Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][O:3][CH2:4][C:5]([OH:7])=[O:6].[NH2:8][CH:9]1[CH:12]2[S:13][CH2:14][C:15]3[CH:19](O)[O:18][C:17](=[O:21])[C:16]=3[N:11]2[C:10]1=[O:22]>O>[NH2:8][CH:9]1[C:10](=[O:22])[N:11]2[C:16]([C:17]([OH:21])=[O:18])=[C:15]([CH:19]=[N:2][O:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:14][S:13][C@H:12]12
Reactant: NC1C(=O)N2C3=C(CSC12)C(O)OC3=O
Reactant: NOCC(=O)O
Agent: Cl
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(C=NOCC(=O)O)CS[C@H]12
Reaction time: 8 h

Procedure:
A solution of 1.86 g of the hydrochloride of aminooxyacetic acid in 20 ml of water is treated under stirring at 0° with 3.16 g of the hydrochloride of 6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazin. The mixture is stirred for ca. 8 hours at 0°. 7-Amino-3-[[(carboxymethoxy)imino]methyl]-3-cephem-4-carboxylic acid precipitates in form of colourless crystals, which are filtered off, washed with 5 ml of cold water and 5 ml of acetone and dried.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1.[N:24](/[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[N:25]/[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>C1COCC1.O>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[N:24]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27]
Reactant: CC(C)(C)OC(=O)/N=N\C(=O)OC(C)(C)C
Reactant: Clc1cccc(Br)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1c(Cl)cccc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a stirred solution of 2.5 M Butyllithium in hexanes (13.79 mL, 34.47 mmol) at −20° C. was added dropwise 2,2,6,6-tetramethylpiperidine (5.82 mL, 34.47 mmol) in THF (30 mL). This was stirred for 30 minutes. This solution was cooled down to −78° C., and a solution of 1-bromo-3-chlorobenzene (6 g, 31.34 mmol) in THF (20 mL) was added dropwise so as to maintain the temperature at <−70° C. After 2 hours (Z)-di-tert-butyl diazene-1,2-dicarboxylate (10.82 g, 47.01 mmol) in THF (30 mL) added dropwise at −78° C. Stirred at this temperature for 2 hours, then allowed to warm to room temperature overnight. Water (150 mL) added. The mixture was extracted with EtOAc (2×300 mL). The extracts were combined, washed with brine (100 mL), dried (MgSO4) and reduced go give a residue which was purified by flash silica chromatography, elution gradient 0-10% EtOAc in hexane. Fractions containing suspected product were combined, and reduced to give di-tert-butyl 1-(2-bromo-6-chlorophenyl)hydrazine-1,2-dicarboxylate (9.59 g, 72.5%) 1H NMR (400 MHz, DMSO) δ 1.30-1.50 (18H, s), 7.28 (1H, m), 7.55 (1H, dd), 7.67 (1H, dd), 9.18 (1H, s). m/z (ES+) (M+Na)+=443; HPLC tR=10.76 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH2:10][S:11][CH3:12].[O-]S(C(F)(F)[F:19])(=O)=O.F[N+]1C(C)=CC(C)=CC=1C.CCCCCC>ClCCCl>[CH3:12][S:11][CH:10]([F:19])[C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:13]
Reactant: CSCC(=O)c1ccc(F)cc1F
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: Cc1cc(C)[n+](F)c(C)c1
Solvent: CCCCCC
Solvent: ClCCCl
Product: CSC(F)C(=O)c1ccc(F)cc1F
Reaction time: 12 h
Yield: 90.8 %

Procedure:
To a 20 ml solution of 0.5 g (2.5 mmol) of 2',4'-difluoro-2-(methylthio)acetophenone [Compound (2a-1)] in 1,2-dichloroethane, 1.1 g (3.8 mmol) of N-fluoro-2,4,6-trimethylpyridinium triflate ("Onoda Florinate FP-T300", trade name; product of Chichibu Onoda Co., Ltd.) were added at room temperature, followed by stirring at the same temperature for 12 hours. The reaction mixture was added to n-hexane. The insoluble matter so precipitated was filtered off. The insoluble matter was then washed with ethyl ether, followed by combination with the hexane layer. The layers so combined were washed successively with water and saturated saline, followed by drying over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, whereby 0.50 g of the title Compound (2b-1) was obtained in the form of a light yellow oil (yield: 91.7%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.C(O)C>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:5][N:6]=1
