Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:10].[C:11]1([CH3:20])[C:12]([C:17](Cl)=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1>>[C:11]1([CH3:20])[C:12]([C:17]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[Cl:10])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: NCCc1ccccc1Cl
Product: Cc1ccccc1C(=O)NCCc1ccccc1Cl

Procedure:
1-Amino-2-(2-chlorophenyl)ethane and o-toluoyl chloride were reacted in the same way as in step (a) of Example 13 to afford 1-(o-toluoylamino)-2-(2-chlorophenyl)ethane having a melting point of 91.6° C. The product was successively reacted in the same way as in steps (b), (c), (d), (e), (f), (g), and (h) of Example 13 to afford 1-(2-methylphenyl)isoquinoline-5-acetonitrile having a melting point of 120.3° to 120.4° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]([CH:24]=O)=[C:4]([OH:26])[CH:3]=1)=[O:9].O.[NH2:28][NH2:29]>C(O)C>[N:28](=[CH:24][C:5]1[C:6]2[O:17][C:16]3[C:15]([C:18]([OH:20])=[O:19])=[CH:14][C:13]([O:21][CH3:22])=[C:12]([CH3:23])[C:11]=3[O:10][C:8](=[O:9])[C:7]=2[C:2]([CH3:1])=[CH:3][C:4]=1[OH:26])[NH2:29]
Reactant: NN
Reactant: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=O)c1O2
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=NN)c1O2

Procedure:
To a stirring solution of psoromic acid (1 mmol) in ethanol (25 mL) was added hydrazine hydrate (1 mmol). The reaction was stirred for half an hour and monitored by TLC. Upon completion, all of the solvent was removed by rotary evaporation. The residue was redissolved in ethanol and dried over anhydrous magnesium sulfate, filtered, and evaporated by a rotary evaporator to yield a white solid product.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[F:11][C:12]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:13]=1[CH2:14][N:15]1[C:20]([CH3:21])=[C:19]([CH:22]=C=O)[C:18](=[O:25])[C:17]([Br:26])=[C:16]1[CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[F:11][C:12]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:13]=1[CH2:14][N:15]1[C:20]([CH3:21])=[C:19]([CH2:22][N:2]([CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[CH3:1])[C:18](=[O:25])[C:17]([Br:26])=[C:16]1[CH3:27]
Reactant: CNCCc1ccccn1
Reactant: Cc1c(Br)c(=O)c(C=C=O)c(C)n1Cc1c(F)cccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1c(Br)c(=O)c(CN(C)CCc2ccccn2)c(C)n1Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2-Methylaminoethyl)pyridine (680 mg, 5.00 mmol) was added to a stirred solution of 1-(2,6-difluorobenzyl)-2,6-dimethyl-3-bromo-5-(carbonylmethyl)4-pyridone (430 mg, 1.16 mmol) in CH2Cl2 (15 mL). After 30 min., NaBH(OAc)3 (1.23 g, 5.80 mmol) was added in small portions, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with H2O (15 mL) and the organic layer was separated and washed with sat. NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated in vacuo. The crude was used in the next step without any further purification. Crude yield 426 mg (75%). LRMS m/z 490.0 (M+−1), 492.0 (M++1).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22](I)=[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][N:16]3[N:15]=2)=[CH:10][CH:9]=1.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([NH:38][C:39](=[O:42])[CH2:40][CH3:41])[CH:33]=2)O1.C(OCC)(=O)C>O1CCOCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([NH:38][C:39](=[O:42])[CH2:40][CH3:41])[CH:33]=3)=[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][N:16]3[N:15]=2)=[CH:10][CH:9]=1
Reactant: Fc1ccc(-c2nn3c(c2I)CCCC3)cc1
Reactant: CCC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCC(=O)Nc1cc(-c2c(-c3ccc(F)cc3)nn3c2CCCC3)ccn1
Temperature: 120 °C
Yield: 79.3 %

Procedure:
Under argon, 1.39 ml of a 2M aqueous Na2CO3 solution are added dropwise to a solution of 200 mg (0.55 mmol) of 2-(4-fluorophenyl)-3-iodo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine, 168 g (0.61 mmol) of N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]propanamide in 2 ml of dioxane, and 32 mg (0.04 mmol) of Pd(PCy3)2Cl2 are added. In a microwave reactor, the reaction mixture is heated at 120° C. for 15 min. After cooling, 50 ml of ethyl acetate are added, the reaction mixture is filtered through kieselguhr and the filtrate is extracted with ethyl acetate. The combined organic phases are washed with water, dried over MgSO4 and freed from the solvent under reduced pressure. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate) gives 159 mg (78%) of the desired product; log P(HCOOH): 1.97; 1H-NMR (MeCN-d3): 8.54 (br.s, 1H), 8.11 (d. 1H), 8.02 (s, 1H), 7.42 (dd, 2H), 7.04 (dd, 2H), 6.77 (d, 1H), 4.16 (dd, 2H), 2.81 (dd, 2H), 2.40 (q, 2H), 1.77 (m, 2H), 1.11 (t, 3H).
