Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N+](C1C=CC([O:30][C:31](=O)[NH:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:35][CH:34]=2)=CC=1)([O-])=O>C(Cl)Cl.CO.N.C(Cl)Cl>[N:39]1([C:36]2[CH:35]=[CH:34][C:33]([NH:32][C:31]([N:18]3[CH2:19][CH2:20][CH:15]([C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH2:16][CH2:17]3)=[O:30])=[CH:38][CH:37]=2)[CH2:40][CH2:41][O:42][CH2:43][CH2:44]1
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(N5CCOCC5)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 85.8 %

Procedure:
A mixture of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (111.4 mg, 408 μmol), prepared as described in Example 1d, but with purification by silica flash chromatography (9:1 DCM/MeOH saturated with NH3), (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester (147 mg, 429 μmol), prepared as described in the previous step, and DCM (700 μL) was treated with TEA (63 μL, 449 μmol) in one portion at rt. The homogeneous amber solution was stirred at rt for 3.5 h, diluted with DCM (1.3 mL), and washed with 2 M K2CO3 (2 mL). The aqueous layer was extracted with DCM (2×2 mL), the organic layers were combined, dried (Na2SO4), and concentrated, and the residue was purified with silica flash chromatography (1:1 DCM/acetone) to afford the title compound (167.1 mg, 86%). 1H-NMR (300 MHz, CDCl3): δ 9.08 (s, 1H), 7.34 (s, 1H), 7.31-7.24 (m, 3H), 6.88 (m, 2H), 6.31 (br s, 1H), 4.32-4.22 (m, 2H), 4.07 (s, 3H), 4.06 (s, 3H), 3.86 (m, 4H), 3.59 (m, 1H), 3.23-3.07 (m, 6H), 2.24-2.07 (m, 2H), 2.05-1.93 (m, 2H). LC/MS (ESI): calcd mass 477.2, found 478.3 (MH+). Select fractions of this material were combined (112.5 mg) and submitted for combustion analysis: Anal. Calcd for C26H31N5O4: C, 65.39; H, 6.54; N, 14.67. Found: C, 65.26; H, 6.58; N, 14.51.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][NH2:13])[CH2:8][CH2:7]1)=[O:5].[C:14](OC(=O)C)(=[O:16])[CH3:15].Cl>N1C=CC=CC=1>[CH3:2][O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:8][CH2:7]1)=[O:5]
Reactant: COC(=O)[C@H]1CC[C@H](CN)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CC[C@H](CNC(C)=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of trans-4-(aminomethyl)cyclohexanecarboxylic acid methyl ester hydrochloride (1.5 mmol, 310 mg) in pyridine (2 mL) is added acetic anhydride (1.8 mmol, 0.31 mL) at room temperature. The mixture is stirred at room temperature for 4 hours, poured into 1M HCl and ice-water, and then extracted with ethyl acetate. The combined organic phase is washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain trans-4-(acetamidomethyl)-1-cyclohexanecarboxylic acid methyl ester (330 mg) as colorless oil. ESI-MS m/z: 214 [M+1]+, Retention time 1.97 min (condition B).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)=[C:7]([Cl:24])[C:6]=1[CH3:25])(=[O:3])[CH3:2].[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>>[C:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[C:15]([C:20]([F:21])([F:23])[F:22])[CH:14]=2)=[C:7]([Cl:24])[C:6]=1[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(C)C(=O)Cl
Reactant: CC(=O)Oc1cc(Cl)c(Oc2ccc(N)c(C(F)(F)F)c2)c(Cl)c1C
Product: CC(=O)Oc1cc(Cl)c(Oc2ccc(NC(=O)C(C)C)c(C(F)(F)F)c2)c(Cl)c1C
Yield: 84.9 %

Procedure:
Methyl[3,5-dichloro-4-(4-amino-3-trifluoromethylphenoxy)phenyl] acetate (70 mg) was coupled with isobutyryl chloride (30 mg), using the method described in Example 1(h). After purification on column (silica gel, ethyl acetate/petrolium ether, 1:9), 70 mg (84%) of methyl(3,5-dichloro-4-[4-isobutyramido-3-trifluoromethylphenoxy]phenyl) acetate was obtained, which was hydrolysed using the method described in Example 1(i). This gave 50 mg (74%) of 3,5-dichloro-4-(4-isobutyramido-3-trifluoromethylphenoxy)phenylacetic acid, m/z 450.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7]C(N)=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12].C1(=O)CCCCC1>CCC(=O)CC>[Br:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][CH:2]([CH2:8][CH3:7])[CH2:3][CH3:4]
Reactant: Nc1ccccc1Br
Reactant: Nc1ccc(Br)cc1
Solvent: O=C1CCCCC1
Solvent: CCC(=O)CC
Product: CCC(CC)Nc1ccccc1Br
Yield: 61 %

