Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[N:3]1([C:9]2[N:10]=[C:11]([CH2:16][C:17]([NH:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25]C)=[O:24])=[O:18])[NH:12][C:13](=[O:15])[CH:14]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>CO>[N:3]1([C:9]2[N:10]=[C:11]([CH2:16][C:17]([NH:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([OH:25])=[O:24])=[O:18])[NH:12][C:13](=[O:15])[CH:14]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(C(=O)O)c1
Temperature: 60 °C

Procedure:
1.8 ml of 2 M sodium hydroxide are added to a solution of 335 mg of methyl 3-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}amino)benzoate in 25 ml of methanol. The reaction mixture is heated at 60° C. for 2 h 30, and it is then concentrated under reduced pressure. The evaporation residue is taken up in 50 ml of water. The aqueous phase is extracted with ethyl acetate and then acidified (pH=6) by adding a 1N solution of hydrochloric acid. The precipitate formed is filtered off and then washed with 20 ml of water, 5 ml of ethyl acetate and, finally, 20 ml of ethyl ether. The solid is dried under vacuum and 175 mg of 3-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}amino)benzoic acid are thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][NH:15][C:14]3=[O:28])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=4)[CH2:16][N:15]([CH3:33])[C:14]3=[O:28])=[CH:11][CH:12]=2)=[CH:29][CH:30]=1
Reactant: O=C1NCC(c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[4-(4-chloro-phenoxy)-phenyl]-5-(3-trifluoromethyl-phenyl)-imidazolidin-2-one (20.0 mg, 0.046 mmol) in anhydrous DMF (0.5 mL) is added NaH (2.2 mg, 60% dispersion in mineral oil, 0.055 mmol) at 0° C. The reaction mixture is stirred at room temperature for 30 minutes before MeI (8.63 μL, 0.138 mmol) is added. The mixture is stirred at room temperature for 2 hours and then partitioned between water and ethyl acetate. The organic layer is concentrated and purified by preparative LC/MC to provide the title compound; HPLC-MS calculated for C23H18ClF3N2O2 (M+H+) 447.1, found 447.1.
Reaction SMILES: Cl.Cl.[I:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[N:10][C:11]=2[NH2:13])[N:6]([CH:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[N:5]=1.[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35]([N:37]([CH3:44])[C:38]([CH3:43])([CH3:42])[C:39](O)=[O:40])=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2N=CC=CC=2N=N1>ClCCl>[NH2:13][C:11]1[N:10]=[CH:9][N:8]=[C:7]2[N:6]([CH:14]3[CH2:19][CH2:18][CH2:17][N:16]([C:39](=[O:40])[C:38]([N:37]([CH3:44])[C:35](=[O:36])[O:34][CH2:33][CH:31]4[C:30]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:24]5[C:32]4=[CH:20][CH:21]=[CH:22][CH:23]=5)([CH3:43])[CH3:42])[CH2:15]3)[N:5]=[C:4]([I:3])[C:12]=12
Reactant: Nc1ncnc2c1c(I)nn2C1CCCNC1
Reactant: CN(C(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C(=O)N1CCCC(n2nc(I)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.9 %

Procedure:
A mixture of 3-iodo-1-(3-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (0.17 g, 0.00042 mol), 2-[[(9H-9-fluorenylmethoxy)carbonyl]-(methyl)amino]-2-methylpropanoic acid (0.175 g, 0.00052 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.1 g, 0.00052 mol), N,N-diisopropylethylamine (0.23 g, 0.0018 mol) and 1-hydroxy-7-azabenzotriazole (0.057 g, 0.00042 mol) in anhydrous dichloromethane (7 mL) was stirred for 18 hours at room temperature. Additional 2-[[(9H-9-fluorenylmethoxy)carbonyl](methyl)amino]-2-methylpropanoic acid (0.044 g, 0.00013 mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.025 g, 0.00013 mol) were added to the reaction and stirred for 16 hours. The solvent was removed under reduced pressure. The residue was partitioned between brine and ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic solvent was removed under reduced pressure, and the residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 20 min with 0.1 M ammonium acetate, 21 mL/min) to yield 9H-9-fluorenylmethyl N-{2-[3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidino]-1,1-dimethyl-2-oxoethyl}-N-methylcarbamate (0.030 g, 0.00005 mol).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH:14]([N:16]2[CH2:26][C:21]3[C:20](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19]2=[O:18])[CH3:15])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: CC(N)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(c1ccc(Oc2ccccc2)cc1)N1Cc2ccccc2C1=O
Reaction time: 16 h
Yield: 44.3 %

