Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:20])[C@@H:12]2[C@H:15]([O:17][CH:18]=[O:19])[CH3:16])[C:9]=1[C:21]([O:23]CC1C=CC([N+]([O-])=O)=CC=1)=[O:22])(=[O:3])[CH3:2].[H][H].C(=O)(O)[O-].[Na+:40]>O1CCOCC1.[Pd]>[C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:20])[C@@H:12]2[C@H:15]([O:17][CH:18]=[O:19])[CH3:16])[C:9]=1[C:21]([O-:23])=[O:22])(=[O:3])[CH3:2].[Na+:40]
Reactant: CC(=O)N/C=C/SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)OC=O)[C@H]2C1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)N/C=C/SC1=C(C(=O)[O-])N2C(=O)[C@H]([C@@H](C)OC=O)[C@H]2C1

Procedure:
The formate ester (e4, 10 mg) was dissolved in 30% aqueous 1,4-dioxan (10 ml) and shaken with hydrogen in the presence of 5% palladium on carbon catalyst (15 mg) for 3.5 hours. Sodium bicarbonate (2.3 mg) was then added and the solution filtered through Celite, washing well with water (20 ml). The filtrate was concentrated at reduced pressure to approximately 15 ml and washed with ethylacetate (3×20 ml). The resulting aqueous solution was estimated to contain 2.2 mg of the title compound (e7) based on εm 14,000 at λmax 307 nm in the uv spectrum,λmax (H2O) 307 nm 229 nm.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[H-].[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.C(O)(=O)C>C1COCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][C:1]([O:5][CH2:6][CH3:7])=[O:8])=[CH:14][CH:13]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
To a suspension of diethyl carbonate (47.4 mL, 391 mmol) and sodium hydride (55 wt % paraffin oil, 23.7 g, 543 mmol) in THF was added 4′-fluoroacetophenone (26.4 mL, 271 mmol) at 60° C. The reaction mixture was heated under reflux for 1 hr, cooled to room temperature, and poured into acetic acid (33.6 ml, 586 mmol) and ice water (1 L). The reaction mixture was extracted with diethyl ether (2×500 mL), the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried, and the solvent was evaporated under reduced pressure to give ethyl 3-(4-fluorophenyl)-3-oxopropanoate (45.7 g, 100%, keto form: enol for m=5:1) as a yellow oil.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:22]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[N:21]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:22]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[N:21]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ncc1F)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(COc3cc(C(CC(=O)O)C4CC4)c(F)cn3)nc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 91.9 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(5-fluoro-2-((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methoxy)pyridin-4-yl)propanoate (379 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at 50° C. for 20 min. To the reaction mixture was added 1N hydrochloric acid (2.0 mL) at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (330 mg) as a white amorphous solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:19](=[O:20])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.[CH:21]([N:24]([CH:27]([CH3:29])C)CC)([CH3:23])C.N1CCCC1.[I-].[Na+]>CN(C)C=O>[C:13]1([C:10]2[C:9]3[C:19](=[O:20])[CH:5]([CH2:4][CH2:3][CH2:2][N:24]4[CH2:21][CH2:23][CH2:29][CH2:27]4)[CH2:6][CH2:7][C:8]=3[O:12][N:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1c2c(-c3ccccc3)noc2CCC1CCCCl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: O=C1c2c(-c3ccccc3)noc2CCC1CCCN1CCCC1
Temperature: 25 °C

Procedure:
To a solution consisting of 5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (3.75 g) and dimethylformamide (37.0 ml) was added diisopropylethyl amine (6.81 ml), pyrrolidine (2.17 ml) and sodium iodide (5.85 g) at room temperature with stirring. The reaction was flushed with nitrogen and warmed at 73°-76° C. for 1.25-2 hours. Upon cooling to room temperature, dilute aqueous sodium bicarbonate and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous layer extracted twice with ethyl acetate and once with ether. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 2% triethylamine/0-10% methanol/ether) afforded 3.10 g of 6,7-dihydro-3-phenyl-5-[3-(1-pyrrolidinyl)-propyl]-1,2-benzisoxazol-4(5H)-one as an oil which solidified on standing. The salicylate was prepared with 1.07 eq. salicylic acid in ether. The resulting solid was redissolved with methanol. Addition of pentane led to precipitation of the target salt. Filtration and washing with pentane gave 6,7-dihydro-3-phenyl-5-[3-(1-pyrrolidinyl)-propyl]-1,2-benzisoxazol-4(5H)-one salicylate, m.p. 106°-107° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O.[C-:26]#[N:27].[Na+].C(=O)(O)[O-].[K+].O>CS(C)=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:26]#[N:27]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1oc(-c2ccccc2)nc1CCC#N
Yield: 97.6 %