Reaction SMILES: [CH:1]([NH:4][S:5](Cl)(=[O:7])=[O:6])([CH3:3])[CH3:2].[C:9]([NH:13][C:14](=[NH:19])[O:15][CH:16]([CH3:18])[CH3:17])([O:11][CH3:12])=[O:10].C(N(CC)CC)C>O1CCCC1>[C:9]([NH:13][C:14](=[N:19][S:5](=[O:7])(=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])[O:15][CH:16]([CH3:17])[CH3:18])([O:11][CH3:12])=[O:10]
Reactant: CC(C)NS(=O)(=O)Cl
Reactant: COC(=O)NC(=N)OC(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)NC(=NS(=O)(=O)NC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In the course of 25 minutes, 95 parts of isopropylaminosulfonyl chloride were stirred into a mixture of 96 parts of N-carbomethoxy-O-isopropylisourea and 73 parts of triethylamine in 700 parts of tetrahydrofuran at 10°-15° C. After then stirring for one hour at 25° C., the reaction mixture was extracted once with water and once with 0.5 N hydrochloric acid, dried and evaporated down under reduced pressure. This gave 130 parts of N-carbomethoxy-N'-isopropylsulfamyl-O-isopropyl-isourea, of melting point 62°-64° C. 33.7 parts of this product were cyclized with 17.6 parts of 50% strength by weight sodium hydroxide solution in 30 parts of water for 5 minutes at 55°-60° C. The mixture was extracted with ether and then acidified, and the product was filtered off, washed with water and dried, giving 22 parts of 6-isopropyl-3-isopropoxy-6H-1,2,4,6-thiatriazin-5-one,1,1-dioxide of melting point 164°-167° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:11]([O:17][C:18](=[O:20])[CH3:19])[C@@H:10]([CH2:21][N:22]=[N+:23]=[N-:24])[O:9][C@@H:6]1OC)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[C:30]([OH:33])(=[O:32])[CH3:31]>C(OC(=O)C)(=O)C>[C:30]([O:33][C@H:6]1[O:9][C@H:10]([CH2:21][N:22]=[N+:23]=[N-:24])[C@@H:11]([O:17][C:18](=[O:20])[CH3:19])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:5]1[O:4][C:1](=[O:3])[CH3:2])(=[O:32])[CH3:31]
Reactant: CC(=O)O
Reactant: CO[C@H]1O[C@H](CN=[N+]=[N-])[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)O[C@H]1O[C@H](CN=[N+]=[N-])[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 82 %

Procedure:
To a solution of methyl 2,3,4-tri-O-acetyl-6-azido-6-deoxy-α-D-glucopyranoside (III, 1.0 g, 2.9 mmol) in acetic acid (20 mL) and acetic anhydride (20 mL) at 0° C. was added sulfuric acid (97%, 1 mL) and the mixture was stirred at rt for 20 hr and then poured into ice (100 g). Extraction with dichloromethane (3×50 mL) and washed with water, saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography, eluting with 1:1 hexane-ethyl acetate, to give IV (886 mg, 82%) as a white foam. 1H NMR (500.1 MHz) (CD3Cl) δ: 6.28 (d, J=4.0 Hz, 1H), 5.41 (t, J=9.5 Hz, 1H), 5.03 (m, 2H), 4.03 (m, 1H), 3.24-3.37 (m, 2H), 2.13 (s, 3H), 2.04 (s, 3H), 1.99 (s, 3H), 1.95 (s, 3H). 13C NMR (125.8 MHz) (CDCl3) δ: 170.11, 169.53, 169.33, 168.62, 88.78, 70.83, 69.58, 69.08, 68.94, 50.61, 20.75, 20.55, 20.46, 20.34.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][C:7]1[C:8]([CH3:28])=[N:9][C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Br:2][CH2:6][C:7]1[C:8]([CH3:28])=[N:9][C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1
Reactant: Cc1nc(-c2ccccc2)cc(-c2cccc([N+](=O)[O-])c2)c1CO
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)cc(-c2cccc([N+](=O)[O-])c2)c1CBr
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 37.2 %

Procedure:
To a solution of phosphorus tribromide (0.93 g) in tetrahydrofuran (10 ml) was dropwise added a suspension of 3-hydroxymethyl-2-methyl-4-(3-nitrophenyl)-6-phenylpyridine (1.65 g) in tetrahydrofuran (10 ml) at 5°-10° C. After stirring for 1.5 hours at the same temperature, the reaction mixture was poured into ice-water (20 ml), adjusted to pH 9.5 with saturated aqueous potassium carbonate and extracted with ethyl acetate (40 ml). The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a column chromatography on silica gel eluting with chloroform. The fractions containing the desired compound were combined and evaporated in vacuo to give 3-bromomethyl-2-methyl-4-(3-nitrophenyl)-6-phenylpyridine (0.49 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][NH:5][CH:6]=1.[Br:11]N1C(=O)CCC1=O>>[Br:11][C:6]1[NH:5][CH:4]=[C:3]([C:7]([O:9][CH3:10])=[O:8])[C:2]=1[CH3:1]
