Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=2)O1>>[NH2:32][C:29]1[N:30]=[CH:31][C:26]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([Cl:17])[CH:3]=2)=[CH:27][CH:28]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(N)nc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (67 mg, 82%), MS (ISP) m/z=327.5 [(M+H)+], mp 250° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (71.5 mg, 0.325 mmol).
Reaction SMILES: C(=O)([O-])OC[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([CH2:13][CH3:14])=[CH:6][C:5]=1[C:15]([CH3:18])([CH3:17])[CH3:16].[OH-:21].[K+].O>CO>[C:15]([C:5]1[CH:6]=[C:7]([CH2:13][CH3:14])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[OH:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: [OH-]
Reactant: CCc1cc(C(C)(C)C)c(COC(=O)[O-])cc1[N+](=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCc1cc(C(C)(C)C)c(O)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of (2-tert-butyl-4-ethyl-5-nitro-phenyl)methyl carbonate (3.9 g, 13.86 mmol) in methanol (100 mL) was added KOH (1.8 g, 32.08 mmol) at room temperature. The mixture was stirred overnight. Water was added and the reaction mixture was extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give 2-tert-butyl-4-ethyl-5-nitrophenol (2.8 g, 91%), which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([I:10])[N:7]=[CH:6]1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>CS(C)=O.O>[I:10][C:8]1[N:7]=[CH:6][N:5]([CH2:4][CH2:3][CH2:2][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:9]=1
Reactant: ClCCCn1cnc(I)c1
Reactant: C1CCNC1
Solvent: CS(C)=O
Solvent: O
Product: Ic1cn(CCCN2CCCC2)cn1
Yield: 78.2 %

Procedure:
A solution of the chloride 292 (1.2 g, 4.44 mmol) and pyrrolidine (1.1 mL, 13.3 mmol) in dry DMSO (2 mL) was heated at 60° C. under nitrogen for 3 h. The reaction mixture was cooled, diluted with water and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent methanol-dichloromethane, 5:95 to 20:80) to afford 293 (1.06 g, 3.47 mmol, 78% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.59 (d, J=1.2 Hz, 1H), 7.39 (d, J=1.2 Hz, 1H), 3.98 (t, J=7.2 Hz, 2H), 2.45-2.33 (m, 4H), 2.29 (t, J=7.2 Hz, 2H), 1.84 (q, J=7.2 Hz, 2H), 1.72-1.62 (m, 4H). MS (m/z): 305.9 (M+H).
Reaction SMILES: [C:1]1([C:13]([C:15]2[C:16](=[O:30])[NH:17][C:18](=[O:29])[C:19]=2[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:14])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[H][H]>O1CCCC1.[Pd]>[C:1]1([C:13]([C@H:15]2[C@@H:19]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH:21]=3)[C:18](=[O:29])[NH:17][C:16]2=[O:30])=[O:14])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1C(=O)c1cn2c3c(cccc13)CCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1NC(=O)[C@H](c2c[nH]c3ccccc23)[C@@H]1C(=O)c1cn2c3c(cccc13)CCC2
Yield: 37.1 %

Procedure:
3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carbonyl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione (500 mg, 1.26 mmol) and 10% Pd—C (300 mg) in anhydrous tetrahydrofuran (60 ml) was stirred at room temperature under 1 atmosphere of hydrogen gas for 1 day. The mixture was filtered through celite and evaporated to dryness. The residue obtained was purified by flash column chromatography (SiO2, 65% EtOAc in hexanes) to yield (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carbonyl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione as a pale yellow powder (186 mg). M.p.=283-285° C.; 400 MHz 1H NMR (DMSO-d6) δ: 11.64 (s, 1H), 11.1 (s, 1H), 8.46 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.42-7.36 (m, 3H), 7.19-6.97 (m, 4H), 4.85 (dd, J=5.0 and 46 Hz, 2H), 4.27-4.15 (m, 2H), 2.98-2.88 (m, 2H), 2.18-2.08 (m, 2H); LCMS: 398 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[F:43][C:44]1[CH:49]=[CH:48][C:47]([C@H:50]([NH2:52])[CH3:51])=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35]([NH:52][C@@H:50]([C:47]1[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=1)[CH3:51])=[O:41]
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: C[C@@H](N)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4ccc(F)cc4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (17 mg, yield 37%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[CH:16]=[C:17](/[CH:22]=[CH:23]/[S:24](Cl)(=[O:26])=[O:25])[CH:18]=[CH:19][C:20]=1[Cl:21]>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:24](/[CH:23]=[CH:22]/[C:17]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([Cl:14])[CH:16]=2)(=[O:26])=[O:25])=[C:3]([S:10]([NH2:13])(=[O:11])=[O:12])[CH:4]=1)#[N:9]
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)c(Cl)c1
Reactant: N#Cc1ccc(N)c(S(N)(=O)=O)c1
Product: N#Cc1ccc(NS(=O)(=O)/C=C/c2ccc(Cl)c(Cl)c2)c(S(N)(=O)=O)c1