Reactant: ClCc1ccccc1
Reactant: Nc1nnc(S)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nnc(SCc2ccccc2)s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
In a mixture of 40 ml of water and 45 ml of ethanol, 21.1 g of 2-amino-5-mercapto-1,3,4-thiadiazole and 6.9 g of sodium hydroxide were dissolved. To this solution, 19.6 g of benzyl chloride was added, and the mixture was stirred at 50° C. for 1 hour. After cooling, water was added to the reaction mixture, the formed precipitate was separated by filtration and washed with water and an ethanol/n-hexane (1:1) mixture respectively. The thus treated precipitate was dried under reduced pressure, and thus 32.5 g of 2-amino-5-benzylthio-1,3,4-thiadiazole was obtained. m.p. 159°-161° C. Yield 94%.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10]O.CS(OS(C)(=O)=O)(=O)=O.CCN(C(C)C)C(C)C.[N:30]1([C:36]2[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=2[C:38]#[N:39])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][N:33]1[CH2:32][CH2:31][N:30]([C:36]2[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=2[C:38]#[N:39])[CH2:35][CH2:34]1
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: OCc1cc2ccccc2s1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccccc1N1CCN(Cc2cc3ccccc3s2)CC1

Procedure:
The product from Example 8A (150 mg 0.9 mmol), methane sulfonic anhydride (159 mg, 0.9 mmol), and DIEA (475 μL 2.7 mmol) were combined. After stirring, 2-(1-piperazinyl)benzonitrile (181 mg, 1.0 mmol) in 2 ml DCM was also combined and stirred at room temperature for 18 hours. The mixture was concentrated and the residue was taken up in hot methanol. The methanol was filtered and the filter cake washed with cold methanol to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 2.69 (m, 4H) 3.04 (s, 4H) 3.76 (m, 4H) 3.86 (s, 1H) 6.74 (m, 2H) 7.29 (m, 3H) 7.75 (m, 1H); (ESI) m/z 334 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1/[CH:14]=[CH:15]/[C:16]1[N:17]=[C:18]2[S:25][CH:24]=[CH:23][N:19]2[C:20](=[O:22])[CH:21]=1)[CH:2]([CH3:4])[CH3:3].[I:26]N1C(=O)CCC1=O>C(#N)C>[I:26][C:21]1[C:20](=[O:22])[N:19]2[CH:23]=[CH:24][S:25][C:18]2=[N:17][C:16]=1/[CH:15]=[CH:14]/[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:6]=1[O:5][CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cccc(/C=C/c2cc(=O)n3ccsc3n2)c1OCC(C)C
Solvent: CC#N
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC(C)C

Procedure:
A solution of Step 1 intermediate (600 mg, 1.683 mmol) was treated with N-iodosuccinimide (416 g, 1.851 mmol) in acetonitrile (10 ml) according to the procedure described in Step 4 of Intermediate 2 to afford 600 mg of the desired compound as a yellow solid; 1H NMR (300 MHz, DMSO-d6) 1.05 (d, J=6.9 Hz, 6H), 2.04-2.08 (m, 1H), 3.71 (d, J=6.3 Hz, 2H), 3.81 (s, 3H), 7.10-7.12 (m, 2H), 7.27-7.30 (m, 1H), 7.48-7.53 (m, 2H), 7.96 (d, J=4.8 Hz, 1H), 8.17 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 483.16 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.O.[NH2:27][NH2:28]>CCO>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:5]=3)=[CH:15][CH:14]=2)[NH:28][N:27]=1
