Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: CCCCCCCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCC/C(=C\C=C\C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.8 %

Procedure:
As in Example 115, (E,E)-5-(4-methoxyphenyl)-2,4-tridecadienoic acid (4.75 g) and 4-nitrophenol (2.5 g) in 25 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (3.1 g) and the mixture was stirred at room temperature for 18 hours. After the usual work up, 4.85 g of (E,E)-5-(4-methoxyphenyl)-2,4-tridecadienoic acid 4-nitrophenyl ester was obtained as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:17](O)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH:13][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=3)[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1N=C(N)N1CCN=C21
Reactant: O=C(O)c1cccnc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Reaction time: 8 h
Yield: 68 %

Procedure:
7-Methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Step 4, 31.2 g, 57.7 mmol), nicotinic acid (10.7 g, 86 mmol) and diisopropylethylamine (30.1 mL, 173 mmol) were suspended in DMF (250 mL), and PyBOP (45 g, 86 mmol) was added portionwise. The reaction soon became much thicker with a new solid. After stirring overnight, the solid was collected by filtration then washed with EtOAc (150 mL). The solid was dissolved in CH2Cl2 (1000 mL), washed with water (600 mL) and the organic layer dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound (12.6 g, 68%): HPLC MS RT=1.18 min, MH+=322.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 4.12 (3H, s), 4.28-4.35 (2H, m), 4.60-4.66 (2H, m), 7.63 (1H, t), 7.72-7.86 (3H, m), 8.76 (1H, d), 8.93 (1H, dd), 9.48 (1H, d).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([O-:3])=[O:2]
Reactant: NCCCCCCCCCCCCN
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1NCCCCCCCCCCCCNc1ccccc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
34 g (0.216 mol) 2-nitro-chlorobenzene and 20 g 1,12-diaminododecane (0.10 mol) are mixed with 40 g potassium carbonate and 200 ml N,N-dimethylformamide (DMF). The mixture is heated with reflux while subjected to a vigorous stirring for four hours. Subsequently, the inorganic salts are filtered off and washed with a small amount of DMF. The entire DMF-phase is distilled under vacuum to remove substantially all DMF. The remanence is cooled, and 200 ml water are added while vigorously stirred. Subsequently, the water phase is decanted off, and the product is caused to crystallize by the addition of approximately 100 ml ethanol. The crystals are filtered off, washed twice with 25 ml ethanol and 100 ml petroleum ether followed by an air-drying of the product. Yield 21.8 g (49%), melting point 79° to 80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH3:15])=[C:10]([C:16]3[C:17](=[O:29])[NH:18][C:19]4([CH2:26][CH2:25][N:24]([O:27][CH3:28])[CH2:23][CH2:22]4)[C:20]=3[OH:21])[CH:9]=2)=[CH:4][CH:3]=1.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].N1C=CC=CC=1.Cl>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH3:15])=[C:10]([C:16]3[C:17](=[O:29])[NH:18][C:19]4([CH2:22][CH2:23][N:24]([O:27][CH3:28])[CH2:25][CH2:26]4)[C:20]=3[O:21][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CON1CCC2(CC1)NC(=O)C(c1cc(-c3ccc(Cl)cc3)c(F)cc1C)=C2O
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CON1CCC2(CC1)NC(=O)C(c1cc(-c3ccc(Cl)cc3)c(F)cc1C)=C2OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4′-chloro-6-fluoro-4-methyl-biphenyl-3-yl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (170 mg) and pivaloyl chloride (98 mg) in acetonitrile (5 ml) is added pyridine (64 mg) and the reaction mixture stirred at room temperature for 8 hours. The mixture is poured on diluted HCl and extracted with ethyl acetate (3×). The combined organic layers are washed with brine, dried over sodium sulfate and concentrated. The residue is triturated with heptane, filtered and dried. Yield: 100 mg of 2,2-dimethyl-propionic acid 3-(4′-chloro-6-fluoro-4-methyl-biphenyl-3-yl)-8-methoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester as a solid, mp: 150-151° C.
Reaction SMILES: [OH2:1].O.[Sn](Cl)Cl.CC1C=C(C([N:15]2[C:21]3[CH:22]=[C:23]([C:26](N4CCCCC4)=[O:27])[CH:24]=[CH:25][C:20]=3[CH2:19][N:18]3[C:34](C(NCC4C=CN=CC=4)=O)=[CH:35][CH:36]=[C:17]3[CH2:16]2)=O)C=CC=1C1C=CC=CC=1C(F)(F)F.[CH3:57]O>Cl>[CH3:57][O:1][C:26]([C:23]1[CH:24]=[CH:25][C:20]2[CH2:19][N:18]3[CH:34]=[CH:35][CH:36]=[C:17]3[CH2:16][NH:15][C:21]=2[CH:22]=1)=[O:27]
Reactant: O
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)NCc4ccncc4)n3Cc3ccc(C(=O)N4CCCCC4)cc32)ccc1-c1ccccc1C(F)(F)F
Reactant: CO
Agent: Cl
Agent: Cl[Sn]Cl
Product: COC(=O)c1ccc2c(c1)NCc1cccn1C2
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tin(II) chloride dihydrate (23 g, 3.5 eq) in 2 N hydrochloric acid (106 mL) was added the [4-(2-formyl-1H-pyrrole-1-yl)methyl]-3-nitro]-benzoic acid methyl ester of Step A (8 g). Methanol (200 mL) was then added to this solution and the reaction mixture was stirred at 40° C. for 2 hours. The reaction was then cooled to room temperature, quenched by the addition of saturated aqueous sodium carbonate (20 mL) and filtered through Celite. The filter pad was washed with methanol and hot ethyl acetate. The filtrate and washings were combined, concentrated in vacuo to a volume of 300 mL and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a volume of 200 mL. Acetic acid (1 g) and 10% palladium on charcoal (1.5 g) were added and the mixture was hydrogenated overnight at atmospheric pressure. The reaction was then filtered through Celite and the solvent removed in vacuo to give a dark brown crystalline solid (16.4 g). This was dissolved in dichloromethane and filtered through a silica pad eluting with dichloromethane to provide the title compound as a yellow crystalline solid (11.7 g). Recrystallization from 1,2-dichloroethane yielded a yellow crystalline solid (5.7 g), m.p. 198–200° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11]>CCN(CC)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:13][Si:12]([C:10]#[C:11][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8])([CH3:15])[CH3:14]
Reactant: O=Cc1cncc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cncc(C=O)c1
Reaction time: 4 h

