Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C=O)C>[Si:14]([O:1][CH:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)CC(C)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)CC(C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
5.91 Grams (50 mmol) of methyl 3-hydroxybutyrate and 3.74 g (55 mmol) of imidazole were dissolved in 20 ml of DMF and thereto 8.29 g (55 mmol) of t-butyldimethylsilylchloride was added in several portions. After stirring the mixture at room temperature for 30 minutes, ice water was added and extraction with diethyl ether was conducted three times. The extract was washed with a saturated solution of NaCl, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was distilled (62° to 68° C./5 mmHg) to give 10.51 g of methyl (-)-3-t-butyldimethylsilyloxybutyrate (yield: 91%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([OH:19])=O)[CH:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([NH:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1)=[O:19])[CH:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C)C(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1nncs1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(C)C(NC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Yield: 81.7 %

Procedure:
9.6 g of N-benzyloxycarbonyl-DL-isoleucine, 3.7 g of triethylamine, 150 ml of chloroform, 3.9 of ethyl chlorocarbonate and 3.7 g of 2-amino-1,3,4-thiadiazole were subjected to a reaction similar to that in Example 1(i) to obtain 10.3 g (yield: 82%) of 2-(N-benzyloxycarbonyl-DL-isoleucylamino)-1,3,4-thiadiazole as white crystals having a melting point of 145°-149° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[H-].[Na+].Cl[C:12]1[CH:33]=[CH:32][C:15]([C:16]([NH:18][C:19]2[CH:24]=[C:23]([C:25]([NH:27][CH:28]3[CH2:30][CH2:29]3)=[O:26])[CH:22]=[CH:21][C:20]=2[CH3:31])=[O:17])=[CH:14][N:13]=1.C(OCC)(=O)C>N1C(C)=CC(C)=CC=1C.[Cu]I>[CH:28]1([NH:27][C:25]([C:23]2[CH:22]=[CH:21][C:20]([CH3:31])=[C:19]([NH:18][C:16](=[O:17])[C:15]3[CH:32]=[CH:33][C:12]([O:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:13][CH:14]=3)[CH:24]=2)=[O:26])[CH2:30][CH2:29]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(Cl)nc1
Reactant: OCc1ccccn1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccccn2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
To 2-pyridinylmethanol (1 mL) was added sodium hydride 60% dispersion in oil (122 mg, 3.05 mmol) under inert atmosphere and the resulting mixture was stirred for 10 minutes then added to a mixture of 6-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}nicotinamide (334 mg, 1.02 mmol) and copper (I) iodide in collidine (3 mL). The resulting mixture was stirred at room temperature for 30 minutes then at 100° C. for 4 h. The mixture was cooled to room temperature, ethyl acetate was added and the mixture filtered. The filtrates were concentrated under reduced pressure and purified by silica column chromatography eluting with 0 to 100% ethyl acetate in isohexane. Trituration with diethyl ether gave the title compound as a colourless solid (105.6 mg, 26%); NMR Spectrum: (DMSOd6) 0.59 (m, 2H), 0.67-0.71 (m, 2H), 2.27 (s, 3H), 2.86 (m, 1H), 5.53 (s, 2H), 7.10 (d, 1H), 7.35 (m, 2H), 7.48 (m, 1H), 7.65 (m, 1H), 7.82 (m, 2H), 8.29 (m, 1H), 8.37 (m, 1H), 8.58 (m, 1H), 8.80 (d, 1H), 9.99 (s, 1H); Mass Spectrum: M+H+ 403.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.[CH2:21]=[O:22].Cl>O1CCCC1>[OH:22][CH2:21][C:11]1[O:10][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)=[CH:13][CH:12]=1
Reactant: C=O
Reactant: FC(F)(F)c1cccc(-c2ccco2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCc1ccc(-c2cccc(C(F)(F)F)c2)o1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
2-(3-Trifluoromethylphenyl)-furan (J. Chem. Soc. (C) 1968, 2737 and Acta Chem Scand. 24, 2379 (1970))(21.2 g; 0.1 mole) was stirred in tetrahydrofuran (100 ml), cooled to -40° C. and n-butyl lithium (0.1 mole, solution in hexane) was added dropwise. After stirring for 1 hour at -40° C., paraformaldehyde (3.3 g; 0.11 mole) was added gradually. The mixture was stirred at -40° C. for 30 minutes, then the temperature was allowed to rise. At 10° C. an exothermic reaction set in and the temperature gradually rose to 40° C. (over 10 minutes), then gradually fell back to 20° C. After stirring for further 1 hour the clear brown solution was poured onto ice/water, adjusted to pH ca 4 with dilute hydrochloric acid and extracted via ethyl acetate. The dried acetate extract (MgSO4) was evaporated to give a brownish yellow viscous oil which was distilled in vacuo to give 2-hydroxymethyl-5-(3-trifluoromethylphenyl)-furan as a colourless liquid b.p. 125° C./0.5 mm., (16.2 g), which on standing gave crystals, m.p. 45° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: COc1c(N)ccc2c1CCC(N1CCOCC1)CC2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: COc1c(Nc2ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n2)ccc2c1CCC(N1CCOCC1)CC2