Reactant: N#Cc1ccc(-c2cc(NCCc3ccccc3)nc(N)n2)cc1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1nc(NCCc2ccccc2)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of 4-{2-amino-6-[(2-phenylethyl)amino]-4-pyrimidinyl}-2-fluorobenzonitrile (800 mg, 2.4 mmol) in EtOH (20 mL) was added hydrazine monohydrate (7 mL), and the resulting suspension was stirred overnight at 95° C. The clear reaction mixture was concentrated, and the resulting residue was purified by RPHPLC (CH3CN/H2O w/0.1% THF) to afford the title compound (500 mg, 42%) as a light yellow powder. LC-MS (ES) m/z=346 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.85 (t, J=7.2 Hz, 2H), 3.53 (m, 2H), 5.37 (s, 2H), 6.02 (s, 2H), 6.28 (s, 1H), 6.94 (s, 1H), 7.18-7.23 (m, 1H), 7.28-7.33 (m, 4H), 7.42 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.85 (s, 1H), 11.5 (s, 1H).
Reaction SMILES: B(Br)(Br)[Br:2].C[O:6][C:7]1[CH:27]=[CH:26][C:10]2[CH:11]([CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[CH2:14][CH2:15][C:9]=2[CH:8]=1.O>ClCCl>[BrH:2].[CH3:25][N:23]([CH3:24])[CH2:22][CH2:21][CH2:20][CH:11]1[C:10]2[CH:26]=[CH:27][C:7]([OH:6])=[CH:8][C:9]=2[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=2
Reactant: COc1ccc2c(c1)CCc1ccccc1C2CCCN(C)C
Reactant: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Br
Product: CN(C)CCCC1c2ccccc2CCc2cc(O)ccc21
Temperature: 24.5 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To 35 ml of freshly distilled dichloromethane was added 1.98 ml of boron tribromide. The reaction mixture was placed in a water bath. To the reaction mixture was added a solution of 1.1 g (3.5 mmol) of 5 in 15 ml of dichloromethane dropwise. The mixture was allowed to stir at room temperature (23-26° C.) for 30 minutes and poured into 50 g of ice/water. An additional 50 ml of water was added and extracted with 3×100 ml of chloroform. The combined organic layer was dried (Na2SO4) and concentrated to give 1.2 g (3.18 mmol, 90%) of 6 as an off-white solid.
Reaction SMILES: C(O[C:6]1[C:11]([F:12])=[CH:10][N:9]=[C:8]([CH:13]2[CH2:15][CH:14]2[CH2:16][C:17]#[N:18])[C:7]=1[CH3:19])(C)(C)C.O=P(Cl)(Cl)[Cl:22]>FC(F)(F)C(O)=O>[Cl:22][C:6]1[C:11]([F:12])=[CH:10][N:9]=[C:8]([CH:13]2[CH2:15][CH:14]2[CH2:16][C:17]#[N:18])[C:7]=1[CH3:19]
Reactant: Cc1c(C2CC2CC#N)ncc(F)c1OC(C)(C)C
Reactant: O=P(Cl)(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2CC2CC#N)ncc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
A sample of 2-(4-t-butoxy-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetonitrile (5.21 g, 19.86 mmol) was dissolved in 50 mL of trifluoroacetic acid, the reaction was stirred under nitrogen for 1 hour at ambient temperature, and the material concentrated to dryness. The residue was dissolved in a mixture of 15.6 mL of DMF and 90 mL of methylene chloride. This solution was cooled in a water bath as 18.8 mL (19.86 mmol) of POCl3 was added, then the reaction was stirred at ambient temperature for 16 hours. The reaction was quenched by pouring it into ice water, and the mixture was extracted with methylene chloride. The aqueous solution was adjusted to pH7 with NaOH and re-extracted with methylene chloride. The extracts were combined and washed with water, dried over MgSO4 and concentrated. The residue was purified by flash chromatography with 1:4 ethyl acetate:hexane to give 3.26 g of 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetonitrile as a colorless liquid after removal of the solvents. MS 225, 227 (M+H)+ ; 1H NMR (CDCl3)∂: 0.48 (m, 1H), 0.59 (m, 1H), 0.66 (m, 1H), 0.77 (m, 1H), 1.50 (m, 1H), 2.48 (s, 3H), 3.80 (d, 1H, J=8 Hz), 8.39 (s, 1H). IR (neat) 2240, 1570, 1460 cm-l.