Procedure:
A mixture of 1-(4-phenoxyphenyl)ethylamine (213 mg, 1 mmol), 2-bromomethyl-benzoic acid methyl ester (250 mg, 1.1 mmol), and K2CO3 (1 g, 7.2 mmol) in toluene (10 mL) was heated at reflux with stirring for 16 h. Workup and silica gel column chromatography using a gradient of hexanes to 30% ethyl acetate in hexanes afforded 2-[1-(4-phenoxyphenyl)-ethyl]-2,3-dihydroisoindol-1-one (146 mg, 44%). GC/MS gave: m/z (rel.int.) 329 (M+, 46), 314 (100), 196 (8) and 77 (8). 1H NMR (300 MHz, CDCl3): δ 1.68 (d, 3H), 4.03 (d, 1H), 4.34 (d, 1H), 5.80 (q, 1H), 6.98 (br t, 4H), 7.10 (t, 1H), 7.49 (dt, 2H), 7.33 (br m, 5H), 7.88 (dd, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]([OH:13])=O)=[CH:6][CH:5]=2.[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:14]1([C:11]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2]([CH3:1])=[CH:10]3)=[O:13])[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12
Reactant: Cc1cc2cc(C(=O)O)ccc2[nH]1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cc2cc(C(=O)N3CCC[C@@H]4c5ccccc5C[C@@H]43)ccc2[nH]1
Yield: 39 %

Procedure:
The title compound is prepared from 2-methyl-1H-indole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 39% of theory; LC (method 4): tR=2.01 min; Mass spectrum (ESI+): m/z=331 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH:11]=[N:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][N:17]=[CH:18]3)=[C:4]([O:30]C)[C:3]=1[F:32].B(Br)(Br)Br.C(=O)(O)[O-:38].[Na+].C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([CH3:28])([CH3:29])[CH2:9][C:10]([OH:27])([C:23]([F:24])([F:25])[F:26])[CH:11]2[NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][NH:17][C:18]3=[O:38])=[C:4]([OH:30])[C:3]=1[F:32]
Reactant: O=C([O-])O
Reactant: COc1c(C(C)(C)CC(O)(C=Nc2cccc3cnccc23)C(F)(F)F)ccc(Cl)c1F
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3c(=O)[nH]ccc23)c2cc(Cl)c(F)c(O)c21
Temperature: 25 °C
Yield: 31.6 %

Procedure:
80.3 mg (0.166 mmol) of (rac.) 5-{[4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}isoquinolin-[1(2H)-one is mixed at room temperature with 1.7 ml of a 1 molar solution of boron tribromide in dichloromethane, and it is stirred for two and one-half hours at room temperature. The reaction mixture is mixed with ice, and then saturated sodium bicarbonate solution is added in drops (pH 8). After the ethyl acetate is added and after ten minutes of vigorous stirring at room temperature, the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with water and with brine, dried, and the residue is chromatographed on a Flashmaster after the solvent is spun off. 24.6 mg (31.6%) of the desired compound is isolated.
Reaction SMILES: [CH3:1][N:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]([C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH2:8][C:9]([O:11]CC)=[O:10])=[O:4].[OH-].[K+]>CO.O>[CH3:1][N:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]([C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH2:8][C:9]([OH:11])=[O:10])=[O:4]
Reactant: CCOC(=O)COc1ccccc1C(=O)N(C)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C(=O)c1ccccc1OCC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
Thus obtained ethyl 2-[2-(N-methyl-N-phenylcarbamoyl)phenoxy]acetate (18.23 g.) was added to 10% solution of potassium hydroxide in methanol (2 parts) and water (1 part), and the solution was stirred at room temperature for an hour and allowed to stand overnight. After concentrating the solution under reduced pressure, ethyl acetate was added to the concentrate. After shaking sufficiently, the aqueous solution was separated, acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated under reduced pressure to give crystals (13.21 g.) of 2-[2-(N-methyl-N-phenylcarbamoyl)phenoxy]acetic acid.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8](Cl)(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1(C)C=CC=CC=1>[CH:1]1([NH:7][C:8](=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: NC1CCCCC1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)NC1CCCCC1
Temperature: 30 °C

