Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]([OH:12])([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]([Cl:18])([Cl:17])[C:15]#[N:16].CO>C(OCC)C>[Cl:13][C:14]([Cl:18])([Cl:17])[C:15](=[NH:16])[O:12][C:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([CH3:11])[CH3:10]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(C)(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CC(C)(OC(=N)C(Cl)(Cl)Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.7 %

Procedure:
A suspension of 60% sodium hydride in mineral oil (0.42 g, 10.50 mmol) in diethyl ether (10 mL) was treated with the dropwise addition of a solution of 2-phenylpropan-2-ol (12.02 mL, 86 mmol) in diethyl ether (30 mL). Upon completion of addition, the mixture was stirred for 30 minutes, during which time a nearly clear solution was observed. After this time, the mixture was cooled to 0° C. and then treated with the dropwise addition of trichloroacetonitrile (8.18 mL, 82 mmol), which caused the mixture to turn dark brown. The reaction was allowed to warm to room temperature over 1 hour, and then was concentrated in vacuo to yield a residue. The residue was dissolved in hexanes (10 mL) and treated with methanol (0.424 mL, 10.48 mmol), and the resulting mixture was stirred vigorously for 5 minutes. The resulting black suspension was filtered through glass fiberglass filter paper, and the collected solids were rinsed 3× with hexanes. The combined filtrates were concentrated in vacuo to yield 2-phenylpropan-2-yl 2,2,2-trichloroacetimidate (23.8 g, 85 mmol, 99% yield) as an amber oil which was used as-is in the next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([O:23][CH3:24])=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C1(OC)C=CC=CC=1>O1CCOCC1>[CH3:24][O:23][C:21](=[O:22])[C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COC(=O)c1cc(Cl)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: COc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)ccc1C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 4-4 (40 mg, 0.11 mmol), dioxane (3 mL), 4N HCl in dioxane (3 mL) and a drop of anisole were added and stirred at rt for 2 hrs. The reaction mixture was concentrated, triturated with ether and dried in vacuo. Compound 4-5 was isolated as a white solid (33 mg, 100%). MS (ES+) m/z 253.7 (M+1).
Reaction SMILES: CN(C)CCCN=C=NCC.[Br:12][C:13]1[CH:14]=[C:15]([NH2:23])[C:16]([NH:19][CH:20]([CH3:22])[CH3:21])=[CH:17][CH:18]=1.[N:24]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)=[C:25]=S>O1CCCC1.C(OCC)(=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]2[N:19]([CH:20]([CH3:21])[CH3:22])[C:25]([NH:24][C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=3)=[N:23][C:15]=2[CH:14]=1
Reactant: CC(C)Nc1ccc(Br)cc1N
Reactant: COC(=O)c1ccc(N=C=S)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2nc3cc(Br)ccc3n2C(C)C)cc1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (EDC, 331 mg, 2.18 mmol) is added to a solution of 4-bromo-N-1-isopropylbenzene-1,2-diamine (180 mg, 0.786 mmol) and methyl 4-isothiocyanatobenzoate (140 mg, 0.725 mmol) in tetrahydrofuran was added. The reaction was heated to reflux for 2 hr and cooled to room temperature. The mixture was diluted with ethyl acetate and washed with 1 N HCl and saturated sodium bicarbonate solution. The organic layer was concentrated and purified by Biotage column chromatography to give methyl 4-(5-bromo-1-isopropyl-1H-benzo[d]imidazol-2-ylamino)benzoate (202 mg)
Reaction SMILES: [NH3:1].[C:2]1([S:8]([C:11]2[C:12]([S:24][CH3:25])=[N:13][N:14]3[C:19](Cl)=[CH:18][C:17]([CH2:21][O:22][CH3:23])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CN(C=O)C>[C:2]1([S:8]([C:11]2[C:12]([S:24][CH3:25])=[N:13][N:14]3[C:19]([NH2:1])=[CH:18][C:17]([CH2:21][O:22][CH3:23])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: COCc1cc(Cl)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Solvent: CN(C)C=O
Solvent: CO
Product: COCc1cc(N)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
10 ml of a 50% solution of NH3 in MeOH was added to a solution of 0.50 g (1.3 mmol) of 3-benzenesulphonyl-7-chloro-5-methoxymethyl-2-methylsulphanyl-pyrazolo[1,5-a]-pyrimidine in 10 ml of DMF and stirred at RT for 2 hrs. The reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 10:1) and crystallization from EtOH yielded 0.38 g (80%) of 3-benzenesulphonyl-5-methoxymethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p.>230°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH3:8])=[N:3]1.Cl[C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11].O>CC(N(C)C)=O>[CH3:1][N:2]1[C:6]([NH:7][C:10](=[O:11])[O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[CH:5][C:4]([CH3:8])=[N:3]1
Reactant: Cc1cc(N)n(C)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)n(C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To a solution of 1,3-dimethyl-1H-pyrazol-5-amine (500 mg, 4.50 mmol) in dimethylacetamide (15 ml) was added 2,2,2-trichloroethyl chloroformate (0.747 ml, 5.40 mmol) with ice-cooling, and the mixture was stirred at 0° C. for 1 hour. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 526 mg (40.8%) of the desired product as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
To a mixture of 2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dione and 30 ml of dry dimethylformamide was added 0.6 g of approximately 50 % sodium hydride. The mixture was stirred for 30 minutes at room temperature and for additional 10 minutes at a temperature of 70°-80°C. To the mixture was further added dropwise 3.4 g of benzyl bromide and stirring was continued for 30 minutes. The solvent was removed from the resulting mixture by distillation, and to the residue was added water to give a crude precipitate. This product was recrystallized from a mixture of methanol and dimethylformamide to yield 3.3 g of 1-(m-nitrophenyl)-3-benzylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione as pale yellow prisms, melting at 219°-220°C.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@H:9]([C:22]([OH:24])=[O:23])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+].[C:27]([O:33][CH2:34]Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O.C(OCC)(=O)C>[C:1]1([C@@H:7]2[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@H:9]([C:22]([O:24][CH2:34][O:33][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:23])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(O)[C@@H]1C[C@H](c2ccccc2)CN1C(=O)OCc1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCOC(=O)[C@@H]1C[C@H](c2ccccc2)CN1C(=O)OCc1ccccc1
Yield: 102.2 %

