Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]1([C:16]2[O:17][C:18]([C:21]3[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=3)[NH2:24])=[N:19][N:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:21]([C:18]3[O:17][C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[N:20][N:19]=3)[CH:22]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1cccc(-c2nnc(-c3ccccc3)o2)c1
Product: Fc1cnc(Cl)nc1Nc1cccc(-c2nnc(-c3ccccc3)o2)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 3-(2-phenyl-1,3,4-oxadiazol-5-yl)aniline gave 2-chloro-5-fluoro-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl)-4-pyrimidineamine. 1H NMR (DMSO-d6): δ 10.28 (s, 1H), 8.62 (s, 1H), 8.39 (d, 1H, J=3.3 Hz), 8.11 (m, 2H), 7.98 (bd, 1H, J=6.9 Hz), 7.88 (bd, 1H, J=8.4 Hz), 7.65 (m, 4H); LCMS: purity: 76%; MS (m/e): 76%.
Reaction SMILES: C(OC([C@@H](CC1C=CC=CC=1)CC(O)=O)=O)(C)(C)C.Cl.N[C@@H](CC1C=CC(C(F)(F)F)=CC=1)CC(O)=O.BrC1C=C2C(=CC=1)NN=C2.N(CC[C@@H](NC(=O)OC(C)(C)C)CC1C=CC=CC=1)=[N+]=[N-].[NH:69]1[C:77]2[C:72](=[CH:73][C:74]([C:78]3[N:79]=[N:80][N:81]([CH2:83][CH2:84][C@@H:85]([NH2:97])[CH2:86][C:87]4[CH:92]=[CH:91][C:90](C(F)(F)F)=[CH:89][CH:88]=4)[CH:82]=3)=[CH:75][CH:76]=2)[CH:71]=[N:70]1>>[NH:69]1[C:77]2[C:72](=[CH:73][C:74]([C:78]3[N:79]=[N:80][N:81]([CH2:83][CH2:84][C@@H:85]([NH2:97])[CH2:86][C:87]4[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=4)[CH:82]=3)=[CH:75][CH:76]=2)[CH:71]=[N:70]1
Reactant: N[C@H](CCn1cc(-c2ccc3[nH]ncc3c2)nn1)Cc1ccc(C(F)(F)F)cc1
Agent: Brc1ccc2[nH]ncc2c1
Agent: CC(C)(C)OC(=O)N[C@H](CCN=[N+]=[N-])Cc1ccccc1
Agent: CC(C)(C)OC(=O)[C@H](CC(=O)O)Cc1ccccc1
Product: N[C@H](CCn1cc(-c2ccc3[nH]ncc3c2)nn1)Cc1ccccc1

Procedure:
Example 39 was synthesized in a similar fashion as Example 37 as shown in Scheme 12 starting with commercially available (S)-3-(tert-butoxycarbonyl)-4-phenylbutanoic acid (commercially available from PepTech Corporation) instead of (S)-3-amino-4-(4-(trifluoromethyl)phenyl)butanoic acid hydrochloride, and 5-bromo-1H-indazole. The synthesis of the required (S)-tert-butyl 4-azido-1-phenylbutan-2-ylcarbamate was performed in a similar manner as described for the (S)-tert-butyl 4-azido-1-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate (Examples 37 and 38) including one additional BOC deprotection step.
