Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([Cl:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25])[CH2:19][NH2:20].CCN(CC)CC>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([S:11]([Cl:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:23]([C:24]([F:25])([F:26])[F:27])=[C:16]([Cl:15])[CH:17]=1)=[O:5]
Reactant: NCc1ccc(C(F)(F)F)c(Cl)c1
Reactant: O=C(Cl)c1ccc(S(=O)(=O)Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(C(F)(F)F)c(Cl)c1)c1ccc(S(=O)(=O)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
To a solution of 2-chloro-4-(chlorosulfonyl)benzoyl chloride (J. Org. Chem, 56, 16, 1991, 4974) (300 mg, 0.877 mmol, 1 eq) in DCM (3 ml) was added 3-chloro-4-(trifluoromethyl)benzylamine (175 mg, 0.835 mmol, 0.95 eq) and Et3N (33 mg, 0.32 mmol, 0.37 eq) and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (10 ml), washed with water (10 ml), dried over sodium sulphate, filtered and evaporated. The crude material was purified by column chromatography eluting with ethyl acetate to yield the title compound (154 mg, 0.34 mmol, 39%).
Reaction SMILES: CN1CCCCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]([C:20]([OH:22])=O)[CH:17]([CH3:19])[CH3:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]([CH3:44])[C:39](=[O:43])[CH:40]([CH3:42])[NH2:41])=[CH:34][CH:33]=1>C(Cl)Cl.O>[C:8]([O:12][C:13]([NH:15][C@H:16]([C:20]([NH:41][CH:40]([C:39]([N:38]([C:35]1[CH:34]=[CH:33][C:32]([Cl:31])=[CH:37][CH:36]=1)[CH3:44])=[O:43])[CH3:42])=[O:22])[CH:17]([CH3:18])[CH3:19])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(N)C(=O)N(C)c1ccc(Cl)cc1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: CC(NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)N(C)c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
0.9 g of N-methylpiperidine was added to a solution containing 2.0 g of N-tert-butoxycarbonyl-L-valine dissolved in 40 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 1.3 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20° C. 2.0 g of N1 -(4-chlorophenyl)-N1 -methyl-DL-alaninamide was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 3.4 g of the desired product in the form of a colorless needle crystal (yield: 87%).
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3=[CH:16][C:17]([C:19]([OH:21])=[O:20])=[N:18][N:10]3[C:9](=[O:22])[C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4].[OH-:23].[Na+]>O>[OH2:20].[CH2:1]([S:5]([C:6]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3=[CH:16][C:17]([C:19]([OH:21])=[O:20])=[N:18][N:10]3[C:9](=[O:22])[C:8]=2[CH:7]=1)=[O:23])[CH2:2][CH2:3][CH3:4].[CH2:1]([S:5]([C:6]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3=[CH:16][C:17]([C:19]([OH:21])=[O:20])=[N:18][N:10]3[C:9](=[O:22])[C:8]=2[CH:7]=1)=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSc1ccc2[nH]c3cc(C(=O)O)nn3c(=O)c2c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CCCCS(=O)c1ccc2[nH]c3cc(C(=O)O)nn3c(=O)c2c1