Procedure:
(cis)-4-Phenyl-1-phenylmethoxycarbonyl-L-proline (3.52 g), dissolved in 25 ml of dry dimethylformamide, is treated with 1.61 g of anhydrous potassium fluoride and 2.0 g of chloromethyl pivalate under argon at room temperature for about 16 hours. The reaction mixture is diluted with ethyl acetate and washed with water (three times), saturated sodium bicarbonate and saturated brine. The aqueous layers are backwashed with fresh ethyl acetate. The combined organic layers are dried (MgSO4) and concentrated in vacuo to give 4.86 g of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12]1([CH:18]=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCC1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:18][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: O=CC1CCCCC1
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1Nc2ccc(Cl)cc2C1=CC1CCCCC1
Yield: 67.3 %

Procedure:
A solution of 10 g of 5-chloro-1,3-dihydroindol-2-one, 6.18 g of cyclohexanecarboxaldehyde and 4.93 ml of pyrrolidine in 250 ml of toluene is refluxed for 1 hour, the water formed being removed by means of a Dean-Stark apparatus. The reaction mixture is concentrated to about 90 ml and left to crystallize. The crystalline product formed is filtered off and washed with toluene and then with iso ether to give 9.7 g of the expected product after recrystallization from toluene. M.p.=203°-204° C.
Reaction SMILES: [OH:1][CH:2]([C:27]1[S:28][CH:29]=[C:30]([C:32](=[O:35])[NH:33][CH3:34])[N:31]=1)[CH2:3][CH:4]([N:8]([CH3:26])[C:9]([CH:11]([NH:16][C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[CH3:25])=[O:18])[CH:12]([CH3:15])[CH2:13][CH3:14])=[O:10])[CH:5]([CH3:7])[CH3:6].[C:36](OC(=O)C)(=[O:38])[CH3:37]>N1C=CC=CC=1>[CH3:7][CH:5]([CH3:6])[CH:4]([N:8]([CH3:26])[C:9](=[O:10])[CH:11]([NH:16][C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[CH3:25])=[O:18])[CH:12]([CH3:15])[CH2:13][CH3:14])[CH2:3][CH:2]([O:1][C:36](=[O:38])[CH3:37])[C:27]1[S:28][CH:29]=[C:30]([C:32](=[O:35])[NH:33][CH3:34])[N:31]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCC(C)C(NC(=O)C1CCCCN1C)C(=O)N(C)C(CC(O)c1nc(C(=O)NC)cs1)C(C)C
Solvent: c1ccncc1
Product: CCC(C)C(NC(=O)C1CCCCN1C)C(=O)N(C)C(CC(OC(C)=O)c1nc(C(=O)NC)cs1)C(C)C
Temperature: 25 °C
Reaction time: 21 h
Yield: 71.7 %

