Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23]1[CH:28]=[C:27]([I:29])[CH:26]=[C:25]([Cl:30])[CH:24]=1>CN(C=O)C>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[C:27]([I:29])[CH:26]=1)[CH2:22][N:12]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:7][O:6][C:5]1[CH:13]=[CH:14][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Fc1ccc(OCc2ncc[nH]2)cc1
Reactant: Clc1cc(I)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(OCc2nccn2Cc2cc(Cl)cc(I)c2)cc1
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of 2-(4-fluoro-phenoxymethyl)-1H-imidazole in DMF was added freshly ground K2CO3 followed by bromomethyl-3-chloro-5-iodo-benzene. The reaction mixture was stirred at room temperature until most of starting material was consumed. The reaction mixture was then diluted with ethyl acetate and washed with water. The organic phase was dried over MgSO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using CH2Cl2:MeOH 95:5 as an eluent to afford the title compound (275 mg, 60%); MS m/z 442 [C17H13ClFIN2O+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10]C)=[O:9])=[CH:4][N:3]=1.[ClH:12]>C(O)C.O=[Pt]=O>[ClH:12].[NH2:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][N:3]=1
Reactant: COC(=O)c1ccc(N)nc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: NC1=NCC(C(=O)O)CC1
Reaction time: 2 h
Yield: 89.1 %

Procedure:
2-Amino-5-methoxycarbonylpyridine (0.912 g, 6.6 mmol) was dissolved in 90% ethanol (137 ml) and conc. HCl (3.5 ml, 40 mmol) was added. The solution was hydrogenated over PtO2 (200 mg) in a Parr shaker apparatus at room temperature and 29 psig for 2 hours. Filtration and evaporation gave 1.05 g (89%) crude white crystals identified as the product by 400 MHz nmr and ir 3350, 3011, 1714 cm-1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.I[CH3:17].[H-].[Na+].[NH4+].[Cl-]>CN(C)C=O.C(OCC)(=O)C>[CH3:17][N:8]([CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCC1CCOCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(CC1CCOCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a solution of tert-butyl N-(4-tetrahydropyranylmethyl)carbamate (610 mg, 2.8 mmol) and iodomethane (805 mg, 5.6 mmol) in 6.0 mL of N,N-dimethylformamide was added sodium hydride (60%, 227 mg, 5.6 mmol) under ice-cooled conditions. After the reaction mixture was stirred at room temperature overnight, the solution was added with saturated NH4Cl aqueous solution, and diluted with ethyl acetate. The separated organic layer was washed with brine, and dried over Na2SO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 70/30) to obtain the title compound (607 mg, 95%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14].[OH-].[K+].[CH3:22]I>CN(C=O)C>[Br:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:22])[CH:6]=[C:5]2[CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14]
Reactant: CI
Reactant: COc1c(Br)cc(F)c2[nH]cc(CC(=O)N(C)C)c12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1c(Br)cc(F)c2c1c(CC(=O)N(C)C)cn2C
Reaction time: 1 h

Procedure:
To the solution of 8-10 (7.0 g, 21.3 mmol) in anhydrous DMF (20 mL) was added KOH (4.34 g, 78.0 mmol), and MeI (4.55 g, 32.0 mmol) at room temperature. After the mixture was stirred for 1 h, TLC showed that the reaction was completed. The mixture was quenched with water and extracted with ethyl acetate (150 mL×3). The organic layers were combined and concentrated in vacuo. 8-11 (7.2 g, crude) was obtained as yellow oil and used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([F:21])[CH:23]=3)[N:3]=[CH:4]2)=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1ccc(Cn2cnc(N)c2C(N)=O)cc1
Reactant: O=C(Cl)c1cccc(F)c1
Product: CC(C)(C)c1ccc(Cn2cnc(NC(=O)c3cccc(F)c3)c2C(N)=O)cc1
Yield: 70 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 1, using 1.54 g (5.65 mmol) of 4-amino-1-(4-t-butylbenzyl)-5-imidazole carboxamide which was prepared in the same manner as in Example 57 and 3-fluorobenzoyl chloride instead of benzoyl chloride to obtain 1.57 g of 1-(4-t-butylbenzyl)-4-(3-fluorobenzoylamino)-5-imidazolecarboxamide (yield 70%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Br.C(N(CC)CC)C>CN(C)C=O>[F:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: OC1CCNCC1
Reactant: Fc1ccccc1CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1CCN(Cc2ccccc2F)CC1
Reaction time: 16 h
Yield: 66.2 %