Reaction SMILES: Cl[Si](C)(C)C.[BH4-].[Li+].[CH3:8][O:9][C:10]1[CH:24]=[CH:23][C:13]([CH2:14][N:15]2[C@H:20]([CH3:21])[CH2:19][O:18][CH2:17][C:16]2=O)=[CH:12][CH:11]=1.[OH-].[K+]>O1CCCC1.CO>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]2[C@H:20]([CH3:21])[CH2:19][O:18][CH2:17][CH2:16]2)=[CH:23][CH:24]=1
Reactant: COc1ccc(CN2C(=O)COC[C@H]2C)cc1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CN2CCOC[C@H]2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
Chlorotrimethylsilane (37 g, 341 mmol) was added to a solution of lithium borohydride (3.7 g, 170 mmol) in tetrahydrofuran (200 ml) and the mixture was stirred for one hour at room temperature. A solution of (5R)-4-(4-methoxybenzyl)-5-methylmorpholin-3-one (19.6 g, 83.3 mmol) in tetrahydrofuran (20 ml) was added to the solution and the mixture was stirred for one hour at room temperature. After careful addition of methanol with ice-cooled solution, pH was adjusted to 12-14 with 6N aqueous potassium hydroxide and the solution was stirred for 2 hours at 80° C. After cooling, the solution was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford (5R)-4-(4-methoxybenzyl)-5-methylmorpholine (17.8 g, 80.3 mmol, 96%) as colorless oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:18]=[CH:17][C:13]([CH:14]=[N:15][OH:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Cl:21]N1C(=O)CCC1=O.O>CN(C)C=O>[OH:16][N:15]=[C:14]([Cl:21])[C:13]1[CH:17]=[CH:18][C:10]([O:9][C:8]2[CH:19]=[CH:20][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)Oc1ccc(Oc2ccc(C=NO)cc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Oc2ccc(C(Cl)=NO)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.2 %

Procedure:
To a solution of Example 17C (1.48 g, 5.56 mmol) in N,N-dimethyl formamide (15 mL) was added N-chlorosuccinimide (0.70 g, 5.24 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was poured into water. The aqueous layer was extracted with ether washed with water, then brine, and dried over MgSO4 and concentrated to give the title compound as an oil (1.67 g, 100%),
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]3[O:16][CH2:17][O:18][C:12]=3[CH:11]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.O(CC)[C:20]([S-])=[S:21].[K+].C(=O)(O)[O-].[Na+].C(O)C>O>[CH2:17]1[O:16][C:13]2[CH:14]=[CH:15][C:10]([N:9]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:3]4[NH:2][C:20]3=[S:21])=[CH:11][C:12]=2[O:18]1
Reactant: Nc1cccnc1Nc1ccc2c(c1)OCO2
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: S=c1[nH]c2cccnc2n1-c1ccc2c(c1)OCO2

Procedure:
A mixture of 2.6 g. (0.01 mole) of 3-amino-2-(3,4-methylenedioxyanilino)pyridine hydrochloride (Example 1, Step B), 1.8 g. (0.011 mole) of potassium ethyl xanthate, and 840 mg. (0.01 mole) of sodium bicarbonate in 45 ml. of ethanol and 10 ml. of water was heated at reflux for 3.5 hours. There was added 3 ml. of 2.5 N sodium hydroxide solution and the mixture was filtered. The filtrate was acidified with acetic acid and the precipitated product was collected (500 mg., m.p. 278° C.). After recrystallization from dioxane there was obtained 1,3-dihydro-3-(3,4-methylenedioxyphenyl)imidazo[4,5-b]pyridin-2-thione, m.p. 285° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=1)[C:38]([O:40][CH3:41])=[O:39]>CN(C)C=O.[Pd](Cl)Cl.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[CH3:41][O:40][C:38]([C:37]1[CH:36]=[C:35]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=2)[CH:44]=[CH:43][CH:42]=1)=[O:39]
Reactant: O=Cc1ccc(Br)cc1F
Reactant: COC(=O)c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2ccc(C=O)c(F)c2)c1
Temperature: 80 °C
Yield: 55 %

Procedure:
A mixture of 2.0 g (9.85 mmol.) 4-bromo-2-fluorobenzaldehyde, 2.8 g (10.8 mmol.) bis(pinacolato)diboron, 2.9 g (29.6 mmol.) potassium acetate and 216 mg (0.3 mmol.) bis(diphenylphosphino)ferrocene palladium dichloride in 60 mL dimethylformamide was heated at 80° C. for 4 hours. The mixture was cooled and 4.2 g (19.7 mmol.) methyl 3-bromobenzoate and 216 mg (0.3 mmol.) bis(diphenylphosphino)ferrocene palladium dichloride was added and the mixture heated at 80° C. for 18 hours. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were combined then washed successively with 1N NaOH, 1N HCl, water, brine then dried (MgSO4) and concentrated in vacuo to give an oil. Chromatography on Silica Gel eluting with ethyl acetate/hexanes (1:5) gave 1.4 g 3′-fluoro-4′-formyl-biphenyl-3-carboxylic acid methyl ester as an oil.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].[H][H]>[Cr].[Cu]>[CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C@@H:7]([CH2:9][CH2:10][OH:11])[CH3:8])[CH3:3]
Reactant: CC(C)=CCC[C@@H](C)CC=O
Reactant: [H][H]
Agent: [Cr]
Agent: [Cu]
Agent: O=C([O-])[O-]
Product: CC(C)=CCC[C@H](C)CCO
Yield: 73 %

Procedure:
Into a 100-ml autoclave were introduced 20.5 g (132.8 mmol) of (R)-citronellal, 1.0 g (5%, wt/wt) of a copper-chromium catalyst, and 0.04 g (0.2%, wt/wt) of sodium carbonate. After the atmosphere in the system was replaced with hydrogen, the reaction mixture was vigorously agitated in a hydrogen atmosphere (3.4 MPa) at 130° C. for 4.5 hours and then cooled. Thereafter, the catalyst was removed by filtration. The crude citronellol obtained was distilled under reduced pressure (70° C./1,870 Pa) to obtain 15.15 g of (S) -citronellol. Yield, 73%. Purity, 98.6% (of which α-citronellol accounted for 3.4%).
Reaction SMILES: N1C=CC=CC=1.[Si:7]([O:14][CH2:15][C@H:16]1[O:20][C@@H:19]([N:21]2[CH:28]=[C:27]([CH3:29])[C:25](=[O:26])[NH:24][C:22]2=[O:23])[C@H:18]([OH:30])[CH2:17]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Si](C(O)[C@H]1O[C@@H](N2C=C(C)C(=O)NC2=O)[C@H](O)C1)(C(C)(C)C)(C)C.C(OC(=O)C)(=O)C>C(Cl)Cl.C(OCC)(=O)C.[O-2].[O-2].[O-2].[Cr+6].[O-2].[O-2].[O-2].[Cr+6].N1C=CC=CC=1>[Si:7]([O:14][CH2:15][C@H:16]1[O:20][C@@H:19]([N:21]2[CH:28]=[C:27]([CH3:29])[C:25](=[O:26])[NH:24][C:22]2=[O:23])[C:18](=[O:30])[CH2:17]1)([C:10]([CH3:13])([CH3:11])[CH3:12])([CH3:8])[CH3:9]
Reactant: Cc1cn([C@@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)C[C@H]2O)c(=O)[nH]c1=O
Agent: [Cr+6]
Agent: Cc1cn([C@@H]2O[C@H](C(O)[Si](C)(C)C(C)(C)C)C[C@H]2O)c(=O)[nH]c1=O
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cn([C@@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)CC2=O)c(=O)[nH]c1=O
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
Chromium trioxide (7.63 g, 76.3 mmol) was added to 150 mL of dry methylene chloride containing 12.059 g (152.6 mmol) of pyridine. The mixture was stirred for 15 minutes. In a separate flask, 793 mg (19.08 mmol) of 5'-O-(t-butyldimethylsilyl)-5-methyl-3'-deoxyuridine from Step 2 was dissolved in approximately 100 mL of methylene chloride. The chromium trioxide-pyridine solution was added to the solution of 5'-(t-butyldimethylsilyl)-5-methyl-3'-deoxy-uridine and 1.946 g (19.08 mmol) of acetic anhydride was added immediately. After stirring at ambient temperature for 0.5 h, the reaction mixture was diluted with approximately 250 mL of ethyl acetate then filtered through Celite filter aid and through florisil eluted with ethyl acetate. The solvent was evaporated and the residue purified on silica gel eluted with 90% ethyl acetate in hexanes. The title compound was obtained in 59.6% yield (4.08 g), [α]D23 =+38.0° (c, 1.31, MeOH). Analysis calculated for C16H26N2O5Si: C, 54.24; H, 7.34; N, 7.91. Found: C, 54.25; H, 7.36; N, 7.88