Reaction SMILES: [CH:1]12[CH2:13][CH:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=31)[CH2:5][CH2:4][NH:3][CH2:2]2.[CH2:14]=O.[OH-].[Na+]>C(O)=O>[CH3:14][N:3]1[CH2:4][CH2:5][CH:6]2[CH2:13][CH:1]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=32)[CH2:2]1
Reactant: c1ccc2c(c1)C1CCNCC2C1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN1CCC2CC(C1)c1ccccc12
Yield: 68 %

Procedure:
To a 10 ml round bottom flask were added 1.50 g (0.00867 ) of 1,2,3,4,5,6-hexahydro-1,6-methano-3-benzazocine, 2ml of formic acid and 2 ml of 40% formaldehyde. The mixture was heated at 95-105° for 3 hours, cooled, 60 ml of 15% sodium hydroxide added, and the aqueous layer extracted with four 60-ml portions of methylene chloride. The combined extracts were concentrated in vacuo in the presence of benzene to remove water. The residue, 1.55 g (0.00829 mol), was distilled (90°-115° bath temperature, 0.1 mm) to give colorless 3-methyl-1,2,3,4,5,6-hexahydro-1,6-methano-3-benzazocine (1.1g, 68% yield). The amine was dissolved in ether and hydrogen chloride gas passed into the solution. The white precipitate obtained was filtered and recrystallized from acetone-ether: m.p. 215°-216° (d); m/e 187 (M+ -HCl).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][CH:11]([OH:17])[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11](=[O:17])[CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CCC(O)CN(C)C(=O)OC(C)(C)C
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)CCC(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a solution of 1-(N-t-butoxycarbonyl-N-methylamino)2-hydroxy-5-methylhexane (2.45 g) and triethylamine (3.03 g) in dimethyl sulfoxide (20 ml) was added sulfur trioxide pyridine complex (4.77 g) under ice-bath cooling. After the mixture was stirred at ambient temperature overnight, the reaction mixture was poured into ice-water (100 ml). The mixture was extracted with diethyl ether (100 ml×2). The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (20% ethyl acetate in n-hexane as eluent) to give 1-(N-t-butoxycarbonyl-N-methylamino)-2-oxo-5-methylhexane (2.15 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[CH:20][CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:29]4[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=4)=[CH:20][CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(Br)c2n1C
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(-c3ccc(C#N)cc3)c2n1C
Temperature: 140 °C
Yield: 33.8 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-1-methyl-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile (100 mg, 0.27 mmol), 4-cyanobenzeneboronic acid (51 mg, 0.35 mmol), Pd(PPh3)4 (31 mg, 0.03 mmol) and Cs2CO3 (175 mg, 0.54 mmol) in dioxane (3 mL) and H2O (1.5 mL) was heated for 30 min by microwave irradiation at 140° C. The reaction solution was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH, followed by 2M NH3 in MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was dissolved in DCM and the fine precipitate filtered and washed with DCM. The filtrate was concentrated in vacuo and purified by column chromatography (Si—PPC, gradient 0-10% 2M NH3 in MeOH/DCM) to afford 423 as a white solid (36 mg, 34%). LCMS (Method K): RT 2.30 min [M+H]+ 395. 1H NMR (DMSO-d6, 400 MHz): δ 8.04 (1H, s), 7.96-7.94 (2H, m), 7.72-7.67 (4H, m), 7.32 (2H, bs), 7.27, (1H, dd, J=8.0, 7.5 Hz), 7.07 (1H, dd, J=7.5, 1.0 Hz), 5.66 (1H, dq, J=7.0, 7.0 Hz), 3.28 (3H, s), 1.60 (3H, d, J=7.0 Hz)