Procedure:
The title compound was synthesized as described for Example 194 a), starting from 2-amino-5-cyanobenzenesulfonamide and (E)-2-(3,4-dichlorophenyl)ethenesulfonyl chloride (1.5 equiv.). Purification by column chromatography, using chloroform/methanol (95:5-9:1) as the eluent.
Reaction SMILES: Cl.NCCC[CH:6]=[C:7]([CH3:11])[C:8]([NH2:10])=[O:9].[C:12](OC(=O)CCC)(=O)[CH2:13][CH2:14]C.C(N(CC)CC)C.C([NH-])(=O)CCC>CO>[CH3:12][CH2:13][CH2:14][NH:10][C:8](=[O:9])[C:7]([CH3:11])=[CH2:6]
Reactant: CCCC(=O)OC(=O)CCC
Reactant: CC(=CCCCN)C(N)=O
Agent: CCCC([NH-])=O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NCCC
Yield: 92 %

Procedure:
0.8 g of 3-aminopropyl methacrylamide hydrochloride was dissolved in a methanol solvent and 1.5 g of butyric anhydride and 0.9 g of triethylamine (TEA) were added thereto. The resultant mixture was stirred under ice-cooling for 4 hours. After the completion of the reaction, the solvent was distilled off with an evaporator and the precipitate was filtered off. The filtrate was recovered and introduced into a silica column. Thus, the eluate fraction containing the target product was taken up and subjected to recrystallization to thereby purify the target butyrylamide, N-3-propyl methacrylamide (yield: 92%).
Reaction SMILES: [C:1]([O:4][NH:5][C:6](=[NH:32])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:31])[NH:26]OC(=O)C)=[CH:21][CH:20]=3)=[CH:16][CH:17]=2)=[N:9][CH:8]=1)(=[O:3])[CH3:2].C(O)C>C(O)(=O)C.[Pd]>[C:1]([OH:4])(=[O:3])[CH3:2].[C:25]([C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C:15]2[O:14][C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]([NH2:32])=[NH:5])=[CH:8][N:9]=3)=[CH:17][CH:16]=2)=[CH:24][CH:23]=1)(=[NH:26])[NH2:31]
Reactant: CC(=O)ONC(=N)c1ccc(Cc2ccc(-c3ccc(C(=N)NOC(C)=O)cn3)o2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: N=C(N)c1ccc(Cc2ccc(-c3ccc(C(=N)N)cn3)o2)cc1
Reaction time: 4 h
Yield: 60 %

Procedure:
To a solution of 37 (170 mg, mmol) in glacial acetic acid (8 mL), and ethanol (10 mL) was added 10% palladium on carbon (70 mg). The mixture was placed on Parr hydrogenation apparatus at 50 psi for 4 h at room temperature. The mixture was filtered off through HYFLO. The filtrate was evaporated under reduced pressure and the precipitate was collected and washed with ether to give 38 in 60% yield, mp 213–216° C.dec. 1H nmr (DMSO-d6); δ 1.78 (s, 6H), 6.43 (d, J=3.3 Hz, 1H), 7.23 (d, J=3.3 Hz, 1H), 7.43 (d, J=7.8 Hz, 2H), 7.49–7.73 (m, 3H), 8.17 (d, J=7.8 Hz, 1H), 8.89 (s, 1H). Calcd. for C18H17N5O-2AcOH-3H2O-0.35EtOH: C, 53.50; H, 6.54; N, 13.74. Found C, 53.57; H, 6.51; N, 13.37.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH:18]=[O:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]([Mg]Br)#[CH:21]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH:18]([OH:19])[C:20]#[CH:21])=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c(-c2cccc(Br)c2)nn2c(Cl)cccc12
Reactant: C#C[Mg]Br
Product: C#CC(O)c1c(-c2cccc(Br)c2)nn2c(Cl)cccc12
Yield: 64.8 %

