Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:10]([NH:12][N:13]1[CH2:17][CH2:16][C@H:15]([N:18]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:14]1)=[O:11].[C:38]([N:45]1[CH2:48][C:47](=O)[CH2:46]1)([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>>[C:38]([N:45]1[CH2:46][CH:47]([NH:8][C@H:9]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:10]([NH:12][N:13]2[CH2:17][CH2:16][C@H:15]([N:18]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:14]2)=[O:11])[CH2:48]1)([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]
Reactant: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@H](N)Cc2ccc(Cl)cc2)C1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC2CN(C(=O)OC(C)(C)C)C2)C1

Procedure:
The title compound was prepared following the procedure described in Step A of Example 3 using (2R)-2-amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA prepared in Example 1 and BOC-3-oxo-azetidine.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH2:10][OH:11])[C:7]([O:12][CH2:13][CH3:14])=[CH:6][C:5]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:3][CH2:2]1>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:9]=[C:8]([CH:10]=[O:11])[C:7]([O:12][CH2:13][CH3:14])=[CH:6][C:5]=2[C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH2:3][CH2:2]1
Reactant: CCOc1cc(-c2ccc(F)cc2)c(C2CC2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCOc1cc(-c2ccc(F)cc2)c(C2CC2)cc1C=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
Manganese dioxide (17.2 g) was added to a toluene (30 mL) solution of (2-cyclopropyl-5-ethoxy-4′-fluorobiphenyl-4-yl)methanol (5.65 g), and the mixture was stirred at 60° C. for 1 hour in a nitrogen atmosphere. The reaction mixture was filtered, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (4.66 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[OH-].[Na+].[C:17](Cl)(=[O:20])[CH:18]=[CH2:19].Cl>O>[C:17]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2)(=[O:20])[CH:18]=[CH2:19]
Reactant: C=CC(=O)Cl
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred mixture of 3.00 g (16 mmol) of 6-hydroxy-2-naphthoic acid, 40 mmol of sodium hydroxide, and 16 g of water, 1.59 g (18 mmol) of acryloyl chloride was added at 20° C., and the reaction was performed for 3 hours. After the reaction, the mixture was acidified by adding 4-mol/l hydrochloric acid dropwise and chilled with ice-water. The resultant precipitate was collected by filtration, dried in an oven at 40° C., and recrystallized from methanol-THF (2:3) mixed solvent to yield the desired product, 6-acryloyloxy-2-naphthoic acid, as while solid (2.07 g, Yield: 53.6%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C@@H:5]1[NH:10][CH2:9][CH2:8][N:7]([C:11]2[C:20]3[N:19]=[C:18]([C:21]([F:24])([F:23])[F:22])[S:17][C:16]=3[NH:15][C:14]3[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=3[N:12]=2)[CH2:6]1.[CH:29](=O)[CH3:30]>>[CH2:29]([N:10]1[CH2:9][CH2:8][N:7]([C:11]2[C:20]3[N:19]=[C:18]([C:21]([F:23])([F:24])[F:22])[S:17][C:16]=3[NH:15][C:14]3[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=3[N:12]=2)[CH2:6][C@@H:5]1[CH2:4][CH2:3][O:2][CH3:1])[CH3:30]
Reactant: CC=O
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1
Product: CCN1CCN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)C[C@@H]1CCOC

Procedure:
Using the method of Example 346 using (5)-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene and acetaldehyde at ambient temperature, and purification by flash chromatography, eluting with a gradient of a 5% solution of 2M ammonia in methanol, in dichloromethane, (0-50% over 25 minutes, 50% for 10 minutes, 50-100% over 23 minutes, 100% for 5 minutes) gives the title compound: mass spectrum (APCI, m/e): 440 (M+1); NMR (1H, 300 MHz, DMSO-d6), δ (ppm): δ 8.47 (s, 1H), 6.96-6.81 (m, 3H), 6.71 (m, 1H), 3.50 (br. m, 3H), 3.35-3.21 (m, 2H), 3.21-3.07 (m, 4H), 2.76-2.51 (m, 3H), 2.37 (m, 2H), 1.67 (m, 2H), 0.96 (t, 3H, J=6.9 Hz).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([SH:11])[CH:5]=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[F:1][C:2]1[C:7]2[C:8](=[O:10])[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[S:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1c(F)cccc1S
Reactant: N#Cc1ccccn1
Solvent: c1ccncc1
Product: O=c1nc(-c2ccccn2)sc2cccc(F)c12
Temperature: 135 °C
Yield: 1.5 %