Procedure:
The title compound was prepared from 1-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner as Example 179 heating at 140° C. Product was isolated as a mixture of diastereomers (27 mg, 20%). LCMS (m/e) 579 (M+H); 1H NMR (400 MHz, CDCl3) δ 12.40 (s, 1H), 12.2 (s, 1H), 10.8 (s, 1H), 10.6 (s, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 7.48 (d, 1H, J=7.32 Hz), 7.00 (m, 1H), 6.90 (m, 2H), 6.74 (m, 1H), 6.32 (s, 1H), 6.20 (s, 1H), 4.03 (m, 8H), 3.30-3.76 (m, 16H), 2.92-3.08 (m, 13H), 2.76 (m, 2H), 2.33-2.59 (m, 6H), 2.08 (m, 4H), 1.86 (m, 2H), 1.76 (m, 2H), 1.12-1.58 (m, 12H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([O:17]C)=[O:16])[N:13]=2)[CH:6]=[CH:5][N:4]=1)[CH3:2].[Li+].[OH-].Cl>C1COCC1.CO.C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=[O:16])[N:13]=2)[CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1cc(-c2nc(CC(=O)OC)cs2)ccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(-c2nc(CC(=O)O)cs2)ccn1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of methyl 2-[2-(2-ethyl-4-pyridyl)-1,3-thiazol-4-yl]acetate (Step a, 0.5 g, 1.9 mmol) and LiOH (2 N, 5.0 mL) in THF (5 mL) and MeOH (2 mL) was stirred at RT for 7 h. HCl (aq. 1 N) was added to adjust the reaction mixture to pH ˜2. The solution was evaporated and the resulting residue was partitioned between EtOAc (20 mL) and H2O (20 mL). The layers were separated and the aqueous layer was extracted again with EtOAc (2×20 mL). The organic layers were combined, dried (Na2SO4), and concentrated to afford a solid, which was suspended in CH2Cl2 and filtered to give the compound as a white solid. MS m/z: 249 (M+1). Calc'd for C12H12N2O2S. 248.06.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH2:9]2)=[CH:5][CH:4]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[C:24]1[CH:28]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO>[NH:23]1[CH:27]=[CH:26][N:25]=[C:24]1[CH2:28][NH:1][CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH2:9]2)=[CH:5][CH:4]=1
Reactant: CCCN(CCC)CCCCC1=Cc2ccc(CN)cc2C1
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN(CCC)CCCCC1=Cc2ccc(CNCc3ncc[nH]3)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
The compound (40.1 mg) obtained in Example 11-13 was dissolved in methanol (2.0 ml) and added with 2-imidazole carboxaldehyde (19.2 mg) and trimethyl orthoformate (42.5 mg) and the whole was stirred at room temperature for 30 minutes. Subsequently, the solution was added with sodium borohydride (15.1 mg) under ice-cooling, followed by stirring at room temperature for additional 30 minutes. The reaction solution was concentrated under reduced pressure. The residue was added with water, and extracted with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (27.3 mg) as a yellow oily substance.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:42]/[CH:43]=[CH:44]\[C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH2:46][CH3:47]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:42]/[CH:43]=[CH:44]\[C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:50][CH3:51])[CH2:52][CH3:53])[CH2:46][CH3:47])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(/C=C\CBr)(CC)O[Si](CC)(CC)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(/C=C\CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 97.7 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5(10 μl) and (Z)-1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene (103 mg, 0.321 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (83.6 mg, 98%).
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([CH:11]([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[C:17]#[N:18].[Na].[CH:20]1([SH:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([S:25][C:2]2[C:10]3[NH:9][C:8]([CH:11]([F:13])[F:12])=[N:7][C:6]=3[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=2[C:17]#[N:18])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: N#Cc1cc([N+](=O)[O-])c2nc(C(F)F)[nH]c2c1Cl
Reactant: SC1CCCC1
Agent: [Na]
Product: N#Cc1cc([N+](=O)[O-])c2nc(C(F)F)[nH]c2c1SC1CCCC1

