Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4]1.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[CH2:27]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[CH2:27][O:14][C:11]1[CH:12]=[CH:13][C:8]([N:3]2[CH:4]=[CH:5][CH:6]=[CH:7]2)=[CH:9][CH:10]=1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(-n2cccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(-n2cccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a 25 mL vial which contained a suspension of NaH (60% in mineral oil, 60 mg, 1.5 mmol) in DMF (5 mL) was added 4-Pyrrol-1-yl-phenol (160 mg, 1 mmol) at 0° C. The mixture was allowed to warm to rt and stir at rt for 30 min then cooled to 0° C. To this reaction mixture was added (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (355 mg, 1 mmol) at 0° C. The resulting mixture was allowed to warm to rt and stir at rt for 30 min and then was heated to 90° C. and stirred at 90° C. for 16 h. After cooled to rt, the mixture was poured into 150 mL ice-water solution and then was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (3×50 mL) and brine (30 mL), dried over Na2SO4. After concentrated in vacuo, the residue was purified by a column chromatography on silica gel eluting with ethyl ethyl acetate:hexane (1:10-1:4) to yield the title compound (270 mg, 80%); LCMS; m/z (ESI+ 243.3, M+1); 99%;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:27]3[C:13](=[CH:14][C:15]4[O:16][CH2:17][CH2:18][CH2:19]S[CH2:21][CH2:22][CH2:23][O:24][C:25]=4[CH:26]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.O[O:29][S:30]([O-:32])=O.[K+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:27]3[C:13](=[CH:14][C:15]4[O:16][CH2:17][CH2:18][CH2:19][S:30](=[O:32])(=[O:29])[CH2:21][CH2:22][CH2:23][O:24][C:25]=4[CH:26]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: Brc1cccc(Nc2ncnc3cc4c(cc23)OCCCSCCCO4)c1
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=S1(=O)CCCOc2cc3ncnc(Nc4cccc(Br)c4)c3cc2OCCC1
Reaction time: 4 h

Procedure:
(3-Bromo-phenyl)-(2,10-dioxa-6-thia-14,16-diaza-tricyclo[9.8.0.013,18]nonadeca-1(11),12,14,16,18-pentaen-17-yl)-amine (21, 17.8 mg, 0.04 mmol) was suspended in MeOH, to which was added a cloudy aqueous solution of oxone (monopersulfate compound) (73 mg, 0.12 mmol) at room temperature. The suspension was stirred and monitored by TLC which indicated that the reaction was completed in 4 h. The reaction mixture was poured into H2O (10 mL), and extracted with EtOAc (3×15 mL). The organic layers were collected, dried and concentrated to give a pale yellow residue which was recrystalized from EtOAc to give the product as an off-white solid: 8 mg (42%). 1H NMR (CD3OD) δ 8.58 (s, 1H), 8.16 (s,1H), 8.11 (s, 1H), 7.81 (d, 1H), 7.72 (d, 1H), 7.48 (d, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 4.35 (t, 4H), 3.70 (t, 2H), 3.40 (t, 2H), 2.40 (m, 2H), 2.15 (m, 2H); ES-MS m/z 478 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][CH:13]=[C:7]2[C:8]([NH:10][C:11](=[O:12])[C:6]=12)=[O:9].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(OCC)C>[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH:18]1[CH2:2][CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][CH:13]=[C:7]2[C:8]([NH:10][C:11](=[O:12])[C:6]=12)=[O:9]
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Reactant: CN1CCNCC1
Solvent: CCOCC
Product: CN1CCNCC1CCCc1cccc2c1C(=O)NC2=O

Procedure:
3-Bromopropylphthalimide (536 mg; 2.0 mmoles) and N-methylpiperazine (0.44 ml; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][NH2:10]>>[CH3:9][NH:10][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=Cc1ccccn1
Reactant: CN
Product: CNCc1ccccn1

