Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][Cl:35].O>CN(C)C=O>[Cl:35][CH2:34][CH2:33][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: ClCCBr
Reactant: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
3-[7-Hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (45 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (187 mg) and 1-bromo-2-chloroethane (0.06 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (46 mg, yield 90%).
Reaction SMILES: C(OC([C:6]1[C:7]([N:15]2[CH2:20][CH2:19][C:18]([NH2:29])([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=O)C.O>[OH-].[K+]>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:18]2([NH2:29])[CH2:19][CH2:20][N:15]([C:7]3[CH:6]=[CH:11][N:10]=[C:9]4[NH:12][N:13]=[CH:14][C:8]=34)[CH2:16][CH2:17]2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1cnc2[nH]ncc2c1N1CCC(N)(Cc2ccc(Cl)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NC1(Cc2ccc(Cl)cc2)CCN(c2ccnc3[nH]ncc23)CC1
Yield: 58.5 %

Procedure:
4-[4-Amino-4-(4-chlorobenzyl)-piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (55 mg, 0.13 mmol) was suspended in 2M potassium hydroxide (1.5 mL) and irradiated in a microwave reactor (250 W) for 2 hours at 120° C. After cooling, water (2 mL) was added and the solids formed were collected by filtration. The filtrate was extracted with ethyl acetate (2×4 mL) and dried (Na2SO4). The extracts were evaporated and the resulting yellow solids were combined with the previous material and dissolved in acetone (10 mL) and n-hexanes (2 mL). The solvents were concentrated until precipitation occurred. The solids were collected by filtration and washed with n-hexanes to give 4-(4-chlorobenzyl)-1-(1H-pyrazolo[3,4-b]pyridin-4-yl)-piperidin-4-ylamine as a light yellow powder (26 mg, 57%). LC-MS (LCT2) m/z 342 [M+H±], Rt 2.07 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.C([O-])(O)=O.[Na+].[Cl:18][CH2:19][C:20](Cl)=[O:21]>CCOC(C)=O>[Cl:18][CH2:19][C:20]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: Nc1cccc2ccc(O)cc12
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCl)Nc1cccc2ccc(O)cc12
Reaction time: 0.33 h

Procedure:
To a solution of 8-amino-2-naphthol (10.0 g, 62.8 mmol) in 240 mL of 1:1 EtOAc/saturated NaHCO3 solution was added chloroacetyl chloride dropwise (5.5 mL, 69.1 mmol). After 20 minutes, the solution was filtered, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product.
Reaction SMILES: [OH:1][CH:2]([C:4]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:10][C:9](=[O:20])[C:8]=2[CH:7]=[C:6]([CH3:21])[CH:5]=1)[CH3:3].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([O:1][CH:2]([C:4]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:10][C:9](=[O:20])[C:8]=2[CH:7]=[C:6]([CH3:21])[CH:5]=1)[CH3:3])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C(C)O)c2oc(-c3ccncc3)cc(=O)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)OS(C)(=O)=O)c2oc(-c3ccncc3)cc(=O)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 8-(1-hydroxyethyl)-2-(4-pyridinyl)-6-methyl-4H-1-benzopyran-4-one (2.4 g) in dichloromethane (100 ml) in an ice bath, was treated with triethylamine (1.3 ml) followed by methanesulfonylchloride (0.67 ml) and the mixture stirred at 0° C. for 30 minutes. The solution was then washed with 0.1N HCl (aq) (2×30 ml), dried (Na2SO4) and the solvent removed to yield a oily brown solid, which was not further purified.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>CCCCCCC.CCOC(C)=O>[CH3:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Reactant: Cc1cccc(B(O)O)c1C
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1C

