Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[NH4+].C([BH3-])#[N:7].[Na+].[Cl:10][C:11]1[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](=O)[CH3:18])=[C:13]([CH3:22])[CH:12]=1>CO>[Cl:10][C:11]1[CH:21]=[CH:20][C:14]([O:15][CH2:16][CH:17]([NH2:7])[CH3:18])=[C:13]([CH3:22])[CH:12]=1
Reactant: CC(=O)COc1ccc(Cl)cc1C
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Cl)ccc1OCC(C)N
Reaction time: 1 h
Yield: 80.3 %

Procedure:
120 g of ammonium acetate and 9.8 g of sodium cyanoborohydride were added to a solution containing 31 g of (4-chloro-2-methylphenoxy)acetone dissolved in 700 mL of methanol, and the resultant mixture was stirred for 20 hours at room temperature. After the reaction mixture was concentrated under reduced pressure. 180 mL of concentrated hydrochloric acid and 100 mL of water were added to the residue. The whole mixture was stirred for 1 hour, and then extracted with 300 mL of diethyl ether. The water layer was alkalified using a 5% aqueous solution of sodium hydroxide, and then extracted with 500 mL of ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. A fraction possessing a low boiling point was removed from the obtained oily products to afford 25 g (yield 81%) of the desired product. Refractive index: 1.5360.
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:13])([CH3:4])([CH3:3])[CH3:2].C(O[CH:21](N(C)C)[N:22]([CH3:24])[CH3:23])(C)(C)C>>[C:1]([Si:5]([CH3:15])([CH3:14])[O:6][CH:7]1[CH2:12][CH2:11][CH2:10]/[C:9](=[CH:21]\[N:22]([CH3:24])[CH3:23])/[C:8]1=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(C)(C)[Si](C)(C)OC1CCCCC1=O
Product: CN(C)/C=C1\CCCC(O[Si](C)(C)C(C)(C)C)C1=O

Procedure:
2-(tert.-Butyldimethylsiloxy)cyclohexanone (118 mg, 0.50 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (85 mg) as a brown oil which was used directly in the next step. MS ISP (m/e): 284.2 (100) [(M+H)+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:28][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:11][C:10]=1[O:37][CH3:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:17][CH2:16][CH:15]([NH:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1)[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([O:37][CH3:38])[CH:11]=1
Reactant: COc1cc(C(CN2C(=O)c3ccccc3C2=O)Nc2ccc(C#N)cc2)ccc1OCc1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc(C(CN)Nc2ccc(C#N)cc2)ccc1OCc1ccccc1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-benzonitrile B was then dissolved in ethanol (60 ml) and hydrazine hydrate (2 g) was added. The solution was heated to 60-70 degrees C. for 1.5 hours. TLC showed reaction was complete. The suspension was filtered to remove by-product and the ethanol removed in vacuo. The residue was submitted to flash chromatography on silica gel (ethyl acetate: 2N NH3 in methanol, 9:1) to yield 372 mg of 4-[2-Amino-1-(4-benzyloxy-3methoxy-phenyl)-ethylamino]-benzonitrile D (100%). 1HNMR(CDCl3): 7.3-7.45 (m, 7H), 6.32 (m, 3H), 6.5 (d, 2H), 5.52 (d, 1H), 4.3 (q, 1H), 3.83 (s, 3H), 3.08 (m, 2H), 1.95 (s,
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH2:10])=[S:9].Br[C:12](=[CH:15]O)[CH:13]=[O:14].C([O-])(=O)C.[Na+]>CC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:12]([CH:13]=[O:14])=[CH:15][N:10]=1
Reactant: NC(=S)Nc1ccccn1
Reactant: O=CC(Br)=CO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=Cc1cnc(Nc2ccccn2)s1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 51.9 %

