Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.CN1CCOCC1.[O:18]=[C:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH2:24][C:25](O)=[O:26].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:25](=[O:26])[CH2:24][N:20]1[CH2:21][CH2:22][CH2:23][C:19]1=[O:18]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)CN1CCCC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1C(=O)CN1CCCC1=O
Temperature: -25 °C
Reaction time: 16 h
Yield: 101.9 %

Procedure:
To a solution of L-proline methyl ester hydrochloride (8.28 g) in DMF (100 ml) were added N-methylmorpholine (5.50 ml), 2-oxo-1-pyrrolidine acetic acid (7.15 g) and HOBt (10.12 g) under ice-cooling. The mixture was cooled to -25° C., added with DCC (10.32 g), and stirred at room temperature for 16 hours. The precipitated dicyclohexylurea was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 12.94 g of N-[(2-oxo-1-pyrrolidinyl)acetyl]-L-proline methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:17]=[C:18]([CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][CH2:30][O:29]3)[C:19]3[CH2:25][NH:24][CH2:23][CH2:22][C:20]=3[N:21]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C=O.[C:35](O)(=O)C.C([BH3-])#N>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:17]=[C:18]([CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][CH2:30][O:29]3)[C:19]3[CH2:25][N:24]([CH3:35])[CH2:23][CH2:22][C:20]=3[N:21]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: CC(=O)O
Reactant: COc1cc(Nc2nc3c(c(CCC4CCCO4)n2)CNCC3)ccc1-n1cnc(C)c1
Agent: C=O
Agent: [BH3-]C#N
Solvent: CO
Product: COc1cc(Nc2nc(CCC3CCCO3)c3c(n2)CCN(C)C3)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
N-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-(2-(tetrahydrofuran-2-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (0.133 g, 0.31 mmol, Example 114a), formaldehyde (8.43 μL, 0.31 mmol) and acetic acid (8.76 μL, 0.15 mmol) in methanol (4 mL) was stirred at room temperature for 20 minutes. Polymer supported cyanoborohydride (0.46 g, 0.92 mmol) was added and the reaction mixture was stirred at room temperature overnight. The polymer supported cyanoborohyride was filtered off and the filtrated was purified by preparative chromatography. The product containing fractions were pooled and the solvent was evaporated. The residue was dissolved in water/acetonitrile-mixture (50:50) and freezedried giving N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-6-methyl-4-(2-(tetrahydrofuran-2-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (0.055 g, 40.1%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH3:12][OH:13]>>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([O:13][CH3:12])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: CO
Product: COc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 15 h

Procedure:
In a vial are introduced 1 ml of MeOH and 50.8 mg (2.21 mmol) of Na. After dissolution of the metal, the solution was added to a suspension of 5-bromo-2-chloro-3-nitropyridine (Matrix, Columbia, USA, 500 mg, 2.11 mmol) in MeOH (2 ml). The reaction mixture is stirred for 1 h at 0° C. and for 15 h at rt, then concentrated and quenched with water. The precipitate was filtered, washed with water (2×) and dried under vacuum to give the title compound as a pale yellow solid (HPLC: tR 3.06 min (Method A).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:12]1[CH2:13][CH2:14][CH:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C#N)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2CCNCC2)c1

Procedure:
A solution of tert-butyl 4-(3-cyanophenyl)piperidine-1-carboxylate (376 mg, 1.31 mmol) in 10 mL of 1:1 TFA/DCM was stirred at rt for 1.25 h. The reaction mixture was concentrated. Purification by preparative TLC (silica, 1% of 28% NH4OH solution/9% methanl/UDCM) gave 3-piperidin-4-ylbenzonitrile as a white solid. ESI-MS calc. for C12H14N2: 186; Found: 187 (M+H).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[CH3:22][O:23][CH:24]([CH3:27])[CH2:25][NH2:26].C(#N)C>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:26][CH2:25][CH:24]([O:23][CH3:22])[CH3:27]
Reactant: COC(C)CN
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Agent: Br
Solvent: CC#N
Solvent: CCO
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NCC(C)OC)c2)N1C