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:36])[C:20]=1[NH:21][C:22]1[C:31]2[C:26](=[C:27]([OH:34])[C:28]([O:32][CH3:33])=[CH:29][CH:30]=2)[O:25][C:24](=[O:35])[CH:23]=1>>[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:36])[C:20]=1[NH:21][C:22]1[C:31]2[C:26](=[C:27]([O:34][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:2]([CH3:3])[CH3:1])[C:28]([O:32][CH3:33])=[CH:29][CH:30]=2)[O:25][C:24](=[O:35])[CH:23]=1
Reactant: CNC
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: BrCCCCCCCCBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCCCCN(C)C

Procedure:
The title compound was prepared from dimethylamine, 1,8-dibromooctane, and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedures outlined in Examples 25 & 27. 1H NMR (400 MHz, DMSO-d6): δ 9.38 (br s, 1H), 8.59 (s, 2H), 7.85 (d, 1H), 7.05 (d, 1H), 4.26 (br s, 1H), 3.95 (t, 2H), 3.87 (s, 3H), 2.50 (br, 2H), 2.34 (s, 6H), 1.67 (m, 2H), 1.45 (m, 4H), 1.28 (m, 6H); MS (ESI): 508.0.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([B:7]([OH:9])[OH:8])=[CH:3][CH:2]=1.O[CH2:12][C:13]([CH3:17])([CH2:15]O)[CH3:14].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1CCCCC1>[CH2:12]([O:8][B:7]([C:4]1[CH:5]=[CH:6][C:1]([CH2:10][Br:18])=[CH:2][CH:3]=1)[OH:9])[C:13]([CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(CO)CO
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: C1CCCCC1
Product: CC(C)(C)COB(O)c1ccc(CBr)cc1
Temperature: 25 °C

Procedure:
p-Toluene boronic acid (750 mg.) and neopentyl glycol (600 mg.) were dissolved in 50 ml cyclohexane and heated at reflux for 1.5 hours. N-Bromosuccinimide (1.15 g.), benzoyl peroxide (25 mg.) and 150 ml cyclohexane were added and the solution was heated at reflux for additional 2 hours. The solution was cooled to room temperature, filtered and evaporated to give a mixture of 8 and 8a (total of 1.3 g, ˜1:1 ratio), the yield of 8=47%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5][Cl:6])[CH3:2].[CH3:8][CH2:9][O-:10].[Na+].[CH2:12]([OH:14])C>>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][C:12]([O:10][CH2:9][CH3:8])=[O:14])[CH3:2].[CH2:1]([O:3][C:4](=[O:7])[CH2:5][Cl:6])[CH3:2].[CH2:1]([O:3][C:4](=[O:7])[CH3:5])[CH3:2]
Reactant: CCO
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CCl
Product: CCOC(=O)CC(=O)OCC
Product: CCOC(C)=O
Yield: 1.6 %
Yield: 95 %

Procedure:
As in Example 1, but at 7.5 at. CO and a pH of 6.0, 490 g (4 moles) of chloroacetic acid ethyl ester is reacted with 1.38 kg of 15.8% sodium ethylate (3.2 moles) in ethanol, for 6 hours. Processing the reaction mixture yields 490 g of malonic acid diethyl ester (95% yield), 4.4 g of acetic acid ethyl ester (1.6% yield), 5.9 g of residue, and 98 g of chloroacetic acid ethyl ester.