Procedure:
To a stirred solution of 5-bromonicotinaldehyde (1 g) and ethynyltrimethylsilane (792 mg) in Et3N (15 ml) was added tetrakis(triphenylphosphine)palladium (124 mg) and copper(I) iodide (51 mg). After 4 hours, the resulting mixture was filtrated and evaporated. The residue was dissolved in EtOAc and washed successively with dil. NH3aq, water and brine. The organic layer was dried over MgSO4 and evaporated. The residue was purified with silica gel column chromatography to give 5-[(trimethylsilyl)ethynyl]nicotinaldehyde as a slightly yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[C:12]([F:19])[CH:11]=2)=[CH:4][CH:3]=1.C[Si]([N:24]=[N+:25]=[N-:26])(C)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:17](=[O:18])[NH:26][N:25]=[N:24]3)=[C:12]([F:19])[CH:11]=2)=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccc(OCc2ccc(F)cc2)cc1F
Reactant: C[Si](C)(C)N=[N+]=[N-]
Product: O=c1[nH]nnn1-c1ccc(OCc2ccc(F)cc2)cc1F
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A mixture of 7.10 g (0.027 mole) of 4-(4-fluorophenylmethoxy)-2-fluorophenyl isocyanate and 7.0 g (0.060 mole) of trimethylsilyl azide was heated at reflux for approximately seventeen hours. The solution was then allowed to cool to room temperature before being poured over ice. A solid formed and was recovered by filtration. The solid was dried, leaving 8.08 g of 1-[4-(4-fluorophenylmethoxy)-2-fluorophenyl]-1,4-dihydro-5H-tetrazol-5-one, m.p. 171°-172° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16](C)([O-])C.[K+].ICC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH3:16])[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCI
Product: CCN1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
1-tert-Butoxycarbonyl-3-oxopiperazine (7.5 g) was dissolved in dry DMF (250 ml) and potassium tert-butoxide (8.4 g) was added. The mixture was stirred at ambient temperature for 30 minutes, then iodoethane (3.3 ml) added, and stirring continued at the same temperature for 24 hours. A further equal portion of iodoethane was added and stirring continued for 24 hours. Solvent was evaporated, and the residue partitioned between ethyl acetate and water. The organic layer was washed with water, evaporated, and purified by chromatography on silica, using as eluant a gradient increasing in polarity from 0 to 25% isopropanol in iso-hexane. Relevant fractions were combined and evaporated to give 1-tert-butoxycarbonyl-4-ethyl-3-oxopiperazine (6.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](C=C[CH:9]=[C:10]2[CH2:13][O:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[NH2:19]O>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][CH:4]=1)[NH:19][CH:9]=[C:10]2[CH2:13][O:14][NH:15][C:16](=[O:18])[CH3:17]
Reactant: NO
Reactant: COc1ccc2cccc(CONC(C)=O)c2c1
Product: COc1ccc2[nH]cc(CONC(C)=O)c2c1