Procedure:
1.28 g (0.0127 mol) of 4-hydroxypiperidine were dissolved in 60 ml of dimethylformamide and cooled to 0°. 3.0 g (0.0159 mol) of 2-fluoro-benzyl bromide and 5.0 ml (0.0349 mol) of triethylamine were added under argon and the mixture was left to come to room temperature. It was stirred for 16 hrs., the solvent was distilled off and the residue was chromatographed on silica gel with dichloromethane/methanol (19:1) as the eluent. 1.76 g (53%) of 2-fluoro-benzyl-piperidin-4-ol were obtained as a yellow oil. MS: me/e=210 (C12H17FNO+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[O:5][CH2:6][CH2:7]Br.C(=O)([O-])[O-].[Na+].[Na+].[CH2:19]([NH2:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[O:5][CH2:6][CH2:7][NH:27][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCN
Reactant: Clc1ccc(OCCBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCNCCOc1ccc(Cl)c(Cl)c1

Procedure:
In 20 ml of ethanol was dissolved 2.06 g (7.63 millimoles) of 2-(3,4-dichlorophenoxy)ethyl bromide, and 1.06 g (10.0 millimoles) of anhydrous sodium carbonate and 3.48 g (27.0 millimoles) of n-octylamine were added to the solution. The mixture was heated and refluxed on an oil bath for 6 hours. After cooling, the reaction mixture was poured into 100 ml of water and extracted with 20 ml of chloroform three times.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([S:7]([NH:10]C(=O)OC(C)(C)C)(=[O:9])=[O:8])[CH2:6][CH2:5]1.Cl>O1CCOCC1>[CH3:1][O:2][CH2:3][C:4]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5]1
Reactant: COCC1(S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COCC1(S(N)(=O)=O)CC1
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To tert-butyl (1-(methoxymethyl)cyclopropyl)sulfonylcarbamate (2.2 g, 8.29 mmol) was added HCl in 1,4-Dioxane (20 ml, 4M solution) at room temperature. The reaction mass was stirred for 2 hr. The reaction mass was evaporated under reduced pressure to get desired compound (1.2 g, 88%) as white solid. 1H NMR (400 MHz, DMSO): δ ppm 6.68 (br, s, 2H), 3.62 (s, 2H), 3.27 (s, 3H), 1.22-1.09 (m, 2H), 0.96-0.91 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)C(C)(C)C.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:40]=[C:39]([OH:41])[C:38]([C:42]([OH:44])=[O:43])=[CH:37][N:36]=2)=[CH:31][CH:30]=1.C(N(CC)CC)C>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[N:40]=[C:39]([OH:41])[C:38]([C:42]([OH:44])=[O:43])=[CH:37][N:36]=2)=[CH:33][CH:34]=1)=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 96.1 %

