Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]2[CH2:15][O:14][CH2:13]2)[CH:3]=1.[OH-].[NH4+:17]>>[Br:1][C:2]1[C:10]2[C:9]([NH2:17])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]2[CH2:15][O:14][CH2:13]2)[CH:3]=1
Reactant: Clc1ncnc2c1c(Br)cn2C1COC1
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1ncnc2c1c(Br)cn2C1COC1
Temperature: 85 °C
Yield: 61.5 %

Procedure:
To 5-bromo-4-chloro-7-(3-oxetanyl)-7H-pyrrolo[2,3-d]pyrimidine (185 mg, 0.641 mmol) was added ammonium hydroxide (24.97 μl, 0.641 mmol) in a 25 ml sealable vial and heated at 85° C. over 24 hr. The solid was isolated by filtration and washed with water (5 mL) and dried to give 5-bromo-7-(3-oxetanyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (106 mg), which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:32][CH2:33][CH3:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:27][C:28](O)=[O:29])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[O:17])[C:7]1=[O:31])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[NH2:47][C:48]1[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=1>ClCCl.C(OCC)(=O)C>[CH2:33]([O:32][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:27][C:28]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)=[O:29])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[O:17])[C:7]1=[O:31])[CH3:34]
Reactant: CCOC(CN1C(=O)C(CC(=O)O)(NC(=O)Nc2cccc(OC)c2)c2ccccc21)OCC
Reactant: Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2cccc(OC)c2)c2ccccc21)OCC
Reaction time: 9 h
Yield: 77.4 %

Procedure:
In 30 ml of dichloromethane was dissolved 0.50 g of (-)-1-(2,2-diethoxyethyl)-3-hydroxycarbonylmethyl-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one, and 0.22 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride and 0.20 g of p-toluidine were successively added thereto. After stirring the mixture for 9 hours, the reaction mixture was diluted with ethyl acetate and washed successively with dilute hydrochloric acid and saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give 0.46 g of the title compound as a white powder. Because the compound is an enantiomer of the compound of Example 188, the NMR data are the same as those of the latter compound.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[F:14])C=C.C(N(CC)[C:18]1[CH:23]=CC=C[CH:19]=1)C>>[CH2:23]([C:10]1[CH:9]=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[C:6]([F:14])[C:5]=1[OH:4])[CH:18]=[CH2:19]
Reactant: CCN(CC)c1ccccc1
Reactant: C=CCOc1ccc([N+](=O)[O-])cc1F
Product: C=CCc1cc([N+](=O)[O-])cc(F)c1O
Yield: 60 %