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH:18]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=1)[OH:19].O>C(O)(C)(C)C>[CH2:26]([C:23]1[CH:24]=[CH:25][C:20]([CH:18]([OH:19])[CH2:17][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[N:21][CH:22]=1)[CH3:27]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCc1ccc(C(O)CBr)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1

Procedure:
Into a solution of 22.6 g (0.181 mol) of 4-hydroxy benzaldehyde dissolved in 75 mL tertiary butanol, was added 38.5 g (0.278 mol) of potassium carbonate in 10 min. Reaction mixture was refluxed for 1 hr. and 15 g (0.06 mol) of 2-bromo-1-(5-ethyl-pyridin-2-yl)-ethanol dissolved in 75 mL tertiary butanol was added slowly in one hr. Reaction mixture was refluxed further for 10 hr. and at 25° C. poured into excess of water. Product was extracted with toluene. Subsequent concentration under reduced pressure and purification gave the desired product. Yield of the product was 12.37 g (70%). m.p. 80° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH3:11].[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].Cl.CN(C)CC(O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.[Cu]I>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:21][C:2]1[CH:3]=[C:4]([F:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH3:11]
Reactant: Cc1c[nH]c2c(Br)cc(F)cc12
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c[nH]c2c(Oc3ccc(Cl)c(Cl)c3)cc(F)cc12
Yield: 34 %

Procedure:
Following general method A-18, 7-Bromo-5-fluoro-3-methyl-1H-indole (727 mg, 3.19 mmol) was reacted with 3,4-dichlorophenol (779 mg, 4.78 mmol), CuI (60.8 mg, 0.319 mmol), N,N-dimethylglycine hydrochloride (134 mg, 0.957 mmol), and Cs2CO3 (2.07 g, 6.38 mmol) in anhydrous dioxane (6.4 mL). The crude product was purified by silica gel column chromatography utilizing a solvent system of 5% EtOAc/Hexanes to yield 506 mg of I-198C as a yellow oil (34%). 1H NMR (400 MHz, CDCl3).
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](SC2C=CC(S(O)(=O)=O)=C(N)C=2)=[CH:4][C:3]=1C(O)=O.N1C(Cl)=NC(Cl)=NC=1Cl.NC1C=C(S(O)(=O)=O)C=CC=1>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cc(Sc2cc(C(=O)O)c(N)c3c2C(=O)c2ccccc2C3=O)ccc1S(=O)(=O)O
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: Nc1cccc(S(=O)(=O)O)c1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
1-Amino-2-carboxy-4-(3'-amino-4'-sulfophenylthio)anthraquinone (9.4 parts) and cyanuric chloride (3.7 parts) were subjected to condensation reaction in an aqueous medium in a usual manner, followed by a condensation reaction with 3-aminobenzenesulfonic acid (3.5 parts) at 20° to 40° C. under a weak acid condition, thereby obtaining an anthraquinone compound of the following formula (free acid form). ##STR394##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Mg]Cl)(C)C.[CH3:14][O:15][CH2:16][C:17](N(C)C)=[O:18].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[OH-].[Na+].[Na+].[Cl-]>C1COCC1.C(OCC)(=O)C>[Br:8][C:4]1[N:3]=[C:2]([C:17](=[O:18])[CH2:16][O:15][CH3:14])[CH:7]=[CH:6][CH:5]=1
Reactant: COCC(=O)N(C)C
Reactant: Brc1cccc(Br)n1
Agent: CC(C)[Mg]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCC(=O)c1cccc(Br)n1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
14.5 g (61.2 mmol) of 2,6-dibrompyridine were dissolved in about 50 ml of THF, and 35 ml of 2 M isopropylmagnesium chloride (corresponds to 70 mmol) were added under argon. The temperature of the mixture increased. The mixture was stirred at room temperature for another 1.5 h and at 30° C. for 2 h and then cooled in a CO2/EtOH bath, and a solution of 8 g (68.2 mmol) of 2-methoxy-N,N-dimethylacetamide in THF was added, the thickened reaction material was diluted with more THF and allowed to thaw, ethyl acetate, aq. citric acid, dil. aqueous sodium hydroxide solution to pH=6, aq. NaCl were added, the aqueous phase was extracted three times with ethyl acetate and the combined organic phases were dried with MgSO4 and concentrated by evaporation. The residue was distilled under reduced pressure in a kugelrohr and the distillate was recrystallized from a little benzotrifluoride.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[CH2:27][C:18]1([C:23](=O)[N:22]([CH3:25])[CH2:21][C:20](=O)[NH:19]1)[CH2:17][CH2:16]2.[OH-].[Na+]>CCOCC>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[CH2:27][C:18]1([CH2:23][N:22]([CH3:25])[CH2:21][CH2:20][NH:19]1)[CH2:17][CH2:16]2