Procedure:
In a similar manner as described in Example 46 from 2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridine-3-carbaldehyde (1.0 g, 2.9 mmol) and ethynylmagnesium bromide (6.4 mL, 0.5 M in tetrahydrofuran, 3.2 mmol) at 0 ° C., was obtained 1-[2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (0.68 g, 68%) as a white solid. 1H NMR (DMSO-d6): δ 8.04 (m, 2 H), 7.87 (d, 1 H), 7.67 (d, 1 H), 7.49 (t, 1 H), 7.38–7.29 (m, 2 H), 6.27 (bs, 1 H), 5.69 (s, 1 H), 3.49 (d, 1 H).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3]C1.C(=O)(O)[O-].[Na+].[C:13]([C:17]1[CH:22]=[CH:21][C:20]([CH:23](Cl)[C:24]2[N:29]=[C:28]([O:30][CH3:31])[C:27]([Cl:32])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].O>C(#N)C>[C:13]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:24]2[CH:25]=[CH:26][C:27]([Cl:32])=[C:28]([O:30][CH3:31])[N:29]=2)[NH:7][CH:1]2[CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1nc(C(Cl)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reactant: NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1nc(C(NC2CCCC2)c2ccc(C(C)(C)C)cc2)ccc1Cl

Procedure:
Cyclohexylamine (0.30 mL) and sodium bicarbonate (259 mg) were sequentially added to a solution of 6-[(4-tert-butylphenyl)(chloro)methyl]-3-chloro-2-methoxypyridine (200 mg) in acetonitrile (4 mL) at room temperature, and then the mixture was heated under reflux for six hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:50→1:10) to give N-[(4-tert-butylphenyl)(5-chloro-6-methoxypyridin-2-yl)methyl]cyclopentanamine as a pale yellow amorphous (201 mg, 87%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[C@@H:4]2[O:9][CH2:8][C@H:6]([CH:7]=1)[O:5]2.[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1C=CC=CC=1>[CH2:12]1[O:13][C:3]2([C:2]([Br:1])=[CH:7][C@H:6]3[CH2:8][O:9][C@@H:4]2[O:5]3)[O:10][CH2:11]1
Reactant: O=C1C(Br)=C[C@H]2CO[C@@H]1O2
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: BrC1=C[C@H]2CO[C@H](O2)C12OCCO2
Temperature: 25 °C
Yield: 74.8 %

Procedure:
22 g of 1,6-anhydro-3-bromo-3,4-dideoxy-β-D-glycero-hex-3-enopyranos-2-ulose was dissolved in 500 ml of dry benzene, and 66 g of ethylene glycol and 3 g of p-toluenesulfonic acid monohydrate were added thereto. The mixture was refluxed under heating while removing formed water. 19 hours later, disappearance of the starting material was confirmed by TLC, and the reaction mixture was cooled to room temperature. Then, 500 ml of ethyl acetate was added thereto, and the mixture was washed three times with 200 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained crude crystals were purified by silica gel column chromatography (ethyl acetate: hexane=1:1) to obtain 20 g of 1,6-anhydro-3-bromo-3,4-dideoxy-β-D-glycero-hex-3-enopyranos-2-ulose ethylene acetal as white crystals. The NMR analytical data of this product are as follows.
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:9][C@H:10]1[CH:14]=[CH:13][C@H:12]([CH3:15])[NH:11]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:9][C@H:10]1[CH:14]=[CH:13][C@H:12]([CH3:15])[N:11]1[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)Br
Reactant: C[C@H]1C=C[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)N1[C@@H](C)C=C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
Ethyl 2-bromopropionate (9.8 g.) was added, dropwise, to a stirred mixture of trans-2,5-dimethyl-3-pyrroline (5 g.), potassium carbonate (6.9 g.), and dimethylformamide (12.5 cm3) maintained below 30° C. by external cooling. After addition was complete the mixture was stirred at room temperature overnight. The mixture was then diluted with water (25 cm3) and the product extracted into ether. The ether extract was dried and evaporated to give an oil which was distilled under vacuum to give ethyl 2-(trans-2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-yl)propionate (2.5 g.) b.p. 90°-97° C./15 mm.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[CH:2]=1.[N:19]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]C(O)=O)[C:27]2C=CN=CC=2N=C1.N1(CC2C=CC(C(O)=O)=CC=2)C2C=CN=CC=2N=C1.[K]>>[CH:28]1([N:19]([CH3:27])[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:3]2[C:4]3[CH:5]=[N:6][CH:7]=[CH:8][C:9]=3[N:1]=[CH:2]2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: O=C(O)CCCCCCn1cnc2cnccc21
Reactant: O=C(O)CCCCCCn1cnc2ccncc21
Agent: O=C(O)c1ccc(Cn2cnc3cnccc32)cc1
Agent: [K]
Product: CN(C(=O)CCCCCCn1cnc2ccncc21)C1CCCCC1

