Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1([CH3:34])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]2[CH:17]=[C:16]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]#N)=[CH:28][CH:27]=3)[CH:15]=[CH:14][C:13]1=2.C(O)(=O)C(C(C(O)=O)O)[OH:37].S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[CH3:11][C:12]1([CH3:34])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]2[CH:17]=[C:16]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]=[O:37])=[CH:28][CH:27]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: CC1(C)CCC(C)(C)c2cc(OCc3ccc(C#N)cc3)ccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc(OCc3ccc(C=O)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
15.5 ml (19.7 mmol) of diisobutylaluminum hydride solution (20% in hexane) were added dropwise under nitrogen to a solution of 3 g (9.4 mmol) of 4-cyanobenzyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl ether in 40 ml of dry ether at 25° C. The mixture was stirred at 25° C. for 40 min and then 250 ml of saturated tartaric acid solution were added dropwise. Subsequently, a little sodium sulfate solution was added, and the phases were separated. The aqueous phase was extracted with ether, and the organic extract was washed with saturated tartaric acid solution and water, dried over Na2SO4 and concentrated. Recrystallization from methanol resulted in 1.4 g of the title compound of melting point 102°-104° C.
Reaction SMILES: Cl[SiH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:4][CH2:3]1.[Cl-].[CH2:25]([Zn+])[CH2:26][CH2:27][CH:28]=[CH2:29].Cl[SiH]1CCC(CC[C@H]2CC[C@H](C3C=CC(F)=CC=3)CC2)CC1.[Cl-].C([Zn+])CCCC>>[F:23][C:18]1[CH:17]=[C:16]([C@H:13]2[CH2:14][CH2:15][C@H:10]([CH2:9][CH2:8][C@H:5]3[CH2:6][CH2:7][Si@H:2]([CH2:29][CH2:28][CH2:27][CH:26]=[CH2:25])[CH2:3][CH2:4]3)[CH2:11][CH2:12]2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: C=CCCC[Zn+]
Reactant: Fc1ccc([C@H]2CC[C@H](CCC3CC[SiH](Cl)CC3)CC2)cc1F
Agent: CCCCC[Zn+]
Agent: Fc1ccc([C@H]2CC[C@H](CCC3CC[SiH](Cl)CC3)CC2)cc1
Agent: [Cl-]
Product: C=CCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(F)c(F)c3)CC2)CC1

Procedure:
The preparation was conducted in the same manner as in Example 6, except that 7.5 g (21 mmol) of 1-chloro-4-(2-(trans-4-(3,4-difluorophenyl)cyclohexyl)ethyl)-1-silacyclohexane and 4-pentenylzinc chloride were used instead of 7.0 g (21 mmol) of 1-chloro-4-(2-(trans-4-(p-fluorophenyl)cyclohexyl) ethyl)-1-silacyclohexane and n-pentylzinc chloride.
Reaction SMILES: [CH3:1][N:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B1OC(C)(C)C(C)(C)O1)[S:3]([CH2:6][CH3:7])(=[O:5])=[O:4].Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=2)=[C:26]([F:37])[CH:25]=1>>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N:2]([CH3:1])[S:3]([CH2:6][CH3:7])(=[O:4])=[O:5])=[CH:25][C:26]=2[F:37])=[N:31][CH:32]=1
Reactant: CCS(=O)(=O)N(C)c1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Product: CCS(=O)(=O)N(C)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using N-methyl-N-(2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanesulfonamide and 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): mass calcd. C19H19FN4O2S, 386.12; m/z found, 387.1 [M+H]+. 1H NMR (400 MHz, CDC3) δ 8.63-8.57 (m, 1H), 8.13-8.09 (d, J=1.5, 1H), 8.04-7.95 (m, 1H), 7.72-7.62 (m, 0.75H), 7.59-7.51 (m, 0.25H), 7.50-7.39 (m, 3.75H), 7.37-7.32 (m, 1H), 7.31-7.28 (m, 0.25H), 4.69 (s, 2H), 3.16 (s, 3H), 2.89 (q, J=7.4, 2H), 1.25 (t, J=7.4, 3H).
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([C:9]2[C:10]([NH:12][C:13](=[O:15])[CH:14]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#C.[CH:16]([O:20]C1C=CC(N)=CC=1)=[CH:17][CH2:18][CH3:19].C1(=O)OC(=O)C=C1.C(OC(=O)C)(=O)C>C([O-])(=O)C.[Ni+2].C([O-])(=O)C.CC(C)=O>[CH:16]([O:20][C:8]1[CH:3]=[CH:4][C:5]([C:9]2[C:10]([NH:12][C:13](=[O:15])[CH:14]=2)=[O:11])=[CH:6][CH:7]=1)=[CH:17][CH2:18][CH3:19]
Reactant: C#Cc1cccc(C2=CC(=O)NC2=O)c1
Reactant: CCC=COc1ccc(N)cc1
Agent: [Ni+2]
Agent: CC(=O)[O-]
Agent: O=C1C=CC(=O)O1
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Product: CCC=COc1ccc(C2=CC(=O)NC2=O)cc1