Procedure:
Toluene-4-sulfonic acid 2-(5-methyl-2-phenyloxazol-4-yl)ethyl ester (5.00 g, 14.0 mmol), sodium cyanide (852 mg, 16.8 mmol), and potassium bicarbonate (1.70 g, 16.8 mmol) were combined and vigorously stirred in DMSO (50 mL) at 50° C. for 2 h, then overnight at 25° C. The mixture was then poured into H2O (50 mL) and extracted with Et2O (2×50ML). The organic layer were combined then washed with H2O (50 mL), sat. NaCl (50 mL), dried over NaCl. The solvent was removed in vacuo to provide 2.90 g (98%) of product as a white powder: 1H NMR (400 MHz, CDCl3) δ 7.93 (m, 2 H), 7.39 (m, 3 H), 2.81 (t, 2 H), 2.71 (t, 2 H), 2.35 (s, 3 H); MS (EI) 213.1 (M+H)+.
Reaction SMILES: [C:1]1([C:7](=[O:16])[CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:19]I>C1COCC1>[CH3:9][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([CH3:19])[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:16]
Reactant: CC(C(=O)c1ccccc1)c1ccccn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C(=O)c1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A solution of compound 3 (3.0 g, 14.2 mmol) in THF (10 mL) is added to a suspension of sodium hydride (60%, 0.63 g, 15.6 mmol) in THF (60 mL) at 0° C. The reaction mixture is kept at the same temperature for 2 hours and methyl iodide (0.93 mL, 14.9 mmol) is added at 0° C. The reaction mixture is allowed to warm up to room temperature overnight and then quenched with water. The mixture is separated and the aqueous phase is extracted with ethyl acetate (2×40 mL). The extracts are combined, washed with brine, dried, concentrated and purified by column chromatography (hexane/ethyl acetate 50:1 to 4:1) to give 4 (2.2 g, 69%) as a yellow solid.
Reaction SMILES: [NH2:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=2)=[N:5][N:4]=[C:3]1[SH:19].[N:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29](O)=O)=[CH:28][C:23]=2[NH:22][CH:21]=1>P(Cl)(Cl)(Cl)=O>[NH:22]1[C:23]2[CH:28]=[C:27]([C:29]3[S:19][C:3]4=[N:4][N:5]=[C:6]([C:7]5[CH:8]=[C:9]([O:17][CH3:18])[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=5)[N:2]4[N:1]=3)[CH:26]=[CH:25][C:24]=2[N:20]=[CH:21]1
Reactant: COc1cc(-c2nnc(S)n2N)cc(OC)c1OC
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(-c2nnc3sc(-c4ccc5nc[nH]c5c4)nn23)cc(OC)c1OC
Yield: 17.5 %

Procedure:
A mixture of 4-amino-3-mercapto-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (80 mg, 0.28 mmol) and 3H-benzo[d]imidazole-5-carboxylic acid (46 mg, 0.28 mmol) in phosphoryl chloride (2 mL) was refluxed for 3 h. The solvent was evaporated and the residue was dissolved in dichloromethane (20 mL). It was neutralized with aqueous sodium carbonate. The organic layer was dried over sodium sulfate, concentrated to give 20 mg (17%) of the title compound as a solid. 1H NMR (CD3OD): 8.55 (s, 1H), 8.35 (s, 1H), 8.01-7.85 (m, 2H), 7.72 (s, 1H), 3.99 (s, 6H), 3.87 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].S(=O)(=O)(O)O.[CH2:21](O)[CH2:22][CH3:23]>>[CH2:21]([O:13][C:12](=[O:14])[CH:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=1)[CH3:15])[CH2:22][CH3:23]
Reactant: CCCO
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CCCOC(=O)C(C)c1ccc(CC(C)C)cc1
Temperature: 0 °C
Yield: 89.7 %

Procedure:
A mixture of 5 g of 2-(4-isobutylphenyl)propionic acid, 7.3 g of n-propyl alcohol and 7.1 g of sulfuric acid was refluxed for 6 hours. After cooling, to the mixture was added ice-water. The resulting mixture was extracted with ether, and the extract was dehydrated. The ether was removed by distillation from the extract to leave an oily product. This product was distilled in vacuo to give 5.4 g of 2-(4-isobutylphenyl)propionic acid-n-propyl ester as a colorless oil, boiling at 100°-103° C./0.3 mmHg. Mass spectrum: parent ion 248 m/e.
Reaction SMILES: [C:1]1([C:7]2([CH2:12][C:13]([OH:15])=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([C:20]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH:29]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:23][C:21]=1[NH2:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH:29]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:30][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)=[CH:23][C:21]=1[NH:22][C:13](=[O:15])[CH2:12][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C(O)CC1(c2ccccc2)CCCC1
Reactant: CC(C)(C)c1ccc(CCC(CC2CCCCC2)O[Si](C)(C)C(C)(C)C)cc1N
Product: CC(C)(C)c1ccc(CCC(CC2CCCCC2)O[Si](C)(C)C(C)(C)C)cc1NC(=O)CC1(c2ccccc2)CCCC1