Procedure:
6.5 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted as prescribed in Example 76 with 5 g of 2-methoxypropyl amine in 100 ml of ethanol and worked up. Colorless crystalline solid substance, melting point: 148° C (acetonitrile/active charcoal).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][C:16]2([CH3:23])[CH3:22])=[CH:10][N:9]=1)(C)(C)C.Cl>O1CCOCC1.CO>[CH3:22][C:16]1([CH3:23])[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][N:15]1[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[N:9][CH:10]=1
Reactant: CN1CCN(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(C)(C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCN(Cc2ccc(N)nc2)C(C)(C)C1
Yield: 75 %

Procedure:
A mixture of [5-(2,2,4-trimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (Step 110.2) (1.94 g, 5.8 mmol), a 4 N solution of HCl in dioxane (20 mL) and MeOH (5 mL) was stirred for 12 h at it and concentrated. The residue was purified by silica gel column chromatography (DCM/NH3aq, 99:1→DCM/MeOH/NH3aq, 95:4:1) to afford 1.02 g of the title compound as a white solid. Title compound: ESI-MS: 235.2 [M+H]+; TLC: Rf=0.11 (DCM/MeOH, 9:1).
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[CH:7]([NH:10][CH:11]([CH3:13])[CH3:12])([CH3:9])[CH3:8]>CO>[CH:7]([N:10]([CH:11]([CH3:13])[CH3:12])[C:3](=[O:4])[CH:2]([Cl:1])[CH3:6])([CH3:9])[CH3:8]
Reactant: CC(C)NC(C)C
Reactant: CC(Cl)C(=O)Cl
Solvent: CO
Product: CC(Cl)C(=O)N(C(C)C)C(C)C

Procedure:
Reaction of 2-chloropropionylchloride with diisopropylamine under the experimental conditions of Example 16, gives the product; b.p. 87°-88° (0.1 mm); Rf=0.67 (methanol); IR (neat) νmax: 2960, 2920, 1650, 1475, 1450, 1370, 1340, 1210, 1040, 620 cm-1 ; Cl (Schoeninger) calculated %: 18.49--Found %: 18.43.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[CH:9][CH:10]=1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1ccc(Cl)cc1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(4-chlorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 427.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C(Cl)(=O)[C:16](Cl)=[O:17]>C(Cl)CCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:8]=[C:16]=[O:17])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 4-chloro-3-(trifluoromethyl)benzamide (0.200 g), oxalyl chloride (0.012 mL) and EDC (15 mL) to afford 0.150 g of the desired product.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[CH:12][CH:11]=1
Reactant: OC1CCNCC1
Reactant: COc1ccc(CBr)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCC(O)CC2)cc1
Reaction time: 18 h
Yield: 80.1 %