Reactant: COc1cc2c(cc1OC)CC1(CC2)NC(=O)CN(C)C1=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: COc1cc2c(cc1OC)CC1(CC2)CN(C)CCN1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
To a suspension of lithium aluminum hydride (114 mg, 3 mmol) and aluminum chloride (400 mg, 3 mmol) in ether (4 ml) was added the suspension of 3,4-dihydro-6,7-dimethoxy-4'-methylspiro[naphthalene-2(1H),2'-piperazine]-3',6'-dione (50 mg, 0.16 mmol) in ether (2 ml). The reaction mixture was stirred at ambient temperature for 45 min and treated with 1N sodium hydroxide. The precipitate was filtered and washed with 1N sodium hydroxide and chloroform. The filtrate was washed with sat. sodium chloride, dried, and concentrated to give the titled compound (42 mg, 86%). A portion was dissolved in ethyl acetate and treated with 4N hydrochloric acid in ethyl acetate. Concentration under reduced pressure followed by addition of isopropylether gave a powder.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([C:17](OCC)=[O:18])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH3:22])=[CH:3][CH:2]=1.[H-].[Li+].[Al+3].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([CH2:17][OH:18])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH3:22])=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(-c4ccccc4)cc3)c2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1nc2ccc(CO)cc2n1Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
Tetrahydrofuran (20 ml) solution of 1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-methylbenzimidazole (5.30 g) is slowly added to a tetrahydrofuran (20 ml) solution of aluminum lithium hydride (2.17 g). Further, the solution is stirred for one hour at room temperature. By adding tetrahydrofuran (30 ml), the reaction solution is diluted. By adding a saturated sodium sulfate aqueous solution, the aluminum lithium hydride is decomposed, solidified and the tetrahydrofuran layer is separated. The solvent is removed through evaporation. Purification using silica gel column chromatography produced 1-(biphenyl-4-ylmethyl)-6-hydroxymethyl-2-methylbenzimidazole (3.72 g). 1H-NMR (CDCl3, δ): 2.59 (3H, s), 4.78 (2H, s), 5.37 (2H. s), 7.11 (2H, d, J=8.3 Hz), 7.24 (1H, d, J=8.3 Hz), 7.30-7.37 (2H, m), 7.42 (2H, t), 7.51-7.56 (4H, m), 7.70 (1H, d, J=8.2 Hz).
Reaction SMILES: C(O[C:4]([C:6]1[O:7][C:8]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:9][N:10]=1)=[O:5])C.[CH2:20]([NH2:22])[CH3:21]>CO.O1CCCC1>[C:16]([O:15][C:13](=[O:14])[NH:12][CH2:11][C:8]1[O:7][C:6]([C:4](=[O:5])[NH:22][CH2:20][CH3:21])=[N:10][N:9]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: CCOC(=O)c1nnc(CNC(=O)OC(C)(C)C)o1
Reactant: CCN
Solvent: C1CCOC1
Solvent: CO
Product: CCNC(=O)c1nnc(CNC(=O)OC(C)(C)C)o1
Reaction time: 1.5 h

Procedure:
To a solution of 5-[[[(1,1-dimethylethoxy)carbonyl]amino]methyl]-1,3,4-oxadiazole-2-carboxylic acid ethyl ester (prepared as described in JOC (1995), 60(10), 3112-20) (0.150 g) in methanol (5 ml) was added a solution of 2.0M ethylamine in tetrahydrofuran (3 ml). The solution was left standing at 20° C. for 1.5 h. The solvent was removed by evaporation using a stream of nitrogen to give the title compound as a yellow gum (0.139 g).
