Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH:2]1[CH2:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH:8]([CH3:14])[CH:7]([CH3:15])[C:6]([CH3:17])([CH3:16])[C:5]=2[C:4](=[O:18])[CH2:3]1.CC1(C)C(C)C(C)C(C)(C)C2CC(=O)CCC1=2>>[CH3:13][C:9]1([CH3:12])[CH:8]([CH3:14])[CH:7]([CH3:15])[C:6]([CH3:17])([CH3:16])[C:5]2[C:4](=[O:18])[CH2:3][CH2:2][CH2:11][C:10]1=2
Reactant: CC1CC(=O)C2=C(C1)C(C)(C)C(C)C(C)C2(C)C
Agent: CC1C(C)C(C)(C)C2=C(CCC(=O)C2)C1(C)C
Product: CC1C(C)C(C)(C)C2=C(CCCC2=O)C1(C)C

Procedure:
The addition of 100 parts by weight of (6RS,7RS)-5,5,6,7,8,8-hexamethyl-3,4,5,6,7,8-hexahydronaphthalen-1(2H)-one to the above-described eau de toilette imparted to the latter a powerful musky and earthy connotation, having also a well appreciated aspect which is slightly ambrette and pine. The overall effect was in-between the one which could have been brought by the addition of CASHMERAN® or TONALIDE®, however the substantivity was by far superior to that which could have been imparted by the addition of CASHMERAN®, and its musky-ambrette character was more elegant than the one provided by TONALIDE®. The addition of (6RS,7RS)-3,5,5,6,7,8,8-heptamethyl-3,4,5,6,7,8-hexahydronaphthalen-1(2H)-one or (6RS,7RS)-5,5,6,7,8,8-hexamethyl-3,4,5,6,7,8-hexahydronaphthalen-2(1H)-one, instead of (6RS,7RS)-5,5,6,7,8,8-hexamethyl-3,4,5,6,7,8-hexahydronaphthalen-1(2H)-one, to the above-described eau de toilette provided a more classic fragrance, wherein the earthy-woody effect was more pronounced than the one which could have been obtained by the addition of TONALIDE®.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]12([CH2:22][NH2:23])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([NH:23][CH2:22][C:12]12[CH2:21][CH:16]3[CH2:15][CH:14]([CH2:20][CH:18]([CH2:17]3)[CH2:19]1)[CH2:13]2)=[O:6]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cc(O)ccc1Cl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(O)ccc1Cl

Procedure:
Prepared according to the method of Example 14 from 2-chloro-5-hydroxybenzoic acid (0.3 g) and 1-adamantanemethylamine (0.31 ml) to give the title compound as a white solid (0.15 g).
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[N+:7]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1)([O-:9])=[O:8].Cl>O1CCCC1>[OH:15][C@@H:14]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:13]1[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:17][CH:16]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COP([O-])OC
Agent: Cl
Solvent: C1CCOC1
Product: COP(=O)(OC)[C@H](O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
Dimethyl phosphite (37 μl, 0.40 mmol) was added to the solution of ALB in tetrahydrofuran (0.1 M, 0.40 ml) obtained in Example 1 at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -78° C., and it was maintained at this temperature for 15 minutes. Then p-nitrobenzaldehyde (0.40 mmol) was added thereto. After the temperature was raised to room temperature, the stirring was continued for 12 hours. Hydrochloric acid (1N) was added thereto to stop the reaction, and the mixture was extracted with ethyl acetate (10 ml×three times). The combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S)-hydroxy(p-nitrophenyl)methylphosphonate as a final product in a yield of 81%. The chemical reaction in this Example is shown in chemical formula 31. ##STR25##
Reaction SMILES: Cl[C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:16])[CH2:11][C:12]2=[O:15])[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6](=[O:20])[C:5]3=[CH:4][C:3]=1[Cl:21].[CH2:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH3:23]>COCCO>[Cl:21][C:3]1[CH:4]=[C:5]2[C:14]3[N:9]([CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6]2=[O:20])[CH:10]([CH3:16])[CH2:11][C:12](=[O:15])[C:13]=3[C:2]=1[N:27]1[CH2:28][CH2:29][N:24]([CH2:22][CH3:23])[CH2:25][CH2:26]1
Reactant: CCN1CCNCC1
Reactant: CC1CC(=O)c2c(Cl)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Solvent: COCCO
Product: CCN1CCN(c2c(Cl)cc3c(=O)c(C(=O)O)cn4c3c2C(=O)CC4C)CC1
Reaction time: 2 h
Yield: 80 %