Procedure:
From 4,9-dihydro-7-(butylthio)-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid (3.17 g, 10 mmole), 1(N) NaOH soln (10 ml) in water (150 ml) and NaIO4 (2.14 g; 10 mmole) in water (50 ml); following the procedure of Example 7, there is obtained 4,9-dihydro-7-(butylsulfinyl)-9-oxo-pyrazolo[5,1-b]-quinazoline-2-carboxylic acid, hemihydrate (2.0 g); mp 205°-210° (d) remelts at 260° (d) after crystallization from aq. methanol.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]([CH:26]([NH:28][C:29]3[N:37]=[CH:36][N:35]=[C:34]4[C:30]=3[N:31]=[CH:32][NH:33]4)[CH3:27])=[CH:17][C:18]([Cl:25])=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.F[Si-2](F)(F)(F)(F)F.[H+].[H+].O.[OH-].[Na+]>C(#N)C>[Cl:25][C:18]1[CH:17]=[C:16]([CH:26]([NH:28][C:29]2[N:37]=[CH:36][N:35]=[C:34]3[C:30]=2[N:31]=[CH:32][NH:33]3)[CH3:27])[C:15]([N:12]2[CH2:11][CH2:10][CH:9]([OH:8])[CH2:14][CH2:13]2)=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:23]2
Reactant: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cccnc2c1N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: [H+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cccnc2c1N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of N-{1-[8-(4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-1-yl)-5-chloroquinolin-7-yl]ethyl}-9H-purin-6-amine (0.200 g, 0.372 mmol) in acetonitrile (1 mL) was added 2.0 M fluorosilicic acid in water (0.929 mL, 1.86 mmol). The reaction was stirred at room temperature for 30 minutes, then neutralized with aq. sodium hydroxide and extracted with dichloromethane. The extracts were combined and evaporated to dryness. The residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product as the free base. LCMS calculated for C21H23ClN7O (M+H)+: m/z=424.2; Found: 424.1. 1H NMR (DMSO-d6, 400 MHz) δ 12.89 (1H, s), 8.95 (1H, m), 8.44 (1H, m), 8.27 (1H, m), 8.11 (1H, s), 8.01 (1H, s), 7.99 (1H, s), 7.58 (1H, dd, J=8.4 and 4.0 Hz), 6.35 (1H, br s), 4.67 (1H, m), 4.01 (1H, m), 3.76 (1H, m), 3.61 (1H, m), 2.78 (1H, m), 1.90 (2H, m), 1.79˜1.61 (3H, m), 1.52 (3H, d, J=7.2 Hz) ppm.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:18]3[C:13](=[C:14]([OH:32])[C:15]4[C:24](=[O:25])[C:23]5[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:22]=5[C:20](=[O:21])[C:16]=4[C:17]=3[OH:19])[CH2:12][C@@:11]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:10]2)[CH2:5][C@H:4]([NH2:38])[C@@H:3]1[OH:39].Cl.I[CH2:42][CH2:43][O:44][CH2:45][CH2:46]I.C(N(CC)CC)C>CN(C=O)C>[CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:18]3[C:13](=[C:14]([OH:32])[C:15]4[C:24](=[O:25])[C:23]5[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:22]=5[C:20](=[O:21])[C:16]=4[C:17]=3[OH:19])[CH2:12][C@@:11]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:10]2)[CH2:5][C@H:4]([N:38]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C@@H:3]1[OH:39]
Reactant: ICCOCCI
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N2CCOCC2)[C@H](O)[C@H](C)O1
Reaction time: 36 h
Yield: 62.3 %

Procedure:
To a solution of adriamycin hydrochloride (20 mg; 0.034 mmoles) in 1 ml of DMF were added 200 mg (0.614 mmoles) of bis(2-iodoethyl)ether and 0.014 ml (0.104 mmoles) of triethylamine, and the reaction was carried out for 36 hours at room temperature. The product was worked up in the same way as in the purification procedure of Example 1 to give 13 mg (yield 61%) of the title compound.
Reaction SMILES: [P:1]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=O>[Cl-].C[N+](C)(C)C.C(O)C>[P:1]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5]
Reactant: CCOP(=O)(OCC)OCC
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: CCO
Product: CCOP(OCC)OCC
Reaction time: 88 h