Procedure:
Scheme III illustrates the preparation of the preferred intermediate (14) useful for reaction with 3 to provide 2. 2-Picolinaldehyde (10) is reacted with methylamine, followed by hydrogenation, to provide 2-(N-methyl)aminomethylpyridine (11). Reaction of 11 with the methyl or benzyl ester of N-phenoxycarbonyl-L-valine (12) provides 13. Hydrolysis (R=Me) or hydrogenation (R=benzyl) of 13 provides 14.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[F:7][C:8]1[N:13]=[C:12]([O:14][CH3:15])[C:11](B(O)O)=[CH:10][CH:9]=1.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([S:30]([NH:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][N:35]=3)(=[O:32])=[O:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22][N:21]=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.O1CCOCC1>[F:7][C:8]1[N:13]=[C:12]([O:14][CH3:15])[C:11]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([S:30]([NH:33][C:34]4[CH:39]=[CH:38][N:37]=[CH:36][N:35]=4)(=[O:31])=[O:32])=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)=[CH:10][CH:9]=1
Reactant: COc1nc(F)ccc1B(O)O
Reactant: O=S(=O)(Nc1ccncn1)c1ccc2c(Cl)nccc2c1
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: [Na+]
Solvent: C1COCCO1
Product: COc1nc(F)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Yield: 40 %

Procedure:
To a microwave vial containing Na2CO3 (1.216 ml, 2.432 mmol), (6-fluoro-2-methoxypyridin-3-yl)boronic acid (0.166 g, 0.973 mmol) and 1-chloro-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.26 g, 0.811 mmol) and Dioxane (4.05 ml) was added tetrakis(triphenylphosphine)palladium (0.094 g, 0.081 mmol) and purged with nitrogen and irradiated at 100° C. for 30 min. The reaction mixture was diluted with DMSO to dissolve the observed yellow ppt. Purification was done on reverse phase HPLC with 0.1% NH4OH in ACN and water as mobile phase to obtain 1-(6-fluoro-2-methoxypyridin-3-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (133.2 mg, 0.324 mmol, 39.9% yield) as yellow solid; m/z (ESI) 412.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11](Br)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[S:28][CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:24]3[CH:25]=[CH:26][C:27]([S:28][CH3:29])=[C:22]([F:21])[CH:23]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ccc(B(O)O)cc1F
Reactant: CC(C)COc1c(Br)cnn(-c2cccc(Cl)c2)c1=O
Product: CSc1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2OCC(C)C)cc1F

Procedure:
The title compound was prepared according to the method of Example 6, starting with 2-(3-chlorophenyl)-4-(2-methylpropoxy)-5-bromo-3(2H)-pyridazinone in place of 2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone and substituting 3-fluoro-4-(methylthio)benzeneboronic acid (Example 72D) in place of 4-fluorobenzeneboronic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:30][C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][N:32]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][N:19]([S:22]([CH2:25][CH2:26][CH2:27]Cl)(=[O:24])=[O:23])[CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:29])=[N:6][CH:7]=1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[C:3]([NH:30][C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][N:32]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][N:19]([S:22]([CH2:25][CH2:26][CH2:27][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)(=[O:24])=[O:23])[CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:29])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(S(=O)(=O)CCCCl)CC4)cc3C)ncc2Cl)n[nH]1
Reactant: C1COCCN1
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(S(=O)(=O)CCCN5CCOCC5)CC4)cc3C)ncc2Cl)n[nH]1