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 98, intermediate a) and 2,3-dimethylphenylboronic acid (CAS RN 183158-34-1) and using gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Colorless solid (81%). MS (ESI): m/z=453.140 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:19]2[N:28]=[C:27]([N:29]([CH3:31])[CH3:30])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1>CO.[Pd]>[NH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:19]2[N:28]=[C:27]([N:29]([CH3:31])[CH3:30])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH2:13][CH2:12]1
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](NC(=O)OCc3ccccc3)CC2)nc2ccccc12
Agent: [Pd]
Solvent: CO
Product: CN(C)c1nc(NC[C@H]2CC[C@H](N)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 25 h
Yield: 109.9 %

Procedure:
To a solution of trans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamic acid benzyl ester obtained in step C of example 3 (330 mg, 0.76 mmol) in MeOH (3.3 mL) was added 10% Pd/C (33 mg). The mixture was stirred at ambient temperature under hydrogen atmosphere for 25 hr, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 50% EtOAc in hexane) to give trans-N2-(4-amino-cyclohexylmethyl)-N4,N4-dimethyl-quinazoline-2,4-diamine (250 mg, 98%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([CH2:22]C(O)=O)[CH:14]=1.Cl>C1COCC1>[Br:12][C:13]1[CH:14]=[C:15]2[C:16](=[CH:20][CH:21]=1)[C:17](=[O:18])[O:10][C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:11])=[CH:22]2
Reactant: O=C(O)Cc1cc(Br)ccc1C(=O)O
Reactant: COC(=O)CCCCC(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)CCCCc1cc2cc(Br)ccc2c(=O)o1
Temperature: 25 °C
Yield: 11.5 %

Procedure:
To a stirred mixture of adipic acid monomethyl ester (9.27 g, 57.9 mmol, 1.50 equiv.) in THF (50 mL) was added N,N′-carbonyldiimidazole (9.39 g, 57.9 mmol, 1.50 equiv.) and the mixture was stirred at room temperature. After stirring for 30 min, the reaction mixture was cooled to 0° C. followed by dropwise addition of 4-bromo-2-(carboxymethyl)benzoic acid (10.0 g, 38.6 mmol) in THF (25 mL). The reaction was stirred gradually from 0° C. to room temperature for 48 h. Upon completion of the reaction, 0.5 N HCl (25 mL) solution was added and extracted with EtOAc (2×25 mL). The organic layer was washed with aqueous sat. NaHCO3, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0-15% EtOAc/hexanes to give 1.5 g of methyl 5-(6-bromo-1-oxo-1H-isochromen-3-yl)pentanoate as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=O.Cl.[NH2:14][OH:15]>N1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6]/[C:7]/2=[N:14]\[OH:15]
Reactant: O=C1CCCc2c(Br)cccc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O/N=C1\CCCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 132.3 %

Procedure:
To a solution of 5-bromo-3,4-dihydronaphthalen-1(2H)-one (1.0 g, 4.44 mmol) in pyridine (15 mL) was added hydroxylamine hydrochloride (0.617 g, 8.89 mmol). The reaction mixture was stirred at room temperature for 1 h and then concentrated. The resulting residue was treated with water (60 mL) and extracted with ethyl acetate (60 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound (1.41 g, 99% yield) as white solid. LCMS, [M+Na]+=240.0.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:11]([C:12]3[C:13](=[O:19])[NH:14][C:15](=[O:18])[NH:16][CH:17]=3)[C:10]3[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31]>>[CH3:1][C:2]1[O:3][C:4]2[CH:11]([C:12]3[C:13](=[O:19])[NH:14][C:15](=[O:18])[N:16]([CH2:26][C:27]4[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=4)[C:30]([O:32][CH3:33])=[O:31])[CH:17]=3)[C:10]3[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Cc1ccc2c(c1)C=Cc1nc(C)oc1C2c1c[nH]c(=O)[nH]c1=O
Product: COC(=O)c1cccc(Cn2cc(C3c4ccc(C)cc4C=Cc4nc(C)oc43)c(=O)[nH]c2=O)c1