Procedure:
The electrolyte was 2.9 g. tetramethylammonium chloride in 60 ml anhydrous ethanol. The electrolysis was carried out at 35° C. for 88 hours at 6.5 v. to give 0.1 a current. Gas chromatographic analysis of the red-brown reaction liquor showed that both triethyl phosphate and triethyl phosphite were formed.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[CH:12]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=2)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][C:5]=1[F:31])(=[O:3])[NH2:2].C(Cl)CCl.[CH3:36][C:37]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:38]=1[C:39](O)=[O:40]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:36][C:37]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:38]=1[C:39]([O:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([CH:12]([CH2:13][NH:14][C:15]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:21])[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:1](=[O:3])[NH2:2])=[C:5]([F:31])[CH:6]=2)=[O:30])=[CH:27][CH:26]=1)=[O:40]
Reactant: Cc1ccc(C(=O)O)c(C)c1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc(C(N)=O)c(F)c1)c1ccc(CO)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)OCc2ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc3ccc(C(N)=O)c(F)c3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 3-(4-carbamoyl-3-fluorophenylamino)-2-(4-(hydroxymethyl)phenyl)-3-oxopropylcarbamate (E337-1) in pyridine was added was added EDC, DMAP, and 2,4-dimethylbenzoic acid, and the solution was stirred overnight at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-5% MeOH/CH2Cl2 gradient) gave pure 4-(3-(tert-butoxycarbonylamino)-1-(4-carbamoyl-3-fluorophenylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (E337-2).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[N:13]=[C:14]([CH2:17]OS(C)(=O)=O)[S:15][CH:16]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].OCC1S[CH:27]=[C:28]([C:30]([N:32]2[CH2:37][CH2:36]N(C(C)C)CC2)=O)N=1.CS(Cl)(=O)=O>C(Cl)Cl>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[N:13]=[C:14]([CH2:17][N:32]3[CH2:30][CH2:28][CH2:27][CH2:36][CH2:37]3)[S:15][CH:16]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2csc(CO)n2)CC1
Reactant: CC(C)N1CCN(C(=O)c2csc(COS(C)(=O)=O)n2)CC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2csc(CN3CCCCC3)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
Methanesulfonic acid 4-(4-isopropyl-piperazine-1-carbonyl)-thiazol-2-ylmethyl ester. (2-Hydroxymethyl-thiazol-4-yl)-(4-isopropyl-piperazin-1-yl)-methanone (0.95 g. 3.5 mmol) and TEA (0.542 mL, 3.89 mmol) were suspended in DCM (50 mL). The suspension was cooled to 0° C. and methanesulfonyl chloride (0.3 mL) was added dropwise. The mixture was stirred at 0° C. for 30 min, then warmed to rt and stirred for 2 h. The mixture was concentrated at rt to yield the title compound (0.50 g, 41%). The crude mesylate was carried forward to the next step. MS (ESI): exact mass calcd. for C14H22N2O4S2, 347.10; m/z found, 348.5 [M+H]+.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[C:19]=1[O:31][CH3:32]>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Cl:30])[C:19]=1[O:31][CH3:32]
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Reactant: C=C(c1cc(Cl)c(OC)c(Cl)c1)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1c(Cl)cc(C2(C(F)(F)F)CC(c3ccc4c(c3)C(C)(C)OB4O)=NO2)cc1Cl
Temperature: 0 °C
Reaction time: 12 h
Yield: 18.9 %

Procedure:
To a solution of crude compound N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxa-borole-5-carbimidoyl chloride (0.29 g, 1.23 mmol) and 1,3-dichloro-2-methoxy-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (0.4 g, 1.48 mmol) in DMF (10 mL) at rt was added TEA (0.51 mL, 3.67 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE-EA (3:2) and then purified by preparative TLC to give the title compound (110 mg, yield 15.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.27 (s, 1 H), 7.82-7.75 (m, 5 H), 4.46 (d, J=18.4 Hz, 1 H), 4.36 (d, J=18.4 Hz, 1 H), 3.93 (s, 3 H), 1.53 (s,6 H) ppm; MS: m/z=472 (M−1, ESI−).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:24]3[CH2:27][C@H:26]([OH:28])[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:28][C@H:26]2[CH2:25][C@H:24]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([C:11]4[CH:12]=[CH:13][C:14]([O:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:15][CH:16]=4)=[N:9]3)[CH2:27]2)=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@H]1C[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1