Procedure:
Following a procedure similar to that described in Example 21, but using 2-(1-phenylcyclopentyl)acetic acid [prepared as described in Preparation 21] and 2-t-butyl-5-[4-cyclohexyl-3-(t-butyldimethylsilyloxy)butyl]aniline [prepared by a procedure similar to that described in Preparation 11(i)] as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a foam-like material.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CN(C=O)C>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Nc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a mixture of NaH (60% oily, 880 mg, 22.0 mmol) in DMF (40 mL) was added a solution of 4-aminophenol (2.40 g, 22.0 mmol) in DMF (30 mL) followed by 1-fluoro-4-nitrobenzene (2.12 mL, 20.0 mmol). The mixture was stirred at 90° C. overnight. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (4.60 g, quant): MS m/e 229 (M−1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:24])([CH3:23])[CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][C:3]([CH3:24])([CH3:23])[CH2:2][NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CNS(C)(=O)=O

Procedure:
Using the general method of Example 242, 1-(3-amino-2,2-dimethylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.22 g, 0.672 mmol) was reacted with methanesulfonyl chloride (125 μL) to provide 270 mg of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropyl}methanesulfonamide as a cream colored powder, m.p. 204.0-206.0° C. Analysis: Calculated for C19H27N5O3S 0.50H2O: % C, 55.05; % H, 6.81; % N, 16.89; % S, 7.74; Found: % C, 55.10; % H, 6.58; % N, 17.23; % S, 7.51. % H2O calculated: 2.17; found: 2.28 (Karl Fisher).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33]([N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)=[N:34][C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[OH:45])=[N:36]2)=[CH:31][CH:30]=1.[OH:52][C@H:53]([CH2:57][CH:58]([CH3:60])[CH3:59])[C:54](O)=[O:55].C(N(CC)CC)C>CN(C=O)C>[OH:52][C@H:53]([CH2:57][CH:58]([CH3:60])[CH3:59])[C:54]([N:49]1[CH2:50][CH2:51][N:46]([C:33]2[C:32]3[C:37](=[CH:38][C:29]([CH3:28])=[CH:30][CH:31]=3)[N:36]=[C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[OH:45])[N:34]=2)[CH2:47][CH2:48]1)=[O:55]
Reactant: CC(C)C[C@@H](O)C(=O)O
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(C(=O)[C@H](O)CC(C)C)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
Under an N2 atmosphere, BOP (138 mg, 0.31 mmol) was added in a single portion to a stirring solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (100 mg, 0.31 mmol), (R)-2-hydroxy-4-methylpentanoic acid (41 mg, 0.31 mmol), and triethylamine (43 μL, 0.31 mmol) in DMF (0.5 ml). After stirring the mixture for 1 h at room temperature, it was partitioned between H2O and ether. The organic phase was washed with H2O (3×20 mL), dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 20% EtOAc and 80% CH2Cl2 gave (R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one as a light yellow solid (89 mg, 60%). LC/MS: m/z 435.1 (M+H)+ at 2.93 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, CDCl3) δ 8.46 (dd, J=7.9, 1.7 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.41-7.37 (m, 1H), 7.30 (dd, J=8.5, 1.5 Hz, 1H), 7.06-7.04 (m, 1H), 6.98-6.94 (m, 1H), 4.51-4.45 (m, 1H), 4.04-3.80 (m, 6H), 3.72-3.62 (m, 3H), 2.56 (s, 3H), 2.12-1.99 (m, 1H), 1.57-1.49 (m, 1H), 1.38-1.32 (m, 1H), 1.05 (d, J=6.6 Hz, 3H), 1.00 (d, J=6.7 Hz, 3H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:21]1([CH2:27][CH:28]([OH:46])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH2:29][CH:28]([OH:46])[CH2:27][N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[CH:32][CH:33]=2)=[CH:3][C:4]=1[O:9][CH:10]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=1[Cl:20])[CH3:11]
Reactant: CC(Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CC1(C)OB(c2ccc(OCC(O)CN3CCOCC3)cc2)OC1(C)C
Product: CC(Oc1cc(-c2ccc(OCC(O)CN3CCOCC3)cc2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
1-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-3-morpholin-4-yl-propan-2-ol was prepared following procedure 3 starting from 5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine and 1-morpholin-4-yl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-propan-2-ol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[NH:10][N:9]=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[C:22]1[N:27]=[C:26]([NH2:28])[C:25]([N+:29]([O-:31])=[O:30])=[C:24]([NH2:32])[N:23]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:22]3[N:23]=[C:24]([NH2:32])[C:25]([N+:29]([O-:31])=[O:30])=[C:26]([NH2:28])[N:27]=3)[N:9]=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:5]2=[N:6][CH:7]=1
Reactant: Fc1cnc2c(Cc3ccccc3F)n[nH]c2c1
Reactant: Nc1nc(Cl)nc(N)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