Procedure:
The subtitle compound was prepared from the product of step (vii) and methyl 3-(bromomethyl)benzoate (690 mg) by the method of example 1 step (viii).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:17].[CH2:23]([S:28]([NH2:31])(=[O:30])=[O:29])[CH2:24][CH2:25][CH2:26][CH3:27].C1CCN2C(=NCCC2)CC1>CN(C)C=O>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([C:14]([NH:31][S:28]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:30])=[O:29])=[O:16])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:17]
Reactant: CCCCCS(N)(=O)=O
Reactant: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccc(Cl)cc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
A mixture of 3-(2,4-dichlorobenzyl)-2-methyl-3H-benzimidazole-5-carboxylic acid (34.1 g, 102 mmol), N,N′-carbonyldiimidazole (21.4 g) and N,N-dimethylformamide (122.7 g) was stirred for one hour at 35° C., into which 1-pentanesulfonamide (20.0 g) and 1,8-diazabicyclo[5.4.0]-7-undecene (20.1 g) were then added, and stirred for 6 hours at 40° C. After the reaction, a portion of N,N-dimethylformamide (62.9 g) was distilled off in vacuo, and, to the residue were added methanol (227.8 g) and water (227.8 g). This solution contained 1,8-diazabicyclo[5.4.0]-7-undecene and imidazole generated from N,N′-carbonyldiimidazole as the bases. This solution was filtered to remove insoluble materials, and the filtrate was heated to 50° C., and conc. hydrochloric acid (20.4 g) was added drop-wise thereto over one hour. After the dropping, crystal form B of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide (119 mg) was added as seed crystal, and the mixture was allowed to be ripen for 2 hours. After the ripening, conc. hydrochloric acid (15.5 g) was further added drop-wise thereto over 2 hours. The slurry was ripened for one hour at 50° C. and cooled down to 30° C., and then the crystals were collected by filtration. The crystals were washed with a mixed solvent of methanol (120 g) and water (120 g), and vacuum-dried to obtain crystal form B of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide.
Reaction SMILES: FC(F)(F)S(O[Si:7]([CH3:18])([CH3:17])[CH:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]1[CH3:16])(=O)=O.[CH3:21][C:22]1[CH:23]=[C:24]([C-:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1.[Li+]>CCOCC>[CH3:28][C:26]1[CH:25]=[C:24]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]([Si:7]([CH3:17])([CH3:18])[CH:8]3[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]3[CH3:16])[CH:30]=2)[CH:23]=[C:22]([CH3:21])[CH:27]=1
Reactant: Cc1cc(C)cc(-[c-]2ccc3ccccc32)c1
Reactant: CC1=C(C)C([Si](C)(C)OS(=O)(=O)C(F)(F)F)C(C)=C1C
Agent: [Li+]
Solvent: CCOCC
Product: CC1=C(C)C([Si](C)(C)C2C=C(c3cc(C)cc(C)c3)c3ccccc32)C(C)=C1C
Reaction time: 19 h

Procedure:
To a solution of dimethyl(2,3,4,5-tetramethylcyclopenta-2,4-dien-1-yl)silyl trifluoromethanesulfonate (Compound C, 7.50 g, 22.8 mmol, 1.00 eq.) in ether (25 mL) at −35° C. was added lithium (1-(3,5-dimethylphenyl)indenide) (5.53 g, 24.4 mmol, 1.07 eq.). The reaction was stirred for 19 hours, and was then evaporated under vacuum. The residue was extracted with pentane (40 mL, then 2×20 mL) and the extract was filtered. The resulting solution was evaporated under vacuum to give a sticky solid. Yield 9.65 g (106%). 1H NMR(C6D6): δ 7.87 (d, 1H), 7.40 (s, 2H), 7.25 (m, 2H), 6.88 (s, 1H), 6.64 (s, 1H), 3.73, (s, 1H), 2.93 (br s, 1H), 2.23 (s, 6H), 1.93 (s, 3H), 1.92 (s, 3H), 1.84 (s, 3H), 1.82 (s, 3H), −0.07 (s, 3H), −0.36 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[CH:9][N:8]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:7]=12.[Li+].CC([N-]C(C)C)C.Cl[C:41]([O:43][CH2:44][CH3:45])=[O:42]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:16][CH:15]=3)=[C:9]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[N:8]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:7]=12
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)n1cc(CCOc2ccc(OC(F)(F)F)cc2)c2ccnc(Cl)c21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CCOc2ccc(OC(F)(F)F)cc2)c2ccnc(Cl)c2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 90.1 %