Procedure:
By carrying out the procedure in the same manner as for the synthesis of the compound of Example 1, but replacing 0-[(7-methoxynaphth-1-yl)methyl]hydroxylamine with O-[5-methoxyindol-3-yl)methyl]hydroxylamine (preparation 10), the title compound is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].[Li+].CC([N-]C(C)C)C.C1C=CC(N[S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])=CC=1>C1COCC1>[F:28][C:27]([F:30])([F:29])[S:24]([O:7][C:3]1[C:2]([CH3:8])([CH3:1])[CH2:6][CH2:5][CH:4]=1)(=[O:26])=[O:25]
Reactant: CC1(C)CCCC1=O
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CCC=C1OS(=O)(=O)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2-dimethylcyclopentanone T6.1 (available from ChemSampCo) (3.00 g, 26.75 mmol) in THF (100 mL), was slowly added LDA (14.7 mL, 2.0 M, in heptane) at −78° C. The resulting mixture was stirred at −78° C. for 1 hour. A solution of N-phenyltriflamide (10.00 g, 28.00 mmol) was added to the mixture at −78° C., and stirring was continued at 0° C. for 2 hours and then at room temperature overnight. The reaction mixture was extracted with hexane (80×2 mL). The organic layer was washed with saturated Na2CO3 (30 mL), brine (20 mL), and dried with MgSO4. The solvent was removed, and the residue was purified by CombiFlash® chromatography (eluant was EtOAc and hexane) to give T6.2. 1H NMR (CDCl3) δ ppm 1.16 (s, 6H), 1.86 (t, J=7.1 Hz, 2H), 2.36 (t, J=7.1 Hz, 2H), 5.56 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9]C(=O)C(F)(F)F)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.CO.C([O-])([O-])=O.[K+].[K+]>O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: O=C(Nc1cc(F)c(Br)cc1[N+](=O)[O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To N-(4-bromo-5-fluoro-2-nitrophenyl)-2,2,2-trifluoroacetamide (3.5 g, 10.5 mmol) was added CH3OH (30 mL) followed by 1.0 M K2CO3 (10.5 mL, 10.5 mmol), and the solution was stirred for 30 minutes (Charifson, P. S.; et al. J. Med. Chem. 2008, 51, 5243-5263). The solution was diluted with H2O and stirred for 1 hour. The resulting orange solid was collected by filtration and dried in a vacuum oven to give the title compound (2.1,g, 8.8 mmol, 84%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.C(OC([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=O)(C)(C)C.N12CCCN=C1CCCCC2>C(#N)C>[NH2:29][CH:30]1[CH2:34][CH2:33][N:32]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([F:17])[C:10]=2[F:16])[CH2:31]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: NC1CCN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Reaction time: 8 h
Yield: 82 %

