Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([OH:18])=O)[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:19][C:20]1[O:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:24]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:19][C:20]3[O:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:24]=3)=[O:18])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)c1cnc(N)o1
Reactant: Cc1c(C(=O)O)nnn1Cc1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (Intermediate 4) (1 g, 3.4 mmol), ethyl 2-amino-1,3-oxazole-5-carboxylate (0.82 g, 5.2 mmol), HOBt (0.708 g, 5.2 mmol), EDCI (1.005 g, 5.2 mmol) and NEt3 (730 μL, 5.2 mmol) in DMF (50 mL) was stirred at room temperature for 2 days. The reaction was not completed and 2.5 eq of EDCI and HOBt were added and the reaction was heated at 40° C. and stirred for a further 14 days. Again no completed reaction was obtained. The solvent was evaporated and the residue was washed with water and extracted with DCM. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with DCM/MeOH (90/10) to give after crystallisation from diisopropyl ether, the title compound as a yellow solid (98 mg, 6%). LC/MS: m/z 424 (M+H)+. Rt: 3.17 min.
Reaction SMILES: [CH:1]12[N:7]([CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[C:18]3[N:19]([CH3:24])[N:20]=[CH:21][C:22]=3[Br:23])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.C1C([N+]([O-])=O)=CC=C([Cl-][C:35]([O-])=[O:36])C=1.[F:38][C:39]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:40]=1[CH2:41][NH2:42].C(N(CC)C(C)C)(C)C>ClCCCl>[CH:4]12[N:7]([CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:35]([NH:42][CH2:41][C:40]4[CH:43]=[CH:44][C:45]([F:47])=[CH:46][C:39]=4[F:38])=[O:36])=[CH:13][C:12]=3[C:18]3[N:19]([CH3:24])[N:20]=[CH:21][C:22]=3[Br:23])[CH:1]([CH2:2][CH2:3]1)[CH2:6][CH2:5]2
Reactant: NCc1ccc(F)cc1F
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1C2CCC1CC2
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Br)c1-c1cc(NC(=O)NCc2ccc(F)cc2F)ccc1OCCN1C2CCC1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine (50.0 mg, 0.13 mmol) was added to a solution of 4-nitrophenylchloroformate (26.0 mg, 0.13 mmol) in 1,2-dichloroethane (4.0 mL) and the mixture stirred at room temperature for 1 hour. To the resulting precipitate mixture was added 2,4-difluorobenzylamine (0.030 mL, 0.25 mmol) and N,N-diisopropylethylamine (0.030 mL, 0.17 mmol), and the mixture stirred an additional 1 hour. The mixture was concentrated and purified by RP-HPLC. The collected fractions were concentrated and 12% sodium hydroxide (aq) (0.2 mL) was added to give pH 9. The solution was extracted into ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to give a white solid (62 mg, 87%). LCMS m/z (%)=560 (M+H79Br, 100), 562 (M+H81Br, 91). 1H NMR (400 MHz, DMSO-d6) δ: 8.59 (bs, 1H), 7.58 (bs, 1H), 7.48-7.38 (m, 2H), 7.29 (bs, 1H), 7.24-7.18 (m, 1H), 7.10-7.04 (m, 2H), 6.60-5.59 (m, 1H), 4.29 (d, J=4.0 Hz, 2H), 4.06-3.96 (m, 2H), 3.64 (s, 3H), 3.11 (bs, 2H), 2.58-2.54 (m, 2H), 1.54-1.52 (m, 4H), 1.15-1.13 (m, 4H).
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3]O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:23]2)=CC=1>C1(C)C=CC=CC=1>[NH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][SH:23]
Reactant: COc1ccc(C(C)(N)CO)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)(N)CS)cc1
Temperature: 25 °C

Procedure:
A solution of 1 mmol of 2-amino-2-(4-methoxyphenyl)propan-1-ol (Example 3k) and 0.5 mmol of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) [19172-47-5] in 10 ml of toluene is heated to reflux for 2 hours. The reaction mixture is cooled to room temperature and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60F).
Reaction SMILES: C([O:3][P:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15]Br.P([O-])([O-])[O-]>>[CH2:9]([O:8][P:4]([CH2:15][C:14]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:12]([Cl:11])[CH:13]=1)(=[O:3])[O:5][CH2:6][CH3:7])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: Clc1ccc(CBr)cc1Cl
Agent: [O-]P([O-])[O-]
Product: CCOP(=O)(Cc1ccc(Cl)c(Cl)c1)OCC
Temperature: 80 °C