Procedure:
3.26 g (0.01 mole) of 8, 9-dichloro-5-methyl-6, 7-dihydro-1,7-dioxo-1H, 5H-benzo[ij]quinolizine-2-carboxylic acid was suspended in 30 ml of methyl cellosolve, 3.43 g (0.03 mole) of N-ethylpiperazine was added thereto, and this mixture was stirred at 100°-110° C. for 2 hours. The resulting reaction solution was evaporated to dryness under reduced pressure. 30 ml of methanol was added to the resulting residue and this mixture was stirred. The insoluble matter was collected by filtration and recrystallized from ethanol to obtain 3.23 g (80.0% yield) of 9-chloro-5-methyl-8-(4-ethyl-1-piperazinyl)-6,7-dihydro-1, 7-dioxo-1H, 5H-benzo[ij]quinolizine-2-carboxylic acid in the form of yellow crystals. These crystals had a melting point of 295°-298° C. (dec.).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.I[CH2:13][CH3:14].Cl>CN(C)C=O>[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:9][CH2:13][CH3:14])=[CH:6][CH:5]=1
Reactant: CCI
Reactant: OCc1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOCc1ccc(Br)cc1
Reaction time: 2 h
Yield: 49.4 %

Procedure:
NaOH (0.1 g, 2.4 mmol) was added to 2 ml of degassed dimethylformamide and 4-bromobenzylalcohol (0.3 g, 1.6 mmol) was further added slowly. Iodoethane (0.14 ml, 1.76 mmol) was added at room temperature followed by stirring for 2 hours. The mixture was added with 50 ml of 2N c HCl and extracted with 50 ml of ethylacetate. The organic layer was washed twice with 50 ml of H2O. After concentration under vacuum and column chromatography (ethylacetate/n-hexane, 1/10), the title compound (0.17 g, 48%) was obtained as yellowish oil.
Reaction SMILES: [CH3:1][N:2]([CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[CH2:17][N:18]3[C:22]([CH3:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[N:19]3)[CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4].C([N-]C(C)C)(C)C.[Li+].Cl[C:48]([O:50][CH2:51][CH3:52])=[O:49]>O1CCCC1>[CH3:1][N:2]([CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[CH:17]([N:18]3[C:22]([CH3:23])=[CH:21][C:20]([C:24]([F:26])([F:25])[F:27])=[N:19]3)[C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)C3CCCc4ccccc43)cs2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)N1CCC(c2nc(C(=O)N(C)C3CCCc4ccccc43)cs2)CC1)n1nc(C(F)(F)F)cc1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-methyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-4-thiazolecarboxamide (120 mg, 0.23 mmol) (i.e. the product of Example 2, Step E) in tetrahydrofuran (5 mL) at −78° C. was added a solution of lithium diisopropylamide in tetrahydrofuran (0.5 M, 2.0 mL, 1 mmol). After stirring at −78° C. for 30 minutes, a solution of ethyl chloroformate (100 μL) in tetrahydrofuran (2 mL) was added. The reaction mixture was stirred at −78° C. for 30 minutes more and then at 0° C. for 30 minutes. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated under reduced pressure, and the residue was purified by medium-pressure liquid chromatography using 75-100% of ethyl acetate in hexanes as eluant to provide 4 mg of the title product, a compound of the present invention.
Reaction SMILES: C([O-])(=O)C.[Na+].I[CH2:7][C:8]#[N:9].[CH3:10][C@@H:11]1[O:16][C@@H:15]([O:17][C@@H:18]2[C:23]3=[C:24]([OH:41])[C:25]4[C:37](=[O:38])[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][C:35]=5[O:39][CH3:40])[C:29](=[O:30])[C:26]=4[C:27]([OH:28])=[C:22]3[CH2:21][C@@:20]([OH:45])([C:42]([CH3:44])=[O:43])[CH2:19]2)[CH2:14][C@H:13]([NH2:46])[C@@H:12]1[OH:47]>CN(C=O)C>[CH3:10][CH:11]1[O:16][CH:15]([O:17][CH:18]2[C:23]3[C:22](=[C:27]([OH:28])[C:26]4[C:29](=[O:30])[C:31]5[CH:32]=[CH:33][CH:34]=[C:35]([O:39][CH3:40])[C:36]=5[C:37](=[O:38])[C:25]=4[C:24]=3[OH:41])[CH2:21][C:20]([OH:45])([C:42]([CH3:44])=[O:43])[CH2:19]2)[CH2:14][CH:13]([NH:46][CH2:7][C:8]#[N:9])[CH:12]1[OH:47]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(C)=O)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Reactant: N#CCI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)CC(O)(C(C)=O)CC3OC1CC(NCC#N)C(O)C(C)O1
Temperature: 25 °C
Reaction time: 44 h