Procedure:
Compound 2 (25 g, 126.8 mmol) was solved in diethyl aniline (150 mL, 937.7 mmol) and the resulting solution was refluxed for 48 h. The crude was evaporated in vacuo and the residue was purified by column chromatography, eluted at 10% ethyl acetate/hexane. Fractions were collected to obtain the desired compound 3 (15 g, yield 60%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3]C(OC1C=CC([N+]([O-])=O)=CC=1)=O.[CH3:16][C@@H:17]([C@@H:29]1[C@@:33]2([CH3:50])[C@@H:34](O)[CH2:35][C@@H:36]3[C@@:41]4([CH3:47])[CH2:42][CH2:43][C@@H:44]([OH:46])[CH2:45][C@H:40]4[CH2:39][C@@H:38](O)[C@H:37]3[C@@H:32]2[CH2:31][CH2:30]1)[CH2:18][CH2:19][C:20](NCCS([O-])(=O)=O)=O.[Na+].[Na]>>[CH3:1][CH:2]([CH2:20][CH2:19][CH2:18][C@H:17]([C@@H:29]1[C@:33]2([CH3:50])[C@H:32]([C@H:37]3[C@H:36]([CH2:35][CH2:34]2)[C@:41]2([CH3:47])[C:40]([CH2:45][C@H:44]([CH2:43][CH2:42]2)[OH:46])=[CH:39][CH2:38]3)[CH2:31][CH2:30]1)[CH3:16])[CH3:3]
Reactant: CCCC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@H](CCC(=O)NCCS(=O)(=O)[O-])[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: [Na+]
Agent: [Na]
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
The assay substrate contained p-Nitrophenyl butyrate (Sigma Cat. No. N9876) MW 209.2. Density 1.2 and Taurocholic acid, sodium salt (Sigma Cat. No. T 4009) MW 537.7 The assay substrate was prepared by dissolving 43 mg Taurocholic acid (6 mM final concentration)+87 μl p-Nitrophenyl butyrate (40 μM final concentration)+50 μl 20% Triton X-100 (0.08% final concentration) in 10 ml of 100 mM MOPS 2 mM CaCl2 pH 7.3. The substrate was shaken to dissolve the ingredients and centrifuged to clarify.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:26])[NH:13][C:14](=[O:25])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=2)=[CH:3]1.[OH-].[Na+]>CC(C)=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:26])[NH:13][C:14](=[O:25])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cccc([N+](=O)[O-])c3)C(=O)NC2=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cn1cc(C2=C(c3cccc(N)c3)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of 3-(1-methylindol-3-yl)-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione (6.5 g, 19 mmol) in acetone (500 mL), was added TiCl3 (45 mL) in 5 portions at 30 minute interval. The reaction mixture was stirred at room temperature overnight and then neuteralized with 10N NaOH. The product was extracted with EtOAc, dried, and concentrated. The crude product was purified on a silica gel column with 3% MeOH in CH2Cl2 to afford 3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (4.9 g, 82.5%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][NH2:27])[CH:20]=1>>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:27][CH2:26][CH2:25][C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: NCCc1cccnc1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CC(C)N1C(=O)C(NCCc2cccnc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and (2-pyridin-3-ylethyl)amine in a similar manner as described for Example 118. 1H NMR (500 MHz CDCl3): δ 1.59 (d, 6H), 2.59 (t, 2H), 3.17 (q, 2H), 4.37-4.45 (m, 1H), 5.47 (t, 1H), 7.06-7.09 (m, 1H), 7.14-7.17 (m, 1H), 7.46-7.55 (m, 5H), 8.07 (s, 1H), 8.44-8.46 (m, 1H); 13C NMR (125 MHz CDCl3): δ 20.38, 33.39, 44.78, 47.88, 107.76, 123.70, 125.15, 129.13, 130.20, 131.84, 133.02, 135.16, 136.13, 148.57, 150.06, 158.61; Mass Spectrum: M+H+ 372.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:48]=[CH:47][C:12]([CH2:13][C@H:14]([NH:35][C:36](=[O:46])[O:37][C@H:38]2[C@H:45]3[C@H:41]([O:42][CH2:43][CH2:44]3)[O:40][CH2:39]2)[C@H:15]([OH:34])[CH2:16][N:17]([CH2:30][CH:31]([CH3:33])[CH3:32])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:51](OC)([CH3:53])[CH3:52].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C@H:14]2[C@@H:15]([CH2:16][N:17]([CH2:30][CH:31]([CH3:33])[CH3:32])[S:18]([C:21]3[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[O:34][C:51]([CH3:53])([CH3:52])[N:35]2[C:36]([O:37][C@H:38]2[C@H:45]3[C@H:41]([O:42][CH2:43][CH2:44]3)[O:40][CH2:39]2)=[O:46])=[CH:47][CH:48]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)O[C@@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 64.5 %

Procedure:
To a solution of (3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-{isobutyl[(4-nitrophenyl)sulfonyl]amino}propylcarbamate (1.00 g, 1.5 mmol) in 20 mL of dichloromethane was added 2,2-dimethoxypropane (1.5 g, 14.6 mmol) and p-toluenesulfonic acid (0.09 g, 0.5 mmol). The solution was refluxed for 12 hours, and the solvent was removed under reduced pressure. The residue was purified on silica gel using ethyl acetate-hexanes (3.5:6.5) as eluent to provide 0.70 g (70%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:27])[C:18]([NH:20][CH:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:36])C=1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:27])[C:18]([NH:20][CH:21]2[CH2:22][CH2:23][S:24](=[O:36])[CH2:25][CH2:26]2)=[O:19])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCSCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCS(=O)CC2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
To a solution of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxo-N-(tetrahydro-2H-thiopyran-4-yl)acetamide (Example 193, 0.25 g, 0.63 mmol), in ethyl acetate (5 mL) was added m-chloroperbenzoic acid (0.19 g, 0.76 mmol) at 0° C. After stirred at 0° C. for 3 h, the mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 50:50 to 0:100 then ethyl acetate/methanol 100/0 to 70/30) to give the title compound (0.14 g, 55%) as a white solid.
Reaction SMILES: [S:1]=[C:2]1[C@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=2[NH:3]1.[H-].[Na+].[CH3:26]I>C1COCC1>[CH3:26][S:1][C:2]1[C@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH2:6][C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=2[N:3]=1
Reactant: O=C(N[C@@H]1CCc2ccccc2NC1=S)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC1=Nc2ccccc2CC[C@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 95.8 %