Procedure:
The procedure is the same for 3-ethynylphenyl maleimide. The following amounts of staring materials were used: 4-butenyloxyaniline (4.0 g, 24.5 mmol), maleic anhydride (2.4 g, 24.5 mmol), acetone (100 ml) triethylamine (5 ml), nickel (II) acetate (0.25 g, 3.5 mmol), and acetic anhydride (2.75 g, 27 mmol). Yield=5.0 g, (84%).
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:20][CH:21]3[CH2:24][CH:23]([NH2:25])[CH2:22]3)=[C:16]([Cl:19])[CH:17]=2)[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1.Cl>CC(O)C>[NH2:25][CH:23]1[CH2:24][CH:21]([O:20][C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][C:16]=2[Cl:19])[C:9](=[O:8])[NH:10][CH:11]=[CH:12]3)[CH2:22]1
Reactant: NC1CC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)C1
Agent: Cl
Solvent: CC(C)O
Product: NC1CC(Oc2cc3cc[nH]c(=O)c3cc2Cl)C1
Yield: 69.5 %

Procedure:
A solution of 377 mg (1.06 mmol) of 3-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-cyclobutylamine (51) in 8 mL of 2-propanol was treated with 8 mL of 2N aqueous hydrochloric acid and stirred until complete conversion. The reaction mixture was evaporated, twice lyophilized from water and recrystallized from 2-propanol. 195 mg of the title compound could be isolated as hydrochloride as unseparable mixture of diastereoisomers. Rt=1.92 min (Method G). Detected mass: 265.1 (M+H+).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:23])[CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:11]=1[C:12](OC)=[O:13])(=[O:9])=[O:8].[CH3:24][CH:25]([CH3:27])[O-:26].[Na+].C(O)(=O)C>C(O)(C)C>[ClH:1].[CH3:2][N:3]([CH3:23])[CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:11]=1[C:12]([O:26][CH:25]([CH3:27])[CH3:24])=[O:13])(=[O:9])=[O:8]
Reactant: CC(C)[O-]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(C)OC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCN(C)C
Yield: 31 %

Procedure:
A solution of methyl 2-[N-(2-dimethylaminoethyl)aminosulfonyl]-6-nitrobenzoate hydrochloride (12.0 g, 32.6 mmol) in dry isopropanol (500 mL) containing sodium isopropoxide (39 mmol) was stirred at reflux under N2 for 18 hours. After adding glacial acetic acid (1 mL) and concentrating under reduced pressure, the residue was partitioned between ethyl acetate and water. The ethyl acetate extract was washed with a saturated aqueous solution of sodium chloride, dried (Na2SO4), filtered and concentrated. The residue was converted to the hydrochloride salt with ethanolic anhydrous hydrogen chloride and recrystallized from methanol - ethyl acetate to give 4.0 g (31%) of product, m.p. 187.0-190.0° dec. Anal Calc'd for C14H21N3O6S.HCl: C, 42.47; H, 5.60; N, 10.61
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>C(Cl)Cl.N1C=CC=CC=1>[C:8]([NH:1][C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncc(Br)s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ncc(Br)s1
Temperature: 25 °C

