Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[C:8]([Br:16])=[CH:7][C:3]=1C(O)=O.C([N:19]([CH2:22]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:31])C=CC=CC=1.Cl>O1CCOCC1.O.C(OCC)(=O)C>[Br:11][C:10]1[C:2]2[NH:1][C:22](=[O:31])[NH:19][C:3]=2[CH:7]=[C:8]([Br:16])[C:9]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1c(Br)cc(C(=O)O)c(N)c1Br
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(Br)cc2[nH]c(=O)[nH]c2c1Br

Procedure:
In 10 ml of dioxane is added 1.00 g of 2-amino-3,5-dibromo-4-(methoxycarbonyl)benzoic acid, to which are successively added 0.6 ml of triethylamine and 0.9 ml of diphenyl phosphoryl azide. The mixture thus obtained is heated under reflux for 1.5 hours. Ethyl acetate and water are added to the reaction mixture, pH is adjusted to 6 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Thus, 0.96 g of methyl 4,6-dibromo-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate is obtained as a light brown-colored solid product.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13].C(N(CC)CC)C.Cl>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:16]([O:15][C:11](=[O:14])/[CH:12]=[CH:13]/[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])[CH3:17]
Reactant: C=CC(=O)OCC
Reactant: O=C(O)c1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cccc(C(=O)O)c1
Temperature: 140 °C
Reaction time: 3 h
Yield: 104.3 %

Procedure:
Under an argon atmosphere, to a solution of 3-iodobenzoic acid (20.2 g) in DMF (130 mL) were added ethyl acrylate (9.00 g), triethylamine (24 mL) and palladium (II) acetate (92 mg), and the mixture was stirred at 140° C. for 3 hr. The reaction mixture was cooled to room temperature, and 1N hydrochloric acid was added. The reaction mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (18.7 g) as an orange amorphous solid.
Reaction SMILES: [CH2:1]([Br:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[CH:13]2[O:14][CH2:15][CH2:16][N:12]2[CH2:11][CH2:10]1>C(OC(C)C)(C)C>[Br-:8].[CH2:1]([N+:12]12[CH2:16][CH2:15][O:14][CH:13]1[O:9][CH2:10][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CN2CCOC2O1
Reactant: BrCc1ccccc1
Solvent: CC(C)OC(C)C
Product: [Br-]
Product: c1ccc(C[N+]23CCOC2OCC3)cc1
Yield: 94.3 %

Procedure:
A solution of 1.710 g (10 mmol) of benzyl bromide and 1.152 g (10 mmol) of tetrahydro-[1,3]oxazolo[2,3-b][1,3]oxazole in 20 ml of diisopropyl ether was stirred at the room temperature for 24 hours. The precipitate was filtered off, washed twice with diisopropyl ether and dried. 2.698 g (94.3%) of white amorphous product was obtained, which can be further purified by recrystallisation from rectified ethanol.
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:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:6](=[O:28])[N:5]([CH3:29])[C:4]=2[N:3]=1.[Cl:30][C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Si:21]([O:20][CH2:19][CH2:18][CH2:17][N:7]1[C:8](=[O:16])[C:9]2[N:10]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]([O:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([Cl:30])[CH:32]=3)=[N:3][C:4]=2[N:5]([CH3:29])[C:6]1=[O:28])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: Oc1cccc(Cl)c1
Reactant: CC(C)CCn1c(Br)nc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCn1c(Oc2cccc(Cl)c2)nc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Temperature: 90 °C
Yield: 99.8 %

Procedure:
Step 1 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-chlorophenol (0.14 g, 1.08 mmol), potassium carbonate (0.29 g, 2.06 mmol) were combined in DMF (5 mL) and heated at 90° C. for 15 h. The reaction was cooled, diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were washed with 1 N LiCl (2×75 mL), dried with magnesium sulfate, filtered and evaporated under reduced pressure to give 1-(3-((tert-butyldimethylsilyl)oxy)propyl-8-(3-chlorophenoxy)-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione (0.55 g, 100% yield) as a yellow oil. LCMS retention time=6.238 min and 85% purity, LCMS MH+=535.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)#[N:19].C(N(C(C)C)C(C)C)C>O1CCOCC1>[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([C:2]2[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=2)[CH2:28][CH2:27]1)#[N:19]
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccccc1N1CCN(c2nc(NCCO)nc(NCCO)c2C#N)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(2-cyanophenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 50° C. to yield 4-[4-(2-cyano-phenyl)-piperazin-1-yl]-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M]+=408.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19]([C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(-c2cccs2)c1
Yield: 22.7 %