Procedure:
Dissolve benzyl N-[(3R)-2-thioxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]carbamate (1.5 g, 4.60 mmol) in THF (40 mL), cool to 0° C., and add sodium hydride (NaH) (192.9 mg, 4.83 mmol, 60% in mineral oil) all at once. Remove the bath and stir the reaction for approximately 1 hour under nitrogen. Add methyl iodide (300 μL, 4.83 mmol) and stir for approximately 1 hour at ambient temperature. Concentrate the reaction under reduced pressure to remove most of the THF, dilute the residue with ethyl acetate, and wash with saturated sodium bicarbonate and brine, dry over sodium sulfate, and concentrate the organic layers under reduced pressure to give the title compound (1.5 g, 96%) as a white solid: MS (m/z): 341 (M+1).
Reaction SMILES: O1CCCC1.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Br:13])[CH:12]=1.C([Mg]Cl)(C)C.[CH2:19]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1)[CH3:20]>O>[Br:13][C:11]1[CH:12]=[C:7]([CH:26]([C:25]2[CH:28]=[CH:29][C:22]([O:21][CH2:19][CH3:20])=[CH:23][CH:24]=2)[OH:27])[CH:8]=[N:9][CH:10]=1
Reactant: CCOc1ccc(C=O)cc1
Reactant: Brc1cncc(Br)c1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(C(O)c2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.9 %

Procedure:
A tetrahydrofuran solution (25 mL) of 3,5-dibromo pyridine (5 g, 0.0211 mol) was added dropwise to a mixture of a tetrahydrofuran solution (21.1 mL) of 1M isopropyl magnesium chloride and tetrahydrofuran (10 mL) at 4° C. for 15 minutes. After stirred at room temperature for 2.5 hours, the reaction mixture was added with 4-ethoxybenzaldehyde (2.93 mL, 0.0211 mol) and stirred for further 1.5 hours. After the reaction mixture was added with water while cooled on ice and extracted with ethyl acetate, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain (5-bromopyridine-3-yl)(4-ethoxyphenyl)methanol (5.0 g, 77%) as a yellow oily substance.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br.[C-:14]#[N:15].[Na+]>CN(C=O)C>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][C:14]#[N:15]
Reactant: FC(F)(F)Oc1ccccc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 2-trifluoromethoxybenzyl bromide (0.95 g, 3.9 mmol) from Step 2 above in DMF (5 mL) was added NaCN (0.21 g, 4.3 mmol). The mixture was stirred at ambient temperature for 14 h and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 15% EtOAc-hexanes as eluant to give 2-trifluoromethoxyphenylacetonitrile as a colorless liquid (TLC Rf =0.6 (solvent)).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:11][N:12]([CH3:25])[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>>[CH3:25][N:12]([CH3:11])[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:21]=[C:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:23][CH:24]=1
Reactant: O=C1CCc2ccccc21
Reactant: CN(C)CCCOc1ccc(C=O)cc1
Product: CN(C)CCCOc1ccc(C=C2Cc3ccccc3C2=O)cc1
Yield: 98.5 %