Procedure:
To a solution of 1-(2-pyridyl)-2-thiourea (765 mg, 5.0 mmol) in acetone (14 mL) was added slowly 2-bromo-3-hydroxypropenal (755 mg, 5.0 mmol, for preparation see J. Org. Chem. 28, 3243, 1963) in acetone (14 mL) over a period of 5 min. After stirring for 1.5 h, a precipitate formed. The solids were separated, washed with acetone (10 mL) and then taken into mixed solvent (ethanol/water=1/1, 9 mL). To this suspension was added sodium acetate (1.23 g, 15.0 mmol) and the resulting mixture was heated at 75° C. for 1 h. After cooling to RT, the mixture was filtered and the solids were washed with water (10 mL), and dried in vacuo to provide compound A, 2-(pyridin-2-ylamino)-thiazole-5-carbaldehyde (533 mg, 52%) as a solid. LC/MS; (M+H)+=206
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH2:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:21][CH3:22]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:26]3[CH2:27][CH2:28][N:23]([CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CCCN1CCNCC1
Product: CCCN1CCN(C(=O)N2Cc3ccccc3Oc3ccc(Cl)cc32)CC1
Yield: 88.4 %

Procedure:
The title compound of Example 2 (1.0 g, 3.4 mmol) was combined with 1-propylpiperazine (0.44 g, 3.4 mmol) and the reaction was carried out by the method of Example 4. Following chromatographic purification, 1.16 g of the title product was obtained as a white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:6][C:5]=1[O:19][CH3:20])[CH3:2].[BH4-].[Na+]>O>[CH2:1]([NH:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([CH:12]([OH:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:6][C:5]=1[O:19][CH3:20])[CH3:2]
Reactant: CCNc1c(OC)cc(C(=O)CS(C)(=O)=O)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCNc1c(OC)cc(C(O)CS(C)(=O)=O)cc1OC

Procedure:
A suspension of 48 g. of 4'-(ethylamino)-3',5'-dimethoxy-2-(methylsulfonyl)-acetophenone and 23.8 g. of sodium borohydride in 1 liter of alcohol was stirred at room temperature for 20 hours, resulting in a solution. After the addition of 1 liter of water, the alcohol was evaporated under vacuum. The crystals formed were removed by filtration with suction, washed with water and dried, whereby there was obtained 4-(ethylamino)-3,5-dimethoxy-α-[(methylsulfonyl)-methyl]-benzyl alcohol having a melting point of 121°-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[C:15]([C:17]1[C:18]([C:31]([F:34])([F:33])[F:32])=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][C:27](=[NH:30])[NH:28]O)[CH:21]=[CH:20]2)#[N:16]>CC#N>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:8][N:30]=[C:27]([CH2:26][N:22]3[C:23]4[C:19](=[C:18]([C:31]([F:34])([F:32])[F:33])[C:17]([C:15]#[N:16])=[CH:25][CH:24]=4)[CH:20]=[CH:21]3)[N:28]=2)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Solvent: CC#N
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(Cl)c(C(F)(F)F)c3)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
4-Chloro-3-(trifluoromethyl)benzoic acid (0.016 g, 0.071 mmol) and CDl (0.012 g, 0.071 mmol) were combined in in CH3CN (3 mL). 2-[5-Cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (0.020 g, 0.071 mmol) was added after 5 min. After stirring at rt for 1 h, the reaction was heated at 150° C. in a microwave for 10 min. Purification (SiO2, EtOAc/hexanes) afforded the title compound (0.022 g): MS (ESI): m/z 471 (M+1).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>OS(O)(=O)=O>[N+:10]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH2:3][NH:2][CH2:1]2)([O-:12])=[O:11]
Reactant: c1ccc2c(c1)CNC2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc2c(c1)CNC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of isoindoline (2 g, 16.8 mmol) at 0° C., was added slowly concentrated H2SO4 (10 mL). Then a mixture of 70% HNO3 (2.1 mL, 33.6 mmol) and concentrated H2SO4 (2 mL) was added. After addition the mixture was stirred at 0° C. for 30 min. The reaction mixture was poured into ice water. The mixture was carefully neutralized with 50% aq. NaOH to pH 10 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 5-nitroisoindoline as a brown solid. LCMS calc.=165.1; found=164.9 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 8.11 (d, J=8.0 Hz, 2H); 7.39 (d, J=7.8 Hz, 1H); 4.33 (s, 4H); 2.31 (br s, 1H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH2:20][CH:21]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:43][C:40]1[CH:39]=[CH:38][C:37]([CH:30]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[N:31]2[CH2:32][CH2:33][N:34]([CH2:21][CH2:20][CH2:19][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:35][CH2:36]2)=[CH:42][CH:41]=1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(C(c4ccc(F)cc4)c4ccc(F)cc4)CC3)nn2-c2ccccc2)cc1