Procedure:
A sample of 0.017 grams (0.21 mmol) of anhydrous sodium acetate and 15 μl (0.033 g, 0.197 mmol) of iodoacetonitrile were added to a solution of 0.065 grams (0.123 mmol) of daunorubicin, free base, in 1 ml of dry DMF, and the dark red mixture thus obtained stirred at room temperature in the dark for 44 hours until thin layer chromatography (TLC) run on aliquots of the reaction mixture showed conversion to the desired product. The reaction mixture was then evaporated at low temperature and pressure (about 35°, <5 mm), the residue dissolved in 10 ml chloroform/methanol (9/1) and the solution washed with acetic acid, water, and sodium bicarbonate and dried. The organic layer was evaporated, and the residue further purified to obtain 0.059 g (84%) of the desired N-cyanomethylDau. Daunorubicin (0.010 g) was recovered from the acetic acid extract.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][N:13]1[S:18]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:35]3[C:30](=[C:31]([F:39])[C:32]([F:38])=[C:33]([F:37])[C:34]=3[F:36])[NH:29][CH:28]=2)[CH2:23][CH2:22]1)(=[O:20])=[O:19])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40][N:41]([CH3:45])[C:42](Cl)=[O:43]>C(Cl)Cl>[CH2:1]([O:8][NH:9][C:10]([C@H:12]1[CH2:17][N:16]([C:42]([N:41]([CH3:45])[CH3:40])=[O:43])[CH2:15][CH2:14][N:13]1[S:18]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:35]3[C:30](=[C:31]([F:39])[C:32]([F:38])=[C:33]([F:37])[C:34]=3[F:36])[NH:29][CH:28]=2)[CH2:23][CH2:22]1)(=[O:20])=[O:19])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: O=C(NOCc1ccccc1)[C@H]1CNCCN1S(=O)(=O)N1CCC(c2c[nH]c3c(F)c(F)c(F)c(F)c23)CC1
Solvent: ClCCl
Product: CN(C)C(=O)N1CCN(S(=O)(=O)N2CCC(c3c[nH]c4c(F)c(F)c(F)c(F)c34)CC2)[C@@H](C(=O)NOCc2ccccc2)C1
Reaction time: 14 h
Yield: 67 %

Procedure:
A solution of N-benzyloxy-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]-piperazine-2-(R)-carboxamide (12 g, 21.08 mmol) [prepared as described in Step 5 above] and 2,6-luitidine (4.0 ml, 33.73 mmol) in methylene chloride (100 ml) was treated with dimethylcarbamoyl chloride (3.10 ml, 33.73 mmol) and stirred for 14 h. The reaction mixture was washed with 3M aqueous HCl solution (20 ml), brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed (SiO2, 30% ethyl acetate/hexane then 5% methanol/methylene chloride). The product was dissolved in ethyl acetate (25 ml) and added dropwise to hexane (200 ml) with vigorous stirring. The solid was filtered to give N-benzyloxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide (67%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][CH:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17]C)[CH:14]=2)[NH:9][C:8]1=[O:19])[CH3:2]>C(O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][CH:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:17])[CH:14]=2)[NH:9][C:8]1=[O:19])[CH3:2]
Reactant: CCOC(=O)CCC1Cc2cc(OC)ccc2NC1=O
Solvent: CCO
Product: CCOC(=O)CCC1Cc2cc(O)ccc2NC1=O

Procedure:
Using the conditions of Example 73 and 3-(6-methoxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-propionic acid ethyl ester in place of (7-methoxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)acetic acid methyl ester and in the presence of ethyl alcohol the title compound was prepared.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[N:7]([CH3:22])[C:6]=2[N:23]=1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][O:32][C:33]2[CH:38]=[N:37][NH:36][C:35](=[O:39])[CH:34]=2)=[N:29][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][O:32][C:33]2[CH:38]=[N:37][N:36]([C:2]3[CH:3]=[CH:4][C:5]4[C:14]5[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=5[N:7]([CH3:22])[C:6]=4[N:23]=3)[C:35](=[O:39])[CH:34]=2)=[N:29][CH:30]=1
Reactant: Cn1c2c(c3ccc(Br)nc31)CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(OCc2ccc(F)cn2)cn[nH]1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ncc(OCc5ccc(F)cn5)cc4=O)nc31)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 110 °C
Reaction time: 6 h
Yield: 0 %