Procedure:
A 0.050 M solution of 25 (12.0 mg, 0.0235 mmol) in pyridine (0.500 mL) was cooled to 0° C., and acetic anhydride (18.0 μL, 0.188 mmol) was added. The reaction mixture was allowed to warm to rt over 2 h and was stirred at rt for 21 h. The solvent was removed under reduced pressure. Reverse-phase HPFC (20:80 to 100:0 MeCN:H2O) followed by lyophilization afforded 9.3 mg (72%) of 11 as an amorphous solid. The 1H NMR corresponds to a 23:1 mixture of rotamers, with the major isomer reported. [α]D23=−2.2 (c=0.6, MeOH). IR: 1221, 1498, 1549, 1643, 1755, 2937 cm−1. 1H NMR (500 MHz, MeOD): δ 0.80 (d, 3H, J=7.0 Hz), 0.92 (t, 3H, J=7.5 Hz), 0.98 (d, 3H, J=7.0 Hz), 1.02 (d, 3H, J=6.5 Hz), 1.13-1.22 (m, 1H), 1.24-1.34 (m, 1H), 1.49-1.67 (m, 4H), 1.72-1.78 (m, 2H), 1.79-1.91 (m, 2H), 2.07 (dt, 1, J=3.0, 11.5 Hz), 2.15 (s, 3H), 2.18 (s, 3H), 2.22-2.31 (m, 1H), 2.34-2.41 (m, 1H), 2.56 (dd, 1H, J=2.5, 11.0 Hz), 2.90-2.95 (m, 1H), 2.94 (s, 3H), 3.11 (s, 3H), 4.40-4.51 (br s, 1H), 4.74 (d, 1H, J=8.0 Hz), 5.70 (dd, 1H, J=2.5, 11.5 Hz), 8.14 (s, 1H). 13C NMR (125 MHz, MeOD) δ 11.2, 16.4, 20.4, 20.6, 20.9, 24.4, 25.6, 26.3, 26.4, 31.1, 31.7, 35.7, 37.7, 44.9, 54.9, 56.7, 70.6, 71.2, 125.0, 150.9, 163.9, 171.82, 171.83, 175.3, 175.6. HRMS (FAB) calcd for C27H46N5O5S (M+H): 552.3220. Found: 552.3218.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[CH3:37]>[I-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=3[CH3:37])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CC(=O)c1ccc(OCCCCl)c(C)c1
Agent: [I-]
Agent: [K+]
Product: CC(=O)c1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(C)c1
Yield: 76 %

Procedure:
Following the procedure of Example 1, [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol and 1-[4-(3-chloropropoxy)-3-methylphenyl]ethanone were reacted using potassium iodide catalyst to give the white title compound (recrystallizing from isopropyl alcohol) in 76% yield, m.p. 116°-117° C.
Reaction SMILES: [CH3:1][C:2]1[O:10][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[F:19][C:20]([F:37])([F:36])[C:21](=[O:35])[CH2:22][C:23]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[O:33][CH3:34])([CH3:25])[CH3:24]>C1COCC1>[F:37][C:20]([F:19])([F:36])[C:21]([CH2:1][C:2]1[O:10][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=1)([OH:35])[CH2:22][C:23]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[O:33][CH3:34])([CH3:25])[CH3:24]
Reactant: Cc1cc2cnccc2o1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc2cnccc2o1)C(F)(F)F
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A solution of 2-methylfuro[3,2-c]pyridine (prepared according to the procedure by T. Kitamura, K. Tsuda, and Y. Fujiwara, Tetrahedron Lett. 1998, 39, pp. 5375-5376) (26.0 mg, 0.195 mmol) in 2 mL of THF was treated with lithium diisopropylamide (LDA; 1.5 M in cyclohexane, 195 μL) dropwise at −78° C. The mixture was stirred for 30 minutes (the color changed from yellow to orange-red) and was slowly treated with a solution of 1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (81.5 mg, 0.293 mmol) in 1 mL of THF. The reaction was stirred at −78° C. for 4.5 hours, quenched with 5 mL of saturated ammonium chloride solution, and diluted with 20 mL of ethyl acetate. The phases were separated and the aqueous layer was extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography (ethyl acetate-hexanes, 5% to 50% gradient) gave 36.0 mg (45% yield) of the title product as a clear oil.
Reaction SMILES: [C:1]([C@H:4]1[CH2:13][C@H:12]([NH:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24]C(OC(C)(C)C)=O)[CH:18]=2)=[O:16])[C:11]2[C:6](=[CH:7][C:8]([Cl:33])=[CH:9][C:10]=2[Cl:32])[NH:5]1)([OH:3])=[O:2].Cl>C(OCC)(=O)C>[ClH:32].[C:1]([C@H:4]1[CH2:13][C@H:12]([NH:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH2:24])[CH:18]=2)=[O:16])[C:11]2[C:6](=[CH:7][C:8]([Cl:33])=[CH:9][C:10]=2[Cl:32])[NH:5]1)([OH:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)N[C@H]2C[C@H](C(=O)O)Nc3cc(Cl)cc(Cl)c32)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCc1cccc(C(=O)N[C@H]2C[C@H](C(=O)O)Nc3cc(Cl)cc(Cl)c32)c1
Reaction time: 6 h
Yield: 124.2 %