156 mg (about 66% pure, 0.636 mmol) of the compound from example 6A were dissolved in DMF (3.5 ml), 28 mg (0.70 mmol) of sodium hydride (60% in mineral oil) were then added and the mixture was stirred at RT for 2 h. 115 mg (0.604 mmol) of 2-chloro-5-nitropyrimidine-4,6-diamine (synthesis: Helvetica Chimica Acta (1951), 34, 835-40) were then added, and the reaction mixture was stirred at 80° C. for another 1 h. After cooling to RT, the mixture was added to water. The suspension obtained in this manner was filtered off and the solid was washed repeatedly with water and then dried under high vacuum. This gave 196 mg (77% of theory) of the title compound in solid form.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH2:17][CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)[C:6](=[O:28])[N:5]([CH3:29])[C:4]=2[N:3]=1.[F:30][C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[F:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][CH:36]=1)[O:37][C:2]1[N:10]([CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])[C:9]2[C:8](=[O:16])[N:7]([CH2:17][CH2:18][CH2:19][OH:20])[C:6](=[O:28])[N:5]([CH3:29])[C:4]=2[N:3]=1
Reactant: CC(C)CCn1c(Br)nc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Reactant: Oc1cccc(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCn1c(Oc2cccc(F)c2)nc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 90 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
8-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione (0.50 g, 1.03 mmol, intermediate 82), 3-fluorophenol (0.098 mL, 1.08 mmol) and potassium carbonate (0.29 g, 2.06 mmol) were combined in DMF (8 mL) and heated at 90° C. for 15 h. The reaction was cooled to room temperature and acidified with 6N HCl to pH=1. The reaction was stirred for 1 h then diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were washed with 1N LiCl (2×100 mL), dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to yield a golden oil. The oil was purified using a 24 g silica gel flash column eluted with a gradient of 20% ethyl acetate/hexanes to 100% ethyl acetate to give 8-(3-fluorophenoxy)-1-(3-hydroxypropyl)-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione (0.20 g, 48% yield) as a white solid. LCMS retention time=3.524 min and 96% purity, LCMS MH+=405.
Reaction SMILES: [K].[C:2]1([S:8]([NH:11][C:12](=[O:24])[C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[C:15]([NH2:23])[CH:14]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])O.[K+]>CN(C)C=O>[C:2]1([S:8]([NH:11][C:12](=[O:24])[C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[C:15]([NH:23][CH2:37][C:36]3[CH:39]=[CH:40][C:33]([O:32][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:34][CH:35]=3)[CH:14]=2)(=[O:9])=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1N
Reactant: BrCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture containing 0.500 g of N-benzenesulfonyl-3-amino-4-acetylaminobenzamide potassium salt, 0.470 g of 4-benzyloxybenzyl bromide, 0.925 g of a 20% potassium hydrogencarbonate aqueous solution and 3 ml of N,N-dimethylformamide was stirred at 90° C. for 1 hour. The reaction solution was concentrated, and was purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 9:1) to obtain crude N-benzenesulfonyl-4-acetylamino-3-(4-benzyloxybenzylamino)benzamide. This crude product was cyclized in the same manner as in Example 183 to give 0.160 g of 6-benzenesulfonylcarbamoyl-1-(4-benzyloxybenzyl)-2-methylbenzimidazole (251).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[C:32]([Cl:39])[CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[C:32]([Cl:39])[CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[CH:24][CH:23]=1)([OH:20])=[O:19]
Reactant: N[C@@H](Cc1ccc(Oc2ccc3cccc(Cl)c3n2)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ccc3cccc(Cl)c3n2)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(8-chloro-quinolin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10](O)=[O:11])=[CH:4][CH:3]=1.C([N:23]1CCOCC1)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N>CN(C=O)C.C(OCC)(=O)C>[NH2:23][C:10](=[O:11])[C@@H:9]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:8][C:5]1[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)nc1)C(=O)O
Reactant: CCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)nc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-3-(6-Bromopyridin-3-yl)-2-(tert-butoxycarbonylamino)propanoic acid (1.72 g), N-ethylmorpholine (1.261 mL) and TBTU (2.4 g) were combined in DMF (5 mL) and the solution was stirred, at room temperature for 0.5 h then it was cooled to 0° C. Aqueous 880 ammonia (0.827 mL) was added and the mixture was allowed to reach RT overnight. The reaction mixture was diluted with ethyl acetate, washed with water then brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the sub-title compound (1.5 g).