Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[S:24][C:25]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:26]=2[N:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:23]2[S:24][C:25]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:26]=3[N:27]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Reactant: COc1ccc2nc(Cl)sc2c1
Product: COc1ccc2nc(Oc3ccc(OC[C@H]4CCCN4C(=O)OC(C)(C)C)cc3)sc2c1
Yield: 77 %

Procedure:
Followed the same procedure as that of step 1 in Example 99 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester ((147 mg, 0.5 mmol) and 2-chloro-6-methoxy-benzothiazole (100 mg, 0.5 mmol) to afford the title product (185 mg, 77% yield); 1H NMR (400 MHz, CDCl3); δ 1.46 (s, 9H), 1.80-2.10 (m, 4H), 3.28-3.46 (m, 2H), 3.70-3.98 (m, 1H), 3.84 (s, 3H), 4.01-4.20 (m, 2H), 6.72-6.82 (m, 4H), 6.92-6.99 (m, 2H), 7.62 (d, J=8.8 Hz, 1H).
Reaction SMILES: C1CCCCC=1.C([O:14][C:15]1[C:16]([CH3:36])=[C:17]([C:24]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[O:25])[N:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2)C1C=CC=CC=1>C(O)C.[Pd]>[OH:14][C:15]1[C:16]([CH3:36])=[C:17]([C:24]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[O:25])[N:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2
Reactant: COC(=O)c1ccc(C(=O)c2c(C)c(OCc3ccccc3)c3ccccn23)cc1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: COC(=O)c1ccc(C(=O)c2c(C)c(O)c3ccccn23)cc1

Procedure:
8.75 ml (86.37 mmol) of cyclohexene are added to 3.45 g (8.64 mmol) of methyl 4-[(1-(benzyloxy)-2-methylindolizin-3-yl)carbonyl]benzoate in 40 ml of ethanol, in the presence of 690 mg of 10% Pd/C, and the medium is heated under reflux for one hour.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[S:13][CH:12]=[CH:11][C:8]2=[N:9][CH:10]=1)(=O)C.[OH-].[Na+]>C(O)C.Cl.O>[NH2:4][C:5]1[CH:6]=[C:7]2[S:13][CH:12]=[CH:11][C:8]2=[N:9][CH:10]=1
Reactant: CC(=O)Nc1cnc2ccsc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cnc2ccsc2c1
Temperature: 80 °C
Yield: 75.5 %

Procedure:
A suspension of 6-acetamidothieno[3,2-b]pyridine (2.29 g, 12 mmol) in ethanol (35 ml) and concentrated hydrochloric acid (15 ml) was warmed at 80° C. for two hours. This mixture was diluted with water and made basic by the addition of sodium hydroxide solution. The product was extracted into methylene chloride, dried over anhydrous sodium sulfate and then filtered through a pad of charcoal and the solvent was evaporated to give pure product (1.36 g, 76% yield), m.p. 121°-123° C.
Reaction SMILES: [OH:1][CH:2]([CH2:16][O:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[N:27]1[CH:31]=[N:30][C:29]([CH3:32])=[N:28]1)[CH2:3][CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.NN>CCO>[NH2:5][CH2:4][CH2:3][CH:2]([OH:1])[CH2:16][O:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[N:27]1[CH:31]=[N:30][C:29]([CH3:32])=[N:28]1
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCC(O)CCN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: CCO
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCC(O)CCN)n1
Temperature: 50 °C
Yield: 81.1 %