Procedure:
To 2.0 g (6.64 mmol) of the 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile was added 1.5 g (8.3 mmol) of 3-t-butoxycarbonylaminopyrrolidine and 1.01 g (6.64 mmol) of 1,8-diazabicyclo[5.4.0]undec-7ene. The mixture was stirred overnight and refluxed for two hours. The solids were filtered and washed with ether. They were treated with 5 ml of trifluoroacetic acid and stirred at 25° C. for 1.5 hours. The trifluoroacetic acid was removed and the mixture taken up in water. The pH was adjusted to 7.0 and the solids were filtered and dried to give 2.0 g of the title compound, mp 290°-292° C.
Reaction SMILES: Cl.Cl.[O:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[N:18][CH:19]=3)=[CH:13][C:8]=2[CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:23]1[C:32]2[CH2:31][C:30]([CH3:34])([CH3:33])[CH:29]=[CH:28][C:27]=2[N:26]=[CH:25][N:24]=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[CH3:33][C:30]1([CH3:34])[CH:29]=[CH:28][C:27]2[N:26]=[CH:25][N:24]=[C:23]([N:6]3[CH2:7][C:8]4[CH:13]=[C:12]([C:14]5[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[N:18][CH:19]=5)[CH:11]=[CH:10][C:9]=4[O:3][CH2:4][CH2:5]3)[C:32]=2[CH2:31]1
Reactant: Nc1cc(-c2ccc3c(c2)CNCCO3)cnc1N
Reactant: CC1(C)C=Cc2ncnc(Cl)c2C1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C=Cc2ncnc(N3CCOc4ccc(-c5cnc(N)c(N)c5)cc4C3)c2C1
Temperature: 90 °C
Yield: 74 %

Procedure:
To a slurry of 5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyridine-2,3-diamine dihydrochloride (0.92 g, 2.8 mmol) and 4-chloro-6,6-dimethyl-5,6-dihydroquinazoline (0.55 g, 2.8 mmol) in NMP was added diisopropylethylamine (2.4 mL, 14 mmol) and the reaction mixture was heated (90° C.) for 12 hours. The resulting dark red solution was loaded directly on to a column of dry silica and elution with MeOH (w/8% NH4OH v/v) in CH2Cl2 (0-5%) provided 5-[4-(6,6-dimethyl-5,6-dihydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]pyridine-2,3-diamine (0.86, 74% yield) as a brown solid. MS (EI) for C24H26N6O: 415.1 (MH+).
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH:13]1([C:17](Cl)=O)[CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.O>[CH:13]1([C:17]2[O:12][C:11]3[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=3)[N:2]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: O=C(Cl)C1CCC1
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1cccc2oc(C3CCC3)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.8 %

Procedure:
To a mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (0.50 g, 2.13 mmol) and cyclobutanecarbonyl chloride (0.24 mL, 2.13 mmol) in dichloromethane (20 mL) was added triethylamine (0.90 mL, 6.41 mmol) dropwise, then the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with dichloromethane, and then washed with 2 N HCl. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in toluene (8 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (676 mg, 3.56 mmol). The reaction mixture was then heated to reflux for 5 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by re-crystallization from ethyl acetate and hexanes to afford 2-cyclobutylbenzoxazole-4-carboxylic acid (420 mg, 73%) as a brown solid: 1H NMR (500 MHz, DMSO-d6) δ 12.96 (br s, 1H), 7.92 (dd, J=8.1, 0.8 Hz, 1H), 7.84 (dd, J=7.6, 0.8 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 3.95-3.85 (m, 1H), 2.46-2.39 (m, 4H), 2.28-2.00 (m, 2H); MS (ESI+) m/z 218 (M+H).
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26].CC(C)([O-])C.[K+]>CN(C)C=O>[C:25]([C:24]1[CH:23]=[C:22]([CH2:21][N:9]2[C:8](=[O:13])[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:11][C:10]2=[O:12])[CH:29]=[CH:28][CH:27]=1)#[N:26]
Reactant: N#Cc1cccc(CBr)c1
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(CN2C(=O)NC(c3ccccc3)(c3ccccc3)C2=O)c1