Procedure:
10 g of cyclohexylamine was dissolved in 80 ml of toluene. The resulting solution was cooled below 20° C. and 30 g of stearic acid chloride was added to the solution with stirring at temperatures below 20° C. The addition required one hour. The mixture solidified entirely. The solidified mixture was maintained at 30° C. for 2 hours. White crystals contained in the mixture was then filtered off, neutralized with alkaline alcohol and washed with water. The material so obtained was recrystallized from alcohol, from which it separated as white needles melting at 93.5° C. to 94.5° C. The yeild was 86%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][C@@H:15]([C:24]([OH:26])=[O:25])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][N:11]=[C:10]1[CH2:27][CH2:28][CH2:29][CH3:30].[CH3:31]I>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][C@@H:15]([C:24]([OH:26])=[O:25])[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:31])=[CH:12][N:11]=[C:10]1[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCc1ncc(C[C@H](NCc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Reactant: CI
Product: CCCCc1ncc(C[C@@H](C(=O)O)N(C)Cc2ccccc2)n1Cc1ccccc1Cl

Procedure:
3-[(2-chlorophenyl)methyl]-2-n-butyl-N-benzylhistidine (prepared in Example 13) is reacted with methyl iodide to give the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1.O=[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C(O)C>[CH3:1][N:2]1[C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:6]2=[CH:7][CH:8]=[CH:9][N:5]2[CH2:4][CH2:3]1
Reactant: CNCCn1cccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CN1CCn2cccc2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 70 °C
Yield: 78 %

Procedure:
N-Methyl-2-pyrrol-1-yl-ethanamine (2.19 g, 17.64 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (3.51 g, 17.64 mmol), and pTsOH.H2O (0.334 g, 1.76 mmol) were combined in ethanol (87.60 mL) and heated at 70° C. for 4 h. The reaction was concentrated and the residue was dissolved in dichloromethane. The organics were washed with a saturated NaHCO3 solution and brine. The organics were dried over sodium sulfate and evaporated. The crude material was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane with 2% triethylamine to give tert-butyl 2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (4.2 g, 78%). ESI-MS m/z calc. 305.4, found 306.3 (M+1)+; Retention time: 0.97 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 6.55-6.52 (m, 1H), 6.15-6.11 (m, 1H), 5.92-5.89 (m, 1H), 3.92 (t, J=6.0 Hz, 2H), 3.91-3.75 (m, 2H), 3.29 (t, J=6.0 Hz, 2H), 3.26-3.12 (m, 2H), 2.36 (s, 3H), 2.10-1.99 (m, 2H), 1.83-1.69 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17](OC)=[O:18])=[CH:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1.[NH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33]>>[F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]([NH:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])=[O:18])=[CH:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, 5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine and 2-amino-2-methylpropanol were reacted to yield 5-fluoro-N2-[2-(2-hydroxy-1,1-dimethylethylamino)carbonylbenzofuran-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.41 (s, 1H), 9.28 (s, 1H), 9.22 (s, 1H), 8.18 (t, 1H, J=2.4, Hz), 8.09 (d, 1H, J=3.6 Hz), 7.56 (dd, 1H, J=2.4 and 8.7 Hz), 7.47 (d, 1H, J=8.7 Hz), 7.32 (s, 1H), 7.26–7.21 (m, 1H), 7.13–7.07 (m, 2H), 6.53 (d, 1H, J=8.7 Hz), 5.05 (t, 1H, J=5.7 Hz), 3.46 (d, 2H, J=5.7 Hz), 1.32 (s, 6H); LCMS: ret. time: 17.93 min.; purity: 97%; MS (m/e): 452 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:16]([N:15]1[C:5]2[C:4]3[CH:3]=[C:2]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=[CH:14]1)[CH:17]([CH3:19])[CH3:18]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Product: CC(C)Cn1cnc2c(N)nc3ccc(-c4ccccc4)cc3c21

Procedure:
8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and benzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from isopropanol followed by recrystallization from methanol afforded 1-isobutyl-8-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a beige solid, m.p. 203-204° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:31])[C@:7]1([OH:30])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([O:26][CH:27]=[O:28])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:29])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].[CH2:32]([O:34][CH2:35]OCC)[CH3:33].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6](=[O:31])[C@:7]1([O:30][CH2:35][O:34][CH2:32][CH3:33])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([O:26][CH:27]=[O:28])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:29])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](OC=O)C[C@@]21C
Reactant: CCOCOCC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: CCOCO[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](OC=O)C[C@@]21C
Reaction time: 2.5 h