Procedure:
To a mixture of 2-(3-hydroxy-4-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)butyl)isoindoline-1,3-dione (2.458 g, 5.62 mmol) in EtOH (28.1 mL) was added hydrazine (8.82 mL, 281 mmol). The mixture was heated at 50° C. for 1.5 h. The reaction mixture was cooled to rt and filtered. The filtrate was concentrated and taken up in CH2Cl2. Again, the solid was filtered off, and the filtrate was concentrated and purified by Prep-HPLC to obtain 4-amino-1-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)butan-2-ol (1.4 g, 81% yield). LC-MS (M+H)+=308.2 1H NMR (500 MHz, methanol-d4) δ 9.25 (s, 1H), 8.12 (d, J=2.1 Hz, 1H), 8.10-7.98 (m, 2H), 4.39-4.26 (m, 2H), 4.26-4.15 (m, 1H), 3.25-3.08 (m, 2H), 2.48 (s, 3H), 2.05-1.86 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[CH:10][C:9]([CH:12]=O)=[CH:8][C:6]=2[N:7]=1.[OH:20][CH:21]([CH3:30])[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23].C(OC)(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[CH:10][C:9]([CH2:12][N:27]3[CH2:26][CH2:25][N:24]([C:22](=[O:23])[CH:21]([OH:20])[CH3:30])[CH2:29][CH2:28]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CC(O)C(=O)N1CCNCC1
Reactant: O=Cc1cnc2c(N3CCOCC3)nc(Cl)nc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: COC(OC)OC
Solvent: ClCCl
Product: CC(O)C(=O)N1CCN(Cc2cnc3c(N4CCOCC4)nc(Cl)nc3c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35.6 %

Procedure:
In a 50 mL round bottom flask, 2-chloro-4-morpholinopyrido[3,2-d]pyrimidine-7-carbaldehyde (0.3 g, 0.0010 mol) and 1,2-dichloroethane (20 mL) were added. To the reaction flask, 2-hydroxy-1-(piperazin-1-yl)propan-1-one (0.204 g, 0.0013 mol) and trimethyl orthoformate (0.228 g, 0.0030 mol) were added and the reaction mixture stirred at room temperature for 12 hours. To the reaction mixture, sodium triacetoxyborohydride (g, 0.683 0.0020 mol) was added and stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to provide the crude product. The crude product was purified by column chromatography (60-12 silica gel, 5% methanol in chloroform) to provide the title compound (0.15 g, 33%). 1H NMR (300 MHz, CDCl3): δ 8.62 (d, J=1.8 Hz, 1H), 7.86 (d, J=1.2 Hz, 1H), 4.72 (br s, 4H), 3.84 (t, J=9.0 Hz, 4H), 3.65 (s, 2H), 3.60-3.52 (m, 1H), 3.41 (d, J=2.7 Hz, 1H), 3.23 (s, 4H), 2.46 (d, J=3.0 Hz, 4H), 1.27 (d, J=6.6 Hz, 3H): LC-MS (ESI): Calculated mass. 420.1, Observed mass [M+H]+: 421.1 (RT=0.24 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O.[OH-].[K+]>C(O)C.Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)CCc1ccc(OC)c(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(CCC(=O)O)cc1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a solution of ethyl 3-(3-fluoro-4-methoxyphenyl)propionate (29.1 g, 129 mmol) in ethanol(50 ml)-water(50 ml) was added potassium hydroxide (9.4 g, 167 mmol) and the mixture was stirred at 80° C. for 1 hour. After cooling, the reaction mixture was poured in diluted hydrochloric acid and the resulting crystals were recovered by filtration and washed with diethyl ether to provide the title compound (yield 24.4 g, 96%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:18][C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([Cl:27])=[CH:21][C:20]=3[Cl:28])=[C:11]([C:16]#[N:17])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:29][CH3:30].[N:31]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>COCCOC>[N:31]1([CH:37]2[CH2:42][CH2:41][N:40]([CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:15]=[C:14]4[C:9]([C:10]([NH:18][C:19]5[CH:24]=[C:23]([O:25][CH3:26])[C:22]([Cl:27])=[CH:21][C:20]=5[Cl:28])=[C:11]([C:16]#[N:17])[CH:12]=[N:13]4)=[CH:8][C:7]=3[O:29][CH3:30])[CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(OCCCCl)c(OC)cc23)c(Cl)cc1Cl
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc(OCCCN4CCC(N5CCCCC5)CC4)c(OC)cc23)c(Cl)cc1Cl
Yield: 10.4 %