Reactant: COC(=O)c1c[nH]cc1C
Reactant: O=C1CCC(=O)N1Br
Product: COC(=O)c1c[nH]c(Br)c1C

Procedure:
By a similar operation as in Reference Example 22 and using methyl 4-methyl-1H-pyrrole-3-carboxylate (1.0 g) and N-bromosuccinimide (1.28 g), the title compound was obtained as a pale-yellow solid (yield 489 mg, 31%).
Reaction SMILES: [CH2:1](N(CC)CC)[CH3:2].[F:8][C:9]([CH:12]([C:16]([F:18])=[O:17])[C:13]([F:15])=[O:14])([F:11])[F:10].S(F)(OCC)(=O)=O>CCOCC>[CH2:1]([C:12]([C:9]([F:11])([F:10])[F:8])([C:13]([F:15])=[O:14])[C:16]([F:18])=[O:17])[CH3:2]
Reactant: O=C(F)C(C(=O)F)C(F)(F)F
Reactant: CCN(CC)CC
Agent: CCOS(=O)(=O)F
Solvent: CCOCC
Product: CCC(C(=O)F)(C(=O)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
A solution of 9.2 g (0.09 mol) of triethylamine in 25 ml of ether was added dropwise to a stirred solution of 17.6 g (0.10 mol) of trifluoromethylmalonyl fluoride in 50 ml of ether at -80°C. To the resulting suspension of solid was added 14.1 g (0.11 mol) of ethyl fluorosulfate and the mixture was then allowed to warm to 25°C with stirring. The homogeneous reaction mixture developed two layers after standing overnight. Distillation gave 15 g (74%) of ethyltrifluoromethylmalonyl fluoride, bp 54°-56°C (260 mm), identified by ir.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH:17]=1>CO.O1CCCC1>[CH3:1][C:2]1([CH3:30])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:23])=[O:24])[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)N3CCCC3)c1)N2
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(S(=O)(=O)N2CCCC2)c1
Yield: 64.4 %

Procedure:
To a stirred solution of methyl 3,3-dimethyl-2-(3-(pyrrolidin-1-ylsulfonyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (57 mg, 0.133 mmol) in methanol/tetrahydrofuran (2 mL/mL) was added 1M aqueous solution (2.0 mL, 2.0 mmol), LC-MS indicated that 2005467-009-01 was consumed. The mixture was concentrated and the residue was dissolved in water. The aqueous layer was basified to pH=4 with 1M hydrochloric acid solution. The precipitated solid was filtered, and dried to give 35.5 mg of 3,3-dimethyl-2-(3-(pyrrolidin-1-ylsulfonyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid. Yield: 64.4%. MS (ESI+APCI) M+1=415.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:30])[C@H:19]([CH2:28][SH:29])[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH3:16][O:17][C:18](=[O:30])[CH:19]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:28][S:29][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: BrCc1ccc(-c2ccc(Br)cc2)cc1
Reactant: COC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CSCc1ccc(-c2ccc(Br)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4′-Bromo-4-bromomethyl-biphenyl, 9.1 g (27.9 mmol), N-(tert-Butoxy-carbonyl)-L-cysteine methyl ester, 5.74 mL (27.9 mmol), cesium carbonate, 18.2 g (55.8 mmol), and 100 mL of N,N-dimethylformamide was stirred at room temperature for 4 h. The mixture was diluted with 200 mL of water and extracted with 2×200 mL of ethyl acetate. The organic layer was washed with 2×200 mL portions of aq. LiCl, sat. aq. NaHCO3, sat. aq. NaCl, and dried (MgSO4). After the solution was concentrated, the residue was purified through a short plug of silica gel (eluted with 20% EtOAc-Heptane) to afford the desired product in 8.8 g (66%) as a white solid. 1H NMR (CDCl3) 7.55 (d, 2H, J=9.3 Hz), 7.50 (d, 2H, J=9.0 Hz), 7.43 (d, 2H, J=9.3 Hz), 7.37 (d, 2H, J=9.0 Hz), 5.31 (d, 1H, J=9.0 Hz), 4.62-4.51 (m, 1H), 3.76 (s, 5H), 2.93 (dd, 1H, 15.7, 5.7 Hz), 2.84 (dd, 1H, 15.7, 6.3 Hz), 1.47 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[CH2:10][OH:11].C(O)(=O)C.[CH:23](=O)[C:24]([CH3:27])([CH3:26])[CH3:25].C([BH3-])#N.[Na+]>CO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:3]([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH2:10][OH:11])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(CO)c1ccccc1Cl