Procedure:
The product from Step 1 was stirred in neat morpholine (0.5 mL) at 100° C. in a sealed vial for one hour. The reaction was purified by RP-HPLC to give 5-Chloro-N2-(2,5-dimethyl-4-(1-(3-morpholinopropylsulfonyl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white powder; ESMS m/z 603.2 (M+H+).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][S:10](Cl)(=[O:12])=[O:11].[C:14]1([C:20]2[S:24][C:23]([S:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][C@@H:29]3[C:34]([NH:36][O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)=[O:35])(=[O:27])=[O:26])=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:14]1([C:20]2[S:24][C:23]([S:25]([N:28]3[CH2:33][CH2:32][N:31]([S:10]([CH2:9][CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=4)(=[O:12])=[O:11])[CH2:30][C@@H:29]3[C:34]([NH:36][O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)=[O:35])(=[O:26])=[O:27])=[CH:22][CH:21]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(NOC1CCCCO1)[C@H]1CNCCN1S(=O)(=O)c1ccc(-c2ccccc2)s1
Reactant: O=S(=O)(Cl)CCc1ccccn1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NOC1CCCCO1)[C@H]1CN(S(=O)(=O)CCc2ccccn2)CCN1S(=O)(=O)c1ccc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
2-(2-Pyridyl)ethanesulfonyl chloride hydrochloride (214 mg) was added to a solution of (2R)-1-(5-phenylthiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (200 mg) and triethylamine (188 mg) in CHCl3 (3 ml) with cooling on an ice bath. The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo, and the residue was purified by SiO2 column chromatography eluted with MeOH in CHCl3 (1%) to give 184 mg of (2R)-1-(5-phenylthiophene-2-sulfonyl)-4-[2-(2-pyridyl)ethanesulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide as an amorphous powder.
Reaction SMILES: C(OC(=O)C1C=CC(N[C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=CC=1)C.ClC1C=CC(C2N(C(C3CCCCC3)C(NC[C@H]3CC[C@H](C(O)=O)CC3)=O)C3C=CC(F)=CC=3N=2)=CC=1.[CH2:77]([O:79][C:80](=[O:89])[CH2:81][C:82]1[CH:87]=[CH:86][C:85]([NH2:88])=[CH:84][CH:83]=1)[CH3:78].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:77]([O:79][C:80](=[O:89])[CH2:81][C:82]1[CH:83]=[CH:84][C:85]([NH:88][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:86][CH:87]=1)[CH3:78]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)ccc21
Product: CCOC(=O)Cc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Yield: 82 %

Procedure:
This compound was synthesized in analogy to example 22, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid (example 20, intermediate c), (4-amino-phenyl)-acetic acid ethyl ester and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate to give the desired compound as a yellow foam (82%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:23]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Br:23])=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)ncn1Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: O=c1c(Br)c(OCc2ccccc2)ncn1Cc1ccccc1
Temperature: 0 °C

Procedure:
3-benzyl-6-(benzyloxy)-pyrimidin-4(3H)-one (from Step 1) (5.00 g, 17.1 mmol) and N-bromosuccinimide (3.15 g, 17.7 mmol) are strirred in 100 ml anhydrous dimethylformamide for 20 hours. The solution is poured onto 1 L of ice with stirring and allowed to come to room temperature, when the product is collected by filtration. (5.97 g). The product is recrystalized from 60 mL hot acetonitrile (4.75 g, 75%) 1H-NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.28–7.44 (overlapping m, 9H), 7.24 (s, 1H), 5.43 (s, 2H), 5.12 (s, 2H). LC/MS tr=5.89 minutes (0–95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 254 nm, at 50° C.) ES-MS m/z 371 (M+H). HRMS m/z 371 (M+H) 371.0399, calc. 371.0395.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20]>N1C=CC=CC=1>[C:19]([O:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:19](=[O:20])[C:18]([CH3:23])([CH3:22])[CH3:17])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)(=[O:20])[C:18]([CH3:23])([CH3:22])[CH3:17]
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)c2ccc(OC(=O)C(C)(C)C)cc2)cc1

Procedure:
A solution of 10 g of 4,4'dihydroxybenzophenone in pyridine (40 ml) was treated with trimethylacetyl chloride and refluxed for 5 hours. The resultant solution was concentrated under reduced pressure and ETOAc added. The organic layer was washed with H2O, 5% aq. K2CO3, 1% aq. NaOH and dried over MgSO4 and concentrated to give approximately 13 g of a beige solid which was further chromatographed using 7/93 ethyl acetate-toluene to yield 2.83 g (20%) of the monoester (a) and 3.42 g (19%) (b) of the title compound; M.P.=166°-167° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[N:12]=[C:11]([CH2:13][C:14]([O:16]C(C)C)=[O:15])[O:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.OS(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[O:10][N:9]=2)=[O:7])=[CH:20][CH:21]=1
Reactant: CC(C)OC(=O)Cc1nc(C(=O)c2ccc(Cl)cc2)no1
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1nc(C(=O)c2ccc(Cl)cc2)no1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.8 %