Procedure:
A mixture of 260 mg (0.56 mmol) of 7-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-6-methoxyquinoline-3-carbonitrile (Boschelli, Diane H.; Ye, Fei; Wang, Yanong D.; Dutia, Minu; Johnson, Steve L.; Wu, Biqi; Miller, Karen; Powell, Dennis W.; Yaczko, Deanna; Young, Mairead; Tischler, Mark; Arndt, Kim; Discafani, Carolyn; Etienne, Carlo; Gibbons, Jay; Grod, Janet; Lucas, Judy; Weber, Jennifer M.; Boschelli, Frank. J. Med. Chem. 2001, 44, 3965-3977) and 380 mg (2.24 mmol) of [1,4′]bipiperidinyl are heated in 3 mL of ethylene glycol dimethyl ether at 85° C. for sixteen hours to yield the crude product. Following removal of the solvent in vacuo, the crude product is purified by silica gel chromatography (eluting with 7:3 methylene chloride/methanol) to give 35 mg of 7-(3-[1,4′-bipiperidin]-1′-ylpropoxy)-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-3-quinolinecarbonitrile as a white solid, mp 130-132° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[C:25]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)=[CH:24][CH:23]=[CH:22][N:21]4[C:33]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>Cl.O1CCOCC1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]2[C:20]3[N:21]([C:33]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:8]5([NH2:7])[CH2:11][CH2:10][CH2:9]5)=[CH:13][CH:14]=4)[N:19]=3)[CH:22]=[CH:23][CH:24]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(-c5ccc(F)cc5)cccn4c3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3nc4c(-c5ccc(F)cc5)cccn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Yield: 58.7 %

Procedure:
81 mg (0.15 mmol) (1-{4-[8-(4-Fluorophenyl)-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutyl)-carbamic acid tert.-butyl ester, intermediate example Int-300-0, were dissolved in 7 mL 4 M hydrogen chloride in dioxane. The reaction mixture was stirred over night at room temperature. After evaporation of the solvent the residue was dissolved in methanol and purified by chromatography on silicagel (amine phase, eluents: methanol/ammonia) followed by an additional chromatography (amine phase, eluents: ethyl acetate/hexane) yielding 38.2 mg (55.2%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.Cl.[N:36]1([C:42](=[O:50])[CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][C:42]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[O:50])[CH2:49][CH2:48]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Agent: Cl
Product: COc1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)c(OC(C)C)c1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 6) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone hydrochloride (Oakwood Chemicals) in an analogous manner as described in example 8. LR-MS: 694.3 [(M+H)+].
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)(Cl)Cl>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH2:19][CH2:18][N:17]([C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:16][CH2:15]3)(=[O:12])=[O:13])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: O=S(=O)(c1cccc2cnccc12)N1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)N1CCN(S(=O)(=O)c2cccc3cnccc23)CC1
Reaction time: 3 h
Yield: 70.9 %

Procedure:
In 50 ml of chloroform were added 2.77 g of 1-(5-isoquinolinesulfonyl)piperazine, i.e., Compound 35 and 1.54 g of anhydrous potassium carbonate, and to the mixture was added dropwise 1.70 g of benzoyl chloride under cooling with ice, and the mixture was stirred at a temperature of 15° C. to 20° C. for three hours. The reaction solution was washed with a 1N aqueous sodium hydroxide solution, then with water and dried with anhydrous magnesium sulfate. After the chloroform was distilled therefrom, the residue thus obtained was subjected to a silica gel column chromatography (silica gel: 70 g; solvent: chloroform) to give 2.7 g of 1-(5-isoquinolinesulfonyl)-4-benzoylpiperazine, i.e., Compound (58) in a yield of 71%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([N+:19]([O-])=O)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1

Procedure:
A solution of 3-tert-butoxycarbonyl-7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (2.1 g) was stirred under a hydrogen atmosphere (50 p.s.i.) in ethanol (40 ml) containing 5% Pd/C (0.21 g) for 3 hours. The catalyst was removed by filtration and the solvent evaporated to give the title compound D2 as a low-melting solid, 2.0 g. MH+ 263
Reaction SMILES: [CH2:1]([CH2:11]/[C:12](/[CH3:25])=[CH:13]/[CH2:14][CH2:15]/[C:16](/[CH3:24])=[CH:17]/[CH2:18][CH2:19][C:20]([O:22]C)=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:20](=[O:22])[CH2:19][CH2:18]/[CH:17]=[C:16](/[CH2:15][CH2:14]/[CH:13]=[C:12](\[CH3:25])/[CH2:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])\[CH3:24])[CH2:29][CH2:28]1
Reactant: COC(=O)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C
Reactant: CN1CCNCC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CCC(=O)N1CCN(C)CC1
Yield: 51.2 %