Reactant: CC(C)(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)CNc1ccc(Cl)cc1C(CO)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a solution of 2-(2-amino-5-chlorophenyl)-2-(2-chlorophenyl)ethanol (4.44 g) in methanol (50 ml) were added acetic acid (1.4 ml) and pivalaldehyde (2.0 g). The mixture was stirred for 30 minutes at room temperature. To the solution was added sodium cyano borohydride (1.5 g), and the mixture was stirred for one hour at room temperature. The reaction mixture was then processed in substantially the same manner as in Example 52-(7) to give 5.5 g of an oily compound.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[C@@H:7]1([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=3[N:18]=[CH:17]2)[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[NH2:26][C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1.CO>O>[OH:9][CH:8]1[C@H:7]([N:16]2[CH:17]=[N:18][C:19]3[C:25]2=[N:24][CH:23]=[N:22][C:20]=3[NH2:21])[O:15][C@H:12]([CH2:13][OH:14])[CH:10]([OH:11])[N:26]1[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: Nc1ncccn1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)C(O)N(c2ncccn2)C1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of sodium metaperiodate (2.13 g) in water (25 ml) was added to a suspension of adenosine (2.67 g) and 2-aminopyrimidine in water (25 ml) at 15° C. The mixture was stirred at ambient temperature for five hours. To the reaction mixture was added methanol (50 ml). A precipitate was filtered off and the filtrate was evaporated in vacuo at 35° C. The residue was triturated with acetone to give 9-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-pyrimidinyl)morpholin-2-yl]adenine (3.64 g).
Reaction SMILES: CO.[H-].[Na+].[C:5]([N:9]=[N:10][C:11]([N:14]=[C:15]=[O:16])([CH3:13])[CH3:12])([CH3:8])([CH3:7])[CH3:6].[N-]=[C:18]=[O:19]>O>[C:5]([N:9]=[N:10][C:11]([NH:14][C:15]([O:19][CH3:18])=[O:16])([CH3:13])[CH3:12])([CH3:8])([CH3:6])[CH3:7]
Reactant: [N-]=C=O
Reactant: CC(C)(C)N=NC(C)(C)N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)NC(C)(C)N=NC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 50 ml of methanol in a 125 ml erlenmeyer flask stirred with a magnetic stirrer was slowly added 3.1 grams (0.075 moles) of 57% sodium hydride. The reaction mixture was cooled back to 25° C. and 12.7 grams (0.075 moles) of 2-t-butylazo-2-isocyanatopropane (from Example XIV) was added dropwise over 5 minutes. The reaction mixture was stirred for approximately 1 hour, poured into 200 ml water and the product extracted with pentane. The pentane extract was washed with water, 10% NaHCO3 solution, dried over anhydrous Na2SO4, filtered and the pentane evaporated under reduced pressure to leave 11.8 grams (78% crude yield) of a yellow liquid. The product contained a strong carbonyl band at approximately 1740 cm-1 and a sharp NH band at approximately 3375 cm-1 in its infrared spectrum and there was no isocyanate band at 2225 cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([S:11]([NH:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])(=[O:13])=[O:12])[N:10]=[C:4]2[N:3]=1.[Br:23]N1C(=O)CCC1=O>C(O)(=O)C.C(OC(=O)C)(=O)C>[Br:23][C:7]1[C:2]([CH3:1])=[N:3][C:4]2[N:5]([N:8]=[C:9]([S:11]([NH:14][C:15]3[C:16]([Cl:22])=[CH:17][CH:18]=[CH:19][C:20]=3[Cl:21])(=[O:13])=[O:12])[N:10]=2)[CH:6]=1
Reactant: Cc1ccn2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1nc2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nn2cc1Br