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH:34]=2)=[CH:29][CH:28]=1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2ccc(F)cc2)CC1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (100 g), triethylamine (50 cc) and 4-(4-fluorophenyl) 1,2,3,6-tetrahydropyridine (77.9 in toluene (950 cc). The mixture is heated for 7 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 8 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, 2-{3-[4-(4-fluorophenyl)-1,2,3,6-tetrahydro-l-pyridyl]propyl}-naphtho[1,8-cd]isothiazole 1,1-dioxide (105.4 g) is obtained in the form of a brown oil [Rf=0.8; thin-layer chromatography on silica gel; eluant: ethyl acetate]. This oil is converted to the hydrochloride, m.p. 224° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.II.C(N(CC)CC)C.[S:18](=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]12[S:18][CH:3]1[CH:4]1[S:8][CH:5]1[CH:6]=[CH:7]2
Reactant: Sc1ccc(Br)cc1
Reactant: O=S([O-])O
Agent: II
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: BrC12C=CC3SC3C1S2
Reaction time: 1 h

Procedure:
To a solution of 4-bromothiophenol (16 g, 85 mmol) in CH2Cl2 (85 mL) was added iodine (10.7 g, 42 mmol, in CH2Cl2) and triethylamine (11.8 mL, 85 mmol). After 3 h the resulting reaction mixture was diluted with a sodium bisulfite solution and ethyl acetate. The organic extracts were washed (1N NaOH, brine), dried (MgSO4), filtered and concentrated. The resulting residue was stirred vigorously in hexane/ether for 1 h then filtered to afford the 4-bromobenzene disulfide compound as a white powder.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]3[N:16]([C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]4)[N:19]=2)[CH:15]=[CH:14][S:13]3)[CH:7]=[CH:8][CH:9]=1.CCN(C(C)C)C(C)C.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>C(Cl)Cl>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([N:27]2[CH2:28][CH2:29][CH2:30][C@@H:25]([NH:24][C:20]3[N:19]=[C:18]([C:17]4[N:16]5[C:12]([S:13][CH:14]=[CH:15]5)=[N:11][C:10]=4[C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=4)[CH:23]=[CH:22][N:21]=3)[CH2:26]2)(=[O:49])=[O:48])=[CH:43][CH:42]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCNC3)n2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
The 4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine hydrochloride (6.81 g, 14.2 mmol) in methylene chloride (DCM) (60 ml) is cooled to 0° C. and is treated with Hunig's base (9.9 ml, 56.8 mmol). The mixture is kept at 0° C. for 30 minutes then the 4-chlorophenylsulfonyl chloride (3.3 g, 15.6 mmol) is added. The reaction mixture is stirred at room temperature overnight. The mixture is diluted with methylene chloride (100 ml) and is washed water (100 ml) and a saturated aqueous sodium chloride solution (100 ml). The organic phase is dried over sodium sulfate and concentrated in vacuo. The crude product is purified by flash chromatography using a gradient (ethyl acetate/hexanes, 40-100%), affording 6.98 g (85%) of the title compound as a pale yellow solid. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.42 (br. s, 1H), 8.12 (d, J=5.1 Hz, 1H), 7.8-7.75 (m, 2H), 7.7-7.65 (m, 2H), 7.43-7.39 (m, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.18-7.1 (m, 2H), 7.05-6.98 (m, 1H), 6.42 (d, J=5.1 Hz, 1H), 4.0-3.9 (m, 1H), 3.78 (s, 3H), 3.74 (d, J=11.7 Hz, 1H), 3.48 (d, J=11.7 Hz, 1H), 2.5-2.4 (m, 1H), 2.33 (t, J=5.3 Hz, 1H), 1.95-1.8 (m, 2H), 1.65-1.5 (m, 1H), 1.45-1.4 (m, 1H). LCMS: 581 [M+H].