Procedure:
To a solution of 2-amino-5-bromothiazole (22.3 g, 85.9 mmol) in methylene chloride (100 mL) and pyridine (60 mL) was added acetic anhydride (11 mL) slowly with stirring. The mixture was allowed to stir for 2.5 hours, warmed to room temperature, and stirred for an additional 4 hours. Most of the solvent was removed in vacuo and the residue was washed with ethyl acetate and aqueous HCl. The organic solution was then washed with water, dried over MgSO4 and concentrated to give a crude solid. This solid was triturated with Et2O, filtered, washed with Et2O, and dried to give 2-acetamido-5-bromothiazole as a solid (15.1 g, 80%, C5H5BrN2OS, MS m/e 222 (M+H)+).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]1([CH:19]2[CH2:23][CH2:22][CH2:21][S:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:24][N:25]=[C:26]=[S:27].C>CCCCCC.C(O)C.C(OCC)(=O)C.O.O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH3:24][NH:25][C:26]([C:19]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:23][CH2:22][CH2:21][S:20]1)=[S:27]
Reactant: c1ccc(C2CCCS2)cc1
Reactant: CN=C=S
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCO
Product: CNC(=S)C1(c2ccccc2)CCCS1
Reaction time: 0.17 h

Procedure:
To 135 cc of a 1.6M solution of n-butyllithium in hexane maintained in an atmosphere of argon at a temperature of about -60° C., add, dropwise, over 10 minutes, a solution of 22 g of di-isopropylamine in 125 cc of a mixture of anhydrous hexamethylphosphoric triamide and anhydrous tetrahydrofuran (47:53 v/v) and stir the mixture for 5 minutes. Then add, dropwise, over 20 minutes, a solution of 28 g of 2-phenyltetrahydrothiophene in 125 cc of the mixture of anhydrous hexamethylphosphoric triamide and anhydrous tetrahydrofuran (47:53 v/v) and stir the mixture for 10 minutes. Then add, dropwise, over 15 minutes, a solution of 18.3 of methyl isothiocyanate in 62 cc of the mixture of anhydrous hexamethylphosphoric triamide and anhydrous tetrahydrofuran (47:53 v/v), stirring the mixture at the same temperature initially for 45 minutes, then for 1 hour, allowing the temperature to increase progressively to +15° C. Lastly, add 600 cc of distilled water and 600 cc of ethyl acetate. After separation, the organic phase is washed successively with 600 cc of distilled water, 250 cc of an aqueous solution of N hydrochloric acid, twice with 600 cc (1200 cc in total) of distilled water, then dried over anhydrous sodium sulphate, filtered and concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 45° C. The product obtained (37.5 g) is dissolved in 100 cc of boiling ethanol and activated charcoal is added to the solution thus obtained; the solution is then filtered, cooled and set aside for 2 hours at a temperature of about 20° C. The crystals formed are separated by filtration, washed with 15 cc of ethanol, then twice with 20 cc (40 cc in total) of di-isopropyl oxide and dried under reduced pressure (15 mm Hg; 2 kPa) at 20° C. The product obtained (17.7 g) is mixed with 1.3 g of the same product prepared beforehand under the same conditions, then dissolved in 70 cc of boiling ethanol. Activated charcoal is added to the solution thus obtained; the solution is then filtered while hot, cooled and set aside for 1 hour at a temperature of about 5° C. The crystals formed are separated by filtration, washed with 10 cc of ethanol and twice with 10 cc (20 cc in total) of di-isopropyl oxide and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 53° C. 15.5 g of N-methyl-2-phenyltetrahydrothiophene-2-carbothioamide, with a melting point of 113° C, is thus obtained.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:5][CH:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.[CH2:17](I)[CH3:18].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH2:17]([C:4]1([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3][C:2]([F:16])([F:1])[CH2:5]1)[CH3:18]
Reactant: CCI
Reactant: O=C(OCc1ccccc1)C1CC(F)(F)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCC1(C(=O)OCc2ccccc2)CC(F)(F)C1
Temperature: -78 °C
Reaction time: 6 h
Yield: 35.6 %

