get (5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)methanol (15.0 mg, 50.0%). LCMS Condition B-12: retention time 2.15 min, [M+1]=406.2. HPLC Condition B-2: retention time 9.20 min, Purity 98.03%. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.64 (d, J=5.7 Hz, 2H), 4.82 (d, J=5.7 Hz, 2H), 5.45 (t, J=5.7 Hz, 1H), 6.64 (t, J=5.2 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 7.22-7.55 (m, 10H), 7.90 (d, J=2.7 Hz, 1H), 8.49 (t, J=2.1 Hz, 1H), 8.59 (d, J=2.0 Hz, 1H), 9.24 (d, J=2.0 Hz, 1H).
Reaction SMILES: CCCCCCCCCCCCCCCC(N[C@H]([C@H](O)/C=C/CCCCCCCCCCC)CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)=O.[CH3:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][C:65]([NH:67][C@H:68]([C@H:82]([OH:96])/[CH:83]=[CH:84]/[CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH3:95])[CH2:69][O:70][C@@H:71]1[O:76][C@H:75]([CH2:77][OH:78])[C@@H:74]([OH:79])[C@H:73]([OH:80])[C@H:72]1[OH:81])=[O:66]>>[CH3:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][C:65]([NH:67][C@H:68]([C@H:82]([OH:96])/[CH:83]=[CH:84]/[CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH3:95])[CH2:69][O:70][C@@H:71]1[O:76][C@H:75]([CH2:77][OH:78])[C@H:74]([OH:79])[C@H:73]([OH:80])[C@H:72]1[OH:81])=[O:66]
Reactant: CCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)NC(=O)CCCCCCCCCCCCCCCCC
Agent: CCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)NC(=O)CCCCCCCCCCCCCCC
Product: CCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)NC(=O)CCCCCCCCCCCCCCCCC

Procedure:
Turbostatins 1 and 2 were obtained in the following order: Turbostatin 1 (10.1 mg) at 20.5 minutes and turbostatin 2 (11.2 mg) at 25.1 minutes. A103-mg fraction with ED50 0.56 μg/mL was separated on a semipreparative reversed-phase HPLC Zorbax SB C18 column with 85:15 CH3OH—H2O (a flow rate of 4 mL/min and the UV detector set at 208 nm). The result was that turbostatin 3 and turbostatin 4 were obtained in the following order: turbostatin 3 at 23.7 minutes and turbostatin 4 (8.3 mg) at 28.5 minutes.
Reaction SMILES: I[C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.O=O.C[Si]([C:16]#[CH:17])(C)C>C(N(CC)CC)C.CN(C=O)C.[Cu]I>[C:16]([C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1)#[CH:17]
Reactant: C#C[Si](C)(C)C
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Agent: [Cu]I
Agent: O=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1c[nH]c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 5-iodouracil (8 g, 30 mmol) in redistilled triethylamine (500 mL) and dry DMF (10 mL) was degassed with oxygen-free nitrogen for 15 minutes. Bis(triphenylophosphine)palladium (II) chloride (0.5 g), copper (I) iodide (0.5 g) and trimethylsilylacetylene (10 g, 102 mmol) were then added and the mixture was heated with stirring at 50° C. for 24 hours. The cooled reaction mixture was filtered, the filtrate evaporated to dryness and the residue dissolved in dichloromethane (500 mL). The organic solution was washed with a 2% aqueous solution of disodium EDTA (3×250 mL), water (3×200 mL), dried (Na2SO4) and evaporated to dryness. The residue was triturated with ethanol to give the first crop of the title compound. The solid filtered from the reaction mixture was also found to contain the required product but in a more impure form and so was worked up as above in a separate batch to give a second crop.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31]Cl)[CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>COC(O)C>[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[NH:9]3)=[CH:4][CH:3]=2)[CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cc(=O)[nH]c2cc(O)ccc12
Reactant: O=C(NC1CCN(CCCCl)CC1)c1ccccc1
Agent: COC(C)O
Product: Cc1cc(=O)[nH]c2cc(OCCCN3CCC(NC(=O)c4ccccc4)CC3)ccc12
Yield: 46 %

Procedure:
In a manner analogous to that described in Example 8, by the reaction of 7-hydroxy-4-methyl-2-oxo-1,2-dihydroquinoline with 3-(4-benzamido-piperidino)-propyl chloride in methoxyethanol, there is obtained, in a yield of 46% of theory, 7-[3-(4-benzamido-piperidino)-propoxy]-4-methyl-2-oxo-1,2-dihydroquinoline; m.p. 275°-276° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][S:14][C:15](SC)=[N:16][C:17]#[N:18].[OH-].[Na+].Cl>C(O)C.O>[C:17]([N:16]=[C:15]([S:14][CH3:13])[NH:12][S:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:10])=[O:11])#[N:18]
Reactant: CSC(=NC#N)SC
Reactant: NS(=O)(=O)c1cc(Cl)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSC(=NC#N)NS(=O)(=O)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Yield: 60.7 %