Procedure:
tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.18 g, 0.48 mmol), 5-((5-fluoropyridin-2-yl)methoxy)pyridazin-3(2H)-one (0.11 g, 0.51 mmol), and Cs2CO3 (0.20 g, 0.63 mmol) were suspended in DMSO (2.8 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (21 mg, 0.15 mmol) and copper iodide (0.23 mg, 1.2 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 110° C. for 18 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (20 mL), and the resulting solution was stirred at ambient temperature for 6 h. The resulting solution was diluted with CH2Cl2, the resulting layers were separated, and the aqueous phase was extracted with CH2Cl2 (3×25 mL). Activated charcoal was added to the combined organic extracts, and the resulting suspension was filtered through a silica gel plug. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes, increased to 50:50 over 10 column volumes and held for 4 column volumes, then increased to 0:100 over 10 column volumes and held for 4 column volumes) gave the title compound (0.12 mg, 56%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J=3.0 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.96 (d, J=3.0 Hz, 1H), 7.86-7.82 (m, 1H), 7.72-7.67 (m, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.51 (d, J=3.0 Hz, 1H), 5.30 (s, 2H), 3.69-3.67 (m, 5H), 3.60-3.57 (m, 2H), 3.08-3.05 (m, 2H), 2.98-2.96 (m, 2H), 1.44-1.42 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12](=[O:20])[NH:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[N:9][C:8]([C@@H:21]([NH:23]C(=O)OCC1C3C=CC=CC=3C3C1=CC=CC=3)[CH3:22])=[CH:7]2>N1CCOCC1>[NH2:23][C@H:21]([C:8]1[N:9]=[C:10]([C:12]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:20])[C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])[CH3:22]
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(C(=O)NC2CCOCC2)n1
Solvent: C1COCCN1
Product: C[C@H](N)c1cc2cccc(Cl)c2c(C(=O)NC2CCOCC2)n1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
(S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-(tetrahydro-2H-pyran-4-ylcarbamoyl)isoquinolin-3-yl)ethylcarbamate (351) (20.0 g, 36.0 mmol, 1.0 eq) was suspended in morpholine (200 mL), and then stirred at 40-50° C. for 1 h. The reaction mixture was concentrated in vacuo and then 1,4-dioxane (200 mL) was added to the residue. The mixture was concentrated in vacuo. The operation was repeated for 3-4 times. The residue was purified by flash column chromatography on silica gel (2-10% MeOH-DCM) to afford (S)-3-(1-aminoethyl)-8-chloro-N-(tetrahydro-2H-pyran-4-yl)isoquinoline-1-carboxamide (352).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[CH:11][N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:15]([O:17]CC)=[O:16])=[N:3]1.C(O)C.[OH-].[K+:24]>>[CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[CH:11][N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:15]([O-:17])=[O:16])=[N:3]1.[K+:24]
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cncnc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(C(=O)[O-])c2c1-c1ncncc1CC2
Yield: 80 %

Procedure:
The suspension of 440 mg (1.74 mmol) of ethyl 1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate in ethanol (30 ml) 300 mg (5.2 mmol) of potassium hydroxide was heated at reflux for 2 hours. The volatiles were removed under vacuum, the residue was diluted with ethanol (3 ml) and the solid filtered to provide potassium 1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate 374 mg (80%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[CH3:9].[C:17]([N:21]1[C:26](=[O:27])[C:25]([Cl:28])=[C:24]([OH:29])[CH:23]=[N:22]1)([CH3:20])([CH3:19])[CH3:18].CN(C)C=O>O>[C:17]([N:21]1[C:26](=[O:27])[C:25]([Cl:28])=[C:24]([O:29][CH:8]([CH3:9])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:23]=[N:22]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Reactant: Cc1ccc(C(C)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(C)Oc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.3 %

