Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:19])=[O:18])[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14](=[S:16])[NH2:15])=[CH:10]2)([CH3:3])[CH3:2].Br[CH:26]([CH:29]=O)[CH:27]=[O:28].CN(C)C(=O)C>O>[OH:28][CH2:27][C:26]1[S:16][C:14]([C:11]2[NH:12][C:13]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]([CH:1]([CH3:3])[CH3:2])[S:17]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:19])=[N:15][CH:29]=1
Reactant: O=CC(Br)C=O
Reactant: CC(C)N(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)N(c1cccc2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 90 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
A mixture of 7-[isopropyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (123 mg), bromomalonaldehyde (103 mg) and N,N-dimethylacetamide (3 mL) was stirred at 90° C. for 2 hr. To the reaction mixture was added water, and the obtained solid was washed with water, and then with hexane. To a mixture of the solid, tetrahydrofuran (5 mL) and methanol (5 mL) was added sodium borohydride (15 mg), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with aqueous sodium bicarbonate and saturated brine, and the ethyl acetate layer was dried over magnesium sulfate, and filtrated. The filtrate was concentrated. The residue was subjected to silica gel column chromatography, and eluted with a mixture of ethyl acetate-hexane (2:1) to give the title compound (124 mg, yield 88%) as crystals. melting point 209° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH2:6][O:5][C:4]2=[CH:7][C:8]3[O:9][CH2:10][C:11]4([C:35]=3[CH:36]=[C:3]12)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[N:13]([CH2:20][CH:21]1[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]1)[C:12]4=[O:34].Br>ClCCl>[CH3:1][C:2]1([CH3:37])[CH2:6][O:5][C:4]2=[CH:7][C:8]3[O:9][CH2:10][C:11]4([C:35]=3[CH:36]=[C:3]12)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[N:13]([CH2:20][CH:21]1[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]1)[C:12]4=[O:34]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2C(=O)C3(COc4cc5c(cc43)C(C)(C)CO5)c3ccccc32)CC1
Agent: Br
Solvent: ClCCl
Product: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)N(CC2CCNCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a stirred solution of tert-butyl 4-[(5,5-dimethyl-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate (80 mg, 0.16 m mol) in 10.0 mL dichloromethane was added hydrobromic acid (0.50 mL of hydrobromic acid ≧33% in glacial acetic acid, 1.60 mmol) slowly at 0° C. The mixture was stirred at ambient temperature for one hour and concentrated in vacuo to dryness. The residue was treated with 10.0 mL of 2 N sodium hydroxide solution and extracted with dichloromethane (3×30.0 mL). The combined organic layers was washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (2% methanol in ethyl acetate) to give 5,5-dimethyl-1′-(piperidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.03 g, 46%), which was treated with 2.0 M HCl in diethyl ether to give the title compound: 1H NMR (300 MHz, CD3OD) δ 7.41 (td, 1H), 7.25-7.12 (m, 3H), 6.43 (s, 1H), 6.37 (s, 1H), 4.87 (d, 1H), 4.72 (d, 1H), 4.23 (s, 2H), 3.80 (d, 2H), 3.51-3.38 (m, 2H), 3.11-2.94 (m, 2H), 2.39-2.19 (m, 1H), 2.06-1.94 (m, 2H), 1.67-1.49 (m, 2H), 1.22 (s, 3H), 1.19 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 181.4, 163.9, 163.4, 144.7, 134.7, 132.3, 131.0, 125.9, 125.8, 122.6, 118.4, 111.3, 94.9, 87.4, 82.6, 60.2, 46.7, 45.7, 45.6, 43.3, 34.6, 28.8, 28.7, 28.6; MS (ES+) m/z 405.4 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6]/[C:7](=[CH:10]\[C:11](OCC)=[O:12])/[CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:18][NH2:19]>CO>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6]/[C:7](=[CH:10]\[C:11]([NH:19][CH3:18])=[O:12])/[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCOC(=O)/C=C1/COc2cc(F)ccc2N1
Reactant: CN
Solvent: CO
Product: CNC(=O)/C=C1/COc2cc(F)ccc2N1
Temperature: 35 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
A mixture of ethyl (2Z)-(7-fluoro-2H-1,4-benzoxazin-3(4H)-ylidene)acetate (Intermediate 11, 2.0 g; 8.4 mmol), MeOH (6.0 mL) and methylamine (7.3 mL of a 40 wt % aq. Solution, 84.3 mmol) was heated on a metal hotplate to 35° C. (block temperature) and stirred for 16 h. A dark brown cloudy solution was obtained. LCMS analysis indicated consumption of starting material and formation of product. The mixture was partitioned between DCM (80 mL) and water (80 mL). The organic phase was separated, then concentrated in vacuo and the residue purified by column chromatography on a 40 g silicycle silica cartridge eluting with 0-10% EtOAc: DCM, to obtain the title compound (1.10 g, 58.9%) of an orange crystalline solid that darkened on standing.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:12]=[C:11]([S:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)[NH:10][N:9]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:33]2[CH2:36][CH:35]([NH:37]C(=O)OC(C)(C)C)[CH2:34]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:33]2[CH2:36][CH:35]([NH:37][C:17](=[O:19])[C:16]3[CH:20]=[CH:21][CH:22]=[C:14]([S:13][C:11]4[NH:10][N:9]=[C:8]([NH:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH:12]=4)[CH:15]=3)[CH2:34]2)(=[O:31])=[O:32])=[CH:28][CH:29]=1
Reactant: O=C(O)c1cccc(Sc2cc(Nc3ccccn3)n[nH]2)c1
Reactant: CC(C)(C)OC(=O)NC1CN(S(=O)(=O)c2ccc(F)cc2)C1
Product: O=C(NC1CN(S(=O)(=O)c2ccc(F)cc2)C1)c1cccc(Sc2cc(Nc3ccccn3)n[nH]2)c1
Yield: 36.9 %