Procedure:
To solution of tert-butyl 7-chloro-3-{2-[4-(trifluoromethoxy)phenoxy]ethyl}-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (349 mg, 0.76 mmol) in THF (15 mL) cooled to −78 C was added LDA (0.57 mL, 1.1 mmol, 2 M). After 30 min at this temperature, ethyl chloroformate (0.15 mL, 1.5 mmol) was added and the mixture was warmed to r.t. slowly. The reaction mixture was then quenched with 5% potassium bisulfate and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified on silica (gradient elution, 0-30% EtOAc/hexanes) to yield the title product (362 mg). HRMS (ESI) calc (M+H)+=529.1348. found 529.1346.
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[NH2:37][C:38]1[CH:42]=[C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:40][C:39]=1[C:49](=O)[CH3:50].[OH-].[K+]>C(O)C>[NH2:37][C:38]1[CH:42]=[C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:40][C:39]=1[C:49]1[CH:50]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]3[N:22]([CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[C:21]4[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=4[N:19]=3)[CH:14]=2)[N:9]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1sc(-c2ccccc2)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(-c2ccccc2)sc1-c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1
Yield: 14 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(3-amino-5-phenyl-thiophen-2-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (19 mg, 14% yield). MS: 545.24 (M+H+); HPLC Procedure B, retention time=8.25 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][Si](C)(C)C)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[CH:17])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(C(C)(C)CCCCC#C[Si](C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#CCCCCC(C)(C)c1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
[7-(3,5-Dimethoxyphenyl)-7-methyl-1-octynyl]trimethylsilane (1 equiv.) was dissolved in anhydrous methanol (0.8 M), anhydrous potassium carbonate (0.2 equiv.) was added and the heterogeneous mixture was stirred at room temperature, under argon, for 24 hours. The reaction mixture was diluted with water and extracted with diethyl ether. The ether extract was dried, concentrated by rotary evaporation and the residue was purified by chromatography on silica gel (5% diethyl ether-petroleum ether) to give the title compound in 76% yield.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]1N[CH:6]([OH:8])[C@H:5]([OH:9])[C@@H:4]([OH:10])[C@@H:3]1[OH:11].[OH2:13]>>[O:12]=[CH:1][C@@H:2]([C@H:3]([C@@H:4]([C@@H:5]([CH2:6][OH:8])[OH:9])[OH:10])[OH:11])[OH:13]
Reactant: OC[C@H]1NC(O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A 300 g amount of nojirimycin was dissolved in 1.5 l of distilled water to which was added 80 g of deoxin-1, i.e., a crude powder of glucose oxidase with 10,000 units per mg which is produced by Penicillium amagasakiensis (produced by Nagase Sangyo Co./Japan). The pH of the reaction mixture was adjusted to 6.0 and then the reaction was conducted at 30°C in a 30 l jar fermenter with agitation at 300 r.p.m. under air-flowing conditions. After 65 hours of reaction, the reaction solution was passed through a column filled with Amberlite IR-120 (H+ type, 1.5 l). The column was then washed with 7 l of water. The treated solution and the washings were combined (22 l), and the combined solution was then neutralized with Amberlite IR-45 (OH- type), followed by decolorization with 50 g of carbon powder. The decolorized solution was then condensed. To the condensed solution (500 ml) was added 100 ml of methanol, which was allowed to stand to cool in order to yield a crystalline product. The crystals were separated from the solution by filtration to give 220 g of D-gluconic-δ-lactam as needle-like white crystals (yield of 77%).
Reaction SMILES: [C:1]1([N:7]=[N+:8]=[N-:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([Sn:14]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]#[CH:16])[CH2:11][CH2:12][CH3:13].C(N(CC)CC)C>C1COCC1.[Cu]I>[C:1]1([N:7]2[CH:16]=[C:15]([Sn:14]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: [N-]=[N+]=Nc1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2ccccc2)nn1