Procedure:
A mixture of 6-fluoro-2-mercaptobenzoic acid (5.00 g, 29.0 mmol), 2-cyanopyridine (3.05 g, 29.3 mmol) and pyridine (30.0 ml) was refluxed at 135° C. for 48 hrs as described in Example 9. The reaction mixture was concentrated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (2:1, v/v). The resultant product was recrystallized from ethanol to give the titled compound (0.11 g, 1%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.C1C=C2N=NN(O)C2=CC=1.N.[NH2:40][CH2:41][C:42]1[C:43]([OH:50])=[N:44][C:45]([CH3:49])=[CH:46][C:47]=1[CH3:48]>O.ClCCl.C(N(CC)CC)C>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([C:14]([NH:40][CH2:41][C:42]2[C:43]([OH:50])=[N:44][C:45]([CH3:49])=[CH:46][C:47]=2[CH3:48])=[O:16])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)cnn1Cc1ccccc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cnn(Cc3ccccc3)c2C)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
A mixture of 1-benzyl-5-methyl-1H-pyrazole-4-carboxylic acid (75 mg, 0.34 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (95 mg, 0.5 mmol), N-hydroxybenzotrizole (67 mg, 0.5 mmol), triethylamine (0.1 mL) and dichloromethane (5 mL) were stirred at 25° C. for 0.5 hours. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (50 mg, 0.33 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (10 ml) was added and the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 1-benzyl-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-5-methyl-1H-pyrazole-4-carboxamide as a white solid (35 mg, 29%). LRMS (M+H+) m/z: calcd 350.17. found 350. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.21 (s, 1H), 7.68 (t, J=5.1 Hz, 1H), 7.38-7.21 (m, 5H), 5.85 (s, 1H), 5.20 (s, 2H), 4.19 (d, J=5.4 Hz, 2H), 2.29 (s, 3H), 2.15 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:6][O:7][N+:8]([O-:10])=[O:9])[C:3](Cl)=[O:4].O1CCCC1.[NH2:17][CH2:18][C:19]([NH:22][CH2:23][CH:24]([OH:37])[CH2:25][O:26][C:27]1[C:35]2[N:34]([CH3:36])[CH:33]=[N:32][C:31]=2[CH:30]=[CH:29][CH:28]=1)([CH3:21])[CH3:20].[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42]>CC(C)=O.C(Cl)Cl>[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42].[CH3:21][C:19]([NH:22][CH2:23][CH:24]([OH:37])[CH2:25][O:26][C:27]1[C:35]2[N:34]([CH3:36])[CH:33]=[N:32][C:31]=2[CH:30]=[CH:29][CH:28]=1)([CH3:20])[CH2:18][NH:17][C:3](=[O:4])[C:2]([CH3:11])([CH3:1])[CH2:6][O:7][N+:8]([O-:10])=[O:9]
Reactant: Cn1cnc2cccc(OCC(O)CNC(C)(C)CN)c21
Reactant: CC(C)(CO[N+](=O)[O-])C(=O)Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cn1cnc2cccc(OCC(O)CNC(C)(C)CNC(=O)C(C)(C)CO[N+](=O)[O-])c21
Reaction time: 2 h

Procedure:
A solution of 1.4 g. 2,2-dimethyl-3-nitroxypropanoyl chloride in 50 ml. dry tetrahydrofuran is added dropwise at ambient temperature to a solution of 2.3 g. 3-(2-amino-1,1-dimethylethylamino)-1-(3-methylbenzimidazol-4-yloxy)-propan-2-ol in 150 ml. dry tetrahydrofuran, followed by further stirring for 2 hours. The reaction mixture is evaporated and chromatographed on silica gel with methylene chloride/methanol (4:2 v/v). The product obtained (2.0 g.) is dissolved in 60 ml. methylene chloride and mixed with 0.54 g. fumaric acid in 100 ml. acetone. The precipitate which separates out after the addition of 200 ml. diethyl ether is filtered off with suction and dried. There are obtained 2.3 g. (53% of theory) of the desired product in the form of crystals; m.p. 187°-190° C.
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][C:8]1([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:40])[CH2:21][C:22]3[CH:38]=[C:37]([CH3:39])[C:25]4[N:26]=[C:27]([NH:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[CH3:36])[O:28][C:24]=4[CH:23]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.ClCCl>O>[CH3:39][C:37]1[C:25]2[N:26]=[C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])[O:28][C:24]=2[CH:23]=[C:22]([CH2:21][C:20]([NH:19][C:16]2[CH:15]=[CH:14][C:13]([C:8]3([CH2:7][C:6]([OH:41])=[O:5])[CH2:12][CH2:11][CH2:10][CH2:9]3)=[CH:18][CH:17]=2)=[O:40])[CH:38]=1
Reactant: Cc1ccccc1Nc1nc2c(C)cc(CC(=O)Nc3ccc(C4(CC(=O)OC(C)(C)C)CCCC4)cc3)cc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1Nc1nc2c(C)cc(CC(=O)Nc3ccc(C4(CC(=O)O)CCCC4)cc3)cc2o1
Yield: 428 %