Reaction SMILES: C(O)(=O)C.O=[C:6]1[CH2:23][CH2:22][C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:8][CH2:7]1.[N:24]1[CH:25]=[N:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][C:28]=12.[Na]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[N:24]1[CH:25]=[N:26][N:27]2[CH2:32][CH2:31][N:30]([CH:6]3[CH2:23][CH2:22][C:9]4([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]4)[CH2:8][CH2:7]3)[CH2:29][C:28]=12
Reactant: c1nc2n(n1)CCNC2
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CCC(N3CCn4ncnc4C3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
Acetic acid (2.34 eq.) was added to a solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (1.122 mmol, 1 eq.) and 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine (1.14 eq.) in methylene chloride (7 ml). Sodium triacetoxyborhydride (1.4 eq) was then added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and sat. NaHCO3 solution. The aqueous phase was washed with methylene chloride (2×20 ml), and the combined organic phases were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (silica, ethyl acetate/ethanol 10:1) to obtain the desired product. Yield: 62%
Reaction SMILES: CS[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)([CH3:6])[C:4]#[N:5].C[S-].[Na+].[Cl-].[NH4+]>CO>[C:13]([C:9]1[CH:8]=[C:7]([CH:3]([CH3:6])[C:4]#[N:5])[CH:12]=[CH:11][CH:10]=1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CSC(C)(C#N)c1cccc(C(=O)c2ccccc2)c1
Agent: C[S-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(C#N)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.9 %

Procedure:
241 mg of alpha-(methylthio)-alpha-(m-benzoylphenyl)propionitrile was dissolved in 1 ml of methanol, and 0.60 ml of a 2.3 M methanol solution of sodium methanethiolate was added dropwise. The mixture was stirred at room temperature for 1.5 hours. An aqueous solution of ammonium chloride (2 g/10 ml) was added, and the mixture was extracted with 10 ml of ether three times. The extract was washed with 20 ml of water three times, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; methylene chloride) to afford 167 mg (yield 79%) of alpha-(m-benzoylphenyl)propionitrile.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15]C)=[CH:4][CH:3]=1.B(Br)(Br)Br.CC(C)=O>ClCCl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[CH:4][CH:3]=1
Reactant: COc1ccccc1Cc1ccc(Cl)nn1
Agent: BrB(Br)Br
Solvent: CC(C)=O
Solvent: ClCCl
Product: Oc1ccccc1Cc1ccc(Cl)nn1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
2-(6-Chloro-3-pyridazinylmethyl)anisole (prepared as described in Example 33(c)) (2.35 g) was dissolved in dry dichloromethane (20 ml) and cooled with stirring to -50°. Boron tribromide (3 ml) was then added dropwise, and the solution was allowed to warm to room temperature. After 0.5 hours the orange reaction mixture was poured into ice/water (200 ml) and acetone added to dissolve the precipitated solid. The mixture was extracted with dichloromethane, the organic extracts were separated, washed with water, dried, and evaporated. The residue was recrystallised from ethyl acetate and petroleum spirit to give 2-(6-chloro-3-pyridazinylmethyl)phenol (1.75 g, 80%), m.p. 132°-132.5°.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.CCN(CC)CC.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15]>C(Cl)Cl>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:6][CH:1]2[CH2:5][CH:4]=[CH:3][CH2:2]2)=[O:22])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: OC1CC=CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OC1CC=CC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
To a solution of 3-cyclopentene-1-ol (7.0 g, 83.0 mmol) and Et3N (14.5 g, 143.0 mmol) in CH2Cl2 (200 mL) was added 4-nitrobenzoyl chloride (18.5 g, 100.0 mmol) as solid in several portions over a period of 30 min. The resulting suspension was stirred at room temperature over night. The precipitate was filtered off and the filtrate was washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage SP1; column 40M; TLC method: n-hexane/ethyl acetate 9/1; Rf=0.50), affording the title product (15.6 g, yield 81%): 1H NMR (500 MHz, CDCl3) δ 8.28 (d, J=8.9 Hz, 2H), 8.20 (d, J=8.9 Hz, 2H), 5.81 (m, 2H), 5.69 (m, 1H), 2.95 (m, 2H), 2.61 (m, 2H).