Procedure:
Triethylphosphite (4.28 ml) was added dropwise to 3,4-dichlorobenzylbromide (6.0 g, 25 mmol) at rt with stirring. After 1 ml of triethylphosphite was added, the mixture was heated to 80° C. until an exothermic reaction was started. The remaining phosphite was added at a rate sufficient to maintain the reflux. After the addition was completed, the mixture was heated to reflux for 1 h and allowed to cool. The crude product was distilled under vacuum at 155–158° C./1–2 torr to afford (3,4-dichlorobenzyl)-phosphonic acid diethyl ester (6.5 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([CH2:24][S:25]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:38]([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.Cl.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:18]=[C:19]3[C:20](=[CH:21][CH:22]=2)[NH:23][N:38]=[C:24]3[S:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(OC2CCN(C(=O)OCc3ccccc3)C2)cc1CS(=O)(=O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)C1
Reaction time: 0.83 h
Yield: 70.1 %

Procedure:
A suspension of 3-[4-amino-3-(naphthalene-1-sulfonylmethyl)-phenoxy]-pyrrolidine-1-carboxylic acid benzyl ester (2.36 g, 4.57 mmol) in ethanol and 1.0 N hydrochloric acid (85 mL) was heated to aid dissolution. The reaction mixture was treated slowly with sodium nitrite (0.549 g, 7.96 mmol) in water, stirred at ambient temperatures for 50 minutes, basified with solid sodium carbonate, stirred at ambient temperatures for 30 minutes and concentrated in vacuo. The resultant residue was partitioned in ethyl acetate and brine. The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. This residue was purified twice by flash chromatography with 2% methanol in chloroform and with 1.5-10% methanol in chloroform to afford 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-pyrrolidine-1-carboxylic acid benzyl ester as a buff-colored foam, 1.69 g (70.1% yield), Mass spectrum (+EI, [M+H]+) m/z 528. 1HNMR (500 MHz, DMSO-d6): δ14.09 (s, 1H), 8.72-8.75 (m, 1H), 8.55 (d, 1H, J=7.44 Hz), 8.17-8.27 (m, 1H), 7.98-8.03 (m, 1H), 7.52-7.74 (m, 4H), 7.19-7.34 (m, 6H), 7.06 (d, 1H, J=8.78 Hz), 4.99-5.09 (m, 3H), 3.61-3.70 (m, 1H), 3.34-3.55 (m, 3H), 2.11-2.28 (m, 1H), 1.99-2.07 ppm (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[C:8]([O:15][CH3:16])=[C:7]([CH3:17])[C:4]=1[CH:5]=O.[CH3:18][C:19]([CH3:21])=[O:20].C[O-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:4]([CH:5]=[CH:18][C:19](=[O:20])[CH3:21])=[C:7]([CH3:17])[C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Reactant: CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1c(C)c(C=CC(C)=O)c(OC)c(OC)c1OC
Yield: 59.8 %

Procedure:
To a solution of 2,3,4,5-tetramethoxy-6-methylbenzaldehyde (1.56 g, 6.5 mmol) and acetone (1.13 g, 19.5 mmol) in methanol (15 ml) was added 28% methanolic sodium methoxide (1.88 g). The mixture was refluxed for 1.5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was chromatographed on a silica gel column elution being carried out with isopropyl ether. The fractions containing the desired compound were concentrated to give 1,2,3,4-tetramethoxy-5-methyl-6-(3-oxo-1-butenyl)benzene (Compound 21, 1.09 g, 60% Oily substance) δ 2.28 (3H), 2.36 (3H), 3.77 (3H), 3.79 (3H), 3.89 (3H), 3.95 (3H), 6.70 (1H), 7.57 (1H),
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:9]=O)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].O>CN(C=O)C>[CH3:8][C:5]1[N:4]=[C:3]2[CH:9]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:1][C:2]2=[CH:7][CH:6]=1
Reactant: Cc1ccc(O)c(C=O)n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2nc(C)ccc2o1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 233.7 %