Procedure:
4-Chloro-7-nitro-5-cyano-2-difluoromethylbenzimidazole is reacted with the sodium salt of cyclopentanethiol to obtain 4-cyclopentylthio-7-nitro-5-cyano-2-difluoromethylbenzimidazole, m.w., 338.3.
Reaction SMILES: C[Si](C)(C)CCOC[NH:7][C:8]([C:10]1[N:14]=[C:13]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:18]=[CH:19][CH:20]=2)[NH:12][N:11]=1)=[O:9]>C(#N)C.O>[C:27]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:13]3[N:14]=[C:10]([C:8]([NH2:7])=[O:9])[NH:11][N:12]=3)[CH:16]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C[Si](C)(C)CCOCNC(=O)c1n[nH]c(-c2cccc(-c3ccccc3-c3ccccc3)c2)n1
Solvent: O
Solvent: CC#N
Product: NC(=O)c1nc(-c2cccc(-c3ccccc3-c3ccccc3)c2)n[nH]1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 0.035 g of 2-Trimethylsilylethoxymethyl-5-[2′-(Phenyl)biphenyl-3-yl]-1,2,4-triazole-3-carboxamide in 3 mL of acetonitrile and 9 mL of a 50% solution of HF in water was stirred at rt for 6 hours. The reaction mixture was then concentrated and the residue was purified by chromatography (silica, CH3OH: CH2Cl2 0-5% gradient) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]2[O:13][C:14](=[O:16])[CH3:15])=[C:4](Cl)[N:3]=1.Cl.[CH3:31][NH:32][CH3:33].C(N(C(C)C)CC)(C)C.O>N1C=CC=CC=1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]2[O:13][C:14](=[O:16])[CH3:15])=[C:4]([N:32]([CH3:33])[CH3:31])[N:3]=1
Reactant: CNC
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N(C)C)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 66.7 %

Procedure:
2-amino-6-chloro-9-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl) purine (1) [M. J. Robins and B. Uznanski, Can. J. Chem., 59, 2601-2607 (1981)](18.6 mmol, 7.96 g) was dehydrated three times azeotropically with anhydrous pyridine, and dissolved in anhydrous pyridine, then dimethylamine hydrochloride (55.8 mmol, 4.55 g) and diisopropylethylamine (74.4 mmol) were added thereto with stirring at room temperature. The mixture was stirred at room temperature for 15 hours. After confirming completion of the reaction by TLC, water was added to the reaction mixture and concentrated in vacuo. Chloroform was added to the residue, and the organic layer was washed 3 times with water, 2 times with 5% aqueous sodium hydrogen carbonate, once with water and 2 times with 10% aqueous citrate solution, then the organic layer was dried with magnesium sulfate, and dried in vacuo after filtration. The residue was treated with azeotropic distillation with toluene until no odor of pyridine was noted, the product was purified by silica-gel chromatography (dichloromethane-ethanol) to obtain the product (2) 5.42 g (12.4 mmol) (67%). 1H-NMR (500.13 MHz, CDCl3) δ: 7.56 (s, 1H, H8), 6.02 (d, 1H, H1′, J=5.0 Hz), 5.95 (dd, 1H, H2′, J=5.0 Hz), 5.79 (t, 1H, H3′, J=5.0 Hz), 4.69 (s, 2H, 2-NH2), 4.42-4.45 (m, 1H, H4′), 4.34-4.40 (m, 2H, H5′, H5″), 3.43 (br, 6H, N—CH3), 2.13, 2.10, 2.08 (s, 3H, Ac).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)=[CH:30][CH:29]=1>>[N:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:39]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:40][CH:41]=2)=[CH:30][CH:29]=1
Reactant: Nc1ccc(Cc2ccncc2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(Cc2ccncc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(pyridin-4-yl-methyl)-aniline Rf value: 0.6 (silica gel, methylene chloride/methanol/ammonia=5:1:0.01) C29H23N3O3
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]4[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=4)[CH:15]=3)[O:10][C:9]([CH3:31])([CH3:30])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][CH:29]=4)[CH:15]=3)[O:10][C:9]([CH3:31])([CH3:30])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccc2)=CC(C)(C)O3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)C=C(c2ccccc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc2O1
Temperature: 35 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a solution of ethyl 4-[[4-phenyl-2,2-dimethyl-(2H)-chromen-6-yl]-ethynyl]-benzoate (Compound 265, 70.0 mg, 0.171 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (120.0 mg, 3.0 mmol, 3.0 mL of a 1M aqueous solution). The resulting solution was heated to 35° C., cooled to room temperature and stirred overnight. The reaction was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before the solvent was removed under reduced pressure. The residual solid was recrystallized from CH3CN to give 48.0 mg (74%) of the title compound as a colorless solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.00 (2H, d, J=8.2 Hz), 7.57 (2H, d, J=8.2 Hz), 7.51-7.37 (6H, d), 7.14 (1H, d, J=2.0 Hz), 6.91 (1H, d, J=8.3 Hz), 5.80 (1H, s), 1.50 (6H, s),
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH3:32])=[CH:11][C:10]=1[CH3:33])[CH2:6][CH3:7])C.[OH-].[Na+]>>[CH3:33][C:10]1[CH:11]=[C:12]([O:15][CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)=[N:19][C:18]=2[CH3:32])[CH:13]=[CH:14][C:9]=1[CH2:8][CH:5]([CH2:6][CH3:7])[C:4]([OH:34])=[O:3]
Reactant: CCOC(=O)C(CC)Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Product: CCC(Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-2-{2-methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzyl}-butyric acid ethyl ester was treated with 3 N NaOH to obtain [rac]-2-{2-methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzyl}-butyric acid as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11]1.[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH3:37])[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH3:37])[C:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:11]1)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)C(=O)OCCN1CCC[C@H](Nc2cc(F)ccc2N)C1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1N[C@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Temperature: 0 °C
Yield: 93 %