Procedure:
To a flask containing 5.2 g of isopropyl [3-(4-chlorobenzoyl)-1,2,4-oxadiazol-5-yl]acetate was added 35 ml of cold concentrated H2SO4. The resulting mixture was stirred and swirled for 15 minutes. The resulting solution was poured slowly into mechanically stirred ice water to precipitate the product. The solid was collected by filtration, washed with excess water and dried under vacuum for 48 hours at room temperature to give 3.9 g of a solid. Recrystallization from acetone/hexane gave 2.5 g (56%) of a solid, m.p. 136°-137°.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:5]2[C:10]3[N:11]=[C:12]([NH2:14])[S:13][C:9]=3[CH2:8][CH2:7][C:6]=12.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28]([NH:14][C:12]1[S:13][C:9]2[CH2:8][CH2:7][C:6]3=[C:2]([Cl:1])[S:3][C:4]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:5]3[C:10]=2[N:11]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)c1sc(Cl)c2c1-c1nc(N)sc1CC2
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1nc2c(s1)CCc1c(Cl)sc(S(C)(=O)=O)c1-2

Procedure:
The title compound was prepared from 6-chloro-8-(methylsulfonyl)-4,5-dihydrothieno[3,4-e][1,3]benzothiazol-2-amine (61 mg, synthesized according to METHOD I from 1-chloro-3-(methylsulfonyl)-4,5,6,7-tetrahydrobenzo-[c]thiophen-4-one) and 2,4-dichloro-6-methylbenzenesulfonyl chloride (54 mg) as described in the synthetic METHOD A to give a white solid (5.9 mg) with a purity >90%: MS-ES (pos) m/z 543.1.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.BrC1C=CC(N[C:19]2[C:28]3[C:23](=[CH:24][C:25](O)=[C:26](OC)[CH:27]=3)[N:22]=[CH:21][N:20]=2)=C(F)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CNCCCO>C(Cl)Cl>[N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[N:20][CH:21]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: CNCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: c1ccc2ncncc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 169 %

Procedure:
Diethyl azodicarboxylate (522 mg, 3 mmol) was added dropwise to a suspension of 4-(4-bromo-2-fluoroanilino)7-hydroxy-6-methoxyquinazoline (364 mg, 1 mmol), (prepared as described for the starting material in Example 48), triphenylphosphine (786 mg, 3 mmol) and 3-methylamino-1-propanol (178 mg, 2 mmol), (J. Am. Chem. Soc., 1954, 76, 2789), in methylene chloride (4 ml) under nitrogen. The mixture was stirred for 1 hour at ambient temperature, neutral alumina (−20 g) was added to the reaction mixture and the solvent was removed by evaporation. The powder was poured onto a column of neutral alumina and was eluted with a mixture of methylene chloride/methanol (95/5 followed by 90/10 and 80/20). The purified product was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)6-methoxy-73-methylaminopropoxy)quinazoline (220 mg, 50%).
Reaction SMILES: [NH2:1][C@H:2]([CH:10]=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:12](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[CH2:13][C:14](O)=[O:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.ClCCl>[NH2:1][C@H:2]([C:10]([NH:12][CH2:13][CH:14]=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: N[C@H](C=O)Cc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N[C@@H](Cc1ccccc1)C(=O)NCC=O