Procedure:
The same procedure was carried out as in Example 2 except that 4-bromoaniline and 3-pentanone were used instead of 2-bromoaniline and cyclohexanone to obtain a colorless oil compound (61%).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[NH:4][CH:3]=[CH:2]1.[H-].[Na+].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>CN(C)C=O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:4]1[C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH:2]=[CH:3]1
Reactant: BrCCCCCBr
Reactant: O=C1NC=COc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2OC=CN1CCCCCBr
Reaction time: 0.5 h

Procedure:
250 mg of 4,5-dihydro-1,4-benzoxazepin-5-one was dissolved in 15 ml of dimethylformamide, then 74 mg (1.2 equivalents) of 60% sodium hydride was added under ice cooling. This was agitated for 30 minutes, then 0.51 ml (2.4 equivalents) of 1,5-dibromopentane was added and the resultant mixture was agitated at room temperature for 6 hours.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([O:20][C:21]1[C:22](=[O:30])[N:23]([CH3:29])[C:24]([CH2:27][OH:28])=[N:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O[N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(N(C)C)=O>[CH2:13]([O:20][C:21]1[C:22](=[O:30])[N:23]([CH3:29])[C:24]([CH2:27][O:28][N:32]2[C:33](=[O:42])[C:34]3=[CH:41][CH:40]=[CH:39][CH:38]=[C:35]3[C:36]2=[O:37])=[N:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cn1c(CO)ncc(OCc2ccccc2)c1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: Cn1c(CON2C(=O)c3ccccc3C2=O)ncc(OCc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
Diethyl azodicarboxylate (4.8 g) (20 mmol) are added dropwise at 0° C. while stirring to a mixture of 3.69 g (15 mmol) of 5-(benzyloxy)-2-(hydroxymethyl)-3-methyl-4(3H)-pyrimidinone, 3.26 g (20 mmol) of N-hydroxyphthalimide and 5.24 g (20 mmol) of triphenylphosphine in 100 ml of absolute dimethylacetamide. The mixture is stirred at 0° C. for 2 hours and at room temperature for 16 hours. Subsequently, the solvent is removed in a high vacuum at room temperature. The residue is crystallized from ethanol/diethyl ether. After drying in a high vacuum for 18 hours at room temperature there are obtained 5.5 g of N-[[5-(benzyloxy)-3,4-dihydro-3-methyl-4-oxo-2-pyrimidinyl]methoxy]phthalimide as white crystals of m.p. 170° C.
Reaction SMILES: CC(C)(OC([NH:7][C@@H:8]([C:27](=[O:36])OCC1C=CC=CC=1)[CH2:9][CH2:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C@H:14]1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:12])=O)C.[C:38]1(OC)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[NH2:7][C@@H:8]([C:27](=[O:36])[CH2:47][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:9][CH2:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C@H:14]1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:12]
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)CC[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)CC[C@@H](N)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the ester product from part (e) (0.39 mmole, 0.2 g.), anisole (0.2 ml.) and trifluoroacetic acid (1.95 ml.) is allowed to stir at room temperature for two hours. The trifluoroacetic acid is stripped in vacuo to yield (S)-1-[(R)-4-amino-1,5-dioxo-5-(phenylmethyl)-pentyl]-2,3-dihydro-1H-indole-2-carboxylic acid, ethyl ester, trifluoroacetate salt as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:7]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][C:31]1=[O:35]>>[CH3:28][C:27]1[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:5]3[CH:4]=[CH:3][C:2]([N:30]4[CH2:34][CH2:33][CH2:32][C:31]4=[O:35])=[CH:7][C:6]=3[N:8]3[CH2:12][CH2:11][CH2:10][C:9]3=[O:13])=[O:15])[CH2:17][CH2:18]2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCCC3=O)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3N3CCCC3=O)CC2)c(C)c1
Yield: 31.7 %