Procedure:
[1-{4-[2-[4-Methyl-2-o-tolylamino-benzoxazol-6-yl]-acetylamino]-phenyl}-cyclopentyl]-acetic acid tert-butyl ester [0.065 g, Reference Example 1(d)] was treated with a mixture of trifluoroacetic acid (2.2 mL), dichloromethane (0.5 mL) and water (0.25 mL). The resultant solution was stirred at room temperature, under argon, for 1.5 hours and then the colourless solution was evaporated. The residue was chased twice with toluene (15 mL) to yield a clear gum. This gum was triturated with pentane and the solid obtained was washed with pentane and then dried at 60° C., under vacuum, to give the title compound (0.25 g) as an off-white solid, m.p. softens at 110° C. then slowly melts from 120–150° C.
Reaction SMILES: CS(O[CH2:6][C:7]1([C:10]([O:12]CC)=[O:11])[CH2:9][CH2:8]1)(=O)=O.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=O)=O.OCC1(C(OCC)=O)CC1>ClCCl.O>[CH3:22][S:23][CH2:6][C:7]1([C:10]([OH:12])=[O:11])[CH2:8][CH2:9]1
Reactant: CCOC(=O)C1(COS(C)(=O)=O)CC1
Reactant: CS(=O)(=O)Cl
Agent: CCOC(=O)C1(CO)CC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CSCC1(C(=O)O)CC1
Temperature: 23 °C
Reaction time: 20 h
Yield: 115.7 %

Procedure:
Preparation of ethyl 1-((methylsulfonyloxy)methyl)cyclopropanecarboxylate—Triethylamine (990 μL, 7.1 mmol, 1.2 equiv) and methanesulfonyl chloride (500 μL, 6.5 mmol, 1.1 equiv) were sequentially added to a stirred solution of ethyl 1-(hydroxymethyl)cyclopropanecarboxylate (840 mg, 5.7 mmol, 1.0 equiv) in dichloromethane (15 mL) at 23° C. The resulting bright yellow solution was stirred at 23° C. for 20 h. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were dried (MgSO4), gravity-filtered, and concentrated by rotary evaporation to afford the title compound as a brown oil (1.1 g, 85%): 1H NMR (300 MHz, CDCl3) δ 4.33 (s, 2H), 4.16 (q, J=7 Hz, 2H), 3.08 (s, 3H), 1.43 (dd, J=7, 4 Hz, 2H), 1.26 (t, J=7 Hz, 3H), 1.04 (dd, J=7, 4 Hz, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].I[CH3:15]>CN(C=O)C.[NH4+].[OH-]>[CH3:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: N#Cc1ccc2cc[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2ccc(C#N)cc21
Temperature: 25 °C
Yield: 604 %

Procedure:
Add slowly a solution of indole-6-carbonitrile (1.0 g, 7.04 mmol) in anhydrous DMF (5 mL) to a suspension of sodium hydride (60% dispersion in mineral oil, 0.6 g, 14.1 mmol) in anhydrous DMF (2 mL) at 0° C. and warm the reaction mixture to ambient temperature. Add iodomethane (0.7 mL, 1.06 mmol) and stir the reaction mixture for 1 h at ambient temperature. Dilute the reaction mixture with 1M aqueous NH4OH (30 mL) and extract with diethyl ether (3×10 mL). Combine the organic layers, dry over anhydrous Na2SO4, remove the solvent and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9: 1, 4:1 and 7:3) to obtain the desired intermediate as a yellow oil (1.0 g, 87%). MS (ES+) m/z: 156 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].O[N:8]=[C:9]1[CH2:14][CH2:13][N:12]([CH:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][O:18][C:17]3[CH:26]=[CH:27][C:28]([Br:30])=[CH:29][C:16]2=3)[CH2:11][CH2:10]1.O>C1COCC1.CCOCC>[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][O:18][C:17]3[CH:26]=[CH:27][C:28]([Br:30])=[CH:29][C:16]2=3)[CH2:11][CH2:10]1
Reactant: ON=C1CCN(C2c3ccccc3COc3ccc(Br)cc32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC1CCN(C2c3ccccc3COc3ccc(Br)cc32)CC1
Temperature: 0 °C
Yield: 69.1 %