Procedure:
150 mg (91%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80 mg, 0.276 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (80 mg, 0.276 mmol), DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)3 (175 mg, 0.828 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][N:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]([CH3:30])([CH3:29])[C:26](Cl)=[O:27].ClCCl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:26](=[O:27])[C:25]([CH3:30])([CH3:29])[CH3:24])[CH2:10][N:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)CN1C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC(OC(=O)C(C)(C)C)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
4-Hydroxypyrazolidine-1,2-dicarboxylic acid 1-benzyl ester 2-tert-butyl ester, 28, (1.42 mg, 4.40 mmol) is dissolved in pyridine (22 mL). 4-Dimethylamino-pyridine (10 mg) is added followed by trimethylacetyl chloride (1.63 mL, 13.2 mmol). The reaction is stirred at ambient temperature for 12 hours. The cloudy reaction mixture is then concentrated in vacuo to afford a white residue. Dichloro-methane (75 mL) is added to the residue and the mixture washed with a 1.0 N aqueous solution of hydrochloric acid (75 mL). The aqueous layer is extracted with dichloro-methane (75 mL), the combined organic layers washed with a saturated aqueous solution of NaHCO3 (75 mL), water (75 mL), brine (75 mL), then dried, filtered and concentrated in vacuo to afford the crude product. The crude product is purified over silica(4:1 to 1:1 hexane/ethyl acetate) to afford 1.76 g (98% yield) of the desired product as a clear, viscous oil.
Reaction SMILES: [O:1]=[C:2]([CH2:10][C@@H:11]1[C@@H:15](/[CH:16]=[CH:17]/[C@@H:18]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:19]([CH3:24])[CH2:20][C:21]#[C:22][CH3:23])[C@H:14]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:13][C@@H:12]1[OH:39])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(O)(C)C>CC(C)=O>[O:1]=[C:2]([CH2:10][C@@H:11]1[C@@H:15](/[CH:16]=[CH:17]/[C@@H:18]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:19]([CH3:24])[CH2:20][C:21]#[C:22][CH3:23])[C@H:14]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:13][C:12]1=[O:39])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC#CCC(C)[C@@H](/C=C/[C@@H]1[C@@H](CC(=O)CCCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CC#CCC(C)[C@@H](/C=C/[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CC(=O)CCCCC(=O)O)OC1CCCCO1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 40.6 %

Procedure:
The solution of 396 mg of (13E)-(9S,11R,15S,16RS)-6-oxo-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)-16-methyl-18,18,19,19-tetradehydro-13-prostenoic acid in 8 ml of absolute dimethylketone was cooled, with exclusion of moisture, to -30° C., was mixed with 270 microliters of Jones solution and stirred for 1.5 h at -30° C. to -20° C. After addition of 2 ml of isopropanol, it was poured onto 50 ml of ice water, extracted several times with a total of 100 ml of diethyl ether, washed neutral with saturated sodium chloride solution, dried on magnesium sulfate, filtered and concentrated by evaporation in a vacuum. The colorless raw oil was chromatographed on plates coated with silica gel with hexane-ethyl acetate. Besides the initial material, 160 mg (41%) of the title compound was isolated as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:16](=[O:17])[N:15]=[C:14]2[N:4]([C@@H:5]3[O:9][C@H:8]([CH2:10][OH:11])[C@@H:7]([OH:12])[C@@H:6]3[O:13]2)[CH:3]=1.[CH3:18][SH:19].CN(C)C(N(C)C)=N>CN(C=O)C>[CH3:18][S:19][C@@H:6]1[C@H:7]([OH:12])[C@@H:8]([CH2:10][OH:11])[O:9][C@H:5]1[N:4]1[CH:3]=[C:2]([CH3:1])[C:16](=[O:17])[NH:15][C:14]1=[O:13]
Reactant: Cc1cn2c(nc1=O)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Reactant: CS
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: CS[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Reaction time: 12 h
Yield: 74.1 %