Procedure:
Phenylazide can be obtained from Pfaltz & Bauer, Inc., or can be synthesized by the method described in J. Biochem., 179, 397-405 (1979). A solution of tributylethynyl stannane (Sigma Aldrich; 400 mg, 1.27 mmol) in THF (4 ml) is treated with phenylazide (169 mg, 1.27 mmol), copper (I) iodide (90 mg, 0.47 mmol), and triethylamine (256 mg, 2.54 mmol) at room temperature over 48 h. The reaction is then filtered through celite to remove copper (I) iodide and chromatographed on silica in a gradient of 5-20% ethyl acetate in petrol. The second fraction is collected and concentrated in vacuo to give the 1-phenyl-4-(tributylstannyl)-1H[1,2,3]triazole as a colourless oil.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3[CH:15]=[CH:16][C:17]([O:19][CH:20]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]4)=[CH:18][C:13]=3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[H-].[Na+].Br[CH2:35][C:36]1[O:37][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:40]=1>CN(C)C=O>[O:1]=[C:2]1[C:10]2([C:14]3[CH:15]=[CH:16][C:17]([O:19][CH:20]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]4)=[CH:18][C:13]=3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:35][C:36]1[O:37][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)OCC32C(=O)Nc3ccccc32)C1
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)OCC32C(=O)N(Cc3ccc(C(F)(F)F)o3)c3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a stirred solution of tert-butyl 3-[(2′-oxo-1,2′-dihydrospiro[1-benzofuran-3,3-indol]-6-yl)oxy]pyrrolidine-1-carboxylate (0.19 g, 0.45 mol) in N,N-dimethyl formamide (10 mL) was added sodium hydride (0.02 g, 0.54 mmol) slowly at 0° C. After 30 min, 2-(bromomethyl)-5-(trifluoromethyl)furan (0.12 g, 0.54 mmol) was added. The mixture was stirred at ambient temperature for 16 h, and then quenched with saturated ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexanes, 1/2) to afford tert-butyl 3-[(2′-oxo-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3-indol]-6-yl)oxy]pyrrolidine-1-carboxylate (0.14 g, 55%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.29 (t, J=7.7 Hz, 1H), 7.16 (d, J=7.4 Hz, 1H), 7.06 (t, J=7.5 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H), 6.76-6.70 (m, 1H), 6.54 (d, J=8.2 Hz, 1H), 6.47 (s, 1H), 6.40-6.35 (m, 1H), 6.30 (d, J=8.2 Hz, 1H), 5.06 (d, J=16.2 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.86 (d, J=16.2 Hz, 1H), 4.80 (br s, 1H), 4.69 (d, J=9.0 Hz, 1H), 3.64-3.37 (m, 4H), 2.22-1.96 (m, 2H), 1.45 (s, 9H); MS (ES+) m/z 593.2 (M+23).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:9])[CH:5]=[C:6]([NH:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[F:10])[N:7]=1
Reactant: NCc1ccccc1F
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc(Cl)cc(NCc2ccccc2F)n1

Procedure:
53 g (323 mmol) of 2-amino-4,6-dichloropyrimidine, 40.4 g (323 mmol) of 2-fluorobenzylamine and 33.4 g (330 mmol) of triethylamine are dissolved in 800 ml of ethanol and the reaction mixture is heated under reflux for 20 hours. After 400 ml of ethanol have been distilled off, the residue is diluted with 500 ml of water, and the precipitated product is filtered off with suction and recrystallised from 1 l of toluene. In this manner 2-amino-4-chloro-6-(2-fluorobenzylamino)-pyrimidine having a melting point of 130°-133° is obtained.