Procedure:
A solution of 5.67 g (30 mmol) of N-t-butoxycarbonyl-L-alanine in 75 ml of acetonitrile is stirred at 0° and 6.36 g (63 mmol) of N-methylmorpholine is added and the mixture cooled to -20° C. Next 3.62 g (30 mmol) of pivaloyl chloride is added and the mixture stirred at -15° C. for 1.5 hrs and a solution cooled to -10° C., containing 3.46 g (15 mmol) of 2-(4-aminophenyl) 4-hydroxy-5-pyrimidine carboxylic acid, 75 ml of acetonitrile, and 4.17 ml (30 mmol) of triethylamine is added. After stirring for 2 hrs at -10° C. the mixture is then kept at room temperature for 18 hrs. The solution is evaporated to near dryness in vacuo and treated with 200 ml of water. The pH is adjusted to 2.8 with citric acid and the product filtered, washed with water and ether, and dried to give 5.8 g of 2-[4-(N-t-butoxycarbonyl-L-alanylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid. [α]D23 -28.5° (cl, pH 7).
Reaction SMILES: [H-].CCCCCC.[CH:8]1([CH:13]([CH3:19])[CH2:14][CH2:15][CH2:16][C:17]#N)[CH2:12][CH2:11][CH2:10][CH2:9]1.[OH:20]S(O)(=O)=O>CC(OC)(C)C.CO>[CH:8]1([CH:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH:17]=[O:20])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(CCCC#N)C1CCCC1
Reactant: O=S(=O)(O)O
Agent: [H-]
Solvent: CCCCCC
Solvent: CO
Solvent: COC(C)(C)C
Product: CC(CCCC=O)C1CCCC1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
Diisobutylaluninum hydride (60 ml of 1.0 M solution in hexane) was added at −65° C. to a hexane (50 ml) solution of 5-cyclopentylhexanenitrile (5.0 g; 30 mmol; from example 11). After stirring at −70° C. for 0.5 hour, and at room temperature for 3 hours, methanol (1.8 ml) was added, and the stirring continued for 20 minutes. 10% H2SO4 (48 ml) was added, and the reaction mixture was diluted with MTBE (150 ml). The organic layer was separated, washed with saturated sodium bicarbonate solution (300 ml) and brine (3×300 ml), dried (MgSO4), concentrated in vacuo, and bulb-to-bulb distilled (100° C./0.2 torr) to give 2.6 g (51.5% yield) of 5-cyclopentylhexanal.
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][O:15][C:16]1[N:21]=[CH:20][C:19]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([O:33]C)=[O:32])=[CH:18][CH:17]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[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][O:15][C:16]1[N:21]=[CH:20][C:19]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([OH:33])=[O:32])=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1ccccc1OCc1ccc(OCCc2nc(-c3ccccc3)oc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(COc2ccccc2CC(=O)O)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
To a mixture of methyl 2-[2-[[6-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-3-pyridyl]methoxy]phenyl]acetate (0.60 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at room temperature for 4 hrs. 1N Hydrochloric acid (3 mL) and water were added to the reaction mixture and the precipitated crystals were collected by filtration and dried with air to give crystals (0.50 g, 86%) of 2-[2-[[6-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-3-pyridyl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 159-160° C.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([B:18]3[O:22]C(C)(C)C(C)(C)O3)=[C:14]([CH:27]=[O:28])[CH:13]=2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[BH4-].[Na+]>C(Cl)Cl.CO>[CH3:29][N:2]([CH3:1])[C:3]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]3[B:18]([OH:22])[O:28][CH2:27][C:14]=3[CH:13]=2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: CN(C)c1nc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2)ccc1C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN(C)c1nc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 198.3 %