Procedure:
Step 4): LiAlH4 (0.14 g, 3.7 mmol) was added to a solution of 11-(4-hydroxyiminopiperidin-1-yl)-2-bromo-6,11-dihydrodibenz[b,e]oxepin (1.5 g, 3.7 mmol) in dry THF (50 ml) under nitrogen atmosphere. The reaction mixture was heated at 60°-70° C. for 3 hours. After cooled at 0° C., the reaction mixture was hydrolyzed with water and diluted with ether, then filtered. The filtrate was concentrated to give 11-(4-aminopiperidin-1-yl)-2-bromo-6,11-dihydrodibenz[b,e]oxepin (69.1%): mp 142°-144° C.
Reaction SMILES: [Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[CH2:13](O)C=C.Cl[C:18](Cl)(Cl)[C:19]([O:21][C@H:22]1[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:23]1[NH:41][C:42](=[O:47])[C:43]([Cl:46])([Cl:45])[Cl:44])=N.CCOC(C)=O>C(Cl)Cl.C(N(CC)CC)C>[C:26]([O:25][C@H:24]1[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[O:35][C@@H:22]([O:21][CH2:19][CH:18]=[CH2:13])[C@@H:23]1[NH:41][C:42](=[O:47])[C:43]([Cl:46])([Cl:45])[Cl:44])(=[O:28])[CH3:27]
Reactant: C=CCO
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](NC(=O)C(Cl)(Cl)Cl)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCO[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1NC(=O)C(Cl)(Cl)Cl
Temperature: -78 °C
Yield: 83.3 %

Procedure:
TMSOTf (830.0 μL, 4.6 mmol, 0.2 eq.) is added to a solution of allyl alcohol (3.1 mL, 46.0 mmol, 2 eq.) and of donor 1 (13.7 g, 23.0 mmol, 1 eq.) in DCM (160 mL), in the presence of molecular sieve 4 Å (8.9 g), stirred under argon at −78° C. After stirring for 30 min, monitoring by TLC (Tol/EtOAc, 8/2) indicates the disappearance of the donor (Rf=0.5) and the appearance of a new, more polar compound (Rf=0.35). The reaction is stopped by adding triethylamine (1 mL) and then the reaction mixture is filtered and concentrated in a rotary evaporator. The yellow oil obtained is purified by silica gel chromatography (Tol/EtOAc, 9/1→75/25) to obtain the allyl glycoside 18 as a white solid (9.4 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:17][OH:18].[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:17][OH:18]
Reactant: COC(=O)CCCC#CCN1C(=O)CCCC1CO
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCCN1C(=O)CCCC1CO
Reaction time: 23 h
Yield: 101.2 %

Procedure:
Palladium on carbon (10 wt. %, 20 mg) was added to a solution of 7-(2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (180 mg, 0.67 mmol) in MeOH (6.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 23 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo to afford 184 mg (quant.) of 7-(2-hydroxymethyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].N1C=CC=CC=1.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][CH:3]([C:2](=[O:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5]
Reactant: N#CCC(=O)c1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: N#CC(Br)C(=O)c1ccccc1
Temperature: 45 °C