Procedure:
To a solution of trans-2-carboxy-5,7-dichloro-4-(3-tert-butyloxycarbonylaminomethylphenyl)carbonylamino-1,2,3,4-tetrahydroquinoline (85 mg) in ethyl acetate (20 ml) was added 25 ml of ethyl acetate saturated with hydrogen chloride gas and the mixture was stirred in a stoppered flask for 6 h. The ethyl acetate and excess hydrogen chloride were removed in vacuo and the solid residue was recrystallised from ethyl acetate/methanol to give the title compound as colourless crystals (46 mg), m.p. 199°-200° C. δ (DMSO, 360 MHz) 1.76 (1H, ddd, J=13.2, 13.1 and 3.9 Hz, CHACHBHCCHD), 2.26 (1H, dm J=13.2 Hz, CHACHBHCCHD), 3.96-4.06 (3H, m, ArCH2NH2 and CHACHBHCCHD), 5.29 (1H, m, CHACHBHCCHD), 6.66 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.85 (1H, s, NH), 6.92 (1H, d, J=2.0 Hz, 6-H or 8-H), 7.48 (1H, t, J=7.8 Hz, Ar-H), 7.63 (1H, d, J=7.8 Hz, Ar-H), 7.88 (1H, d, J=7.8 Hz, Ar-H), 8.03 (1H, s, Ar-H), 8.38 (1H, br s, NH2), 8.72 (1H, d, J=7 Hz, NHCO); m/e (FAB+), 394 (M+1), 93 (100%).
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[C:4]1[CH:9]=[C:8]([C:10]([NH:12][NH:13][C:14](=O)[C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:17]([CH2:30][CH3:31])[CH:16]=2)=O)[CH:7]=[C:6]([CH3:33])[N:5]=1)[CH3:2].C(N(CC)C1C=C(C2OC(C3C=C(C)C(O)=C(CC)C=3)=NN=2)C=C(C)N=1)C.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:72])=CC=1>C1COCC1.CC(=O)OCC>[CH2:23]([O:22][C:18]1[C:19]([CH3:21])=[CH:20][C:15]([C:14]2[S:72][C:10]([C:8]3[CH:7]=[C:6]([CH3:33])[N:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH2:34][CH3:35])[CH:9]=3)=[N:12][N:13]=2)=[CH:16][C:17]=1[CH2:30][CH3:31])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCc1cc(C(=O)NNC(=O)c2cc(C)nc(N(CC)CC)c2)cc(C)c1OCc1ccccc1
Agent: CCc1cc(-c2nnc(-c3cc(C)nc(N(CC)CC)c3)o2)cc(C)c1O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc(-c2nnc(-c3cc(C)nc(N(CC)CC)c3)s2)cc(C)c1OCc1ccccc1
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-benzyloxy-3-ethyl-5-methyl-benzoic acid N′-(2-diethylamino-6-methyl-pyridine-4-carbonyl)-hydrazide (1.29 g, 2.72 mmol, intermediate from Example 81 step a)) in THF (15 mL), Lawesson reagent (1.21 g, 2.99 mmol) is added. The mixture is stirred at 110° C. for 15 min under microwave irradiation (300 W, external cooling). The mixture is cooled to rt, diluted with EA (100 mL) and washed with sat. aq. Na2CO3-solution (3×50 mL) followed by brine (1×50 mL). The org. extract is dried over MgSO4, filtered, concentrated and dried to give crude {4-[5-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-[1,3,4]thiadiazol-2-yl]-6-methyl-pyridin-2-yl}-diethyl-amine (2.43 g) as a yellow oil; LC-MS: tR=1.01 min, [M+1]+=473.20.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].O(C1C=C(C=CC=1)CBr)C1C=CC=CC=1>C(O)C.O.CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)[C@H](N)C(=O)O
Agent: BrCc1cccc(Oc2ccccc2)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)[C@H](Nc1ccc([N+](=O)[O-])cc1)C(=O)O
Reaction time: 24 h