Procedure:
A solution of 2-dimethylamino-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile (7) (370 mg, 0.94 mmol) in CH2Cl2 (5 mL) was added to a mixture of NaBH4 (26 mg, 0.66 mmol) in anhydrous methanol (10 mL) at room temperature. Additional solid NaBH4 (82 mg, 2.2 mmol) was then added portionwise over a period of 10 minutes. The reaction mixture was then stirred for a further 1 h at room temperature. The reaction was quenched by the addition of a solution of glacial acetic acid (0.2 mL) and distilled water (0.2 mL) followed by stirring for 10 minutes. The reaction was concentrated to give an oil (˜550 mg). The oil was dissolved in a mixture of acetic acid/methanol/CH2Cl2 (1/2/100 v/v/v, 100 mL) followed by the addition of silica gel (5 g, 230-400 mesh) and concentrated to dryness to give a free flowing impregnated silica. This was loaded onto a silica column (10 g, 230-400 mesh) and eluted with acetic acid/methanol/CH2Cl2 (1/2/100 v/v/v). The fractions containing D95 were collected and concentrated to give a light yellow coloured oil. The oil was freeze dried by first diluting with MeOH/CH2Cl2 (1/1 v/v, 15 mL) followed by the addition of deionised water (200 mL), the resultant white suspension was frozen in a dry-ice acetone bath and placed overnight on freeze-dryer. A white solid of D95 was obtained (70 mg, 25% isolated yield). 1H NMR 400 MHz (d6-DMSO) δ9.23 (s, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.23 (d, J=0.5 Hz, 1H), 7.16 (dd, J=7.8, 0.5 Hz, 1H), 6.31 (d, J=8.6 Hz, 1H), 4.98 (s, 2H), 3.14 (s, 6H). Mass Spectrum [M+H+]=296. HPLC purity 95.04% (Maxplot), 94.63% (220 nm), 92.41% (254 nm).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21]C)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:23][CH:24]([CH2:26][C:27]([OH:30])([CH3:29])[CH3:28])[CH3:25])[CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:23][CH:24]([CH2:26][C:27]([OH:30])([CH3:29])[CH3:28])[CH3:25])[CH:3]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)CC(C)(C)O)c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC(C)CC(C)(C)O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-(4-fluoro-2-(4-hydroxy-4-methylpentan-2-yloxy)phenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (710 mg) was dissolved in methanol (50 ml) and aqueous NaOH (4M; 5 ml) was added. The reaction was stirred at room temperature overnight and then heated at 60° C. for 2 h. Finally the solution was neutralised and concentrated in vacuo. The residue was triturated with water. The resultant precipitate was filtered and dried.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:37]=[CH:36][C:16]([CH2:17][N:18]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:19]2)=[CH:15][CH:14]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:37]=[CH:36][C:16]([CH2:17][N:18]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:19]2)=[CH:15][CH:14]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc4ccccc4n3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1c(COc2ccc(Cn3cc(CCC(=O)O)c(-c4ccccc4)n3)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
After a mixture of ethyl 3-[1-[4-(1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (520 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (2 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[4-(1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (420 mg, yield: 86%). This was recrystallized from ethanol-hexane. Melting point: 225–226° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[NH:24][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:3]=1
Reactant: Cc1cccc(-c2nc(C)cc(Cl)n2)c1
Reactant: COc1cccc(N)c1
Product: COc1cccc(Nc2cc(C)nc(-c3cccc(C)c3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(3-methylphenyl)pyrimidine (100 mg, 0.457 mmol) and m-anisidine (51 μl, 0.457 mmol) similar to Example 11 as a pale yellow solid (11 mg, 8%). 1H NMR (DMSO-d6): 8.09 (s, 1H), 8.05 (d, J=7.5 Hz, 1H), 7.54–7.49 (m, 4H), 7.35 (t, J=8.1 Hz, 1H), 7.21 (s, 1H), 6.78 (s, 2H), 3.81 (s, 3H), 2.43 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([O:13][CH2:14][C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])[CH:3]=1.CO.[OH-].[Na+].Cl>O>[NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:13][CH2:14][C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])[CH:3]=1
Reactant: CCN(CC)C(=O)COc1cc(N)c(Cl)cc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN(CC)C(=O)COc1cc(N)c(Cl)cc1C(=O)O
Temperature: 60 °C
Yield: 68.1 %

Procedure:
A solution of 4-amino-5-chloro-2-[2-(diethylamino)-2-oxoethoxy]benzoic acid, methyl ester (7.87 g, 25 mmol) in water (70 g) containing methanol (40 g) was treated with 50% sodium hydroxide (10 g) and heated to 60° C. for 30 minutes. The mixture was neutralized with 3N HCl until a precipitate formed (pH 3), and the solid was collected, washed with water, air dried, and recrystallized from 2-propanol to afford (2 crops) 5.12 g (68%) of fine colorless needles; mp 186.5°-188.0° C.
Reaction SMILES: C[O:2][C:3]([C:5]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]#[C:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:10][CH2:9][N:8]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Li+]>>[C:11]([N:8]1[CH2:7][CH2:6][C:5]([S:19]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]#[C:31][CH3:32])=[CH:26][CH:27]=2)(=[O:21])=[O:20])([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)c3ccccc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)c3ccccc3)CC2)cc1