Procedure:
0.97 g (0.00959 mol) of 4-hydroxypiperidine was dissolved in 20 ml of dimethylformamide and cooled to 0°. 1.93 g (0.0096 mol) of 4-methoxybenzyl bromide and 3.0 ml (0.0215 mol) of triethylamine were added under argon and the mixture was left to come to room temperature. It was stirred for 18 hrs., the solvent was distilled off and the residue was taken up in ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated and the residue was chromatographed on silica gel with dicloromethane/methanol (19:1) as the eluent. 1.7 g (80%) of 1-(4-methoxy-benzyl)-piperidin-4-ol were obtained as a brown oil. MS: me/e=222 (C13H20NO2+).
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:26])([F:25])[C:5]1[CH:10]=[CH:9][N:8]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([O:20]CC)=[O:19])=[CH:13][C:12]=2[Cl:23])[C:7](=[O:24])[CH:6]=1.C(O)C>>[F:26][C:4]([F:3])([F:25])[C:5]1[CH:10]=[CH:9][N:8]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=2[Cl:23])[C:7](=[O:24])[CH:6]=1
Reactant: CCOC(=O)c1cc(Cl)c(-n2ccc(C(F)(F)F)cc2=O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(Cl)c(-n2ccc(C(F)(F)F)cc2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of potassium hydroxide [51 g (1.1 mol) in 50 ml of water] was added to a stirred solution of 4-trifluoromethyl-1-(2,6-dichloro-4-ethoxycarbonylphenyl)-2-pyridone (Compound C) in ethanol [35 g (0.09 mol) in 500 ml of ethanol]. The reaction was stirred for one hour at room temperature. The ethanol mixture was removed in vacuo and the residue treated with dilute HCl and extracted with ethylacetate (2×300 ml). The combined organic portions, were washed well with water, dried over magnesium sulphate and evaporated in vacuo to give a white solid of 4-trifluoromethyl-1-(2,6-dichloro-4-carboxyphenyl)-2-pyridone (31.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[OH:14].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12>CC(O)=O.O>[O:19]=[C:18]1[C:17]2[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:20])[N:1]1[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:12])[CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[OH:14]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CN(C)S(=O)(=O)c1ccc(N)c(O)c1
Solvent: CC(=O)O
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(N2C(=O)c3ccccc3C2=O)c(O)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
A suspension of 4-amino-3-hydroxy-N,N-dimethylbenzenesulfonamide (120 mg, 0.555 mmol) and phthalic anhydride (82 mg, 0.555 mmol) in AcOH (3 mL) was stirred at 120° C. under microwave irradiation for 60 minutes. The reaction was cooled and diluted with water to afford a suspension. The precipitate was filtered, washed with water and dried under high vacuum to afford the title compound as a pink solid (142 mg, 74%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([N:11]=[C:12]=[O:13])[CH2:4][CH2:3]1.Cl.[CH3:15][O:16][NH2:17].C(N(CC)CC)C>CCOCC>[CH3:15][O:16][NH:17][C:12]([NH:11][CH:5]1[C:6]2[CH:10]=[CH:9][S:8][C:7]=2[C:2](=[O:1])[CH2:3][CH2:4]1)=[O:13]
Reactant: O=C=NC1CCC(=O)c2sccc21
Reactant: CON
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CONC(=O)NC1CCC(=O)c2sccc21
Temperature: 25 °C
Reaction time: 36 h

Procedure:
The crude ether solution of 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl isocyanate prepared in Example 4 is added dropwise to a mixture of methoxyamine hydrochloride (9.02 g), triethylamine (13.67 g) and ether (50 ml) under a nitrogen atmosphere. After stirring for 36 hours at room temperature, the solid in the reaction mixture is collected and washed with water. The water-insoluble solid is recrystallized twice from acetone-hexane to afford the title urea, m.p. 185° to 188.5° C.
Reaction SMILES: C([NH:9][C:10](=[O:27])[NH:11][C:12]1[S:16][C:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:14]([CH3:24])[C:13]=1[C:25]#[N:26])(=O)C1C=CC=CC=1.[OH-].[Na+]>CCO>[NH2:26][C:25]1[C:13]2[C:14]([CH3:24])=[C:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:16][C:12]=2[NH:11][C:10](=[O:27])[N:9]=1
Reactant: Cc1c(C(=O)OC(C)(C)C)sc(NC(=O)NC(=O)c2ccccc2)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)OC(C)(C)C)sc2[nH]c(=O)nc(N)c12
Temperature: 25 °C
Yield: 63 %

Procedure:
To a suspension of tert-butyl 5-(3-benzoylureido)-4-cyano-3-methylthiophene-2-carboxylate (example 64a) (18 g, 60.52 mmol) in EtOH (200 mL) was added NaOH (75 mL, 2N). The suspension became clear, and the mixture was heated to reflux for 30 min. After cooling to rt, the reaction was filtered, and the filtrate was cooled to 0° C. in an ice/water bath. The solution was neutralized with 10% acetic acid. The precipitated solid was collected by filtration, and heated in EtOH at 80° C. under N2 for 20 min. After cooling to rt, the product was collected by filtration and washed with 10% EtOH in H2O to yield tert-Butyl 4-amino-5-methyl-2-oxo-1,2-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (10.73 g, 63%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 1.51 (s, 9H), 2.73 (s, 3H), 3.18 (s, 2H). MS 282.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](Br)[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: OB(O)c1ccccc1
Product: Nc1c(F)cc(-c2ccccc2)cc1F
Yield: 81.4 %