Procedure:
Utilizing the procedure described in Example 5(b) employin a mixture of 7-(3H-imidazo[4,5-c]pyridin-3-yl)heptanoic acid and 7-(1H-imidazo[4,5-c]pyridin-1-yl)heptanoic acid, potassium salts in lieu of 4-(1H-imidazo[4,5-c]pyridin-1-ylmethyl) benzoic acid, potassium salt yielded an impure mixture of isomers. The mixture was purified by column chromatography (silica gel, 5% ethanol in chloroform) to yield a less polar isomer N-cyclohexyl-N-methyl-7-(3H-imidazo[4,5-c]pyridin-3-yl)heptanamide as a pale-yellow oil, having the following physical characteristics:
Reaction SMILES: [H-].[Na+].O1CCC[CH2:4]1.[CH3:8][CH:9]([C:13](=[O:15])[CH3:14])[C:10](=[O:12])[CH3:11].IC>O>[CH3:8][C:9]([CH3:4])([C:13](=[O:15])[CH3:14])[C:10](=[O:12])[CH3:11]
Reactant: C1CCOC1
Reactant: CC(=O)C(C)C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC(=O)C(C)(C)C(C)=O
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To 0.1 mol sodium hydride was added 100 ml anhydrous tetrahydrofuran, and slowly added dropwise 0.12 mol 3-methyl-2,4-pentandione at room temperature. Upon completion, the mixture was stirred for 0.5 hours, then 0.12 mol iodomethane was slowly added dropwise. After stirred at room temperature for 10 hours, 20 ml water was added to dissolve solid. The mixture was extracted with ethyl acetate. The solvent was removed. Distillation was carried out under reduced pressure, and cut fraction 82-84° C./1 kPa was collected. The yield was 98%.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].C(N(CC)CC)C.[C:18]([NH:20][C:21](=[N:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH2:39][CH2:40][CH2:41][N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])=[C:32]([O:47][CH3:48])[CH:31]=1)OC1C=CC=CC=1)#[N:19].FC(F)(F)C(O)=O.C(N(CC)CC)C>CC(N(C)C)=O>[CH2:45]([N:42]([CH2:43][CH3:44])[CH2:41][CH2:40][CH2:39][O:38][C:33]1[C:32]([O:47][CH3:48])=[CH:31][C:30]([NH:29][C:21]2[N:20]=[C:18]([NH2:19])[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[F:2])[N:10]=2)=[CH:35][C:34]=1[O:36][CH3:37])[CH3:46]
Reactant: CCN(CC)CCCOc1c(OC)cc(N=C(NC#N)Oc2ccccc2)cc1OC
Reactant: NNc1ccccc1F
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCN(CC)CCCOc1c(OC)cc(Nc2nc(N)n(-c3ccccc3F)n2)cc1OC
Temperature: 120 °C
Reaction time: 20 h
Yield: 4 %

Procedure:
A solution of 2-fluoro-phenylhydrazine hydrochloride (0.15 g, 0.91 mmol) and triethylamine (0.13 mL, 0.91 mmol) in dimethylacetaimde (1 mL) was stirred 0.5 h at room temperature. N-cyano-N′-(4-(3-diethylamino-propoxy)-3,5-dimethoxy-phenyl)-O-phenylisourea (0.30 g as a mixture with triethylamine-trifluoroacetic acid salt, 0.45 mmol) in dimethylacetamide (1 mL) was added and the reaction was stirred at 120° C. for 20 h. The precipitate was removed and the filtrate was washed with ether. The remaining aqueous phase was evaporated and was purified by semi-preparative HPLC to provide the title compound (0.01 g, 4% yield) as a yellow lyophilate.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.[H-].[Na+]>CN(C=O)C>[CH:2]([C:11]1[CH:6]=[CH:7][C:8]([O:1][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[CH:4][C:3]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:9][CH:10]=1)=[O:1]
Reactant: COc1cccc(-c2ccc3cc(OC)ccc3c2O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(C=O)cc2)c1
Temperature: 70 °C

