Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:9][C:3]1[CH:4]=[C:5]([NH2:6])[CH:7]=[CH:8][C:2]=1[C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([C:11]([F:22])([F:21])[F:10])[CH:17]=1
Reactant: Nc1ccc(Br)c(F)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Product: Nc1ccc(-c2cccc(C(F)(F)F)c2)c(F)c1
Temperature: 90 °C
Yield: 43.3 %

Procedure:
A mixture of 4-bromo-3-fluoroaniline (4.3 g), 3-trifluoromethylphenylboronic acid (4.4 g), sodium carbonate (6.5 g), palladium(II) acetate (0.22 g) and 2-(di-t-butylphosphino)biphenyl (0.60 g) were weighed into a reaction tube and flushed with nitrogen. A 70:30 mixture of dioxane/water (50 mL) was then added and the mixture was heated at 90° C. for 16 h. Ethyl acetate and water was added and the phases separated. The organic phase was dried and concentrated. The residue was purified by column chromatography on silica to give a solid (2.5 g).
Reaction SMILES: [CH2:1]([Li])CCCCC.[F:8][C:9]1[CH:10]=[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH3:28])=[CH:22][CH:21]=2)[CH:12]=[CH:13][C:14]=1[C:15]1[Se:16][CH:17]=[CH:18][CH:19]=1.CI.N>C1COCC1.CC(OC)(C)C.[Cl-].[NH4+]>[F:8][C:9]1[CH:10]=[C:11]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH3:28])=[CH:24][CH:25]=2)[CH:12]=[CH:13][C:14]=1[C:15]1[Se:16][C:17]([CH3:1])=[CH:18][CH:19]=1
Reactant: [Li]CCCCCC
Reactant: CCCc1ccc(-c2ccc(-c3ccc[se]3)c(F)c2)cc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: COC(C)(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CCCc1ccc(-c2ccc(-c3ccc(C)[se]3)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
3.5 ml (20.6 mmol) of TMP are initially introduced at −20° C. in THF, and 7.7 ml (19.3 mmol, 2.5 M in hexane) of n-HexLi are metered in. After 25 min at this temperature, a solution of 5.5 g (16.0 mmol) of 2-(3-fluoro-4′-propylbiphenyl-4-yl)selenophene in 50 ml of THF is added. When the addition is complete, the batch is warmed to RT over the course of 45 min and left at this temperature for 20 min. The solution is cooled to −70° C., and 13.6 g (95.8 mmol) of methyl iodide are added. The reaction mixture is warmed to RT and stirred for 20 h. The solution is diluted with MTBE, and sat. ammonium chloride soln. and conc. ammonia soln. are added successively. The mixture is stirred vigorously for a few minutes, and the organic phase is separated off. The aqueous phase is extracted with MTBE, and the combined organic phases washed successively with water, 2 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by chromatography. The further purification is carried out by recrystallisation from n-heptane. 2-(3-Fluoro-4′-propylbiphenyl-4-yl)-5-methylselenophene is obtained as a solid having an m.p. of 97° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[S:29][CH:30]=[CH:31][N:32]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.O>ClC(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][N:27]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)[C:40](=[O:47])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:23][CH2:24]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCNc4nccs4)CC3)nc3ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)N(CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1nccs1
Reaction time: 8 h
Yield: 48 %

Procedure:
To a stirred mixture of 6.76 parts of 1-[(4-fluorophenyl)methyl]-N-[1-[2-(2-thiazolylamino)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine, 1.5 parts of N,N-diethylethanamine and 225 parts of trichloromethane was added dropwise a solution of 2.1 parts of benzoyl chloride in trichloromethane. Upon completion, stirring was continued overnight. The reaction mixture was poured into water. The layers were separated. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane and 2-propanone. The product was filtered off and dried, yielding 4 parts (48%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-N-(2-thiazolyl)benzamide; mp. 155.9° C. (compound 100).
Reaction SMILES: [Na+].[I-].[F:3][C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:5]=1[CH2:6][NH:7][C:8]([NH2:10])=[O:9].[CH2:19]=[C:20]1O[C:22](=[O:23])[CH2:21]1.C[Si](Cl)(C)C>C(#N)C.O>[F:3][C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:5]=1[CH2:6][N:7]1[C:20]([CH3:19])=[CH:21][C:22](=[O:23])[NH:10][C:8]1=[O:9]
Reactant: C=C1CC(=O)O1
Reactant: NC(=O)NCc1c(F)cccc1C(F)(F)F
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.6 %