Procedure:
To a solution of benzyl 3,3-difluorocyclobutanecarboxylate (500 mg, 2.210 mmol) and EtI (0.714 mL, 8.84 mmol) in THF (15 mL) at −78° C. under a N2 atmosphere was added a solution of KHMDS (8.84 mL, 4.42 mmol, 0.5 M in toluene). The resulting solution was stirred at −78° C. for 6 h. The reaction was then allowed to warm to RT and stirred overnight. The reaction mass was then quenched with a saturated aq. solution of NH4Cl and the aqueous layer was extracted with diethyl ether (3×25 mL) The combined organic fractions were washed with water, dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by silica gel chromatography (4 g REDISEP® column, eluting with 15% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 301A as a pale yellow liquid (200 mg, 35.6%). 1H NMR (300 MHz, chloroform-d) δ ppm 7.32-7.44 (m, 5H), 5.19 (s, 2H), 2.90-3.11 (m, 2H), 2.38-2.57 (m, 2H), 1.28 (dt, J=8.97, 7.03 Hz, 2H), 0.79-0.93 (m, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:29])=O>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(O)c2cc(SC3CCCCC3)ccc2c1O
Reactant: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1nc(Br)c2cc(SC3CCCCC3)ccc2c1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
To a mixture of 7-cyclohexylsulfanyl-1,4-dihydroxy-isoquinoline-3-carboxylic acid butyl ester (2.95 g, 7.87 mmol) in toluene (40 mL) was added POBr3 (3.38 g, 11.8 mmol) was refluxed for 3 h. Reaction mixture was cooled to 0° C. and quenched with saturated NaHCO3 aqueous solution (100 mL). It was stirred for 15 min., and then was extracted with EtOAc. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound 2.55 g (5.82 mmol), which was used directly to the next reaction without further purification. 1H NMR (200 MHz) CDCl3, δ in ppm: 11.85 (s, 1H), 8.23 (d, J=8.8 Hz, 1H), 8.05 (s, 1H), 7.65 (d, J=8.5 Hz, 1H), 4.47 (t, J=7.0 Hz, 2H), 3.46 (br S, 1H), 2.10 (br m, 2H), 1.85-1.42 (m, 12H), 0.99 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:16]=3[N:17]=[C:18]([CH3:20])[N:19]=2)[CH2:4][CH2:3]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:32][CH2:33]4)=[O:26])[C:16]=3[N:17]=[C:18]([CH3:20])[N:19]=2)[CH2:3][CH2:4]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f57) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].[CH:14]1([CH2:17]Br)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:14]1([CH2:17][N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[C:6]2[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:16][CH2:15]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1nc([N+](=O)[O-])c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc([N+](=O)[O-])cn1CC1CC1