Procedure:
3-(3-(Pyridine-2-ylamino)-1H-pyrazol-5-ylthio)benzoic acid (0.050 g, 0.160 mmol) and tert-butyl 1-(4-fluoro-phenylsulfonyl)azetidin-3-ylcarbamate (0.063 g, 0.19 mmol) were treated as described in Example 3, except that the mixture was purified on Prep HPLC (MeCN/H2O/0.1% TFA). This afforded the title material (0.031 g, 30%, trifluoroacetic acid salt) as a solid. 1H NMR 400 MHz DMSO-d6 δ (ppm): 3.72 (2H, dd, J=8.46, 6.44 Hz), 4.00 (2 H, t, J=8.08 Hz), 4.35-4.52 (1 H, m), 6.43 (1 H, s), 6.91-7.03 (1 H, m), 7.18 (1 H, d, J=8.08 Hz), 7.34-7.40 (1 H, m), 7.44 (1 H, t, J=7.71 Hz), 7.50-7.59 (2 H, m), 7.60-7.69 (2 H, m), 7.82-7.98 (3 H, m), 8.20 (1 H, d, J=4.55 Hz), 8.96 (1 H, d, J=6.06 Hz), 10.62 (1 H, br.s). HPLC ret. time (Condition B): 4.125 min.; 91%. LCMS (+ESI, M+H+) m/z 525. HRMS: calc. 525.1179, found 525.1191.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([NH:7][C@H:8]([C:17]([NH:19][C@@H:20]([C:22]([NH:24][C@H:25]([C:32]([NH:34][C@H:35]([C:43]([N:45]1[CH2:54][CH2:53][CH2:52][C@H:46]1[C:47]([NH:49][CH2:50][CH3:51])=[O:48])=[O:44])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:42])[NH2:41])=[O:33])[CH2:26][S:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:23])[CH3:21])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:6])[CH2:3][OH:4].[CH3:55][C:56]([CH2:58][C:59]([OH:61])=[O:60])=[O:57].[NH2:62][C@H:63]([C:69]([NH:71][C@H:72]([C:79]([NH:81][C@H:82]([C:93](NN)=[O:94])[CH2:83][C:84]1[C:92]2[C:87](=[CH:88][CH:89]=[CH:90][CH:91]=2)[NH:86][CH:85]=1)=[O:80])[CH2:73][C:74]1[N:78]=[CH:77][NH:76][CH:75]=1)=[O:70])[CH2:64][CH2:65][C:66](=[O:68])[OH:67]>>[NH2:62][C@H:63]([C:69]([NH:71][C@H:72]([C:79]([NH:81][C@H:82]([C:93]([NH:1][C@H:2]([C:5]([NH:7][C@H:8]([C:17]([NH:19][C@@H:20]([C:22]([NH:24][C@H:25]([C:32]([NH:34][C@H:35]([C:43]([N:45]1[CH2:54][CH2:53][CH2:52][C@H:46]1[C:47]([NH:49][CH2:50][CH3:51])=[O:48])=[O:44])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:41])[NH2:42])=[O:33])[CH2:26][S:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:23])[CH3:21])=[O:18])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)=[O:6])[CH2:3][OH:4])=[O:94])[CH2:83][C:84]1[C:92]2[C:87](=[CH:88][CH:89]=[CH:90][CH:91]=2)[NH:86][CH:85]=1)=[O:80])[CH2:73][C:74]1[N:78]=[CH:77][NH:76][CH:75]=1)=[O:70])[CH2:64][CH2:65][C:66](=[O:67])[OH:68].[CH3:55][C:56]([CH2:58][C:59]([OH:61])=[O:60])=[O:57]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CSC(C)(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CO
Reactant: NNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)CCC(=O)O
Agent: CC(=O)CC(=O)O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CSC(C)(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)CCC(=O)O