Procedure:
A mixture of 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-bromo-6-chloropyridine from Example 69a (1.5 g, 3.8 mmol), 2-thienylboronic acid (1.46 g, 11.5 mmol), 2 M Na2CO3 (5 mL) and Pd(0) (190 mg) were mixed together in toluene (20 mL), and the mixture was heated at reflux for 48 h. The mixture was cooled and extracted with EtOAc. The EtOAc was removed under reduced pressure, and the residue was chromatographed (silica gel; hexane/EtOAc, 4:1) to afford the title compound (340 mg, 32% yield): 1H NMR (CDCl3, 300 MHz) δ 1.47 (s, 9H), 1.84-2.11 (m, 4H), 3.31-3.46 (m, 2H), 3.89 (m, 1H), 4.05-4.26 (m, 2H), 7.14 (dd, 1H, J=4.5, 6.0 Hz), 7.42-7.50 (m, 2H), 8.05 (d, 1H, J=3.0 Hz), 8.07 (m, 1H); MS (CI/NH3) m/z 395 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C@H:35]4[CH2:40][CH2:39][C@H:38]([C:41]([O:43]CC)=[O:42])[CH2:37][CH2:36]4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:46]([F:49])([F:48])[F:47])=[CH:19][N:18]=2)=[C:12]([O:50][CH3:51])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C1COCC1.CO.O.[OH-].[Li+].O>>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C@H:35]4[CH2:40][CH2:39][C@H:38]([C:41]([OH:43])=[O:42])[CH2:37][CH2:36]4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:46]([F:47])([F:49])[F:48])=[CH:19][N:18]=2)=[C:12]([O:50][CH3:51])[CH:11]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)[C@H]1CC[C@H](c2ccc(Nc3nc(Nc4ccc(CP(=O)(OCC)OCC)cc4OC)ncc3C(F)(F)F)c3c2CN(C)C3=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](C(=O)O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Ethyl trans-4-(7-{[2-({4-[(diethoxyphosphoryl)methyl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylate (Example 88, 40.0 mg, 0.055 mmol) was taken up in THF (0.073 mL, 0.90 mmol) and MeOH (0.073 mL, 1.8 mmol). This was treated with a solution of Lithium hydroxide, monohydrate (11.4 mg, 0.27 mmol) in H2O (0.073 mL, 4.1 mmol) and allowed to stir at rt for 30 hrs during which, the reaction mixture transformed from a thick slurry to a homogenous solution. The reaction was concentrated in vacuo to a solid. The product was purified by CombiFlash®Rf 4X Organic Purification System [24 g RediSep® Normal-phase GOLD Silica Flash Column, dried loaded, elution gradient: 0→5% MeOH in DCM] to afford 38.7 mg (100% yield) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.95 (s, 1H), 8.38 (s, 1H), 7.52 (br. s., 1H), 7.19 (br. s., 1H), 7.05 (s, 1H), 6.90 (d, J=8.59 Hz, 1H), 4.50 (s, 2H), 3.95-4.06 (m, 4H), 3.77 (s, 3H), 3.21-3.29 (m, 2H), 3.08 (s, 3H), 2.67 (br. s., 1H), 2.60 (br. s., 1H), 2.15 (d, J=7.83 Hz, 2H), 1.55-1.69 (m, 6H), 1.21 (t, 6H). MS (ES+): m/z 706.22 [MH+]. HPLC: tR=1.55 min (UPLC TOF, polar—3 min). Example 90 may be further prepared as a salt. Non-limiting examples include the sodium, potassium, ammonium, and 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium salts. This can be achieved by dissolving the compound in methanol or ethanol with a suitable co-solvent such as DCM or THF and treating the resulting solution with the necessary amount of an aqueous stock solution of known concentration of sodium hydroxide, potassium hydroxide, or 2-amino-2-(hydroxymethyl)propane-1,3-diol. The resulting mixture can be thoroughly stirred or sonicated to ensure dissolution and mixing. The solvents can then be removed under reduced pressure to afford the appropriate salt.
Reaction SMILES: O1CCCC1.C(CC[N:10]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[N:12]=[C:11]1[S:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)#N.Cl.O>C(OCC)(=O)C>[N+:15]([C:13]1[N:12]=[C:11]([S:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)[NH:10][CH:14]=1)([O-:17])=[O:16]
Reactant: N#CCCn1cc([N+](=O)[O-])nc1Sc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Sc2nc([N+](=O)[O-])c[nH]2)cc1
Reaction time: 3 h
Yield: 57.7 %