Procedure:
Prepared by reacting 25.5 g (0.101 Mol) of 5,5-diphenylhydantoin with 21.15 g (0.108 Mol) of 3-(bromomethyl)-benzonitrile in the presence of 12.0 g (0.107 Mol) of potassium tert.-butoxide and 200 ml of anhydrous dimethylformamide. After conventional working up 34.0 g (92% of theory) of colourless crystals were obtained, mp. 160°-164° C.
Reaction SMILES: C(OC([N:11]1[CH:16]=[CH:15][N:14]([CH2:17][C:18]2([OH:30])[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[C:13](=[O:31])[CH2:12]1)=O)C1C=CC=CC=1.[ClH:32]>CO.C(OCC)(=O)C.[Pd]>[ClH:32].[OH:30][C:18]1([CH2:17][N:14]2[CH2:15][CH2:16][NH:11][CH2:12][C:13]2=[O:31])[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[CH2:22][CH2:23]1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C=CN1CC1(O)CCN(c2ccncc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CNCCN1CC1(O)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4-benzyloxycarbonyl-1-[4-hydroxy-1-(4-pyridyl)piperidin-4-ylmethyl]-2-oxo-1,2,3,4-tetrahydropyrazine (6.93 g) in methanol (100 ml) were added 4N hydrochloric acid in ethyl acetate (4 ml) and 10% palladium on carbon (2.0 g), and the mixture was stirred, under hydrogen atmosphere, at room temperature for 15 hours. The catalyst was removed by filtration, and the filtrate was concentrated and dried under reduced pressure to give colorless syrup of the title compound (5.39 g).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][CH2:14][O:15][CH2:16][C:17]([CH:19]([CH3:21])[CH3:20])=[CH2:18]>C(Cl)Cl>[CH:19]([C:17]1([CH2:16][O:15][CH2:14][O:13][CH3:12])[CH2:18][O:9]1)([CH3:21])[CH3:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(COCOC)C(C)C
Solvent: ClCCl
Product: COCOCC1(C(C)C)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
m-Chloroperbenzoic acid (213 g, 861 mmol) was gradually added to a solution of 2-methoxymethoxymethyl-3-methyl-l-butene (89 g, 615 mmol) in methylene chloride (800 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was washed with 10% potassium sulfide aqueous solution and sodium hydrogencarbonate aqueous solution, dried over sodium sulfate, and then concentrated under reduced pressure to afford 2-isopropyl-2-methoxymethoxymethyloxirane (98 g, quantitative) as a colorless oil.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=[O:15])=[CH:6]1)[CH2:2][CH2:3][CH3:4].[CH3:17][C:18]([N:26]1[N:30]=[N:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[CH:42]=[CH:41][C:40]([CH:43]=[O:44])=[CH:39][CH:38]=2)=[N:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19]>>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=[O:15])=[C:6]1[CH:43]([C:40]1[CH:39]=[CH:38][C:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:28]2[N:29]=[N:30][N:26]([C:18]([CH3:19])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:17])[N:27]=2)=[CH:42][CH:41]=1)[OH:44])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc(C(=O)O)c2ccccc21
Reactant: CC(C)(c1ccccc1)n1nnc(-c2ccccc2-c2ccc(C=O)cc2)n1
Product: CCCCn1c(C(O)c2ccc(-c3ccccc3-c3nnn(C(C)(C)c4ccccc4)n3)cc2)c(C(=O)O)c2ccccc21

Procedure:
reacting the 2-lithiated 1-butyl-1H-indole-3-carboxylic acid with protected 2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-carbaldehyde to give 1-butyl-2-{2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-yl(hydroxy)methyl}-1H-indole-3-carboxylic acid;
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].C(N(CC)CC)C.[C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]#[CH:36])#[N:29]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]#[C:36][C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])#[N:29]
Reactant: C#CCCCCCC#N
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCCCCCC#Cc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 60 °C
Reaction time: 24 h
Yield: 199.3 %

Procedure:
Under argon, to a solution of 2-iodoadenosine (200 mg, 0.51 mmol) and bis(triphenylphosphine)palladium dichloride (36 mg, 10 mol %) dissolved in N,N-dimethylformamide (5 mL), triethylamine (0.09 mL, 0.61 mmol, 1.2 eq.) and 7-cyano-1-heptyne (74 mg, 0.1 mmol, 1.2 eq.) were added, and, under ice-cooling conditions, cuprous iodide (10 mg, 5 mol %) was added thereto, followed by stirring at 60° C. for 24 hours. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by dry packed silica gel column chromatography (chloroform:methanol=10:1), to thereby yield the above-titled compound as a pale yellow powder (yield: 77 mg, percent yield: 39%).