Procedure:
Using 1-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}pyrrolidin-2-one (206 mg) described in Preparation Example 169 and pyrrolidin-2-one (43 mg) and by the reaction and treatment in the same manner as in Example 352, the title compound (73 mg) was obtained.
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH:20][C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[H-].[Na+].[CH2:36](Br)[CH:37]=[CH2:38].O>CN(C=O)C>[CH2:38]([N:20]([C:19]1[C:14]2[CH:13]=[CH:12][N:11]([S:1]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=3)(=[O:3])=[O:2])[C:15]=2[N:16]=[CH:17][N:18]=1)[C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)[CH:37]=[CH2:36]
Reactant: C=CCBr
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)ncnc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN(c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a solution of (R)-tert-butyl 3-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (1.0 g, 2.1 mmol) in DMF (5 mL), NaH (60% suspension in mineral oil, 100 mg, 2.5 mmol) was added at 0° C. and the reaction mixture was stirred for 1 h. To the reaction mixture was added allyl bromide (308 mg, 2.12 mmol) and the reaction mixture was stirred for 6 h. The solution was diluted with ice-cooled water and stirred for 15 min, the solution was then extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to give the crude product that was purified by column chromatography (silica gel, gradient, EtOAc in hexanes) to give (0.9 g, 83%) of the titled compound. 1H NMR (400 MHz, CDCl3): δ 8.42 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.43 (d, J=3.2 Hz, 1H), 7.31 (d, J=8.0 Hz, 2H), 6.57 (d, J=3.2 Hz, 1H), 5.98-5.90 (m, 1H), 5.26-5.19 (m, 2H), 4.62-4.51 (m, 1H), 4.29-4.09 (m, 4H), 2.85 (t, J=11.6 Hz, 1H), 2.68-2.60 (m, 1H), 2.41 (s, 3H), 1.97-1.93 (m, 1H), 1.83-1.72 (m, 2H), 1.65-1.58 (m, 1H), 1.42 (s, 9H). LCMS [M+1]: 512.
Reaction SMILES: [F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14](I)[N:13](S(C3C=CC=CC=3)(=O)=O)[C:10]2=[N:11][CH:12]=1)=[O:5].FC1C(NS(CCC)(=O)=O)=CC=C(F)C=1[C:41]([NH:43]C1C=C2C(I)=CN(S(C3C=CC=CC=3)(=O)=O)C2=NC=1)=O>>[C:41]([C:14]1[NH:13][C:10]2=[N:11][CH:12]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:26]([F:37])=[CH:27][CH:28]=[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[C:2]=3[F:1])[CH:8]=[C:9]2[CH:15]=1)#[N:43]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(I)n3S(=O)(=O)c2ccccc2)c1F
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccccc2)c1F
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(C#N)cc3c2)c1F