Procedure:
To tetrahydrofuran (1 ml) solution of 1-(2-cyanoethyl)-4-nitro-2-(4-nitrophenylthio)imidazole (27 mg) was added 1,8-diazabicyclo[5.4.0]undecene-7 (0.02 ml) at a room temperature, and stirred at the same temperature for 3 hours. To the reaction mixture were added 1N hydrochloric acid (0.7 ml), water and ethyl acetate, then the organic layer was taken by liquid separation. The ethyl acetate layer was washed with water and an aqueous solution being saturated with sodium chloride, then dried over anhydrous sodium sulfate. The residue obtained by removal of the solvent by distillation was purified by use of a thin layer chromatography (eluent: dichloromethane/ethyl acetate=9/1), there was obtained 4-nitro-2-(4-nitrophenylthio)imidazole (13 mg, yield 58%) as reddish brown powdery product.
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BrH:13].S(=O)(=O)(O)O.N([O-])=O.[Na+]>O>[C:4]1([CH2:3][C@H:2]([Br:13])[C:10]([OH:12])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@H](Br)Cc1ccccc1
Reaction time: 8 h
Yield: 79.4 %

Procedure:
Slurry L-phenylalanine (23.6 g, 143 mmol), 49% hydrobromic acid (500 g), water (500 mL) and concentrated sulfuric acid (50 mL) and cool to -5° C. Add, by dropwise addition, a solution of sodium nitrite (9.87 g, 143 mmol) in water (70 mL) over a period of about 1 hour. Stir at -5° C. to 0° C. overnight extract into ethyl ether (3×250 mL), combine the organic phases and wash with water (1×) and brine (2×). Dry (MgSO4) and evaporate the solvent in vacuo to give 3-phenyl-2(S)-bromopropionic acid as a yellow oil (26 g, 80%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([NH:22][C:23]4[CH:28]=[C:27]([O:29]C(OC)=O)[C:26]([CH3:34])=[CH:25][C:24]=4[F:35])=[N:17][CH:18]=[N:19]3)=[CH:14][C:13]=2[O:36][CH3:37])[CH:7]=[C:6]([CH3:38])[N:5]=1>CO>[ClH:3].[Cl:3][C:4]1[CH:9]=[C:8]([CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([NH:22][C:23]4[CH:28]=[C:27]([OH:29])[C:26]([CH3:34])=[CH:25][C:24]=4[F:35])=[N:17][CH:18]=[N:19]3)=[CH:14][C:13]=2[O:36][CH3:37])[CH:7]=[C:6]([CH3:38])[N:5]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4cc(C)nc(Cl)c4)c(OC)cc23)c(F)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCc1cc(C)nc(Cl)c1
Product: Cl
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 158.7 %

Procedure:
2M Aqueous sodium hydroxide solution (700 μl, 1.4 mmol) was added to a suspension of 7-((2-chloro-6-methyl-4-pyridyl)methoxy)-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline (360 mg, 0.7 mmol) in methanol (10 ml) cooled at 5° C. and the mixture was then stirred for 30 minutes at ambient temperature. The solvent was removed by evaporation, the residue diluted with water (10 ml) and the mixture adjusted to pH7 with 1M hydrochloric acid. The resulting solid was collected by filtration, washed with water and ether, and dried under vacuum. This solid was dissolved in methanol (5 ml) and a 7M solution of hydrogen chloride in methanol (3 ml) was added. The precipitate was collected by filtration, washed with methanol and dried under vacuum to give 7-((2-chloro-6-methyl-4-pyridyl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (273 mg, 74%).
Reaction SMILES: COC1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([C@@H:13]([OH:24])[C@H:14]3N4C[C@H](C=C)[C@@H](CC4)[CH2:15]3)[CH:7]=[CH:8]N=2)C=1.[CH3:25]O.II.I.C([O:32][CH2:33][CH2:34]O)C>C(O)CCCCCCCCC>[C:33]([O:24][CH2:13][CH:6]([CH2:7][CH3:8])[CH2:5][CH2:10][CH2:11][CH3:12])(=[O:32])[CH:34]=[CH2:25].[C:13]([OH:24])(=[O:32])[CH:14]=[CH2:15]
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Reactant: CCOCCO
Reactant: CO
Agent: I
Agent: II
Solvent: CCCCCCCCCCO
Product: C=CC(=O)O
Product: C=CC(=O)OCC(CC)CCCC