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4.0 g (11 mmol) of 5-methyl-N-(2,6-dichlorophenyl)-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide in 50 ml of glacial acetic acid and 10 ml of acetic anhydride was stirred at 90° C. for 30 minutes. N-Bromosuccinimide (2.4 g, 13 mmol) was added to this hot solution, and the reaction mixture was stirred at 90° C. for 60 minutes. The solution was cooled and poured into 200 ml of ice water. A solid which separated was collected and dried. This crude product was purified by dissolving the sample in methylene chloride, filtering the solution through silica gel and triturating the filtrate with pentane. The desired product was obtained as a solid, mp 215°-216° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][OH:23])[CH2:18][CH2:17]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:23][CH2:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([NH:15][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[N:3]=3)[N:8]=[CH:7][C:6]=2[C:12](=[O:14])[CH3:13])[CH2:17][CH2:18]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-{6-chloro-4-[trans-4-(hydroxymethyl)cyclohexylamino]-1,5-naphthyridin-3-yl}ethanone (140 mg, 0.42 mmol) in methylene chloride (10 mL) was added triethylamine (0.12 mL, 0.84 mmol) and methanesulfonyl chloride (65 μL, 0.84 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with satd. aq. sodium bicarbonate, the layers were separated and the organic layer was concentrated to afford the crude product (180 mg) as a yellow solid which was used without further purification: 1H NMR (500 MHz, CDCl3) δ 10.90 (br s, 1H), 8.95 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 5.10-4.95 (m, 1H), 4.11 (d, J=6.5 Hz, 2H), 3.03 (s, 3H), 2.68 (s, 3H), 2.39-2.26 (m, 2H), 2.01-1.92 (m, 2H), 1.90-1.78 (m, 1H), 1.47-1.24 (m, 4H); ESI MS m/z 412 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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>[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[N:7][N:6]=[CH:5]4)[CH:25]=2)[CH2:20][CH2:21]1
Reactant: CN1CCN(c2nncc3cc(Br)ccc23)CC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCN(C)CC3)nncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A mixture of 6-bromo-1-(4-methylpiperazin-1-yl)phthalazine (0.13 g, 0.42 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide (0.13 g, 0.42 mmol), tetrakis(triphenylphosphine)palladium (24mg, 0.021 mmol) and 2 M potassium carbonate (0.7 mL, 1.4 mmol) in 5 mL DME/EtOH (4: 1) was stirred at 90° C. for 2 h. The mixture was directly purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 10% 2 M ammonia in MeOH/DCM to give the title compound (0.15g) as a yellow solid. Found MS (ES+): 402(M+H)+.
Reaction SMILES: [Si]([C:8]1[O:9][C:10]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:11]=2[C:12]=1[C:13](=[O:26])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:25][O:24][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([O:20][CH3:21])[C:17]=1[O:22][CH3:23])[C:13]([C:12]1[C:11]2[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:10]=2[O:9][CH:8]=1)=[O:26]
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c([Si](C)(C)C(C)(C)C)oc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)coc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-t-butyldimethylsilyl-3-(3,4,5-trimethoxy-benzoyl)-6-methoxy-benzofuran (30 mg, 0.066 mmol) in tetrahydrofuran (1 mL) was added tetrabutylammoniumfluoride (76.5 μL, 0.076 mmol, 1M solution in tetrahydrofuran). The reaction mixture was stirred at room temperature for 20 minutes (tlc), diluted with ethyl acetate (10 mL) and washed with 1M hydrochloric acid (5 mL). The organic layer was dried over magnesium sulphate and the solvent was removed under vacuum. The crude product was purified by flash chromatography (silica gel, eluent=hexane/diethyl ether; 7:3) to afford the title product as a creamy crystalline solid; (19.3 mg, 86%); 1H NMR (300 MHz, CDCl3) δ 8.02 (d, 1H, J=8.97 Hz), 8.01 (s, 1H, C2H), 7.14 (s, 2H, benzoyl Hs), 7.05 (d, 1H, J=2.11 Hz), 7.00 (dd, 1H, J=8.63, 2.11 Hz), 3.93 (s, 3H, OMe), 3.90 (s, 6H, 2×OMe), 3.87 (s, 3H, OMe); 13C NMR (75 MHz, CDCl3) δ 188.71 (CO), 158.64, 156.31, 152.82, 150.22, 141.72, 133.97, 122.58, 120.87, 118.12, 113.11, 106.07, 95.53, 60.63, 55.99, 55.40.