Procedure:
In analogy to Example 7(e) 448.5 mg (0.5 mol) of H-Ser-Tyr-D-Ala-Cys(But)-Arg-Pro-NH-C2H5 -diacetate were reacted with Glu-His-Trp-NH-NH2, worked up and purified over Dowex 1 × 2 (acetate form) and carboxymethyl cellulose. Since the substance was not completely pure, it was purified in analogy to Example 1(a) on Sephadex LH 20.
Reaction SMILES: [CH2:1]([NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[S:18](N)([NH2:21])(=[O:20])=[O:19]>>[CH2:1]([NH:17][S:18]([NH2:21])(=[O:20])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NS(N)(=O)=O
Reactant: CCCCCCCCCCCCCCCCN
Product: CCCCCCCCCCCCCCCCNS(N)(=O)=O
Yield: 16 %

Procedure:
The title compound was prepared following the procedure previously described in Example 1, using 0.5 g (2.0 mmol) of N-hexadecylamine and 0.195 g (2.0 mmol) of sulfamide as starting reagent. 0.087 g of a white solid were obtained. Yield 16%; m.p. 102-104° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:8]2[N:9]=[C:10]([Cl:13])[N:11]=[CH:12][C:7]=2[NH:6][CH:5]=1.Cl[C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[Br:3][C:4]1[C:8]2[N:9]=[C:10]([Cl:13])[N:11]=[CH:12][C:7]=2[N:6]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:5]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Clc1ncc2[nH]cc(Br)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ncc2c(n1)c(Br)cn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.33 h
Yield: 100.3 %

Procedure:
A suspension of NaH (300 mg, 60% in mineral oil, 7.5 mmol) in THF (30 mL) was added a solution of 7-bromo-2-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.16 g, 5.0 mmol) in THF (20 mL) dropwise at 0° C. After 20 min, a solution of TrCl (1.674 g, 6 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred for 6 hours, quenched with brine and extracted with EtOAc (3×). The combined organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by ISCO to provide the desired product (2.38 g, >99%). 1H NMR (400 MHz, CD3OD) δ 7.63 (s, 1H), 7.57 (s, 1H), 7.37-7.32 (m, 9H), 7.14-7.11 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[CH3:17])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:14]=[CH:15][C:16]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C=O)cc1OCc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc(C)c(OCc2ccccc2)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 76.3 %

Procedure:
Under a nitrogen atmosphere, to a solution of 3-(benzyloxy)-4-methylbenzaldehyde (2.50 g) in toluene (50 mL) was added ethyl (triphenylphosphoranylidene)acetate (4.20 g), and the mixture was stirred at 70° C. for 15 hr. The reaction mixture was concentrated, diethyl ether (100 mL) was added, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.50 g) as a colorless oil. This compound was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Pd].C1COCC1.CO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1
Reactant: O=C(Nc1cc([N+](=O)[O-])ccc1F)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(F)c(NC(=O)c2ccccc2)c1
Yield: 91 %

Procedure:
A mixture of N-(2-fluoro-5-nitro-phenyl)-benzamide (4.86 g, 18.7 mmol) and 10% Pd/C (486 mg) in a 1:1 mixture of THF-MeOH (80 ml) was hydrogenated at 23° C. After 2.5 h the reaction mixture was filtered through celite and concentrated to give N-(5-Amino-2-fluoro-phenyl)-benzamide (3.92 g, 91%). MS (ESI+) [M+H]/z Calc'd 231. found 231.
Reaction SMILES: I.[CH3:2][NH:3][C:4](=[NH:7])[S:5][CH3:6].[CH:8]1([N:14]([C:18](Cl)=[O:19])[C:15](Cl)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([N:14]2[C:18](=[O:19])[NH:7][CH:4]([S:5][CH3:6])[N:3]([CH3:2])[C:15]2=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(Cl)N(C(=O)Cl)C1CCCCC1
Reactant: CNC(=N)SC
Agent: I
Product: CSC1NC(=O)N(C2CCCCC2)C(=O)N1C