Procedure:
A three-necked flask equipped with a thermometer and a stirrer was charged with 69.2 g of methyl geranylgeranylacetate and 17.0 g of N-methylpiperazine. They were heated at 150° to 200° C. in an atmosphere of nitrogen for 3 hours with stirring. After cooling, the reaction mixture was chromatographed on a column of 3 kg of silica gel using a mixture of chloroform and methanol (7:1 by volume) as an eluent, and then further chromatographed on a column of 1.5 kg of silica gel using a mixture of ethyl acetate, ethanol and benzene (1:1:1 by volume) as an eluent to give 36 g of pure N-methyl-N'-geranylgeranylacetyl piperazine [compound (2)] as an oil. The structure of the product was determined from the following analytical results.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([N:14]1[CH2:30][CH2:29][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][NH:19][C:18]3=[O:28])[CH2:16][CH2:15]1)[CH2:8]2.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[ClH:2].[C:31]([N:19]1[C:18](=[O:28])[C:17]2([CH2:29][CH2:30][N:14]([CH:7]3[CH2:6][CH2:5][C:4]4[C:9](=[C:10]([Cl:13])[CH:11]=[CH:12][C:3]=4[Cl:2])[CH2:8]3)[CH2:15][CH2:16]2)[N:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCc3c(Cl)ccc(Cl)c3C1)CC2
Agent: Cl
Product: O=C(c1ccccc1)N1CN(c2ccccc2)C2(CCN(C3CCc4c(Cl)ccc(Cl)c4C3)CC2)C1=O

Procedure:
The title compound, m.p. 220° C. dec. was prepared in accordance with the general method of example 4 from 8-(5,8-dichloro-1,2,3,4-tetrahydro-2-naphthyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one hydrochloride and benzoyl chloride.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].[Cl:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19][N+:20]2[C:25]([O-:26])=[C:24](I)[C:23](=[O:28])[N:22]3[CH:29]=[CH:30][CH:31]=[CH:32][C:21]=23)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C1(P([Pd](Cl)(Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl.CO>[Cl:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19][N+:20]2[C:25]([O-:26])=[C:24]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[C:23](=[O:28])[N:22]3[CH:29]=[CH:30][CH:31]=[CH:32][C:21]=23)=[CH:15][CH:14]=1
Reactant: O=c1c(I)c([O-])[n+](Cc2ccc(Cl)nc2)c2ccccn12
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1ccc(-c2c([O-])[n+](Cc3ccc(Cl)nc3)c3ccccn3c2=O)cc1
Temperature: 100 °C

Procedure:
To a mixture of 53 mg (0.36 mmol) (4-cyanophenyl)boronic acid, 100 mg (0.24 mmol) 1-[(6-chloro-3-pyridyl)methyl]-3-iodo-4-oxo-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Synthesis described in WO 2009/099929), 35 mg (0.05 mmol) bis(triphenylphosphino)-palladium dichloride and 17 mg (0.05 mmol) caesium carbonate was added 160 ml of dioxane. The mixture was heated to 100° C. for 18 hours. Silica was added and the product was obtained by column chromatographie (dichloromethane/methanol) (24 mg).
Reaction SMILES: [SH:1][C:2]([CH3:9])([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][OH:5].[N+:10]([C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[C:16](Cl)=[O:17])([O-:12])=[O:11].C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl>[SH:1][C:2]([CH3:9])([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][O:5][C:16](=[O:17])[C:15]1[CH:14]=[C:13]([N+:10]([O-:12])=[O:11])[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CCCC(C)(S)CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC(C)(S)CCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 72 h
Yield: 84.2 %