Procedure:
A copolymer of 2-ethylhexyl acrylate/acrylic acid, 50%/50% by weight was prepared. 42.5 grams of the solution of the copolymer was prepared as a 25% by weight solution in 2-ethoxyethanol to which was added 3.75 grams of quinine bisulphate and 8.50 grams of methanol. As in Example 1, an alcoholic solution of a plasticizer, iodine, and hydriodic acid was reacted with the above ingredients to form a wet paste. The dried paste, using heat to aid dispersion, was then suspended in decyl alcohol. The substance was placed in a light valve and satisfactory operation was achieved.
Reaction SMILES: [CH2:1]([O:3][C:4](=[N:6][OH:7])[CH3:5])[CH3:2].C(O[K])(C)(C)C.[CH2:14]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1F)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[N:6][O:7][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:30])[CH3:5])[CH3:2]
Reactant: O=C(OCc1ccccc1)c1ccccc1F
Reactant: CCOC(C)=NO
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(C)=NOc1ccccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 64.4 %

Procedure:
To a stirring solution of ethyl-N-hydroxyacetimidate (2.06 g, 20.0 mmol) in anhydrous DMF (60 mL) under Ar was added tBuOK (2.21 g, 19.7 mmol) all at once. After 30 min benzyl-2-fluorobenzoate 16 (4.13 g, 17.9 mmol) was added as a solution in DMF (20 mL) and the reaction was stirred at room temperature. After 3 h the reaction was diluted with H2O (400 mL), extracted with EtOAc (3×100 mL), and the combined organics were washed with H2O (3×50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated. Flash chromatographic purification over silica (5-10% gradient EtOAc in hexanes) afforded 18 as a clear syrup (3.61 g, 64%). 1H-NMR (500 MHz, CDCl3) δ 1.34 (t, J=7.0 Hz, 3H), 2.00 (s, 3H), 4.18 (q, J=7.0 Hz, 2H), 5.34 (s, 2H), 6.96 (dt, J=1.1, 7.7 Hz, 1H), 7.30-7.35 (m, 1H), 7.35-7.39 (m, 2H), 7.42-7.48 (m, 3H), 7.55 (dd, J=1.1, 8.4 Hz, 1H), 7.90 (dd, J=1.8, 7.7 Hz, 1H); 13C-NMR (125 MHz, CDCl3) δ 14.4, 14.5, 63.1, 66.6, 114.5, 117.0, 120.4, 128.2, 128.4, 128.5, 131.7, 133.8, 136.1, 159.5, 165.8, 166.7; GC-MS 313 m/z[M]+, C18H19NO4 requires 313, 228 m/z [M-85]+, benzyl-2-hydroxybenzoate C14H12O3 requires 228.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([NH2:17])=[O:16])[CH3:2].[CH3:18][CH2:19][C:20](=O)[CH2:21][CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[C:4]2[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[S:6][C:5]=2[C:15](=[O:16])[NH:17][C:20]1([CH2:21][CH3:22])[CH2:19][CH3:18])[CH3:2]
Reactant: CCNc1cc(-c2ccncc2)sc1C(N)=O
Reactant: CCC(=O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCN1c2cc(-c3ccncc3)sc2C(=O)NC1(CC)CC
Temperature: 120 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
A mixture of 3-(ethylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.100 g, 0.400 mmol), 3-pentanone (3.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (3.0 mL) was stirred for 1 h at 120° C. in a sealed tube. Then, this mixture was stirred for 2 h at 150° C. and stirring was continued for 2 days at 110° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate (100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 40 g silica gel, dichloromethane to ethyl acetate), then recrystallized from ethyl acetate, and the precipitate was collected by filtration to afford the title compound (0.0194 g, 12%) as a yellow solid:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:10]=[C:11]([CH:13]=2)[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22].C(N(CC)CC)C>C(Cl)Cl>[C:1]1([C:7]2[CH:8]=[C:9]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:10]=[C:11]([NH:12][C:21](=[O:22])[O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(-c2ccccc2)cc(-c2cccnc2)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(-c2ccccc2)cc(-c2cccnc2)c1)Oc1ccccc1
Yield: 99.8 %