Procedure:
Analogously to Example 24, N,S-dimethyl-isothiourea hydroiodide and N-cyclohexyl-bis-(chlorocarbonyl)-amine (prepared analogously to Synthesis 1970, pages 542-543; boiling point 80°-82° C/0.3 mm Hg) yielded 1-cyclohexyl-3-methyl-4-methylmercapto-tetrahydro-1,3,5-triazine-2,6-dione as a colorless powder of melting point 135°-137° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][CH2:21][CH2:22][OH:23]>C(Cl)(Cl)Cl>[OH:12][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][O:23][CH2:22][CH2:21][O:20][CH3:19])=[CH:8][C:7]=1[C:9](=[O:11])[CH3:10]
Reactant: COCCO
Reactant: CC(=O)c1cc(CCl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COCCOCc1ccc(O)c(C(C)=O)c1
Reaction time: 24 h
Yield: 17.8 %

Procedure:
A mixture of 5'-(chloromethyl)-2'-hydroxyacetophenone (1.85 g, 10.0 mmol), potassium carbonate (1.38, 10.0 mmol), 2-methoxyethanol (0.91 g, 12.0 mmol) and 10 mL chloroform was stirred 24 hours, filtered, and the filtrate concentrated in vacuo to give a residue. The residue was purified by flash chromatography eluting with 30:70 ethyl acetate:hexane to give 0.40 g (18%) product as an oil.
Reaction SMILES: O.ON1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2N=N1.C(N(C(C)C)[CH:15]([CH3:17])[CH3:16])C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:16]1[C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:17][CH2:15]1
Reactant: On1nnc2ccccc21
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: c1ccc2c(c1)CCC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-Hydroxybenzotriazole hydrate (0.3 eq.) and N-ethyl-diisopropylamine (4 eq.) were added to a solution of (G) (1.5 eq.) in methylene chloride. The reaction mixture was cooled to 0° C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 eq.) was then added. The mixture was stirred at this temperature for 15 min, before the amine (1 eq.) was finally added. The reaction mixture was then stirred at room temperature overnight. For working up, the reaction mixture was washed 3× with 0.5 M KOH solution and the organic phase was dried over MgSO4, filtered and concentrated. The crude product was either purified by column chromatography (silica; methylene chloride/methanol or aluminium oxide; methylene chloride/methanol) or recrystallized from methylene chloride to obtain the product (H) in a pure form.
Reaction SMILES: CC1C=CC(S([O:11][C:12]2[C:13]([C:30]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[S:41]([N:44]([CH3:46])[CH3:45])(=[O:43])=[O:42])=[O:31])=[N:14][C:15]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][S:23]3(=[O:29])=[O:28])=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)(=O)=O)=CC=1.C[O-].[Na+].C(O)(=O)C.C(O)C>CN(C=O)C.CO>[CH3:45][N:44]([CH3:46])[S:41]([C:35]1[CH:36]=[C:37]([F:40])[CH:38]=[CH:39][C:34]=1[CH2:33][NH:32][C:30]([C:13]1[C:12]([OH:11])=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[N:20]2)=[C:15]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][S:23]2(=[O:29])=[O:28])[N:14]=1)=[O:31])(=[O:43])=[O:42]
Reactant: Cc1ccc(S(=O)(=O)Oc2c(C(=O)NCc3ccc(F)cc3S(=O)(=O)N(C)C)nc(N3CCCCS3(=O)=O)c3cccnc23)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)S(=O)(=O)c1cc(F)ccc1CNC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Dissolved 7-[({2-[(dimethylamino)sulfonyl]-4-fluorobenzyl}amino)carbonyl]-5-(1,1-dioxido-1,2-thiazinan-2-yl)-1,6-naphthyridin-8-yl 4-methylbenzenesulfonate (271 mg, 0.39 mmol) in DMF (0.5 mL) and added to a solution of sodium methoxide (53 mg, 0.98 mmol) in methanol (3.0 mL). The reaction was stirred at 50° C. for one hour, cooled, and glacial acetic acid (56 μL, 0.78 mmol) was added. The reaction was stripped down three times from methanol. Ethanol was added while sonicating the flask to crash out the product. Collected the solids by vacuum filtration to afford the desired compound as a yellowish solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:22]=[CH:21][C:18]([CH2:19]Br)=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:27]#[N:28].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:22]=[CH:21][C:18]([CH2:19][C:27]#[N:28])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CBr)c(C(F)(F)F)c2)CC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC#N)c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 4-(N-tert-butyloxy-carbonyl-4-piperidinyloxy)-2-trifluoromethylbenzyl bromide (0.37 g, 0.87 mmol) from Step 4 above in DMF (4 mL) was added NaCN (0.064 g, 1.3 mmol). The mixture was stirred at ambient temperature for 14 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (2×25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-trifluoromethylphenylacetonitrile was a pale yellow gum (HPLC retention time=11.4 min (method A)).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1cccc(Cl)c1
Product: O=c1cc(N2CCN(Cc3cccc(Cl)c3)CC2)nc[nH]1