Procedure:
A solution of 10.6 g (43.2 mmol) of 2,5-dichlorobenzenesulfonamide, 7.15 g (44.0 mmol) of 90 percent dimethyl N-cyanodithioiminocarbonate and 1.8 g (44 mmol) of NaOH in 60 ml of ethanol and 10 ml of H2O was heated at reflux for 6 hours. After cooling to room temperature the reaction mixture was poured into 600 ml of ice water. The resulting solution was acidified with 6N HCl to separate 2.2 g of the desired product as a white solid. Concentration of the filtrate gave an additional 8.5 g of the desired product. The total yield of material was 10.7 g (76 percent) of white solid, mp 145° C. IR and 1H NMR spectra were consistent with the assigned structure.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11](=[O:13])(=[O:12])[N:10]([CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9][CH2:8][C:7]=2[CH:23]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11](=[O:13])(=[O:12])[N:10]([CH2:14][CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:9][CH2:8][C:7]=2[CH:23]=1
Reactant: COc1ccc2c(c1)CCN(CCCc1ccccc1)S2(=O)=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S1(=O)c2ccc(O)cc2CCN1CCCc1ccccc1

Procedure:
6-Methoxy-2-(3-phenylpropyl)-3,4-dihydro-2H-1,2-benzothiazine-1,1-dioxide (1.2 g, 4 mmol) is dissolved in CH2Cl2 (200 mL) and the resulting solution is cooled to -78°. Boron tribromide (1.1 mL, 12 mmol) is then added and the reaction is allowed to come to ambient temperature. After 12 hours the mixture is cooled to 0° and subsequently neturalized with saturated NaHCO3 solution (100 mL). The aqueous phase is then extracted with CH2Cl2 (1×100 mL). The combined organics are washed with saturated NaCl solution (2×200 mL), dried over Na2SO4 and concentrated in vacuo to give 6-hydroxy-2-(3-phenylpropyl)-3,4-dihydro-2H-1,2-benzothiazine-1,1-dioxide.
Reaction SMILES: [I-].C[N+]1C=CN([C:8](/[N:10]=[C:11]2\[S:12][C:13]([CH3:26])=[CH:14][N:15]\2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[O:9])C=1.C(NC(C)C)(C)C.[CH2:34]([NH:41][CH2:42][CH3:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(#N)C>[CH2:34]([N:41]([CH2:42][CH3:43])[C:8](/[N:10]=[C:11]1\[S:12][C:13]([CH3:26])=[CH:14][N:15]\1[C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=1)=[O:9])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)n2cc[n+](C)c2)s1
Reactant: CCNCc1ccccc1
Agent: [I-]
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: CCN(Cc1ccccc1)C(=O)/N=c1\sc(C)cn1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial, a solution of 3-methyl-1-({[(2Z)-5-methyl-3-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-1H-imidazol-3-ium iodide (45 mg, 0.09 mmol, Example 18B) dissolved in acetonitrile (0.6 mL) was added followed by the addition of diisopropylamine (21 μL, 0.12 mmol) dissolved in acetonitrile (0.6 mL). Then to the solution was added N-benzylethanamine (14 mg, 0.1 mmol) dissolved in acetonitrile (0.5 mL). The vial was capped and shaken overnight at room temperature. The reaction was concentrated to dryness. The residue was purified by reverse phase HPLC (C18, gradient 10-95% acetonitrile/water/0.1% trifluoroacetic acid) to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.NC1C=CC(C)=NC=1.N(OCCCC)=[O:18].CCOCC>C(O)C.F[B-](F)(F)F.[H+]>[F:1][C:2]1[CH:7]=[N+:6]([O-:18])[C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cn1
Reactant: CCCCON=O
Agent: Cc1ccc(N)cn1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccc(F)c[n+]1[O-]
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Preparation of 5-fluoro-2-picoline was based on E. J. Blanz, F. A. French, J. R. DoAmaral and D. A. French, J. Med. Chem. 1970, 13, 1124–1130. 5-Amino-2-picoline (12.5 g) in ethanol (105 ml) and 50% fluoroboric acid (44.5 ml) was stirred at −5° C. and treated dropwise over 45 mins. with n-butyl nitrite (31.25 ml). The solution was maintained at this temp. for 3 hours, treated with ether (100 ml, precooled to −20° C.) and the solid filtered off, quickly transferred to a flask and covered with hexane (precooled to −20° C.). After allowing to warm to approx. 20° C. and standing for 3 days the hexane was decanted and 2M NaOH solution added until basic (pH10). The mixture was filtered and the filtrate extracted with dichloromethane (10×200 ml). The organic solution was dried, evaporated to 200 ml and treated with m-chloroperbenzoic acid (26.5 g). After stirring 16 hours the solution was washed with excess aqueous sodium bicarbonate and the aqueous re-extracted with dichloromethane (10×200 ml). The organic fraction was dried and evaporated and the residue chromatographed (15% EtOH/EtOAc) to give the product (5.5 g).
Reaction SMILES: [NH:1]([C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:35][C:32]1[CH:31]=[CH:30][C:29]([N:26]2[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][CH2:20][N:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[S:10](=[O:18])(=[O:17])[N:9]=3)[CH2:28][CH2:27]2)=[CH:34][CH:33]=1
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Reactant: O=S1(=O)N=C(Nc2ccccc2)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Product: O=S1(=O)N=C(N(CCCN2CCN(c3ccc(F)cc3)CC2)c2ccccc2)c2ccccc21
Temperature: 20 °C
Yield: 24.3 %