Procedure:
Under argon, 15 g (81 mmol) of ethyl 4-nitro-1H-imidazole-2-carboxylate are stirred with 13.13 g (97.2 mmol) of cyclopropylmethyl bromide and 22.4 g (162 mmol) of potassium carbonate in 165 ml of DMF at 80° C. for 1 h. After cooling, the reaction mixture is diluted with water and extracted four times with ethyl acetate. The combined organic phases are washed once with water and three times with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated in vacuo. The crystalline residue is directly used further for the next reaction.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[I:13]N1C(=O)CCC1=O.C(#N)C>C(OCC)(=O)C>[I:13][C:3]1[CH:4]=[N:5][N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:2]=1[CH3:1]
Reactant: Cc1ccnn1-c1ccccn1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1c(I)cnn1-c1ccccn1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2-(5-methyl-1H-pyrazol-1-yl)pyridine (100 mg, 0.63 mmol) and N-iodosuccinimide (212 mg, 0.942 mmol) were added to acetonitrile (5 ml). The reaction mixture was heated to 60° C. After 1 hour, the reaction mixture was diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide and brine, then dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/isohexane gradient) to afford 2-(4-iodo-5-methyl-1H-pyrazol-1-yl)pyridine. LRMS (ESI) calculated for C9H9IN3 [M+H]+, 286.0; found 286.0.
Reaction SMILES: [C:1]([C:3](=[CH:9][CH:10]1[CH2:12][CH2:11]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH3:13][Mg]Br>[Cu]I.C(OCC)C>[C:1]([CH:3]([CH:9]([CH:10]1[CH2:11][CH2:12]1)[CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: C[Mg]Br
Reactant: CCOC(=O)C(C#N)=CC1CC1
Agent: [Cu]I
Solvent: CCOCC
Product: CCOC(=O)C(C#N)C(C)C1CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.4 %

Procedure:
7.3 g (44 mmol) of ethyl 2-cyano-3-cyclopropyl-2-propenoate and 0.15 g of copper(I) iodide were introduced into 100 ml of dry diethyl ether. 16.9 ml of etheric 3 M methylmagnesium bromide solution (51 mmol) was then added dropwise at reflux temperature, and the mixture was subsequently stirred for 14 hours at room temperature. For working-up, the mixture was poured into 300 ml of ice-water and stirred for 10 minutes. The aqueous phase was separated off and washed with ether. The combined organic phase [sic] were washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated. The residue was subjected to fractional distillation in vacuo. This gave 4.9 g (yield 61%) of ethyl 2-cyano-3-cyclopropylbutanoate (b.p. 90° C./2 mbar).
Reaction SMILES: C[C@@H]1[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@@]2(O)O[C@H]([C@H](C(O)=O)[C@@H](O)C2)C[C@@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H:58]([NH2:64])[C@@H]2O)C=CC=CC=CC=CC=CC=CC=C1.[O:66]=[CH:67][C@@H:68]([C@H:70]([C@@H:72]([C@@H:74]([CH2:76]O)[OH:75])[OH:73])[OH:71])[OH:69]>CN(C)C=O>[CH3:58][NH:64][CH2:76][C@@H:74]([C@H:72]([C@@H:70]([C@@H:68]([CH2:67][OH:66])[OH:69])[OH:71])[OH:73])[OH:75]
Reactant: C[C@@H]1[C@H](O)[C@@H](C)C=CC=CC=CC=CC=CC=CC=C[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: C[C@@H]1[C@H](O)[C@@H](C)/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Solvent: CN(C)C=O
Product: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 18 h
Yield: 426 %

Procedure:
20 g of amphotericin B and 6 g of glucose was dissolved in 200 ml of dimethyl formamide and allowed to stand at a temperature of 35° C. for 18 hours. The resulting solution was filtered and 500 ml of 5% ammonium sulphate, aqueous solution, was added to the filtrate the mixture was then allowed to stand at a temperature of +40° C. for 2 hours. The precipitate was filtered and washed with water. 1500 ml of methanol at a temperature of 50° C. and 6 g of N-methylglucamine salt dissolved in 60 ml of water was added to the precipitate whereupon the mixture was stirred for 30 minutes, then 1 l of n-butanol was added. The resulting solution was evaporated at a temperature of 45° C. under reduced pressure until the methanol and water were removed. The residue was allowed to stand at a temperature of +4° C. for crystallization. The sediment was filtered, washed with n-butanol then with petroleum ether and dried at the room temperature. 18 g of the N-methylglucamine salt of N-glycosyl derivative of amphotericin B of E1 cm1% =1140 at 380 nm and IC50 =0.1 mcg/ml were obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH:8]=2)[CH:3]=[CH:2]1.CC(C)([O-])C.[Na+].Cl.Br[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>[C].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[N:34]1[CH:35]=[CH:36][C:31]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N:10]4[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]4)[CH:8]=3)[CH:3]=[CH:2]2)=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3cc[nH]c3c2)CC1
Reactant: Brc1ccncc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3ccn(-c4ccncc4)c3c2)CC1
Temperature: 100 °C
Reaction time: 24 h
Yield: 58.7 %