Procedure:
To a solution of 5.0 g (34 mmol) of (rac)-3-mercapto-3-methyl-hexan-1-ol in 20 ml of CCl4 was added in portions 8.6 g (37 mmol) of 3,5-dinitrobenzoyl chloride. The mixture was stirred for 72 h, then 10 ml of a saturated NaHCO3 solution was added, the organic layer was separated, washed with 15 ml of brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash-chromatography (silicagel, hexane/EtOAc 4:1) and gave 9.8 g (84%) of (rac)-3,5-dinitro-benzoic acid 3-mercapto-3-methyl-hexyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.C[N:22]1CCOCC1.C(OC(Cl)=O)C(C)C.N>C1COCC1.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:22])=[O:14])=[CH:11][CH:10]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: Cc1ccc(Sc2ccc(C(=O)O)cc2)c([N+](=O)[O-])c1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Sc2ccc(C(N)=O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
The product from Example 30a (0.3 g, 1.04 mmol) was dissolved in THF (15 mL) and treated with N-methylmorpholine (0.131 mL, 1.19 mmol) followed by cooling in an ice bath and addition of isobutylchloroformate (0.148 mL, 1.14 mmol). The resulting mixture was allowed warm to room temperature with stirring for thirty minutes. Subsequent cooling in an ice bath was followed by addition of ammonia gas and warming to room temperature. The title compound was isolated by the addition of water and collection of the solid by vacuum filtration was used without further purification (0.289 g, 96%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[C:17]3[O:16][CH2:15][C:14](=[O:18])[NH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.Br[CH2:20][CH2:21][O:22][C:23]1[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:34])=[N:28]2>>[Cl:33][C:31]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27]([CH3:34])=[N:28]2)=[C:23]([O:22][CH2:21][CH2:20][N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][C:8]3[C:17]4[O:16][CH2:15][C:14](=[O:18])[NH:13][C:12]=4[CH:11]=[CH:10][CH:9]=3)[CH2:3][CH2:2]2)[CH:32]=1
Reactant: O=C1COc2c(CC3CCNCC3)cccc2N1
Reactant: Cc1ccc2c(OCCBr)cc(Cl)cc2n1
Product: Cc1ccc2c(OCCN3CCC(Cc4cccc5c4OCC(=O)N5)CC3)cc(Cl)cc2n1

Procedure:
The title compound was prepared from 8-(piperidin-4-ylmethyl)-4H-benzo[1,4]oxazin-3-one and 5-(2-bromoethoxy)-7-chloro-2-methylquinoline in a similar manner to Example 1.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=[CH2:43]>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=[CH2:43]
Reactant: C=CCCCCC(=O)O
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCCCCC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 128 mg (1 mmole) of 6-heptenoic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 175 mg (Yield: 44%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:38][C:39]1([CH3:47])[C:41]([CH3:43])([CH3:42])[CH:40]1[C:44](Cl)=[O:45]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:44]([CH:40]2[C:41]([CH3:43])([CH3:42])[C:39]2([CH3:47])[CH3:38])=[O:45])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C3C(C)(C)C3(C)C)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Yield: 68.5 %

Procedure:
A procedure similar to that described in Example 4, above, was followed, but using 1.0 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], and 1.17 g of 2,2,3,3-tetramethylcyclopropanecarbonyl chloride, to provide 833 mg of the title compound.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]3[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH2:22](Br)[CH2:23][CH2:24][CH2:25][CH3:26]>>[CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]3[CH2:16][CH2:17][C:18](=[O:21])[N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:20]=3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CCCCCBr
Reactant: CS(=O)(=O)N1CCOc2ccc(C3=NNC(=O)CC3)cc21
Product: CCCCCN1N=C(c2ccc3c(c2)N(S(C)(=O)=O)CCO3)CCC1=O

Procedure:
6-(3,4-Dihydro-4-methanesulfonyl-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one was reacted with pentyl bromide in place of methyl iodide following the procedure of Example 9. The title compound was recovered, yield 1.46 g, mp 138°-139° C.