Procedure:
N-(2-Cyano-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide was prepared following Example 17 substituting 2,6-difluoro-N-(2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide for 2,6-difluoro-N-(3-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide. 1H NMR (400 MHz, d6-DMSO) δ 12.98 (br s, 1H), 11.08 (s, 1H), 9.80 (br s, 1H), 8.60 (s, 2H), 7.59-7.52 (m, 1H), 7.43 (s, 1H), 7.30-7.24 (m, 1H), 3.15-3.09 (m, 2H), 1.80-1.73 (m, 2H), 1.02-0.97 (m, 3H); m/z (APCI-neg) M−1=418.1.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:8])[CH:3]([OH:7])[C:4]([OH:6])=[O:5].Cl.[CH2:10](N(CC)CC)C.CCOCC>CO>[NH2:1][C@@H:2]([CH3:8])[CH:3]([OH:7])[C:4]([O:6][CH3:10])=[O:5]
Reactant: C[C@H](N)C(O)C(=O)O
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(O)[C@H](C)N
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Into a suspension of (3S)-3-amino-2-hydroxybutanoic acid (1.0 g, 8.4 mmol) in methanol (25 ml) was bubbled anhydrous hydrogen chloride gas until a solution resulted. After a solution resulted, the reaction was cooled in an ice bath and saturated with hydrogen chloride. The cooling bath was removed and the reaction stirred at room temperature for 3.5 hours. The solvent was removed on a rotary evaporator at ambient temperature and the resultant residue dissolved in methanol (25 ml), cooled in an ice bath and saturated with hydrogen chloride gas. Warming of the reaction solution to room temperature and removal of the solvent on a rotary evaporator gave an oil. To this oil was added triethylamine (15 ml) followed by the minimum amount of methanol (about 15 ml) needed to dissolve the initial gummy solid. The solution was cooled in an ice bath and ether (75 ml) added in portions with stirring. The precipitated triethylamine hydrochloride was filtered and the filtrate evaporated to give methyl (3S)-3-amino-2-hydroxybutanoate.
Reaction SMILES: [CH:1]1([NH:11][C:12]([CH:14]2[CH2:18][N:17]([C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[CH:16]3[CH2:24][CH2:25][N:26]([C:27](=[O:36])[CH:28]([NH2:35])[CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:15]23)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:37]([N:47]([CH3:53])[C@H:48]([C:50](O)=[O:51])[CH3:49])([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:40]([O:39][C:37](=[O:38])[N:47]([CH:48]([C:50](=[O:51])[NH:35][CH:28]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:27]([N:26]1[CH2:25][CH2:24][CH:16]2[N:17]([C:19]([CH:21]3[CH2:22][CH2:23]3)=[O:20])[CH2:18][CH:14]([C:12](=[O:13])[NH:11][CH:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)[CH:15]12)=[O:36])[CH3:49])[CH3:53])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: NC(C(=O)N1CCC2C1C(C(=O)NC1CCCc3ccccc31)CN2C(=O)C1CC1)C1CCCCC1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(C(=O)NC1CCCc3ccccc31)CN2C(=O)C1CC1)C1CCCCC1)N(C)C(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 95.2 %

Procedure:
A solution of 47 (330 mg, 0.67 mmol) in DCM (10 mL) was cooled to 0° C. and treated with Cbz-N(Me)Ala-OH (159 mg, 0.67 mmol), EDC (154 mg, 0.80 mmol), HOBt (109 mg, 0.80 mmol) and DIPEA (0.36 mL, 2.08 mmol), respectively. After 18 h, the solution was diluted with DCM, washed successively with 1M HCl, saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 48 (454 mg) as a white foam that was used without further purification. Mass spectrum, m/z [712.9] (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].Br[C:12]1[CH:17]=[C:16](F)C(F)=[CH:14][C:13]=1O[C@H](CC=C)C>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[O:10][C@H:17]([CH2:12][CH:13]=[CH2:14])[CH3:16]
Reactant: C=CC[C@H](C)Oc1cc(F)c(F)cc1Br
Reactant: Oc1c(F)cc(F)cc1Br
Product: C=CC[C@H](C)Oc1c(F)cc(F)cc1Br
Yield: 92 %

Procedure:
Prepared in 92% yield from 2-bromo-4,6-difluorophenol following the procedure for (S)-1-bromo-4,5-difluoro-2-(pent-4-en-2-yloxy)benzene. 1H NMR (400 MHz, CDCl3) δ 7.19-7.06 (m, 1H), 6.85 (ddd, J=10.9, 8.2, 3.0 Hz, 1H), 5.90 (ddt, J=17.2, 10.1, 7.0 Hz, 1H), 5.19-5.07 (m, 2H), 4.46-4.30 (m, 1H), 2.65-2.48 (m, 1H), 2.48-2.39 (m, 1H), 1.31 (dd, J=6.1, 0.6 Hz, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([OH:14])=O.[CH3:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH2:21][CH2:20][CH2:19]2>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:22]1[C:23]2[C:18](=[CH:17][C:16]([CH3:15])=[CH:25][CH:24]=2)[CH2:19][CH2:20][CH2:21]1)=[O:14]
Reactant: O=C(O)CSc1nc2ccccc2s1
Reactant: Cc1ccc2c(c1)CCCN2
Product: Cc1ccc2c(c1)CCCN2C(=O)CSc1nc2ccccc2s1
Yield: 85 %