Procedure:
To a solution of 3-hydroxy-6-methylpyridine-2-carbaldehyde (4.92 mmol, 35.9 mmol) in DMF (70 mL) were added potassium carbonate (9.93 g, 71.8 mmol) and ethyl bromoacetate (5.97 mL, 53.9 mmol), and the mixture was stirred at 100° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 3:2) to give the title compound (2.36 g, yield 32%) as an oil.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.CCN(C(C)C)C(C)C.[NH2:26][CH:27]([C:29]1[CH:36]=[C:35]([CH3:37])[C:32]([C:33]#[N:34])=[C:31]([C:38]2[CH:39]=[N:40][CH:41]=[C:42]([S:44]([CH3:47])(=[O:46])=[O:45])[CH:43]=2)[C:30]=1[O:48][CH2:49][CH3:50])[CH3:28]>C(O)C>[CH2:49]([O:48][C:30]1[C:31]([C:38]2[CH:39]=[N:40][CH:41]=[C:42]([S:44]([CH3:47])(=[O:45])=[O:46])[CH:43]=2)=[C:32]([C:35]([CH3:37])=[CH:36][C:29]=1[CH:27]([NH:26][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH3:28])[C:33]#[N:34])[CH3:50]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CCOc1c(C(C)N)cc(C)c(C#N)c1-c1cncc(S(C)(=O)=O)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(C)c(C#N)c1-c1cncc(S(C)(=O)=O)c1
Temperature: 120 °C

Procedure:
6-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (35 mg, 0.15 mmol, from Example 176, Step 4) and DIPEA (0.04 mL, 0.2 mmol) were added to 4-(1-aminoethyl)-3-ethoxy-6-methyl-2-[5-(methylsulfonyl)pyridin-3-yl]benzonitrile in ethanol (2 mL). The reaction was heated to 120° C. overnight. The reaction was allowed to cool to room temperature and was concentrated in vacuo to give 3-ethoxy-6-methyl-2-[5-(methylsulfonyl)pyridin-3-yl]-4-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)benzonitrile as a solid residue. This intermediate was dissolved in 4.0 M HCl in dioxane (1 mL) and was stirred for 10 minutes. The reaction was concentrated and was purified on prep HPLC on a C-18 column eluting with water:acetonitrile gradient buffered with TFA to give 3-ethoxy-6-methyl-2-[5-(methylsulfonyl)pyridin-3-yl]-4-[1-(9H-purin-6-ylamino)ethyl]benzonitrile as a white solid (0.010 g, 16%). LCMS calculated for C23H24N7O3S (M+H)+: m/z=478.1. found: 478.1. 1H NMR (300 MHz, DMSO-d6) δ 9.18 (d, J=2.2 Hz, 1H), 9.09 (d, J=2.0 Hz, 1H), 8.75 (m, 1H), 8.54 (t, J=2.1 Hz, 1H), 8.33 (m, 2H), 7.68 (s, 1H), 5.80 (m, 1H), 3.99-3.79 (m, 1H), 3.40 (s, 3H), 3.34 (m, 1H), 2.47 (s, 3H), 1.58 (d, J=6.9 Hz, 3H), 0.98 (t, J=6.9 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]([NH2:22])=[O:21])[C:15](=[O:23])[CH2:14]2.BrC1OC(C(Cl)=O)=CC=1>S(Cl)(Cl)=O.CN(C1C=CN=CC=1)C.CN(C)C=O>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]([NH2:22])=[O:21])[C:15](=[O:23])[CH:14]2[C:7]([C:5]1[O:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: O=C(O)c1ccc(Br)o1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1ccc(Br)o1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: NC(=O)N1C(=O)C(C(=O)c2ccc(Br)o2)c2cc(Cl)ccc21

Procedure:
Using the procedure of Example 32, 1.91 g (10.0 mmoless) of commercially available 5-bromo-2-furancarboxylic acid was dissolved in 10 ml of thionyl chloride and heated to reflux under nitrogen for 1 hour and the acid chloride product was recovered. A 40 ml N,N-dimethylformamide solution of 1.75 g (8.3 mmoles) of 5-chloro-2-oxindole-1-carboxamide and 3.05 g (25 mmoles) of 4-(N,N-dimethylamino)pyridine was reacted with 2.09 g (10 mmoles) of 5-bromo-2-furan carbonyl chloride in 10 ml of N,N-dimethylformamide. After a reaction time of about 45 minutes, the mixture was acidified by pouring into 250 ml of 1N HC1. The product was recrystallized from acetic acid, washed with acetic acid, then hexane and dried overnight in vacuo at room temperature. The resulting product then was dried over refluxing isopropanol under high vacuum to yield 1.37 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[CH:11]1([N:14]=[C:15]=S)[CH2:13][CH2:12]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[CH:11]1([NH:14][C:15]2[NH:9][C:5]3[CH:6]=[C:7]([Cl:8])[C:2]([Cl:1])=[CH:3][C:4]=3[N:10]=2)[CH2:13][CH2:12]1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: S=C=NC1CC1
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: Clc1cc2nc(NC3CC3)[nH]c2cc1Cl
Yield: 70.5 %