Procedure:
2,2′-Anhydro-5-methyluridine (17.02 g, 70.6 mmol), methanethiol (16.3 g, 339 mmol), 1,1,3,3-tetramethylguanidine (40.6 g, 353 mmol) and DMF (150 mL) were heated at 60° C. After 12 hours, the products were cooled and concentrated under reduced pressure. The residual oil was purified by short silica gel column chromatography (300 g). Pooling and concentrating appropriate fractions, which were eluted with CH2Cl2—MeOH (93:7), furnished the title compound as a white foam (15.08 g, 74.1%), which was crystallized from EtOH—CH2Cl2 as white needles.
Reaction SMILES: C([O:5][C:6](=[O:71])[CH2:7][N:8]1[CH2:16][CH2:15][N:14]([CH2:17][CH:18]([NH:54][CH2:55][C:56]([O:58]C(C)(C)C)=[O:57])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:53])[CH2:28][CH2:29][CH:30]([CH:32]3[C:48]4([CH3:49])[CH:35]([CH:36]5[CH:45]([CH2:46][CH:47]4[OH:50])[C:44]4([CH3:51])[CH:39]([CH2:40][CH:41]([OH:52])[CH2:42][CH2:43]4)[CH2:38][CH2:37]5)[CH2:34][CH2:33]3)[CH3:31])=[CH:22][CH:21]=2)[CH2:13][CH2:12][N:11]([CH2:63][C:64]([O:66]C(C)(C)C)=[O:65])[CH2:10][CH2:9]1)(C)(C)C.Cl.CCOCC>O1CCOCC1>[C:6]([CH2:7][N:8]1[CH2:16][CH2:15][N:14]([CH2:17][CH:18]([NH:54][CH2:55][C:56]([OH:58])=[O:57])[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:53])[CH2:28][CH2:29][CH:30]([CH:32]3[C:48]4([CH3:49])[CH:35]([CH:36]5[CH:45]([CH2:46][CH:47]4[OH:50])[C:44]4([CH3:51])[CH:39]([CH2:40][CH:41]([OH:52])[CH2:42][CH2:43]4)[CH2:38][CH2:37]5)[CH2:34][CH2:33]3)[CH3:31])=[CH:24][CH:25]=2)[CH2:13][CH2:12][N:11]([CH2:63][C:64]([OH:66])=[O:65])[CH2:10][CH2:9]1)([OH:71])=[O:5]
Reactant: CC(CCC(=O)Nc1ccc(CC(CN2CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC2)NCC(=O)OC(C)(C)C)cc1)C1CCC2C3CCC4CC(O)CCC4(C)C3CC(O)C12C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(CCC(=O)Nc1ccc(CC(CN2CCN(CC(=O)O)CCN(CC(=O)O)CC2)NCC(=O)O)cc1)C1CCC2C3CCC4CC(O)CCC4(C)C3CC(O)C12C
Temperature: 25 °C
Reaction time: 1.8 h
Yield: 115 %