Procedure:
NaI (43.9 g, 293 mmol) was added to N-[2-fluoro-6-(trifluoromethyl)benzyl]urea 1b (46.2 g, 19.6 mmol) in 365 mL of acetonitrile. The resulting mixture was cooled in an ice-water bath. Diketene (22.5 mL, 293 mmol) was added slowly via dropping funnel followed by addition of TMSCl (37.2 mL, 293 mmol) in the same manner. The resulting yellow suspension was allowed to warm to room temperature slowly and was stirred for 20 hours. LC-MS showed the disappearance of starting material. To the yellow mixture 525 mL of water was added and stirred overnight. After another 20 hours stirring, the precipitate was filtered via Buchnner funnel and the yellow solid was washed with water and EtOAc to give 1c as a white solid (48.5 g, 16 mmol). 1H NMR (CDCl3) δ 2.15 (s, 3H), 5.37 (s, 2H), 5.60 (s, 1H), 7.23–7.56 (m, 3H), 9.02 (s, 1H); MS (CI) m/z 303.0 (MH+).
Reaction SMILES: CN(C)C=O.[CH3:6][CH:7]1[CH2:16][C:15]2[N:14]=[N:13][C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[CH:11][C:10]=2[CH:9]([OH:27])[CH2:8]1.Cl.CN(C)CCCN=C=NCC.[C:40]([O:44][C:45]([NH:47][C@@H:48]([C:56](O)=[O:57])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>C(O)C.C(OCC)(=O)C>[C:40]([O:44][C:45]([NH:47][C@@H:48]([C:56]([O:27][C@H:9]1[CH2:8][C@@H:7]([CH3:6])[CH2:16][C:15]2[N:14]=[N:13][C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[CH:11][C:10]1=2)=[O:57])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:46])([CH3:42])([CH3:43])[CH3:41]
Reactant: CC1Cc2nnc(-c3cccc(C(F)(F)F)c3)cc2C(O)C1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCO
Product: C[C@H]1Cc2nnc(-c3cccc(C(F)(F)F)c3)cc2[C@@H](OC(=O)[C@@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C1
Yield: 29.5 %

Procedure:
To a N,N-dimethylformamide solution (181 mL) of 7-methyl-3-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydrocinnolin-5-ol (27.8 g, 90.4 mmol) obtained in Example 6 were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (26 g, 135.7 mmol) and N-(tert-butoxycarbonyl)-D-phenylalanine (31.2 g, 117.6 mmol) with washing in N-methylpyrrolidone (36 ml), followed by adding N,N-dimethylaminopyridine (1.2 mg, 9.0 mmol) to the mixed liquid under ice cooling, stirring over night, adding ethyl acetate (0.6 mL) and distilled water (0.3 L) and washing thus extracted organic layer with a 5% by weight aqueous solution of potassium hydrogen sulfate (400 mL), a saturated aqueous solution of sodium bicarbonate (300 mL) and a 10% saline solution (300 mL) sequentially. To residue obtained after concentration of the organic layer was added ethanol (187 mL) and stirred over night at room temperature. Crystal generated was filtered and washed with ethanol (35 mL) to obtain the titled objective compound (14.8 g).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[NH:16][CH2:15]2.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>C1COCC1>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:15]2
Reactant: O=C1NCc2cc(Cl)ccc21
Reactant: COc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3cc(Cl)ccc3C2=O)cc1
Reaction time: 0.17 h
Yield: 104.3 %