Procedure:
A solution was prepared of 9.8 g (35 mmol) of 1-hydroxy-2-(3-methoxyphenyl)-6-methoxynaphthalene in 490 mL of DMF under a nitrogen atmosphere and to this solution was slowly added 1.47 g (36.8 mmol) of 60% NaH in mineral oil. After ten minutes, 7.5 mL (70 mmol) of 4-fluorobenzaldehdye was added and the reaction mixture was heated to 70° C. for sixty-four hours. The reaction mixture was evaporated to dryness and the residue partioned between water and EtOAc. The EtOAc layer was dried with Na2SO4 and chromatographed on a silica gel column eluted with EtOAc-hexane (1:9)(v/v). The final product was further purified by crystallization from MeOH. This yielded 2.4 g of the title compound as a tan solid, mp 145–146° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:5]([CH2:27][CH2:28][CH2:29]O)[CH:4]=[N:3]1.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.Cl>O1CCCC1.O1CCOCC1.O>[NH2:7][C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[CH2:27][CH2:28][CH2:29][N:35]1[C:31](=[O:41])[C:32]2=[CH:40][CH:39]=[CH:38][CH:37]=[C:33]2[C:34]1=[O:36]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cn1ncc(CCCO)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: Cn1ncc(CCCN2C(=O)c3ccccc3C2=O)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
To a solution of 3-(1-methyl-5-triphenylmethylaminopyrazol-4-yl)propanol (4.0 g, 10 mmol), phthalimide (1.5 g, 10 mmol) and triphenylphosphine (4.0 g, 15 mmol) in tetrahydrofuran (20 ml) was added diisopropyl azodicarboxylate (3.0 g, 15 mmol), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 4 mol/l hydrogen chloride solution in dioxane (10 ml), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added water, and the mixture was washed with ethyl acetate. The organic layer was separated, and the aqueous layer was adjusted to pH 9 with 10% aqueous sodium carbonate solution. The solution was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate and dried in vacuo to give 5-amino-1-methyl-4-(3-phthalimidopropyl)pyrazole (2.2 g) as a solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C(N(CC)CC)C>O1CCOCC1>[CH3:14][C:15]1[CH:16]=[C:17]([NH:18][C:2]2[C:3]3[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: CSc1ncc2ncnc(Cl)c2n1
Reactant: Cc1cccc(N)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CSc1ncc2ncnc(Nc3cccc(C)c3)c2n1

Procedure:
4.9 g of 4-chloro-6-methylthio-pyrimido[5,4-d]pyrimidine, 2.0 g of 3-methylaniline, 2.4 ml of triethylamine and 100 ml of dioxane are heated at 100° C. for 3 hours. After cooling, the reaction mixture is concentrated and partitioned between water and methylene chloride. The organic phase is separated off, dried and concentrated and the residue is purified by chromatography over a silica gel column (petroleum ether/ethyl acetate=2:1). The solid is triturated with diethyl ether, filtered off with suction and dried.
Reaction SMILES: [CH2:1]([C@H:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7](=[O:16])[C@H:6]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C@H:5]1[O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH:2]=[CH2:3].C(O)(=O)[C@H]([C@@H](C(O)=O)O)[OH:35].[OH-].[Na+].OO>O1CCCC1.C(OCC)(=O)C.O>[CH2:9]([N:8]1[C@H:4]([CH2:1][CH2:2][CH2:3][OH:35])[C@H:5]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[C@@H:6]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[C:7]1=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Reactant: C=CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)N1Cc1ccccc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1[C@@H](CCCO)N(Cc2ccccc2)C(=O)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
100 g of (3R*,4S*,5R*)-5-allyl-1-benzyl-3,4-bis(tert-butyidimethylsilyloxy)-2-pyrrolidinone which had been prepared according to the procedure described in J. Org. Chem. 60, 103-108 (1995) by using D-tartaric acid as the starting material was added to 670 ml of tetrahydrofuran, and cooled with ice. Then, 87.1 ml of a 1.0M solution of borane-tetrahydrofuran complex in tetrahydrofuran was added thereto. After this mixture was stirred at room temperature for 1 hour, 7 ml of water was added dropwise thereto, and 33.4 ml of a 5N aqueous solution of sodium hydroxide was added at a time. Then, 33.4 ml of a 30% aqueous solution of hydrogen peroxide was added thereto at such a rate as to give a reaction temperature of 30-50° C., followed by stirring overnight. Thereafter, water and ethyl acetate were added to the reaction mixture so as to extract the product in an organic layer. After this organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (using chloroform as the eluent) to obtain 33.4 g of (3R*,4S*,5R*)-1-benzyl-3,4-bis(tert-butyidimethylsilyloxy)-5-(3-hydroxypropyl)-2-pyrrolidinone.