Procedure:
1-Benzoyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic acid was prepared, starting from 1-benzoyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic acid methyl ester (300 mg, 0.66 mmol) and lithium hydroxide (18 mg, 0.75 mmol). The resulting reaction mixture was worked up as outlined in Example 64, (step 5). Yield: 250 mg (86%) of the acid. HR-MS: m/z Calculated for C25H23NO6S 442.1319; Found 442.1317.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[SH:9].[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Cc1cccc(C)c1S
Reactant: CCCCCCBr
Product: CCCCCCSc1c(C)cccc1C

Procedure:
This compound was synthesized from 2,6-dimethylthiophenol and hexyl bromide according to general method 4 as described above.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]=1[CH3:23])=[O:5])C.[OH-].[Na+]>CO.O>[CH3:23][C:7]1[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9](=[O:16])[C:10]2[C:15]([C:6]=1[C:4]([OH:5])=[O:3])=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CCOC(=O)c1c(C)n(-c2ccccc2)c(=O)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)c2ccccc2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
3-Methyl-1-oxo-2-phenyl-1,2-dihydro-isoquinoline-4-carboxylic acid ethyl ester (4.2 g, 13.7 mmol) was dissolved in 100 ml of hot methanol and a solution of NaOH (6 g) in water (20 ml) was added. The reaction mixture was heated at reflux for 2 hrs, diluted with water (200 ml) and stirred overnight at ambient temperature. Organic volatiles were removed under reduced pressure and the obtained aqueous solution was extracted with ethyl acetate (2×50 ml). The aqueous solution was poured into ice/2M HCl (150 ml). The obtained suspension was sonicated, and the product was separated by filtration, washed with water and dried in vacuo to give 2.9 g of a colourless solid, yield 76%. LC-MS (m/z) 280.2 (MH+); tR=0.9. 1H NMR (500 MHz, DMSO-d6): 2.01 (s, 3H), 7.36 (d, 2H), 7.50 (t, 1H), 7.56 (q (overlapping m), 3H), 7.72 (d, 1H), 7.81 (t, 1H), 8.22 (d, 1H), 13.5 (br, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCCCCCCCCCBr
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCOc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
A mixture of 4-cyano-4′-hydroxybiphenyl (56) (10.10 g, 0.052 mol), 1-bromodecane (14.38 g, 0.065 mol), anhydrous potassium carbonate (37.32 g, 0.27 mol), butanone (300 ml) and a trace of potassium iodide was heated under reflux overnight. The cooled solution was filtered to remove inorganic salts and the solvent was removed in vacuo. The residual oil was distilled (to remove excess bromide) and finally purified by column chromatography (dichloromethane) to yield a colourless, low melting solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:15]3([CH2:19][CH2:18][CH2:17][CH2:16]3)[C:14](=[O:20])[N:13]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:44])=[C:39]([CH:43]=1)[C:40](O)=[O:41])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:44])=[C:39]([C:40]([N:24]2[CH2:23][CH2:22][CH:21]([N:13]3[N:12]=[C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:15]4([CH2:16][CH2:17][CH2:18][CH2:19]4)[C:14]3=[O:20])[CH2:26][CH2:25]2)=[O:41])[CH:43]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C23CCCC3)cc1OC
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCc5ccccc5)ccc4C)CC3)C(=O)C23CCCC3)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 4-(3,4-dimethoxyphenyl)-2-piperidin-4-yl-2,3-diazaspiro[4.4]non-3-en-1-one (compound B10) and 5-(benzyloxy)-2-methylbenzoic acid (compound F1) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by a second chromatography (silica gel and cyclo hexane/EA=6:4) to yield the title compound.