Procedure:
Similar to comparative example 4, CTC-Phe-H was synthesized by the solid phase reaction method using CTC as a solid phase carrier. Then, to dichloromethane (2 ml) were added CTC-Phe-H (110 mg (0.145 mmol)), Fmoc-Gly-OH (120 mg (0.4 mmol)), HBTU (165 mg (0.4 mmol)), HOBt (60 mg (0.4 mmol)), dimethylformamide (1 ml) and diisopropylethylamine (75 μl (0.4 mmol)), respectively, and the mixture was stirred to react at room temperature for 2 hours. After the reaction, the solid phase was washed with dimethylformamide (3×2 ml), methanol (3×2 ml) and dichloromethane (3×2 ml), respectively. Subsequently, to the solid phase was added the previously prepared Fmoc deprotection solution (dimethylformamide:piperidine:DBU=96:2:2) (2 ml), and the mixture was stirred to react at room temperature for 1 hour to obtain CTC-Phe-Gly-H. This CTC-Phe-Gly-H was dissolved in dichloromethane (2 ml), and Fmoc-Ala-OH.H2O (130 mg (0.4 mmol)), HBTU (165 mg (0.4 mmol)), HOBt (60 mg (0.4 mmol)), dimethylformamide (1 ml) and diisopropylethylamine (75 μl (0.4 mmol)) were added, respectively, and the mixture was stirred to react at room temperature for 2 hours. After the reaction, the solid phase was washed with dimethylformamide (3×2 ml), methanol (3×2 ml), and dichloromethane (3×2 ml), respectively. Subsequently, to the solid phase was added the previously prepared Fmoc deprotection solution (dimethylformamide:piperidine:DBU=96:2:2) (2 ml), and the mixture was stirred to react at room temperature for 1 hour to obtain CTC-Phe-Gly-Ala-H.
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:22])([CH3:21])[C:10]1[O:11][CH:12]=[C:13]([CH2:15]OS(C)(=O)=O)[N:14]=1)([CH3:6])([CH3:5])[CH3:4].[N+:23]([C:26]1[CH:27]=[N:28][NH:29][CH:30]=1)([O-:25])=[O:24].[Br-].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:3]([SiH2:7][O:8][C:9]([CH3:22])([CH3:21])[C:10]1[O:11][CH:12]=[C:13]([CH2:15][N:28]2[CH:27]=[C:26]([N+:23]([O-:25])=[O:24])[CH:30]=[N:29]2)[N:14]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1nc(COS(C)(=O)=O)co1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: CC(C)(C)[SiH2]OC(C)(C)c1nc(Cn2cc([N+](=O)[O-])cn2)co1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methanesulfonic acid 2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazol-4-ylmethyl ester (430 mg, 1.33 mmol), 4-nitro-1H-pyrazole (172 mg, 1.33 mmol) and TBA bromide (86 mg, 0.26 mmol) in acetone (15.0 mL) was treated with K2CO3 (935 mg, 6.69 mmol) and the reaction mixture was stirred at rt until completion. The solvent was removed under reduced pressure and water (10 mL) and EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:0 to 17:3 hept-EA) gave the title compound as a pale yellow solid. TLC: rf (1:1 hept-EA)=0.46. LC-MS-conditions 02: tR=1.09 min; [M+H]+=339.44.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[C:5](=[S:10])([O:7][CH2:8][CH3:9])[S-:6].[K+]>C(O)C.O>[O:7]([CH2:8][CH3:9])[C:5]([S:10][CH2:2][C:3]#[N:4])=[S:6]
Reactant: CCOC(=S)[S-]
Reactant: N#CCBr
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=S)SCC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.7 %

Procedure:
A solution of bromoacetonitrile (12.4 g) and potassium O-ethyl dithiocarbonate (16.0 g) in ethanol (200 mL) were allowed to stir at room temperature for 16 hours. The reaction was diluted with water (100 mL) and the organics extracted with diethyl ether. The combined organic layers were washed twice with water, then brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue purified by column chromatography (silica-gel 60, 70-230 mesh) eluting with 4:6 ethyl acetate:petroleum spirit 40-60° C. to afford the title compound as a yellow oil (14.6 g, 90.7%). 1H-nmr (CDCl3) δ 1.48 (t, 3H); 3.88 (s, 2H); 4.72 (q, 2H). 13C-nmr (CDCl3) δ 13.7, 21.3, 71.5, 115.7, 209.2.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:22])([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH3:14])=[CH:9][CH:8]=1)=[O:5].[N:27]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=1.[BH4-].[Na+]>CCO>[CH3:14][C:13]([C:10]1[CH:9]=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=2[NH:1][CH2:33][C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)=[CH:12][CH:11]=1)([CH:15]1[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]1)[CH3:22]
Reactant: CN1CCC(C(C)(C)c2ccc(NC(=O)c3ccccc3N)cc2)CC1
Reactant: O=Cc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN1CCC(C(C)(C)c2ccc(NC(=O)c3ccccc3NCc3ccncc3)cc2)CC1

Procedure:
A mixture of 2-amino-N-{4-[1-methyl-1-(1-methyl-piperidin-4-yl)ethyl]phenyl}benzamide (600 mg, Step B) and 4-pyridinecarboxaldehyde (0.22 mL) was heated at reflux in EtOH (50 mL) overnight. NaBH4 (250 mg) was added and the mixture was heated at reflux for 10 min and evaporated. The residue was mixed with CH2Cl2 and washed with H2O twice, followed by brine. The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography using 10% MeOH/CH2Cl2 to provide the title compound. MS (ES+): 443 (M+H)+. Calc'd. for C28H34N4O-442.27.