Procedure:
1.5 g of anhydrous potassium carbonate and 1.3 g of 4-(α-chloroethyl)toluene were added to 1.5 g of 2-tert.-butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone dissolved into 10 ml of N,N-dimethylformamide, and the resulting mixture was heated under stirring in an oil bath of 80° to 110° C. for 4 hours. After being allowed to cool to room temperature, 100 ml of water was added to the reaction mixture, followed by stirring. Oily matter separated from the reaction mixture was extracted with 50 ml of chloroform. The aqueous layer was extracted with 30 ml of chloroform again, the chloroform layers were combined, washed with water, and dried over anhydrous sodium sulfate. Chloroform was distilled off under reduced pressure, and the residue was recrystallized from isopropyl ether-petroleum ether mixer to obtain 1.1 g of the intended compound (Compound No. 1.78) having m.p. 104°-105.5° C. (yield: 48.1%)
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2].C(O)(=O)C.C(O)(=O)C.[CH:64]1[C:73]2[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=2)[CH:67]=[CH:66][C:65]=1[Bi](C1C=CC2C(=CC=CC=2)C=1)C1C=CC2C(=CC=CC=2)C=1.C(O)(=O)C.C(=O)(O)O.C1C2C(=CC=CC=2)C=CC=1[Bi](C1C=CC2C(=CC=CC=2)C=1)C1C=CC2C(=CC=CC=2)C=1>C(Cl)Cl.C([O-])(O)=O.[Na+].CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:66]3[CH:65]=[CH:64][C:73]4[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=4)[CH:67]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: c1ccc2cc([Bi](c3ccc4ccccc4c3)c3ccc4ccccc4c3)ccc2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5ccccc5c4)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 40 °C
Reaction time: 6 h

Procedure:
To a stirred mixture of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-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 (300 mg, 0.39 mmol, 1 eq) and Cu(OAc)2 (15 mg, 0.083 mmol, 0.21 eq) in CH2Cl2 (5 ml) in a round bottom flask equipped with a magnetic stir-bar was added tri(2-naphthyl)bismuth diacetate [prepared immediately prior to use by addition of acetic acid to a suspension of tri(2-naphthyl)bismuth carbonate (300 mg, 0.461 mmol, 1.2 eq) in CH2Cl2 (5 ml)]. The reaction flask was fitted with a reflux condenser and the mixture warmed to 40° C. After 6 hours the mixture was allowed to cool to room temperature and stirred an additional 16 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted 2 times with CH2Cl2. The extracts were combined, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The product was isolated and purified by preparative TLC (3:1 hexanes/acetone) to give 109 mg of 17-ethyl-1-hydroxy-12-[2'-(4"-(naphth-2-yloxy)-3"-methoxycyclohexyl)-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. (1H NMR and 13C NMR analysis were consistent with the desired structure).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O.O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cn2)CC1
Temperature: 100 °C
Yield: 83.3 %

Procedure:
A mixture of 0.678 g (3 mmol) of 2-bromo-5-(trifluoromethyl)pyridine, 0.901 g (4.5 mmol) of tert-butyl 4-aminopiperidine-1-carboxylate and 0.829 g (6 mmol) of potassium carbonate in 5 ml of dimethyl sulphoxide is heated at 100° C. for 20 hours. The mixture is cooled to ambient temperature and then 50 ml of ethyl acetate and 15 ml of water are added. The organic phase is separated by settling and washed twice with 15 ml of water and then with 15 ml of a saturated aqueous sodium chloride solution. It is dried over sodium sulphate and evaporated under vacuum. The product is purified by chromatography on silica gel, elution being carried out with a 20:80 and then 30:70 mixture of ethyl acetate and cyclohexane in order to obtain 0.864 g (2.5 mmol) of product in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([NH:13]C(OC(C)(C)C)=O)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1>Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][C@@H:9]([C:10]([OH:12])=[O:11])[NH2:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(Br)c1)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1cccc(Br)c1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
(2S)-3-(3-Bromophenyl)-2-(tert-butoxycarbonylamino)propionic acid (5.0 g, 14.5 mmol) was suspended in 4M HCl in 1,4-dioxane (75 mL) and stirred for 16 h at r.t. The white precipitate was filtered and washed with Et2O to give the title compound as a white solid (3.2 g, 89%) that required no farther purification. δH(CDCl3) 8.32 (2H, s), 7.50-7.48 (2H, m), 7.34-7.29 (2H, m), 4.22 (1H, t, J 6.2 Hz), 3.13-3.11 (2H, m). An exchangeable proton was not observed.