Procedure:
The title compound (0.401 g) was prepared from 2,6-difluoro-4-bromo aniline (0.5 g, 2.4 mmol) and phenylboronic acid (0.38 g, 3.12 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.60 (d, J 7.4, 2H), 7.38 (t, J 7.5, 2H), 7.30-7.25 (m, 3H), 5.33 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([F:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[OH:32]>>[Cl:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[O:32][C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([F:23])=[CH:4][N:3]=1
Reactant: Oc1ccc(F)cc1Cl
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(F)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(F)cnc2Oc2ccc(F)cc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2-chloro-5-fluoropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1) and 2-chloro-4-fluorophenol: 1H-NMR (CDCl3) δ 8.32 (1H, dd, J=8.1, 2.9 Hz), 8.19 (1H, d, J=7.3 Hz), 8.02–7.99 (3H, m), 7.45 (2H, d, J=8.3 Hz), 7.32–7.25 (2H, m), 7.14–7.08 (1H, m), 5.39 (1H, m), 3.90 (3H, s), 1.61 (3H, d, J=7.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([O:12][CH3:13])[CH:3]=1.[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH2:17]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([O:11][CH2:17][C:16]2[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:15]=2[F:14])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1O
Reactant: COc1cccc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Cl)c([N+](=O)[O-])cc1OCc1c(F)cccc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.2 %

Procedure:
To a solution of 4-chloro-2-methoxy-5-nitrophenol (0.67 g) and 2-fluoro-6-methoxy-benzyl bromide (0.66 g) in N,N-dimethylformamide (3 mL) was added potassium carbonate (0.54 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the resulting mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration. The collected crystals were washed with water and a mixed solvent (diethyl ether/n-hexane=1/3), and dried under reduced pressure to give 5-chloro-2-(2-fluoro-6-methoxybenzyloxy)-4-nitroanisole (0.97 g). This material was dissolved in tetrahydrofuran (15 mL). To the solution were added methanol (15 mL) and nickel(II) bromide (31 mg). To the mixture was added sodium borohydride (0.32 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−3/2) to give the title compound (0.79 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13].Cl>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[C:11]([CH:16]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1OCc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C)c(Cc2ccc(OCc3ccncc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.9 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(4-pyridylmethyloxy)benzoate (0.600 g, 1.28 mmol) was dissolved in a mixed solution of an aqueous 1N NaOH solution (3 ml) and 1,4-dioxane (3 ml) and the resulting solution was stirred at room temperature for 6 hours. The reaction solution was diluted with water, rendered acidic with concentrated hydrochloric acid and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=1:2) to obtain the titled compound (0.500 g, 1.10 mmol, 86%).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([C@@]1(O)[C@@H](CO)O[C@@](C(=O)C)([N:19]2[C:29]3[N:28]=[C:26]([NH2:27])[NH:25][C:23](=[O:24])[C:22]=3[N:21]=[CH:20]2)[C@]1(C(=O)C)O)(=O)C.Cl>C(#N)C>[CH2:1]([N:21]1[C:22]2[C:23](=[O:24])[NH:25][C:26]([NH2:27])=[N:28][C:29]=2[N:19]=[CH:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[C@@]1(O)[C@@](O)(C(C)=O)[C@@H](CO)O[C@@]1(C(C)=O)n1cnc2c(=O)[nH]c(N)nc21
Reactant: ClCc1ccccc1
Agent: Cl
Solvent: CC#N
Product: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Reaction time: 4 h
Yield: 78.5 %