Procedure:
5.0 g. of 21-acetoxy-11β-formyloxy-17α-hydroxy-1,4-pregnadiene-3,20-dione is dissolved in 150 ml. of methylene chloride and 30 ml. of formaldehyde diethylacetal and cooled to 0° C. Under agitation, a mixture of 5 g. of phosphorus pentoxide and 10 g. of kieselguhr is inroduced, and the mixture is stirred for 2.5 hours in an ice bath, whereafter it is filtered, washed with methylene chloride, and brought to pH 9 with triethylamine. After the solvent has been distilled off, 10.5 g. of crude 21-acetoxy-17α-ethoxymethoxy-11β-formyloxy-1,4-pregnadiene-3,20-dione is obtained as a semisolid mass.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11]([CH3:15])([CH3:16])[C:12]([NH:23][C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2[nH]ccc2c1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C(=O)Nc1nccs1)C(c1ccccc1)c1ccc2[nH]ccc2c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 72.7 %

Procedure:
To a stirred solution of 3-(1H-indol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid (0.31 g, 1.1 mmol), 2-aminothiazole (0.2 g, 2 mmol), and diisopropylethylamine (0.5 mL) in anhydrous DMF (3 mL) was added HATU (1 g, 2.7 mmol) under argon. After the reaction mixture was stirred at rt for 14 hr and 80° C. for 6 hr, it was concentrated, dissolved in ethyl acetate (20 mL), washed with saturated aqueous sodium bicarbonate solution (10 mL), brine (10 mL), dried (Na2SO4), and concentrated. Silica gel flash chromatography gave 3-(1H-indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide (Example 107, 0.3 g, 0.8 mmol, 75% yield) as a yellow solid. MS found: (M+H)+=376. 1H-NMR (400 MHz, MeOD) δ ppm 7.60 (1H, s) 7.43 (2H, d, J=7.12 Hz) 7.38 (1H, d, J=3.56 Hz) 7.20-7.29 (3H, m) 7.12-7.20 (2H, m) 7.10 (1H, d) 7.04 (1H, d, J=3.56 Hz) 6.38 (1H, d, J=3.05 Hz) 4.70 (1H, s) 4.62 (1H, s) 1.43 (6H, d, J=4.07 Hz).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[N:38]([C:39]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:37]=[N:36][N:35]=2)=[CH:24][CH:23]=1.O>CS(C)=O>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38]([C:39]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:37]=[N:36][N:35]=3)=[CH:26][CH:27]=2)[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
0.87 g (5 mmol) of 2-n-butyl-benzimidazole is dissolved in 20 ml of dimethylsulphoxide and 0.61 g (5.5 mmol) of potassium tert.butoxide is added with stirring. After 1/2 hour, 4'-bromomethyl-2-(1-triphenylmethyl-1H-tetrazol-5-yl)-biphenyl is added and the mixture is stirred for 3 hours at ambient temperature. It is poured into about 50 ml of iced water and extracted by shaking 3 times using 30 ml of ethyl acetate each time. The ethyl acetate phase is extracted by shaking using 30 ml of water, dried over sodium sulphate and evaporated to dryness. The crude product is purified over a silica gel column (grain size: 0.063-0.2 mm, eluting agent: methylene chloride/ethanol=100:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:28]1([CH2:34][C:35](Cl)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:35](=[O:36])[CH2:34][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Product: C[C@H](NC(=O)Cc1ccccc1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and phenylacetyl chloride (23 mg, 150 μmol). Yield 22 mg (80%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.[CH3:21][O:22][C:23]([C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]3OC(C)(C)O[C:40](=[O:42])[CH:41]=3)[CH:31]=2)[O:28][CH:29]=1)=[O:24].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][O:22][C:23]([C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]3[CH2:41][C:40](=[O:42])[NH:19][C:9]4[CH:10]=[C:11]([N:14]5[CH:18]=[CH:17][CH:16]=[CH:15]5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:31]=2)[O:28][CH:29]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Reactant: COC(=O)c1coc(-c2cccc(C3=CC(=O)OC(C)(C)O3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1coc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J2) (680 mg) and 2-[3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-phenyl]-oxazole-4-carboxylic acid methyl ester (Example L7) (820 mg) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (770 mg).