Procedure:
A mixture of 10 g of 4-fluoronitrobenzene, 5 g of valine and 10 g of sodium bicarbonate is dissolved in 200 ml of ethanol and 100 ml of water. The reaction mixture is refluxed for 3 hours and cooled. Excess 4-fluoronitrobenzene is removed by ether extraction and the aqueous phase is brought to pH 3 to 4 with hydrochloric acid. The oily precipitate is extracted with methylene chloride. After drying and removal of solvent, the residue is treated with 3 equivalents of sodium carbonate and 1 equivalent of m-phenoxybenzyl bromide in dimethylformamide as solvent. After stirring 24 hours the mixture is diluted with water and extracted with ether. The organic phase is washed with water, dried and the solvent removed. The crude ester is purified by preparative TLC to give the m-phenoxybenzyl ester of N-(p-nitrophenyl)valine.
Reaction SMILES: C[O:2][C:3]1[C:8]2[O:9][C:10]([C:12]3[N:16]=[C:15]([CH3:17])[O:14][N:13]=3)=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[C:8]2[O:9][C:10]([C:12]3[N:16]=[C:15]([CH3:17])[O:14][N:13]=3)=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2cc(-c3noc(C)n3)oc12
Agent: BrB(Br)Br
Product: Cc1nc(-c2cc3cccc(O)c3o2)no1
Yield: 94 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 5 using 3-(7-methoxybenzo(b)furan-2-yl)-5-methyl-1,2,4-oxadiazole (1.7 g) and boron tribromide (6.5 ml), the title compound (1.5 g) was obtained as white crystals.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[CH:18]=2)[C@@H:10]1[CH3:26])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>C1COCC1>[Cl:25][C:19]1[CH:18]=[C:17]([N:11]2[C@H:10]([CH3:26])[C@H:9]([OH:8])[C:13]3([CH2:15][CH2:14]3)[C:12]2=[O:16])[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: C[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)C2(CC2)C(=O)N1c1ccc(C#N)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1[C@H](O)C2(CC2)C(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.6 %

Procedure:
To a solution of rac-4-((6R,7R)-7-(tert-butyldimethylsilyloxy)-6-methyl-4-oxo-5-azaspiro[2.4]hept-5-yl)-2-chlorobenzonitrile (140 mg) in THF (5 mL) was added tetrabutylammonium fluoride-THF solution (2.00 mL, 1 mol/L), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/0→3/1) to give the title compound as a colorless solid (yield: 32.3 mg, 32.5%).
Reaction SMILES: OCCCCCCCCCCCCCCC[C:17]([O:19][CH:20]([O:22][C:23](=[O:40])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]CCCCCCCCCO)C)=[O:18].N1C=CC=CC=1.C(OCCCCCCCCCCCCCCCC([Cl:82])=O)(=O)CCCCCCCCCCCCCCC>C1COCC1>[Cl:82][C:17]([O:19][CH2:20][O:22][C:23](=[O:40])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:18]
Reactant: CC(OC(=O)CCCCCCCCCCCCCCCO)OC(=O)CCCCCCCCCCCCCCCO
Reactant: CCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Cl)OCOC(=O)c1ccccc1
Reaction time: 2 h
Yield: 145.8 %

Procedure:
Ethylidene bis (16-hydroxyhexadecanoate) (4.38 g, 7.67 mmol) was dissolved in THF (80 ml) and pyridine (0.61 g, 7.71 mmol) was added. 16-hexadecanoyloxyhexadecanoyl chloride (4.18 g, 7.90 mmol) was dissolved in THF (20 ml) and added dropwise. After 3 days at room temperature the mixture was filtered and the filtrate was left at -20° C. for 2 hours. The precipitated product was filtered and purified by flash chromatography (silicagel, chloroform) to give 2.4 g (29%) of the title compound. 1H NMR (300 MHz, CDCl3): δ0.85 (t, 3H, CH3), 1.2-1.4 (s, 90H, 1.45 (d, --O--CH(CH3)--O--), 1.5-1.7 (m, 14H, --CH2 --), 2.25 (m, 8H, --CH2 --C(O)--O--), 3.60 (t, 2H, --CH2 --OH), 4.05 (t, 4H, --C(O)--O--CH2 --), 6.85 (q, 1H, --O--CH(CH3)--O--). 13C NMR (75 MHz, CDCl3): δ13.7, 19.1, 22.2, 24.2, 24.6, 25.2, 25.5, 28.2, 28.5, 28.7, 28.8, 29.0, 29.2, 31.5, 32.3, 33.7, 34.0, 62.5, 64.0, 88.0, 171.5, 173.5.