Procedure:
To a solution of Compound 8 (20 mg, 0.02 mmol) in 1,4 dioxane (1 mL) was dropwise added 4M HCl in 1,4-dioxane (1 mL) at 0-5° C. After the addition, the reaction mixture was gradually increased to room temperature and stirred for 1.8 h. To this solution, ether (30 mL) was added and continuously stirred for 30 min. The resulting mixture was placed in the freezer for 2 h. Solid residue was quickly filtered, washed with ethyl ether (5 mL), and immediately dissolved in DI H2O and lypophilized to provide pure DCA-NE3TA as a light brownish solid (19 mg, 98%). 1H NMR (CD3OD) 0.71 (s, 3H), 0.92-3.90 (m, 55H), 3.97 (s, 1H), 4.09 (s, 1H), 7.28 (d, 2H), 7.57 (d, 2H); 13C NMR (CD3OD) 11.86, 16.39, 22.35, 23.50, 26.09, 27.02, 27.33, 28.53, 29.68, 31.79, 33.43, 33.63, 33.73, 33.91, 35.04, 35.55, 35.79, 36.05, 42.21, 44.44, 46.17, 71.16, 72.65, 120.41, 129.55, 130.54, 167.99, 173.96 HRMS (Positive ion FAB) Calcd for C45H72N5O9 [M+H]+ m/z 826.5330. Found: [M+H]+ m/z 826.5355.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:31])[C@@H:14]([NH:16][C:17](=[O:30])[C@@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6].C([O-])(=O)C.[NH4+]>O1CCCC1.O.[Zn]>[C:26]([O:25][C:23]([NH:22][C@@H:18]([CH:19]([CH3:21])[CH3:20])[C:17]([NH:16][C@@H:14]([CH3:15])[C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:7]([C:5]([OH:6])=[O:4])[NH:8]1)=[O:31])=[O:30])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)O)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Zinc dust (273 mg, 4.18 mmol) was added to a solution of (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (98 mg, 0.19 mmol) in tetrahydrofuran (15 mL). This suspension was treated with a solution of ammonium acetate (220 mg, 2.85 mmol) in water (5 mL). After stirring at room temperature for 3 h, zinc residues were filtered off and the volatiles were removed in vacuo. The residue was partitioned between ethyl acetate and saturated potassium hydrogen sulfate solution and the volatiles were removed in vacuo. The residual acetic acid was removed by azeotroping with toluene (3×10 mL) to give crude (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid which was combined with crude (E)-2,2-dimethyl-4-[2-((R)-1-methylamino-ethyl)-quinolin-7-yl]-but-3-enoic acid methyl ester in anhydrous acetonitrile (10 mL) and N,N-diisopropylethylamine (0.165 mL, 0.95 mmol). This solution was then treated with 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (94 mg, 0.25 mmol). After stirring at room temperature for 16 h, the volatiles were removed in vacuo. The residue was dissolved in ethyl acetate, and subsequently washed with saturated ammonium chloride solution and sodium bicarbonate solution. The organics were combined and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 10 g Biotage cartridge eluted with a continuous gradient of iso-hexanes/acetone 1:0 to 1:1 to afford the title compound (90 mg, 68%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 0.82-1.00 (m, 6H), 1.28-1.40 (m, 3H), 1.50-1.55 (m, 15H), 1.69 (d, J=6.9 Hz, 3H), 1.73-2.12 (m, 5H), 2.76-2.92 (m, 5H), 3.74 (s, 3H), 3.84-4.00 (m, 1H), 4.25-4.45 (m, 1H), 5.22-5.40 (m, 1H), 6.25 (q, J=6.9 Hz, 1H), 6.57-6.74 (m, 2H), 7.35-7.48 (m, 1H), 7.69-7.77 (m, 1H), 7.80-7.88 (m, 1H), 7.90-8.00 (m, 2H), 8.18-8.30 (m, 1H). LCMS (m/z) 695.4 [M+H], Tr=3.00 min.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH:18]=O)[CH3:13].Cl>CO>[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:18]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH3:13]
Reactant: CCOc1ccc(C=O)cc1OCC
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CO
Product: CCOc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OCC
Temperature: 25 °C