Procedure:
A solution of cis 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclobutanol (0.113 g, 0.000302 mol), 4-nitrobenzoic acid (0.101 g, 0.000605 mol) and triphenylphosphine (0.159 g, 0.000605 mol) in tetrahydrofuran (5 mL) was cooled to 0° C. Diethyl azodicarboxylate (0.096 mL, 0.159 g, 6.000605 mol) was added dropwise, keeping the temperature below 10° C. The mixture was allowed to come to room temperature over eighteen hours. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica using heptane/ethyl acetate (3:1). The solvent was removed in vacuo to give trans 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutyl 4-nitrobenzoate (0.081 g, 0.000164 mmol) as a tan solid.
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[Cl:16].[CH3:18][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>C1COCC1>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([C:8](=[O:17])[CH3:18])=[C:10]([Cl:16])[CH:11]=1
Reactant: O=C(Sc1ccccn1)c1ccc(Br)cc1Cl
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(Br)cc1Cl
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 80 %

Procedure:
4-Bromo-2-chloro-thiobenzoic acid S-pyridin-2-yl ester (1.86 g, 5.66 mmol) from Step 1 above was dissolved in dry THF (30 mL) and cooled to −78° C. A solution of methyl magnesium bromide in 75:25 toluene/THF (1.4 M, 4.45 mL, 6.23 mmol) was added dropwise. After stirring 35 min, the cooling bath was removed. The reaction mixture was quenched with saturated 1N HCl and extracted with EtOAc (30 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (10% EtOAc in hexanes) to give the product (1.05 g, 80%) as a colorless oil. 1H NMR (CDCl3) δ 2.64 (s, 3H), 7.46-7.48 (m, 2H), 7.61 (s, 1H).
Reaction SMILES: [C@@H:1]12[O:9][CH2:8][C@@H:6]([O:7]1)[CH2:5][CH2:4][C@H:2]2[OH:3]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:8]1[O:9][C@@H:1]2[O:7][C@H:6]1[CH:5]=[CH:4][C:2]2=[O:3]
Reactant: O[C@@H]1CC[C@H]2CO[C@@H]1O2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C1C=C[C@H]2CO[C@@H]1O2
Temperature: 25 °C
Yield: 83.1 %

Procedure:
[D] 19 g of 1,6-anhydro-3,4-dideoxy-β-D-galactopyranose (7) prepared in the step [C] was dissolved in 100 ml of dichloromethane, forming a solution. Then, 50 g of active manganese dioxide was added to this solution, and the solution was stirred for 2 at room temperature, thus causing a reaction. Upon completion of the reaction, manganese dioxide was filtered off, and the solvent was distilled off under reduced pressure, whereby 15.3 g of levoglucosenone (8) (i.e., 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranos-2-ulose) was obtained at a yield of 82%. This substance exhibited the following physical properties:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([N:16]2[CH2:22][CH2:21][CH2:20][C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[CH2:17]2)[CH:7]=1)=[O:4].[N-:27]=[N+:28]=[N-:29].[Na+]>C(#N)C.C(OCC)(=O)C>[N:27]([CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([N:16]2[CH2:22][CH2:21][CH2:20][C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[CH2:17]2)[CH:7]=1)=[O:4])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCl)Nc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCC(=O)Nc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.9 %

Procedure:
To a solution of 2-chloro-N-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]acetamide (70 mg, 0.19 mmol) in acetonitrile (2 mL) was added sodium azide (62 mg, 0.95 mmol). The resulting mixture was stirred at room temperature for 6 hours. The reaction was diluted with ethyl acetate (20 mL), and then washed with water (10 mL). The ethyl acetate fraction was dried over sodium sulfate, and then concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 1:4) to give 65 mg of product as a white powder (yield was 91.8%). MS obsd. (ESI+) [(M+H)+] 373.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH:7]([CH2:9][CH:10]=[CH:11][C:12]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.[CH3:30][O+](C)C>C(Cl)Cl>[N+:22]([C:19]1[CH:20]=[CH:21][C:12]([CH:11]=[CH:10][CH2:9][CH:7]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([O:1][CH3:30])=[N:8]2)=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])([O-:24])=[O:23]
Reactant: C[O+](C)C
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1C=CCC1CCCCC(=O)N1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc([N+](=O)[O-])ccc1C=CCC1CCCCC(OC)=N1