Procedure:
To an ice-cooled mixture of 2,2-dimethylpropionic acid 2-[(S)-3-(2-amino-5-fluorophenylamino)piperidin-1-yl]ethyl ester (1.464 g, 4.34 mmol), (S)-2-tert-butoxycarbonylaminopropionic acid (0.904 g, 4.77 mmol) and HOAt (0.591 g, 4.34 mmol) in DCM (40 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.0 g, 5.21 mmol) portion wise over 10 min. The reaction mixture was stirred in the ice bath for 2 h, then diluted with DCM, washed with 2M Na2CO3 then water. The organic fractions were dried (Na2SO4) then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 40-70% EtOAc in cyclohexane) affording the title compound as a dark red gum (2.054 g, 93%). LCMS (Method B): RT 2.46 min [M+H]+ 509.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([Cl:10])=[C:12]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 4-chloro-3-trifluoromethylaniline gave 2-chloro-N4-(4-chloro-3-trifluoromethylphenyl)-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.15 (d, 1H, J=2.1 Hz), 7.96 (d, 1H, J=3 Hz), 7.91 (dd, 1H, J=2.7 Hz and 8.7 Hz), 7.53 (d, 1H, J=8.1 Hz), 7.06 (bs, 1H); 19F NMR (CDCl3): −17892 and −44402; LCMS: purity: 93%; MS (m/e): 326 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5]([OH:7])=O.[NH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5]([C:29]1[CH:28]=[C:27]([CH2:26][CH2:25][NH2:24])[CH:32]=[CH:31][C:30]=1[S:33]([NH2:36])(=[O:35])=[O:34])=[O:7]
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(Oc2c(Br)cc(C(=O)O)cc2Br)cc1C(C)C
Product: CC(C)c1cc(Oc2c(Br)cc(C(=O)c3cc(CCN)ccc3S(N)(=O)=O)cc2Br)ccc1O
Yield: 46.7 %

Procedure:
3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol) was coupled with 4-(2-aminoethyl)benzenesulphonamide (0.175 mmol) using the method described in Example 58. Purification on HPLC of the residue gave 10 mg (47%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[CH:17][N:16]([CH:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:20][C:21]([O:23]CC)=[O:22])[C:15]=3[CH:32]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]>Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[CH:17][N:16]([CH:19]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][C:21]([OH:23])=[O:22])[C:15]=3[CH:32]=2)=[O:9])=[CH:33][CH:34]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cc21
Agent: Cl
Product: O=C(O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cc21

Procedure:
A solution of ethyl 3-{6-[(4-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (40 mg, 87 μmol) in hydrochloric acid (20 mL of a 5N solution) was stirred at room temperature for 110 hours. The solution was then evaporated in vacuo, and the residue was purified by RP-HPLC to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=3.89 min, MH+ 431].