Procedure:
3-Oxo-3-phenylpropionitril (1.5 g, 10 mmol) was dissolved in dry chloroform (10 mL) at 0° C., and pyridine (0.81 mL, 10 mmol) was added. Bromine (4.7 mL, 10 mmol) dissolved in chloroform (4.7 mL) was added dropwise over an hour, then the reaction mixture was heated at 45° C. over night. The reaction mixture was diluted with chloroform and washed with water. The organic phases were dried over sodium sulfate and evaporated to give the crude product, which was used in the next reaction without any further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]3[O:20][C:19]([CH3:22])([CH3:21])[CH:18]=[CH:17][C:14]=3[CH:15]=2)[C:10](=O)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CN(C=O)C.O.NN>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]3[O:20][C:19]([CH3:21])([CH3:22])[CH:18]=[CH:17][C:14]=3[CH:15]=2)[CH2:10][C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)C=Cc2cc3c(cc2O1)C(=O)C(=O)N3Cc1ccccc1
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C=Cc2cc3c(cc2O1)CC(=O)N3Cc1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
To a solution of N-benzyl-6,6-dimethyl-1H-pyrano[2,3-f]indole-2,3-dione (500 mg, 1.57 mmol) in DMF (5 mL), hydrazine monohydrate (2.5 mL) was added, and the resulting mixture was stirred at 100° C. for 1.5 hour. Water was added thereto, and the resulting solution was extracted with ethyl acetate. The resulting organic phase was washed with saturated ammonium chloride aqueous solution and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column (hexane/ethyl acetate=3/1) to obtain the aimed product (yield: 65%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[CH:26][C:20]=1[CH:21]=[CH:22][C:23](O)=O>>[CH2:13]([N:4]1[C:3](=[O:16])[C:2]2[NH:1][C:23](/[CH:22]=[CH:21]/[C:20]3[CH:26]=[C:27]([O:32][CH3:33])[C:28]([O:30][CH3:31])=[CH:29][C:19]=3[O:18][CH3:17])=[N:8][C:7]=2[N:6]([CH2:9][CH2:10][CH3:11])[C:5]1=[O:12])[CH2:14][CH3:15]
Reactant: COc1cc(OC)c(OC)cc1C=CC(=O)O
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cc(OC)c(OC)cc3OC)nc2n(CCC)c1=O
Yield: 22.9 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 2.00 g (8.85 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.32 g (9.73 mmol) of 2,4,5-trimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from 2-propanol/water to give 870 mg (yield 23%) of Compound 23 as a pale yellow powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([CH3:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1(CO)C2C=CC=C[C:20]=2N=N1.[BH4-].[Na+].O>CN(C)C=O.CO.C(OCC)(=O)C>[CH3:20][NH:13][C:12]1[CH:14]=[CH:15][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[CH3:16]
Reactant: Cc1cc(OCc2ccccc2)ccc1N
Reactant: OCn1nnc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CNc1ccc(OCc2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
After dissolving 4-benzyloxy-2-methylaniline (6.55 g, 30.72 mmol) in N,N-dimethylformamide (10 ml) and methanol (60 ml), 1H-benzotriazole-1-methanol (4.58 g, 30.72 mmol) was added and the mixture was stirred for 30 minutes at room temperature. N,N-Dimethylformamide (20 ml) was added for complete dissolution of the precipitated crystals, sodium borohydride (2.32 g, 61.44 mmol) was added in small portions at a time at room temperature (internal temperature increase), and the mixture was stirred for 30 minutes. Water was added to the reaction solution, extraction was performed ethyl acetate, the extract was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was adsorbed onto silica gel and purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (4.364 g, 19.20 mmol, 62.49%) as a brown oil.
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:53])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([OH:52])[CH2:46]2)[CH:8]([CH3:54])[CH:7](O)[CH2:6][C:5]1=[O:56])[CH:2]=[CH2:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[H][H]>C1(C)C=CC=CC=1.CO.[Pd]>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:53])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([OH:52])[CH2:46]2)[CH:8]([CH3:54])[CH2:7][CH2:6][C:5]1=[O:56])[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Yield: 40.7 %

Procedure:
To a solution of 17-Allyl-1,14-dihydroxy-12-[2-(3,4-dihydroxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (100 mg) in toluene (20 ml) was added p-toluenesulphonic acid (5 mg) and the resulting solution was warmed for 90 minutes on a steam bath. Evaporation of volatiles in vacuo and chromatography of the residue on silica eluting with ethyl acetate gave an oil which was dissolved in methanol (5 ml). To this was then added 10% palladium-on-carbon (20 mg) and the mixture was stirred in an atmosphere of hydrogen for 1 hour at room temperature. The reaction mixture was then filtered through celite, concentrated in vacuo and purified by chromatography on silica eluting with ethyl acetate to give the title compound as an oil (40 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:31]=[CH:30][C:10]2[N:11]([CH3:29])[C:12]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:13][C:9]=2[CH:8]=1)=[O:6].[O:32]1[C:34]([CH3:36])([CH3:35])[CH2:33]1.[OH-].[K+]>CN(C=O)C>[OH:32][C:34]([CH3:36])([CH3:35])[CH2:33][O:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:31]=[CH:30][C:10]2[N:11]([CH3:29])[C:12]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:13][C:9]=2[CH:8]=1)=[O:6]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCO)ccc21
Reactant: CC1(C)CO1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCOCC(C)(C)O)ccc21
Yield: 4.3 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-2-methyl-propoxy)-ethyl]-amide (5 mg) was prepared by following General Procedure X starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethyl)-amide (100 mg), 1,2-epoxy-2-methyl-propane (19 mg), and KOH (19 mg) in DMF. LC/MS: m/z 524.7.