Procedure:
The product of Example 159 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: [CH2:1]([C:3]([CH2:11][CH3:12])([CH2:7][C:8]([OH:10])=O)[C:4]([OH:6])=[O:5])[CH3:2].[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[F:24])[N:20]=[C:19]([CH2:25][O:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30])[CH:18]=[CH:17]2>>[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[F:24])[N:20]=[C:19]([CH2:25][O:26][C:27]1[CH:28]=[C:29]([NH:30][C:8](=[O:10])[CH2:7][C:3]([CH2:1][CH3:2])([CH2:11][CH3:12])[C:4]([OH:6])=[O:5])[CH:31]=[CH:32][CH:33]=1)[CH:18]=[CH:17]2
Reactant: CCC(CC)(CC(=O)O)C(=O)O
Reactant: Nc1cccc(OCc2ccc3cc(F)c(F)cc3n2)c1
Product: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3cc(F)c(F)cc3n2)c1)C(=O)O

Procedure:
Analogously to Example 3, the title compound is prepared from 2,2-diethylsuccinic acid and 3-(6,7-difluoro-2-quinolinylmethoxy)aniline. It is obtained in the form of a white solid; 1H-NMR, 200 MHz, DMSO, delta (ppm)=9.90 (s, 1H), 8.42 (d, 1H), 8.10 (m, 2H), 7.70 (d, 1H), 7.45 (m, 1H), 7.07 (m, 2H), 6.73 (d, 1H), 5.35 (s, 2H), 2.58 (s, 2H), 1.80 (m, 4H), 0.80 (t, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:32])=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[C:28](=[O:29])[N:27]([CH3:30])[CH2:26][CH2:25][N:24]4[CH3:31])=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[O:33]=[C:34]1[C:39]2[S:40][C:41]([C:43](O)=[O:44])=[CH:42][C:38]=2[CH2:37][CH2:36][CH2:35]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O.CN(C=O)C>[CH3:31][N:24]1[CH2:25][CH2:26][N:27]([CH3:30])[C:28](=[O:29])[CH:23]1[C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:10]2[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=[C:8]([C:4]3[C:3]([CH3:32])=[C:2]([NH:1][C:43]([C:41]4[S:40][C:39]5[C:34](=[O:33])[CH2:35][CH2:36][CH2:37][C:38]=5[CH:42]=4)=[O:44])[CH:7]=[CH:6][CH:5]=3)[N:9]=2)=[CH:22][CH:21]=1
Reactant: Cc1c(N)cccc1-c1cn(C)c(=O)c(Nc2ccc(C3C(=O)N(C)CCN3C)cc2)n1
Reactant: O=C(O)c1cc2c(s1)C(=O)CCC2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(NC(=O)c2cc3c(s2)C(=O)CCC3)cccc1-c1cn(C)c(=O)c(Nc2ccc(C3C(=O)N(C)CCN3C)cc2)n1
Reaction time: 4 h
Yield: 52.2 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 15 (249 mg, 1.27 mmol), 16 (500 mg, 1.16 mmol), N,N-diisopropylethylamine (600 mg, 4.64 mmol) and anhydrous DMF (5 mL). Benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 616 mg, 1.39 mmol) was added, and the reaction was stirred for 4 h. After this time, the reaction was diluted with water (10 mL), and the resulting suspension was filtered. The filter cake was dissolved in methylene chloride (20 mL), and the solution was washed with 10% aqueous citric acid (10 mL), saturated aqueous sodium bicarbonate (10 mL), and water (10 mL), and dried over sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash chromatography to afford a 52% yield of 17 (370 mg) as a white solid: mp 154-155° C.; 1H NMR (500 MHz, CD2Cl2) δ 8.31 (s, 1H), 7.81 (dd, 1H, J=7.5, 1.5 Hz), 7.76-7.72 (m, 3H), 7.50 (s, 1H), 7.28-7.23 (m, 4H), 6.73 (s, 1H), 3.64 (td, 1H, J=11.5, 4.5 Hz), 3.57 (s, 1H), 3.55 (s, 3H), 3.14 (dt, 1H, J=11.5, 3.5 Hz), 2.93 (m, 1H), 2.88-2.86 (m, 5H), 2.62-2.57 (m, 3H), 2.36 (s, 3H), 2.17 (m, 2H), 2.09 (s, 3H); MS (ESI+) m/z 611.2 (M+H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[CH:26]1([S:29](Cl)(=[O:31])=[O:30])[CH2:28][CH2:27]1>>[CH:26]1([S:29]([N:2]2[CH2:3][CH2:4][CH:5]([N:8]3[N:12]=[C:11]([CH2:13][O:14][C:15]4[CH:16]=[CH:17][C:18]([N:21]5[CH:25]=[N:24][N:23]=[N:22]5)=[N:19][CH:20]=4)[CH:10]=[N:9]3)[CH2:6][CH2:7]2)(=[O:31])=[O:30])[CH2:28][CH2:27]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Agent: Cl
Product: O=S(=O)(C1CC1)N1CCC(n2ncc(COc3ccc(-n4cnnn4)nc3)n2)CC1