Procedure:
Sodium bis(trimethylsilyl) amide (2 mL, 2 M in THF, 2 mmol) was added dropwise at 0° C. to a solution of 5-chloro-2,3-dihydro-isoindol-1-one (0.34 g, 2 mmol) in THF (10 mL). After stirring for 10 min, 1-bromomethyl-4-methoxy-benzene (0.52 g, 2.6 mmol) was added dropwise. The resulting reaction mixture was allowed to stir at room temperature for 48 hours before quenching with saturated aqueous ammonium chloride solution. After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give the crude product (0.6 g, 100%) as a yellow oil. MS: 288.0 (M+H+). It was used directly in the next step, without further purification.
Reaction SMILES: N#N.Br[C:4]1[CH:9]=[C:8]([C:10]([CH3:18])([CH3:17])[O:11][SiH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[CH:6][N:5]=1.[Li]CCCC.CN(C)[C:26](=[O:28])[CH3:27].[NH4+].[Cl-]>CCOCC>[C:13]([SiH2:12][O:11][C:10]([CH3:18])([CH3:17])[C:8]1[CH:7]=[CH:6][N:5]=[C:4]([C:26](=[O:28])[CH3:27])[CH:9]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccnc(Br)c1
Reactant: CC(=O)N(C)C
Agent: N#N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(=O)c1cc(C(C)(C)O[SiH2]C(C)(C)C)ccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 2-bromo-4-(tert-butyl-dimethyl-silanyloxymethyl)-pyridine (1.04 g, 3.44 mmol) in dry Et2O (50 mL) was added n-BuLi (1.60 mL of a 2.5M solution in hexanes, 3.96 mmol) at −78° C. The reaction mixture was then stirred for 1 h at −78° C. before N,N-dimethylacetamide (0.64 mL, 6.88 mmol) was added dropwise. The reaction mixture was allowed to warm up to rt and stirred at this temperature for 10 min. Sat. aq. NH4Cl (20 mL) was added, the layers separated and the aq. layer extracted with Et2O (3×30 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1 to 5:1 hept-EA) gave the title compound as a pale yellow oil. TLC: rf (1:2 hept-EA)=0.64. LC-MS-conditions 02: tR=1.12 min; [M+H]+=265.84.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16](Cl)[C:17]#[CH:18].[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:10]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:18][C:17]#[CH:16])[C:8]#[N:9])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: C#CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: C#CCC(C#N)(c1ccccc1)c1ccccc1
Reaction time: 6 h

Procedure:
To a mixture of 2,2-diphenylacetonitrile (135.77 g), 2-propynyl chloride (52.35 g) and tetrabutylammonium hydrogen sulfate (0.51 g) was added dropwise 50% aqueous solution of sodium hydroxide (100 ml) at room temperature. After being stirred for 6 hours, the mixture was poured into water and extracted with diethyl ether. The extract was washed successively with diluted hydrochloric acid and brine, and evaporated in vacuo. The residue was distilled in vacuo to give 2,2-diphenyl-2-(2-propynyl)acetonitrile.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]([CH3:19])([CH3:18])[CH2:16]O.ClCCl.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.O.CC(OC)(C)C>[CH3:14][C:15]([CH3:19])([CH3:18])[CH2:16][O:9][C:8](=[O:10])[C:7]([CH3:12])([CH3:11])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:13]
Reactant: CC(C)(C)CO
Reactant: CC(C)(C)OC(=O)C(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: COC(C)(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)COC(=O)C(C)(C)C(=O)OC(C)(C)C

Procedure:
To a mixture of 2,2-dimethylmalonic acid mono-t-butyl ester (10 g), 2,2-dimethyl-1-propanol [CAS No. 75-84-3] (5.15 g), DMAP (1.3 g), and dichloromethane (100 mL), WSC (12.2 g) was added with stirring under ice-cooling, and the resulting mixture was stirred at room temperature for 2 days. TBME and water were added to the mixture, and the resulting mixture was extracted. The organic layer was sequentially washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain 2,2-dimethylmalonic acid t-butyl ester(2,2-dimethylpropyl)ester (12 g).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:10]=[C:11]([CH:22]=[CH:23][CH:24]=2)[O:12][CH:13]([CH2:19][CH2:20][CH3:21])[C:14]([O:16]CC)=[O:15])[N:5]=1.CO>O>[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:10]=[C:11]([CH:22]=[CH:23][CH:24]=2)[O:12][CH:13]([CH2:19][CH2:20][CH3:21])[C:14]([OH:16])=[O:15])[N:5]=1
Reactant: CCCC(Oc1cccc(-c2noc(C)n2)c1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC(Oc1cccc(-c2noc(C)n2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.1 I of 1N sodium hydroxide solution are added to a solution of 347 g (1.14 mol) of ethyl 2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-pentanoate in 1.4 I of methanol, and the mixture is stirred at room temperature for 24 hours. The reaction mixture is diluted with 1 I of water and extracted twice with 1 I of tert-butyl methyl ether each time. The aqueous phase is acidified to a pH of 2 using concentrated hydrochloric acid and extracted twice with 2 I of tert-butyl methyl ether each time. The combined organic phases are evaporated, and the residue is recrystallised from 100 ml of toluene: 2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]pentanoic acid is obtained as colourless crystals of m.p. 98-100°.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[C:10]([O:14][C:15]([N:17]1[CH2:24][C@H:23]2[C@H:19]([CH2:20][CH:21]([CH3:25])[CH2:22]2)[C@H:18]1[CH2:26][NH2:27])=[O:16])([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:24][C@H:23]2[C@H:19]([CH2:20][CH:21]([CH3:25])[CH2:22]2)[C@H:18]1[CH2:26][NH:27][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])=[O:16])([CH3:12])([CH3:13])[CH3:11]
Reactant: CC1C[C@H]2CN(C(=O)OC(C)(C)C)[C@H](CN)[C@H]2C1
Reactant: CCOC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: CC1C[C@H]2CN(C(=O)OC(C)(C)C)[C@H](CNC(=O)C(F)(F)F)[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl trifluoroacetate (0.7 mL, 1.4 eq) was added to a solution of (1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]-octane-3-carboxylic acid tert.-butyl ester (1.1 g) in dry THF (14 mL). The reaction mixture was stirred at RT for 1 h. Solvent and excess ethyl trifluoroacetate were evaporated in vacuo. The resulting product was then used for the next step without purification
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[CH3:15].C(N(CC)CC)C.[OH-].[Na+].CC(OC)(C)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]([CH2:9][C@@H:10]([OH:14])[C:11]([OH:13])=[O:12])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(CC(=O)C(=O)O)cc(C)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](O)C(=O)O)cc(C)c1Cl
Reaction time: 2 h