Procedure:
The title compound (0.289 g, 100%) was prepared by methodology of description 67 using 5-phenyl-3-(pyrid-3-yl) aniline (0.194 mg, 0.79 mmol), phenyl chloroformate (0.12 ml, 0.87 mmol) and triethylamine (0.12 ml, 0.81 mmol) in DCM (10 ml)
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]([F:9])=[C:6]([F:8])[F:7].[C:10](=[O:12])=[O:11].Cl>C(OCC)C>[F:9][C:5](=[C:6]([F:8])[F:7])[CH2:4][CH2:3][C:10]([OH:12])=[O:11]
Reactant: O=C=O
Reactant: FC(F)=C(F)CCBr
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: O=C(O)CCC(F)=C(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.8 %

Procedure:
To a stirred mixture of 2.4 grams (0.1 mole) of magnesium turnings in 100 ml of diethyl ether was added 18.9 grams (0.1 mole) of 4-bromo-1,1,2-trifluoro-1-butene. Upon completion of addition the reaction mixture was heated under reflux until the reaction was complete. The reaction mixture was cooled to 0° C. and 9.0 grams (0.2 mole) of carbon dioxide was bubbled in slowly. Upon completion of addition the reaction mixture was stirred for one hour, then 100 ml of aqueous 20% hydrochloric acid was added to destroy the excess magnesium. The reaction mixture was extracted with three 40 ml portions of diethyl ether. The combined extracts were cooled and 40 ml of aqueous 25% sodium hydroxide was added slowly. The organic layer was separated and extracted with one 40 ml portion of aqueous 25% sodium hydroxide. The combined base layers were cautiously acidified with aqueous 20% hydrochloric acid. The mixture was extracted with two 100 ml portions of diethyl ether. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 6.9 grams of 4,5,5-trifluoro-4-pentenoic acid as an oil. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: FC(F)(F)S([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]4[C:23]5[CH:24]=[C:25](OS(C(F)(F)F)(=O)=O)[CH:26]=[CH:27][C:28]=5[CH2:29][C@H:18]34)=[O:16])=[CH:14][C:9]=2[N:8]=[CH:7]1)(=O)=O.N1C2C=CC=CC=2NC=1.C(N(CC)CC)C.CN(C)[CH:58]=[O:59].[CH3:61][OH:62]>>[CH3:61][O:62][C:58]([C:25]1[CH:26]=[CH:27][C:28]2[CH2:29][C@H:18]3[C@@H:19]([C:23]=2[CH:24]=1)[CH2:20][CH2:21][CH2:22][N:17]3[C:15]([C:13]1[CH:12]=[CH:11][C:10]2[NH:6][CH:7]=[N:8][C:9]=2[CH:14]=1)=[O:16])=[O:59]
Reactant: O=C(c1ccc2c(c1)ncn2S(=O)(=O)C(F)(F)F)N1CCC[C@@H]2c3cc(OS(=O)(=O)C(F)(F)F)ccc3C[C@@H]21
Reactant: CO
Reactant: CN(C)C=O
Agent: c1ccc2[nH]cnc2c1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1C2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A flask charged with a stir bar, trifluoromethanesulfonic acid cis-1-(1-trifluoromethane-sulfonyl-1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester (mixture of isomers regarding sulfonyl group attachment to N-1 or N-3 of the benzimidazole, 0.50 g), triethylamine (0.18 mL), N,N-dimethylformamide (2 mL), and methanol (1 ml) is sparged with argon for 5 min. [1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium dichloromethane complex (53 mg) is added and the mixture is sparged with carbon monoxide for another 5 min. The mixture is then heated to 70° C. under carbon monoxide atmosphere (4 bar) and shaken at this temperature overnight. After cooling to room temperature, the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0→9:1) to afford the title compound. Yield: 0.27 g (87% of theory); LC (method 1): tR=2.43 min; Mass spectrum (ESI+): m/z=376 [M+H]+.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][C@H:11]([CH2:13][S:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:10][C:9]1=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-:35].[Na+].Cl>CO.C1COCC1.O>[OH:35][C@@H:11]([CH2:13][S:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:12][C@@H:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:9]([OH:10])=[O:34]
Reactant: CCCCCCC[C@@H]1C[C@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCC[C@H](C[C@@H](O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.72 g (7.88 mmol) of the product of Example 17 in 10 mL of methanol/THF (1:1) at room temperature was added 16.7 mL of 1.0N NaOH solution. The reaction was stirred at room temperature for 1 h and then diluted with 100 mL of H2O and carefully acidified to pH 6 with 5% HCl solution. The resulting mixture was extracted with EtOAc and the combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue, 3.72 g (100%) of the crude hydroxy-acid was used in the next step (Example 25) without further purification. Electrospray Mass Spec: 489.4 (M-H)-.