Procedure:
6-[4-(3-Chloro-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-chlorobenzaldehyde. Mass spectrum (ES) MH+=305.
Reaction SMILES: [CH2:1]([CH:3]([CH2:33][CH3:34])[CH:4]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]([CH3:32])[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[CH:18][CH:17]=1)[C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:2].O1CCCC1.[OH-].[Na+]>C(O)C>[CH2:33]([CH:3]([CH2:1][CH3:2])[CH:4]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([N:24]([CH3:32])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[CH:20][CH:21]=1)[C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:34]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2sc3ccccc3c2C)C(CC)CC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(CC)C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)c1sc2ccccc2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a mixture of ethyl 3-{[(4-{[2-ethyl-1-(3-methyl-1-benzothiophen-2-yl)butyl]amino}phenyl)carbonyl](methyl)amino}propanoate (253 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (225 mg, 95%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][C:5]2[N:6]([CH:23]3[CH2:27][N:26](CC4C=CC(OC)=CC=4)[C:25](=[O:37])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1>CC#N.O.CCOC(C)=O>[Cl:1][C:2]1[CH:39]=[CH:38][C:5]2[N:6]([CH:23]3[CH2:27][NH:26][C:25](=[O:37])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(CN2CC(n3c(Cn4nc(S(C)(=O)=O)c5ccncc54)nc4cc(Cl)ccc43)CC2=O)cc1
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CNC(=O)C2)c2cnccc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-(5-chloro-2-{[3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-1-yl]methyl}-1H-benzimidazol-1-yl)-1-(4-methoxybenzyl)pyrrolidin-2-one (208 mg, 0.37 mmol) in 60 mL of CH3CN and 12 mL of H2O was added (NH4)2Ce(NO3)6 (1.01 g, 1.84 mmol). The resulting mixture was stirred at RT for 6 hours. The solution was diluted with 40 mL of water and 15 mL of EtOAc. The separated aqueous phase was extracted with EtOAc (15 mL×3) and THF (5 mL×3). The combined organic phases were washed with 30 mL of brine, and then dried over Na2SO4, then filtered and concentrated. The residue was purified by column chromatography (DCM: MeOH=20:1) to afford 4-(5-chloro-2-{[3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-1-yl]methyl}-1H-benzimidazol-1-yl)pyrrolidin-2-one.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[CH:17]=1.[F:27][C:28]1[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=1>>[F:27][C:28]1[CH:29]=[C:30]([NH:34][C:22](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([N:16]3[CH:17]=[C:13]([C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[CH:15]3)=[CH:26][CH:25]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Nc1cccc(F)c1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)Nc3cccc(F)c3)cc2)cn1
Yield: 10 %

Procedure:
As described for Example 71c, 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) was converted, using 3-fluorophenylamine instead of cyclopropylmethylamine, to the title compound (13 mg, 10%) which was obtained as an off-white solid. MS: m/e=438.9 [M+H]+.
Reaction SMILES: CC(C)(C)C(OC[N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][N:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][CH:24]=3)[CH2:20][C:21]#[CH:22])[CH:14]=2)[N:9]=[CH:8]1)=O.N>CO>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([N:19]([CH2:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][NH:7][C:16]3=[O:17])[CH2:20][C:21]#[CH:22])=[CH:28][CH:27]=1)(=[O:31])[CH3:30]
Reactant: C#CCN(Cc1ccc2ncn(COC(=O)C(C)(C)C)c(=O)c2c1)c1ccc(C(C)=O)cc1
Agent: N
Solvent: CO
Product: C#CCN(Cc1ccc2nc[nH]c(=O)c2c1)c1ccc(C(C)=O)cc1
Temperature: 25 °C

Procedure:
To 2.34 g (5.25 mmol) of 2,2-dimethylpropanoic acid, [6-[[(4-acetylphenyl)-2-propynylamino]methyl]-4-oxo-3(4H)-quinazolinyl]methyl ester (Example 1) is added a solution of 500 ml of methanol saturated with ammonia at 20° C. The solution is stirred at room temperature for eighteen hours. The solution is concentrated to give a solid which is recrystallized from ethanol to give the product as a pink solid; mp 197°-199° C.