Procedure:
Interaction of 56 g of 1-indanone and 88 g of 4-(3-dimethylaminopropoxy)benzaldehyde according to the procedure described in Example 1A, gives 134.2 g of an oily product.
Reaction SMILES: O1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([CH2:21][CH:22]([CH:27]([CH3:29])[CH3:28])[C:23]([NH:25][OH:26])=[O:24])(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.CC(C)C(CS([N:40]1CCN(C2C=CC(C3C=NC=CC=3)=CC=2)C[CH2:41]1)(=O)=O)C(O)=O>>[N:40]1[CH:5]=[CH:4][CH:3]=[C:2]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH2:21][CH:22]([CH:27]([CH3:29])[CH3:28])[C:23]([NH:25][OH:26])=[O:24])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][CH:7]=2)[CH:41]=1
Reactant: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(-c3cccnc3)cc2)CC1)C(=O)O
Reactant: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(-c3ccco3)cc2)CC1)C(=O)NO
Product: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(-c3cccnc3)cc2)CC1)C(=O)NO
Yield: 76 %

Procedure:
Prepared according to the method for the preparation of 2-[4-(4-furan-2-yl-phenyl)piperazine-1-sulfonylmethyl]-N-hydroxy-3-methylbutyramide, from 3-methyl-2-[4-(4-pyridin-3-yl-phenyl)piperazine-1-sulfonylmethyl]butyric acid (0.075 g), to yield the title compound as a white solid (0.059 g, 76%).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([F:16])=[CH:11][CH:10]=3)=[CH:5][N:6]=1.[NH2:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1>CC(O)C>[F:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]([C:4]1[O:3][C:2]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=3)=[N:6][CH:5]=1)=[CH:15]2
Reactant: Nc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)n1c(-c2cnc(Cl)o2)cc2cc(F)ccc21
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)n1c(-c2cnc(Nc3cccc(O)c3)o2)cc2cc(F)ccc21
Temperature: 80 °C
Yield: 40 %

Procedure:
A mixture of tert-butyl 2-(2-chlorooxazol-5-yl)-5-fluoro-1H-indole-1-carboxylate 50 (0.308 g, 0.916 mmol) and commercially available 3-aminophenol 8 (0.10 g, 0.916 mmol) in 2-propanol (20 mL) was heated to 80° C. for 18 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide tert-butyl 5-fluoro-2-(2-((3-hydroxyphenyl)amino)oxazol-5-yl)-1H-indole-1-carboxylate 51 (0.15 g, 40% yield) as solid. MS (ES) m/z 410 (M+H+).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:2]([CH3:5])([CH3:4])[CH3:3].[C:12]1(=[O:22])[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[O:22])=[CH:10][CH:11]=1)[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)Cc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Product: CC(C)(C)Cc1ccc(C(=O)c2ccccc2C(=O)O)cc1

Procedure:
In the novel process, neopentylbenzene (1) is acylated in a first step with phthalic anhydride (2) under Friedel-Crafts conditions to give 2-(4-neopentylbenzoyl)-benzoic acid (3). ##STR3##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C@@H:20]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:21]([O:23][CH3:24])=[O:22]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C@@H:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccn1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2) and methyl (S)-2-amino-3-(2-pyridyl)propionate hydrochloride (Synthetech), the tide compound was prepared as a solid (mp=121-124° C.). The reaction was monitored by tlc (Rf=0.39 in 10% MeOH/DCM) and the product was purified by silica gel column chromatography.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([C:17](OCC)=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[H-].C([Al+]CC(C)C)C(C)C.O>C1(C)C=CC=CC=1>[OH:18][CH2:17][C:4]1([CH2:3][O:2][CH3:1])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1(COC)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: COCC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a solution of 1-tert-butyl 4-ethyl 4-(methoxymethyl)piperidine-1,4-dicarboxylate (2.05 g) in toluene (21 ml) was added 0.99 M solution of diisobutyl aluminum hydride in toluene (16.5 ml) under at 0° C. It was stirred at room temperature for 2 hours. Water was added and extracted with EtOAc. The organic phase was washed with water and brine, dried over MgSO4, evaporated off. The residue was purified by silica gel column to give tert-butyl 4-(hydroxymethyl)-4-(methoxymethyl)piperidine-1-carboxylate (0.95 g) as oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH2:17][CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21].C(N(CC)CC)C>ClCCl>[CH2:20]([O:19][CH:18]([O:22][CH2:23][CH3:24])[CH2:17][CH2:16][NH:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:21]
Reactant: CCOC(CCN)OCC
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(CCNc1c([N+](=O)[O-])cnc2ccccc12)OCC
Yield: 98.4 %