Procedure:
A mixture of 2.2 g of 3-anilino-1,2-benzisothiazole 1,1-dioxide, 2.1 g of 1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine, 3.4 g of potassium carbonate, 1.1 g of tetrabutylammonium bromide and 25 cm3 of dimethylformamide is refluxed for 24 hours. The mixture is then cooled to a temperature of about 20° C. The filtrate is evaporated to dryness at 40° C. under reduced pressure (10 mm of mercury; 1.35 kPa). The residue is taken up in 20 cm3 of water and extracted with 75 cm3 of dichloromethane. The organic phase thus obtained is dried over anhydrous magnesium-sulphate and evaporated to dryness at 40° C. under reduced pressure (20 mm of mercury; 2.7 kPa). The oil obtained is purified by flash chromatography on a silica column, under a nitrogen stream at moderate pressure (0.1-1.5 bar) with ethyl acetate as eluent. 1.0 g of a beige meringue is obtained which, when recrystallization from 10 cm3 of hot ethanol yields 0.95 g of 3-{{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}phenylamino}-1,2-benzisothiazole 1,1-dioxide; melting point =134° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:26]1[CH:25]=[C:24]([C:23]2[CH2:22][C:21](=[O:37])[NH:20][C:9]3[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:13][C:8]=3[N:7]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)ccc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccccn3)c2)=Nc2cc(OCC(F)(F)F)ccc2N1

Procedure:
The title compound was prepared from [2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example M52) (380 mg, 0.72 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (201 mg).
Reaction SMILES: F[C:2]1(C)[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH2:3]1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N+:8]([C:4]1[CH:3]=[C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1(F)C=CC=C([N+](=O)[O-])C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc([N+](=O)[O-])c2)CC1
Reaction time: 72 h
Yield: 413.6 %

Procedure:
5.0 g (3.54 mmol) of 1-fluoro-3-nitrotoluene, 9.89 g (5.31 mmol) of tert-butyl 1-piperazinecarboxylate and 27.0 g (19.5 mmol) of potassium carbonate are solubilized under an argon atmosphere in DMSO (60 ml), then the reaction medium is taken to 100° C. for 72 hours. The reaction medium is then cooled down using an ice bath then poured into ice-cold water. The product is extracted using 3 times 50 ml of dichloromethane. The organic solution is dried over magnesium sulphate, followed by filtration and concentration under vacuum. Purification on a silica column is then carried out (eluent=heptane 70%/ethyl acetate 30%) in order to produce a yellow solid. The yellow solid is further purified by recrystallization from diisopropyl ether in order to produce 4.5 g of the expected product (yield 42.0%). Melting point: 82.0-92.0° C.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:9])[CH2:6][C:7]#[N:8])[CH3:3].Br.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[O:14].CCN(C(C)C)C(C)C>CCO.C1COCC1>[CH2:2]([O:4][C:5](=[O:9])[CH:6]([C:7]#[N:8])[CH2:12][C:13](=[O:14])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH3:3]
Reactant: O=C(CBr)c1ccncc1
Reactant: CCOC(=O)CC#N
Agent: Br
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)C(C#N)CC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a suspension of sodium metal (81 mg, 3.5 mmol) in 10 mL anhydrous EtOH, ethylcyanoacetate (0.37 mL, 3.5 mmol) was added at 0° C. The solution was stirred until sodium was completely dissolved. The solvent was evaporated to obtain a white solid that was added portionwise to a stirred solution of bromoacetylpyridine 1 (1.0 g, 3.5 mmol) in anhydrous THF (20 mL) and DIEA (0.6 mL, 3.5 mmol). The reaction mixture was stirred overnight at rt. The solvent was removed, the residue was suspended in water and extracted with DCM. The organic extracts were dried over Na2SO4 and concentrated. The crude was purified by flash chromatography (DCM/MeOH 95:5) to give 710 mg (87%) of 2-cyano-4-oxo-4-pyridin-4-yl-butyric acid ethyl ester as a reddish oil.