Procedure:
tert-Butyl 4-(1H-indol-6-yl)piperazine-1-carboxylate (500 mg, 1.66 mmol), sodium tert-butoxide (447 mg, 4.65 mmol), 4-bromopyridine hydrochloride (355 mg, 1.83 mmol) and toluene (11 mL) were sequentially acted to a reactor. Then, the gas dissolved in the mixture was removed using ultrasonic waves and nitrogen gas. After adding 10% (w/w) palladium-carbon (Pd—C, 177 mg, 0.083 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP; 52 mg, 0.083 mmol), the mixture was stirred at 100° C. for 24 hours in a sealed state. After cooling to room temperature and filtering using a diatomite pad, water was added and the mixture was extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous sodium sulfate. The residue was purified by chromatography (silica gel, EA:Hx=1:1→EA only). The target compound (369 mg, 59%) was obtained as white solid.
Reaction SMILES: [BH4-].[Na+].[OH:3][CH:4]([CH2:33]O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:29](=[O:30])[C:28]2[N:27]([CH3:31])[CH:26]=[N:25][C:24]=2[N:23]([CH3:32])[C:21]1=[O:22].Cl>C(O)C>[OH:3][CH:4]([CH3:33])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:29](=[O:30])[C:28]2[N:27]([CH3:31])[CH:26]=[N:25][C:24]=2[N:23]([CH3:32])[C:21]1=[O:22]
Reactant: Cn1cnc2c1c(=O)n(CCCCCCCCCCCCCCCC(O)CO)c(=O)n2C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)CCCCCCCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
0.25 g of 1-(16,17-oxidoheptadecyl)-3,7-dimethylxanthine (0.58 mmol) was dissolved in ethanol (5 ml). Sodium borohydride (0.34 g, 0.93 mmol) was added to the ethanol solution and the reaction stirred at 60° C. for 16 hours. Hydrochloric acid (1.0M, 10 ml) was added and extracted with dichloromethane (2×30 ml). The combined extracts were dried over magnesium sulfate. Evaporated solvent left 0.225 g of 1-(16-hydroxyheptadecyl)-3,7-dimethylxanthine as a white solid (90% yield).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[CH3:10][C:11]1[C:17](=[O:18])[C:16]2[N:19]3[C@@:23]([O:30][CH3:31])([C@H:24]([CH2:25][O:26][C:27]([NH2:29])=[O:28])[C:15]=2[C:13](=[O:14])[C:12]=1OC)[C@H:22]1[N:32]([CH3:33])[C@H:21]1[CH2:20]3>>[NH2:29][C:27]([O:26][CH2:25][CH:24]1[C:15]2[C:13]([OH:14])=[C:12]([N:2]=[O:3])[C:11]([CH3:10])=[C:17]([OH:18])[C:16]=2[N:19]2[CH2:20][CH:21]3[N:32]([CH3:33])[CH:22]3[C:23]12[O:30][CH3:31])=[O:28]
Reactant: NO
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@@H]3[C@H](CN21)N3C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC12C(COC(N)=O)c3c(O)c(N=O)c(C)c(O)c3N1CC1C2N1C
Yield: 97.7 %

Procedure:
In a similar manner to that described in Example 1, hydroxylamine hydrochloride (0.038 g), anhydrous sodium carbonate (0.033 g) and mitomycin F (0.100 g) are used to obtain the desired product (0.098 g; yield 87.0%).