Procedure:
The general method described in Step 1 of Example 1 was used to react 4-chloro-3-nitroquinoline (20.3 g, 97.1 mmol), 1-amino-3,3-diethoxypropane (25.0 g, 116 mmol) and triethylamine (33.8 g, 333 mmol) in dichloromethane for 15 hours to provide (3,3-diethoxypropyl)-(3-nitroquinolin-4-yl)amine (30.5 g) as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][CH:22]([F:34])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[O:32][CH3:33]>>[F:21][CH:22]([F:34])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:1]2[CH:2]([C:11]3[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]2=[O:7])=[CH:26][C:25]=1[O:32][CH3:33]
Reactant: COc1cc(C=O)ccc1OC(F)F
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cc(CN2C(=O)C(C)CC2c2c(OC)cccc2OC)ccc1OC(F)F

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 4-(difluoromethoxy)-3-methoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.85 min.; [M+H]+: 422.01 g/mol.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=2)=[C:8]([CH:21]=1)[C:9]([O:11]CC1C=CC=C(C#N)C=1)=[O:10]>O.C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=2)=[C:8]([CH:21]=1)[C:9]([OH:11])=[O:10]
Reactant: N#Cc1cccc(COC(=O)c2cc(Br)ccc2OCc2cccc(C#N)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc(COc2ccc(Br)cc2C(=O)O)c1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of lithium hydroxide (386 mg, 9.19 mmol) in water (20.00 mL) was added dropwise to a stirred solution of (3-cyanophenyl)methyl 5-bromo-2-{[(3-cyanophenyl)methyl]oxy}benzoate (may be prepared as described in Description 25; 411 mg, 0.92 mmol) in THF (20 ml) over 1 min. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was evaporated and the aqueous phase (20 ml) was extracted by ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml). The aqueous phase was then extracted with ethyl acetate (3×20 ml). The organic phase was evaporated in vacuo to yield the title compound as an off-white solid. 200 mg.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[NH:3]1.[CH3:9][CH:10]([CH3:14])[C:11](Cl)=[O:12]>>[CH3:9][CH:10]([CH3:14])[C:11]([N:3]1[CH:4]([CH3:8])[CH2:5][N:6]([C:11](=[O:12])[CH:10]([CH3:14])[CH3:9])[CH2:7][CH:2]1[CH3:1])=[O:12]
Reactant: CC(C)C(=O)Cl
Reactant: CC1CNCC(C)N1
Product: CC(C)C(=O)N1CC(C)N(C(=O)C(C)C)C(C)C1
Yield: 55.8 %

Procedure:
The reaction of 5.7 g (0.05 mole) of 2,6-dimethylpiperazine with 13.85 g (0.13 mole) of 2-methylpropionyl chloride is carried out as described in Example VI, and yields 13.3 g of crude product as a solid. Recrystallization from acetone provides 7.1 g of the pure product: mp, 160°-161° C. An additional 4.0 g of pure product is obtained by concentrating the mother liquor and adding hexane. The assigned product structure is consistent with IR and NMR data.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][CH2:33][NH2:34])[N:18]=[C:17]([C:35]3[N:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[S:46](Cl)(=[O:48])=[O:47]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][CH2:33][NH:34][S:46]([C:42]3[S:41][CH:45]=[CH:44][CH:43]=3)(=[O:48])=[O:47])[N:18]=[C:17]([C:35]3[N:36]=[CH:37][CH:38]=[CH:39][N:40]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCCN
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCCNS(=O)(=O)c1cccs1

Procedure:
According to the procedure described in Example 4a) 100 mg 4-tert.-butyl-N-[6-(3-aminopropoxy)-5-(o-methoxyphenoxy)-2-pyrimidinyl-4-pyrimidinyl]-benzene-sulfonamide was reacted with 2-thiophenesulfonylchloride to give 50 mg 4-tert.-butyl-N-[6-(3-(2-thiophenesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-pyrimidinyl-4-pyrimidinyl]-benzene-sulfonamide. LC-MS: tR=5.63 min, [M+1]+711.28, [M−1]−=709.36.