Procedure:
The title compound was synthesized according to General Procedure B using 2-(benzo[d]thiazol-2-ylthio)acetic acid and 6-methyl-1,2,3,4-tetrahydroquinoline to yield 38 (450.5 mg, 85%): MS (APCI): m/z 355 [M+H]+. Anal. Calcd. for C19H18N2OS2: C, 64.39; H, 5.12; N, 7.90. Found: C, 64.55; H, 5.01; N, 7.88.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[O:17][CH3:18])[C:6]([CH2:8][C:9]([O:11]CC)=O)=O.[C:22]1([NH:28][NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[CH2:8][C:9](=[O:11])[N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:29]=2)[CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[O:17][CH3:18]
Reactant: NNc1ccccc1
Reactant: CCOC(=O)CC(=O)c1cc(OC)c(OC)c([N+](=O)[O-])c1
Product: COc1cc(C2=NN(c3ccccc3)C(=O)C2)cc([N+](=O)[O-])c1OC

Procedure:
10.0 g of ethyl (3,4-dimethoxy-5-nitrobenzoyl)acetate are reacted with 4.0 g of phenylhydrazine in analogy to Example 53a. After recrystallization from methylene chloride/ethanol, there is obtained 3-(3,4-dimethoxy-5-nitrophenyl)-1-phenyl-2-pyrazolin-5-one in the form of yellow crystals of m.p. 190°-192°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[Br:16][CH2:17][C:18](Br)=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:8]([C:7]1[C:2]([NH:1][C:18](=[O:19])[CH2:17][Br:16])=[N:3][CH:4]=[CH:5][N:6]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1nccnc1C(=O)c1ccccc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CBr)Nc1nccnc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2 g. (0.01 mol) of 2-amino-3-benzoylpyrazine and 20.2 g. (0.1 mol) of 2-bromo-acetyl bromide in 50 ml. of methylene chloride was layered with 25 ml. of 10% aqueous sodium carbonate solution. The two-phase mixture was stirred for 1 hour at room temperature. The methylene chloride layer was separated, washed several times with 10% aqueous sodium carbonate solution and was dried over sodium sulfate. The residue obtained after evaporation was crystallized from methylene chloride/hexane to yield 2.9 g. (90.6%) of the above-named product as tan crystals, m.p. 130°-135° dec.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([NH:18][O:19]C4CCCCO4)=[O:17])[CH:12]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.Cl>C(O)(C)C>[OH:19][NH:18][C:16]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5])[CH2:15][CH2:14]2)=[O:17]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)C1CC1)C2
Agent: Cl
Solvent: CC(C)O
Product: O=C(NO)c1ccc2c(c1)CCN(C(=O)C1CC1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 148.9 %

Procedure:
A mixture of 80 mg of 2-(cyclopropylcarbonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 3 ml isopropanol and 3 ml of an aqueous, 0.1 N hydrochloric acid is stirred 4 h at ambient temperature. The reaction mixture is evaporated and the residue is dissolved in a mixture of 0.5 ml water and 0.5 ml acetonitrile and lyophilized. 90 mg of the title compound are obtained as solid with mp=90° C. MH+=261.1
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:39])=[C:36]([OH:38])[CH:37]=1>C1COCC1>[OH:38][C:36]1[CH:37]=[C:32]([NH:31][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])[CH:33]=[CH:34][C:35]=1[CH3:39]
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: Cc1ccc(N)cc1O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(C)c(O)c3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 120 mg, 0.298 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methylphenol (44 mg, 0.357 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 56% yield (0.084 g, 0.1655 mmol).
Reaction SMILES: C([O:4][CH:5]([C:8]1[C:9]([S:14]([NH:17][C:18]([NH:20][C:21]2[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=2)=[O:19])(=[O:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][Cl:7])(=O)C.O[Li].O.O.Cl>CO>[Cl:7][CH2:6][CH:5]([C:8]1[C:9]([S:14]([NH:17][C:18]([NH:20][C:21]2[N:22]=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[N:26]=2)=[O:19])(=[O:15])=[O:16])=[N:10][CH:11]=[CH:12][CH:13]=1)[OH:4]
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ncccc2C(CCl)OC(C)=O)n1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ncccc2C(O)CCl)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 140 mg of 3-(1-acetoxy-2-chloroethyl)-N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-pyridinesulfonamide in 20 ml of methanol is added 20 mg of LiOH.H2O and 0.5 ml of water. After stirring at room temperature for 3 hours the solution is acidified to pH 4.5 with 5% aq. HCl. The resultant solution is extracted three times with CH2Cl2. The organic phase is evaporated and the trituration of the residue with Et2O yields the solid product.