Procedure:
Eight milliliters of acetonitrile and 2.13 ml (10 equivalents) of benzyl chloride were added to 0.758 g (1.85 mmols) of triacetylguanosine, and the mixture was reacted at 70° C. for 47 hours. The temperature was returned to room temperature, and 3.13 ml (20 equivalents) of conc. hydrochloric acid were added thereto. The reaction was conducted for 4 hours. After 2 hours of the reaction, the solid was precipitated. Ten grams of methanol were added thereto, and the slurry was stirred overnight, and then filtered. The crystals were washed twice with 5 ml of methanol, and dried at 50° C. under reduced pressure to give 0.456 g of 7-benzylguanine crystals in a yield of 78.5%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[C:16]2[N:15]=[CH:14][N:13]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]=2[C:11](=[O:36])[NH:10][C:9]1=[O:37].[Cl:38][C:39]1[CH:49]=[CH:48][C:42]([CH2:43][O:44][CH2:45][CH2:46]Cl)=[CH:41][CH:40]=1.O>CN1CCCC1=O>[Cl:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:43][O:44][CH2:45][CH2:46][N:10]2[C:11](=[O:36])[C:12]3[N:13]([C:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:14]=[N:15][C:16]=3[N:8]([CH3:7])[C:9]2=[O:37])=[CH:48][CH:49]=1
Reactant: ClCCOCc1ccc(Cl)cc1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cn1c(=O)n(CCOCc2ccc(Cl)cc2)c(=O)c2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
1.3 g (9.44 mmol) of potassium carbonate were added at 60° C. to a solution of 2.4 g (5.9 mmol) of 3-methyl-7-tritylxanthine (prepared according to Example 17a) in 50 ml of N-methylpyrrolidone and the mixture was stirred at this temperature for one hour. 1.57 g (7.67 mmol) of 2-(4-chlorobenzyloxy)ethyl chloride were then added dropwise and the mixture was stirred at 80° C. for one hour. A further 1.0 g (4.9 mmol) of 2-(4-chlorobenzyloxy)ethyl chloride was then added and the mixture was stirred again for one hour. 50 ml of water were then added, the mixture was extracted three times using 60 ml of methyl tert-butyl ether each time, and the combined organic phases were washed twice with 30 ml of water each time, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, heptane/ethyl acetate (3/2).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:12])[O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[N+:13]([O-])=O.[BH4-].[Na+]>CO.O.Cl[Ni]Cl>[NH2:13][C:3]1[CH:4]=[CH:5][C:6]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[N:7][C:2]=1[Br:1]
Reactant: COC(=O)Nc1ccc([N+](=O)[O-])c(Br)n1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)Nc1ccc(N)c(Br)n1
Reaction time: 0.01 h
Yield: 97.5 %

Procedure:
To a solution of methyl 6-bromo-5-nitropyridin-2-ylcarbamate (700 mg, 2.5 mmol) in CH3OH (20 mL) was added NiCl2 (1.2 g, 5.1 mmol) and NaBH4 (300 mg, 7.6 mmol) successively at 0° C. The mixture was stirred for 20 seconds. The reaction mixture was diluted with water and extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give methyl 5-amino-6-bromopyridin-2-ylcarbamate (600 mg, 96%). 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J=8.4 Hz, 1H), 7.13 (brs, 1H), 7.09 (d, J=8.8 Hz, 1H), 3.81 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH2:8])=[O:7])=[CH:2]1.[Cl:9][CH2:10][C:11]([CH2:13]Cl)=O>>[Cl:9][CH2:10][C:11]1[N:8]=[C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)[O:7][CH:13]=1
Reactant: NC(=O)c1ccoc1
Reactant: O=C(CCl)CCl
Product: ClCc1coc(-c2ccoc2)n1
Yield: 44 %

Procedure:
In substantially the same manner as in Reference Example 47, 3-furancarboxamide was reacted with 1,3-dichloroacetone to give 4-chloromethyl-2-(3-furyl)oxazole. The yield was 44%. Recrystallization from diethyl ether-hexane gave colorless prisms. mp 70-71° C.