Procedure:
12.3 g (54.4 mmol) 3-(4-chloro-3,5-dimethyl-phenyl)-2-oxo-propionic acid in 130 mL THF and 7.6 mL (54.4 mmol) triethylamine were combined at −35° C. with a solution of 21.0 g (65.3 mmol) (1R)—B-chlorodiisopinocampheylborane in 65 mL THF within 30 min and stirred for 2 h at this temperature. After the reaction had ended the reaction mixture was made alkaline at 0° C. with 50 mL 1 M NaOH (exothermic), stirred for 3 h, combined with 30 mL TBME and the phases were separated. The organic phase was washed with 50 mL water and 30 mL 1 M NaOH. The combined aqueous phases were acidified with 2 M HCl and extracted with TBME. The organic phases were dried over Na2SO4 and evaporated down i. vac. The product was reacted further without purification.
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([N:18]([CH2:23][C:24](O)=[O:25])[CH2:19][C:20](O)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[O:1]([CH2:8][CH2:9][N:10]1[C:20](=[O:21])[CH2:19][N:18]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:23][C:24]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Reactant: NCCOc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1CN(Cc2ccccc2)CC(=O)N1CCOc1ccccc1
Yield: 64.8 %

Procedure:
2-Phenoxyethylamine (1.37 g) and N-benzyliminodiacetic acid (2.23 g) were mixed and heated to 225°, and maintained at this temperature for 15 min. After cooling, chloroform was added and the product purified by column chromatography (SiO2 /CHCl3) to give the title compound as a reddish oil (2.1 g).
Reaction SMILES: [C:1]([C:7]1[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]2[O:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][C:11]=2[CH:18]=1)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].C=O.Cl.[CH3:24]NC.Cl>CN(C)C=O.C(O)(=O)C>[CH2:24]=[C:2]([CH:3]([CH3:5])[CH3:4])[C:1]([C:7]1[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]2[O:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][C:11]=2[CH:18]=1)=[O:6]
Reactant: Cc1c(C(=O)CC(C)C)cc2c(c1C)OC(C(=O)O)C2
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C=C(C(=O)c1cc2c(c(C)c1C)OC(C(=O)O)C2)C(C)C
Temperature: 0 °C

Procedure:
A mixture 2,3-dihydro-5-isovaleryl-6,7-dimethylbenzofuran-2-carboxylic acid (8.5 g.), paraformaldehyde (2.0 g.), dimethylamine hydrochloride (3.3 g.) and acetic acid (1 ml.) is heated at 95° for 2.5 hours, treated with dimethylformamide (75 ml.), heated an additional 3.5 hours then poured into ice water (300 ml.) containing hydrochloric acid (5 ml.). The product is extracted into ether, washed with water, dried over magnesium sulfate and the solvent evaporated at reduced pressure to afford 2,3-dihydro-5-(2-methyleneisovaleryl)-6,7-dimethylbenzofuran-2-carboxylic acid which melts at 97°C. after recrystallization from cyclohexane.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Mg].[CH:13]1[C:26]2[C:25](=O)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][C:17]=2[CH:16]=[CH:15][CH:14]=1>C(OCC)C>[C:2]1([C:18]2[C:19]3[C:24]([CH:25]=[C:26]4[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]4)=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2Cc2ccccc21
Reactant: Brc1cccc2ccccc12
Agent: [Mg]
Solvent: CCOCC
Product: c1ccc2c(-c3c4ccccc4cc4ccccc34)cccc2c1