Procedure:
4,5-Dichloro-1,2-phenylenediamine (6.04 g, 34.1 mmol), cyclopropyl isothiocyanate (3.69 g, 37.2 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (20.1 g, 47.4 mmol) and pyridine (135 mL) were used according to general procedure I. The product was recrystallized from acetonitrile to afford 5.82 g (70%) of a yellow solid; m.p. 223-225° C. 1H NMR (DMSO-d6) δ: 11.2 (s, 1H, NH), 7.43 (s, 1H, NH), 7.27 (s, 2H, ArH), 2.49 (m, 1H, CH), 0.70 (m, 2H, CH), 0.49 (m, 2H, CH).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:10][N:11](C)C=O.NOS(O)(=O)=O>CO>[O:3]1[C:1]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)=[CH:2][CH:10]=[N:11]1
Reactant: CN(C)C=O
Reactant: CC(=O)c1cccnc1
Agent: NOS(=O)(=O)O
Solvent: CO
Product: c1cncc(-c2ccno2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 10.3 %

Procedure:
A mixture of 12.1 g (0.1 mol) 3-acetyl pyridine and 15 g (0.11 mol) dimethyl formamide dimethylacetale was heated at 90° C. for 2 h. Upon concentration in vacuo the product was titrated with ethylether and filtrated. The compound was dissolved in 50 ml methanol and 11.5 g (0.1 mol) hydroxylamine-O-sulfonic acid dissolved in 50 ml MeOH was added. The reaction mixture was stirred at room temperature for 2 h, concentrated in vacuo and poured on water (150 ml). The solution was made alkaline with solid potassium carbonate and extracted with 4×40 ml methylenchloride. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography giving 1.5 g 3-(5-isoxazolyl)-pyridine, which was dissolved in 20 ml acetone. 3 ml methyliodide was added to the solution, and the reaction mixture was stirred at room temperature for 24 h. The precipitated compound was filtered and dissolved in 30 ml methanol. To this solution sodiumborohydride (600 mg) was added in small portions. The reaction mixture was concentrated in vacuo and water (100 ml) was added. The water solution was extracted with 3×30 ml methylenchloride. The organic phase was dried over magnesiumsulfate and concentrated in vacuo. Crystallization as the oxalate salt from acetone gave the title compound in a 1.1 g yield. M.p. 164°-165° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.58 mmol), 1-(2-bromo-ethoxy)-2-methoxy-ethane (566 mg, 3.09 mmol) and Cs2CO3 (840 mg, 2.58 mmol) in DMF (5 mL) was stirred at 95° C. for 18 h. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to afford the title compound as an oil. (MH+=297.1, 1H-NMR in CDCl3: 7.77 (m, 1 or 2H) 4.31 (t, 2H); 3.85 (t, 2H); 3.54 (m, 2H); 3.48 (m, 2H); 3.35 (s, 3H); 1.31 (s, 12H)).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].[NH:22]1[C:30]2[C:25](=CC=C[CH:29]=2)[C:24]2(COC3C=C4C(=[CH:41][C:31]2=3)CCO4)C1=O.ClCC1C=NC(OC)=NC=1>>[N:22]1[CH:41]=[CH:31][CH:24]=[CH:25][C:30]=1[CH2:29][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)CCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: COc1ncc(CCl)cn1
Product: O=C1N(Cc2ccccn2)c2ccccc2[C@]12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using (3S)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and (2-bromomethyl)pyridine hydrobromide to replace 5-(chloromethyl)-2-methoxypyrimidine, (3S)-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (77%) as a colorless solid: mp 154-156° C. (diethyl ether); mp 84-85° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ8.53-8.51 (m, 1H), 7.82-7.77 (m, 1H), 7.38-7.13 (m, 4H), 7.05-6.99 (m, 1H), 6.98-6.92 (m, 1H), 6.61 (s, 1H), 6.42 (s, 1H), 5.10 (d, J=16.4 Hz, 1H), 5.00 (d, J=16.4 Hz, 1H), 4.86 (d, J=9.3 Hz, 1H), 4.75 (d, J=9.3 Hz, 1H), 4.49 (t, J=8.7 Hz, 2H), 2.98 (t, J=8.7 Hz, 2H); 13C NMR (75 MHz, DMSO-d5) δ177.0, 161.0, 160.4, 155.2, 149.2, 142.4, 137.0, 132.2, 128.5, 123.4, 122.8, 122.6, 121.5, 120.6, 119.7, 119.2, 109.2, 92.3, 79.7, 72.0, 56.8, 44.7, 28.2; MS (ES+) m/z 371.0 (M+1).
Reaction SMILES: C(O[N:4]=[C:5]([C:7]1[N:8]=[CH:9][N:10]([C@@H:13]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]2[OH:15])[C:11]=1[NH2:12])[NH2:6])C.[C:22](=S)=[S:23]>N1C=CC=CC=1.CO>[CH:9]1[N:10]([C@@H:13]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]2[OH:15])[C:11]2[C:7](=[C:5]([NH2:6])[NH:4][C:22]([N:12]=2)=[S:23])[N:8]=1
Reactant: CCON=C(N)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N
Reactant: S=C=S
Solvent: c1ccncc1
Solvent: CO
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 65 %