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3,4-diethoxybenzaldehyde 1.58 ml were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.27 g.
Reaction SMILES: CC([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9]C=2)[C:5]=1[OH:14])=O.C12C(=[O:24])C(CCC1)CCC2.N1CCCC1>C1(C)C=CC=CC=1>[O:14]1[C:5]2[C:6](=[CH:11][CH:12]=[CH:13][CH:4]=2)[CH2:7][CH2:8][CH:9]1[OH:24]
Reactant: O=C1C2CCCC1CCC2
Reactant: CC(=O)c1ccc2ccccc2c1O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: OC1CCc2ccccc2O1
Reaction time: 10 h

Procedure:
A solution was prepared by dissolving 10 g (0.054 mole) of 1-hydroxy-2-acetonaphthone, 8.29 g (0.06 mole) of bicyclo[3,3,1]nonan-9-one and 8 g (0.113 mole) of pyrrolidine in 300 cc of toluene, and the solution was boiled for 10 hours and water was separated. After termination of the reaction, toluene was removed under reduced pressure, and the remaining chromanone compound was crystallized with acetone. Then, the chromanone compound was dissolved in 200 cc of methanol and sodium boron hydride was gradually added to the solution to form a chromanol compound. Then, 7.47 g of this chromanol compound was heated at 150° C. to 160° C. together with 4.5 g of anhydrous copper sulfate in a carbon dioxide current for 10 minutes, and the obtained brown viscous liquid was purified by the chromatography on silica gel to obtain 6.9 g of a chromene compound represented by the following formula: ##STR161##
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10](OC(C)(C)C)=[O:11])=[CH:6][C:5]([Br:17])=[CH:4][N:3]=1.C[O-].[Na+].O>CO>[Br:17][C:5]1[CH:6]=[C:7]2[C:2](=[N:3][CH:4]=1)[NH:1][C:10](=[O:11])[CH:9]=[CH:8]2
Reactant: CC(C)(C)OC(=O)/C=C/c1cc(Br)cnc1N
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=c1ccc2cc(Br)cnc2[nH]1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A solution of (E)-tert-butyl 3-(2-amino-5-bromopyridin-3-yl)acrylate (2.5 g, 8.35 mmol) in anhydrous methanol (50 mL) was treated with sodium methoxide (8.5 mL of a 4.9 M solution, 41.75 mmol). The solution was heated at reflux for 2 h then cooled to room temperature. The mixture was cooled in an ice-H2O bath and treated with H2O (100 mL) under rapid stirring to give a precipitate. The solid was filtered and washed with H2O (20 mL). The filtrate was neutralized with 1 M HCl(aq) to form a precipitate. The solid was filtered and washed with H2O (20 mL). The solids were combined and dried under reduced pressure to give an off-white solid (1.75 g, 93%). NMR (300 MHz, DMSO-d6) δ 8.43 (d, 1H, J=2.5 Hz), 8.06 (d, 111, J=2.5 Hz), 7.60 (d, 1H, J=9.1 Hz), 6.44 (d, 1H, J=9.1 Hz); ESI MS m/z 225 (100%); 227 (100%) [C8H5N2OBr+H]+
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:11])([CH2:9][CH3:10])[NH:3]1.[OH-].[K+]>C(O)COCCO.O>[CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][CH2:5][C:4]([CH3:11])([CH2:9][CH3:10])[NH:3]1
Reactant: CCC1(C)CC(=O)CC(C)(C)N1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCC1(C)CCCC(C)(C)N1
Yield: 19.3 %

Procedure:
33.8 g (0.2 mol) 2,2,6-trimethyl-6-ethyl-4-oxopiperidine, 14 g (0.28 mol) hydrazinhydrate and 13 g KOH in 80 ml diethylenglykol are stirred for 4 h at 160° C. Subsequently an additional amount of 30 g KOH dissolved in 30 ml water are added. 30 ml are distilled off. To the residue two times 40 ml of water are added and removed by distillation. The combined distillates are saturated with solid K2CO3 and extracted with methyl-tert.-butylether. From the extracts 6 g ( 19%) 2,2,6-trimethyl-6-ethyl-piperidin are isolated by fractionated distillation. A colorless liquid is obtained with a b. p. of 78-88° C./15 mbar.