Procedure:
The title compound was synthesized using Intermediate 15 and cyclopropanesulfonyl chloride in a similar manner as described in Example 39. 1H NMR (DMSO-d6): δ 9.45 (1H, s), 8.28 (1H, d), 8.03 (1H, d), 7.73 (1H, s), 7.58 (1H, dd), 5.28 (2H, s), 4.62 (1H, m), 3.87 (2H, m), 3.12 (2H, m) 2.31 (5H, m), 1.86 (2H, m), 1.02 (2H, m).
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[C:4](=[O:26])[NH:5][C@H:6]1[CH2:20][C@H:19]2[C@@H:9]([CH2:10][C:11]3[C:21]4[C:14](=[CH:15][C:16]([CH:22]=[O:23])=[CH:17][C:18]2=4)[NH:13][C:12]=3[CH3:24])[N:8]([CH3:25])[CH2:7]1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(Cl)(Cl)Cl>[CH2:27]([N:3]([CH2:1][CH3:2])[C:4]([NH:5][C@H:6]1[CH2:20][C@H:19]2[C@@H:9]([CH2:10][C:11]3[C:21]4[C:14](=[CH:15][C:16]([CH2:22][OH:23])=[CH:17][C:18]2=4)[NH:13][C:12]=3[CH3:24])[N:8]([CH3:25])[CH2:7]1)=[O:26])[CH3:28]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(C=O)cc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(CO)cc4[nH]c(C)c(c34)C[C@H]2N(C)C1

Procedure:
370 mg of 8alpha-(3,3-diethylureido)-2,6-dimethyl-ergoline-13-carbaldehyde (1 mmol) is dissolved in 50 ml of tetrahydrofuran and reduced with 200 mg of lithium aluminum hydride at room temperature for 1 hour. The mixture is cooled off in an ice bath and mixed in succession with 0.2 ml of water, 0.2 ml of 15% sodium hydroxide solution and 0.6 ml of water, the precipitate is filtered off and the filtrate is evaporated to dryness. The residue is chromatographed on silica gel with dichloromethane/methanol. 243 mg of alcohol, which crystallizes from ethyl acetate, is isolated. Yield 166 mg (44% of theory), [α]D =+6° (0.5% in chloroform).