Procedure:
A Grignard reagent was prepared from 1-bromonaphthalene and magnesium in diethyl ether under an inert atmosphere. The reagent was reacted with 9-anthrone. The reaction was quenched with hydrochloric acid, and the mixture was purified as usual, to give the desired 9-α-naphthylanthracene.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+:18]([O-])=O)[N:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO.[Pd]>[NH2:18][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[CH:17][C:8]([CH2:7][N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)=[N:9]2
Reactant: O=[N+]([O-])c1cccc2nc(CN3CCOCC3)ccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1cccc2nc(CN3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
190 mg (0.7 mmol) of 2-(morpholin-4-ylmethyl)-5-nitroquinoline is dissolved in 10 ml of methanol. After the addition of 19 mg of palladium on carbon and 19 mg of potassium carbonate, the reaction mixture is allowed to stir for 4 hours at room temperature under hydrogen atmosphere. It is then filtered on Celite and washed with ethyl acetate. After removal of the solvent in a vacuum and chromatography on silica gel with hexane-ethyl acetate (0-100%) as well as with ethyl acetate-methanol (0-100%), 134 mg (79% of theory) of the product is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][C:22](=[O:26])[CH2:23][CH2:24][NH2:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22](=[O:26])[CH2:23][CH2:24][NH:25][C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: NCCC(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)NCCC(=O)NCCC(=O)OCc1ccccc1

Procedure:
N-(t-butoxycarbonyl)-β-alanine and β-alanine benzyl ester were coupled analogously to the above examples to give N-[N-(t-butoxycarbonyl)-β-alanyl]-β-alanine benzyl ester, mp. 84°-85° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[C:19](OC(=O)C)(=[O:21])[CH3:20]>OS(O)(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]([C:19](=[O:21])[CH3:20])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cc3ccccn3n2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (2.00 g, 9.42 mmol) in acetic anhydride (20 mL) and conc. H2SO4 (2 drops) was stirred and heated at reflux for 30 min. The mixture was cooled to room temperature, poured into ice water (300 mL), and basified (pH=10) using 1N NaOH(aq). The resulting orange precipitate was collected by filtration, washed with water, air-dried, then dried under high-vacuum to afford the title compound as an orange solid, 2.60 g (quant.). 1H NMR (CDCl3) δ 8.56 (d, 1H, J=6.9 Hz), 8.45 (d, 1H, J=9.3 Hz), 7.62 (m, 2H), 7.54 (m, 1H), 7.24 (m, 2H), 7.08 (m, 1H), 2.20 (s, 3H): MS (+ve ion electrospray) 255 (100), (MH+).
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:7][CH2:6][CH:5]([C:8]([CH3:15])([CH3:14])[C:9]([O:11]CC)=[O:10])[CH2:4][CH2:3]1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1([F:16])[CH2:3][CH2:4][CH:5]([C:8]([CH3:14])([CH3:15])[C:9]([OH:11])=[O:10])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C(C)(C)C1CCC(F)(F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C(=O)O)C1CCC(F)(F)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 68.2 %

Procedure:
To a solution of Intermediate 232B (0.15 g, 0.640 mmol) in ethanol (2 mL) and water (1 mL) was added NaOH (0.256 g, 6.40 mmol) and the reaction mixture was stirred at 80° C. for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was acidified with an aqueous solution of 1.5N HCl and extracted with EtOAc (2×20 mL) The combined organic layer was dried over Na2SO4, filtered and the filtrate concentrated to afford Intermediate 232C as a yellow solid (90 mg, 68%). 1H NMR (300 MHz, DMSO-d6) δ ppm 12.20 (br. s., 1H), 2.11-1.94 (m, 2H), 1.91-1.55 (m, 5H), 1.34-1.14 (m, 2H), 1.09-0.96 (m, 6H).