Procedure:
0.45 g of 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide O-ethyl-oxime was dissolved in a mixture of 0.3 ml of pyridine, 5 ml of methanol and 0.5 ml of carbon disulfide. The resulting mixture was allowed to react in an autoclave at 120° C for 6 hours under autogenous pressure (about 10 Kg/cm2). The reaction mixture was concentrated to dryness, and the residue was dissolved in water. The aqueous solution was adjusted to a pH of 2 with hydrochloric acid to precipitate the crude product, which was then recovered by filtration. The filter cake was dissolved in aqueous ammonia, the solution was filtered, and the filtrate was adjusted to a pH of 2 with hydrochloric acid to obtain 0.31 g of pure 2-thioadenosine as crystals having a melting point of 199° C (with decomposition) in a 65% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([Cl:20])=[CH:15][CH:16]=2)[N:11]=1.C(#N)C>O>[Cl:20][C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)c1ccsc1
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccsc1
Temperature: 4 °C
Yield: 27.7 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3-thiophenecarboxylic acid (16 g), N,N'-carbonyldiimidazole (20.1 g) and 2-amino-7-chloro-1,8-naphthyridine (16.8 g). The product produced by precipitation in water (10.6 g; m.p. 250° C.) is dissolved in boiling acetonitrile (980 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×25 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-3-thiophenecarboxamide (7.5 g) is produced, m.p. 254° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[CH:4][N:3]=1.[N:10]1([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1>O>[NH:8]([C:6]1[CH:7]=[C:2]([N:18]2[CH2:19][CH2:20][CH:15]([N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:16][CH2:17]2)[N:3]=[CH:4][N:5]=1)[NH2:9]
Reactant: c1cc(N2CCCC2)ccn1
Reactant: NNc1cc(Cl)ncn1
Solvent: O
Product: NNc1cc(N2CCC(N3CCCC3)CC2)ncn1

Procedure:
A mixture of 2.0 g (13.8 mmol) of the compound from Example 7A and 4.3 g (27.7 mmol) 4-pyrrolidin-1-ylpyridine is stirred in 20 ml water at 100° C. for 16 h. The solid which has precipitated out is filtered off, washed first with ethanol and then with diethyl ether and dried in vacuo.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[Cl:13][C:14](OC(Cl)(Cl)Cl)=[O:15]>O1CCCC1>[Cl:13][C:14]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])=[O:15]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: C1CCOC1
Product: O=C(Cl)ON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To an ice-cooled solution of 6.5 g (40 retool) of N-hydroxyphthalimide in 200 mL dry tetrahydrofuran (THF) was added 10.0 mL (15.8 g, 80 mmole) of trichloromethyl chloroformate (diphosgene). The solution was then stirred for 6 hrs at room temperature. The solvent and excess trichloromethyl chloroformate were removed under reduced pressure to give a white crystalline solid, which was recrystallized from dry n-hexane to give colorless plates; m.p. 113°-115° C.