Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Li])CCC.C[Si]([N:21]=[C:22]=[S:23])(C)C.Cl>CCCCCC.O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:22](=[S:23])[NH2:21])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: C[Si](C)(C)N=C=S
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: Cc1cnc2c(c1)CCCC2C(N)=S
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
A solution of 3-methyl-5,6,7,8-tetrahydroquinoline (7.3 g., 0.05 mol.) in hexane (50 ml.) was cooled to 0° C and treated dropwise with stirring with a 15% w/w solution of butyl lithium in hexane (26 ml., 0.06 mol.) in an atmosphere of nitrogen. The reaction mixture was stirred at 0° C for an additional 1 hour and was added portionwise to a solution of trimethylsilylisothiocyanate (13.1 g., 0.1 mol.) in hexane (50 ml.) and under nitrogen keeping the internal temperature at -20° C. The reaction mixture was stirred for an additional 30 minutes at -20° C, allowed to warm to room temperature and diluted with water (50 ml.). The pH was adjusted to 2.0 with conc. HCl and the hexane layer separated and discarded. The aqueous solution was adjusted to pH 10.0 with sodium carbonate and extracted with ethyl acetate (3 × 50 ml.). The combined extracts were dried (MgSO4) and the solvent removed in vacuo. The residue was triturated with n-hexane and solid filtered and recrystallised from benzene to give the title compound as colourless needles (3.5 g., 39%) m.p. 153° identical in all respects to authentic material. (Found: C, 64.6; H, 7.0; N, 13.9%. C11H14N2S Requires: C, 64.1; H, 6.8; N, 13.6%). The hexane soluble material was distilled to give recovered 3-methyl-5,6,7,8-tetrahydroquinoline (3.5 g., 50%) b.p. 120°/15 mm.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(COC)OC.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CC(C)([O-])C.[Na+]>O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[C:6]3[C:10](=[C:2]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:3]=[CH:4][CH:5]=3)[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=2)=[CH:15][CH:16]=1
Reactant: C1COCCN1
Reactant: CCCn1nc(-c2ccc(OC)cc2)c2cccc(Cl)c21
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCCn1nc(-c2ccc(OC)cc2)c2cccc(N3CCOCC3)c21
Temperature: 25 °C
Yield: 61.6 %

Procedure:
To a stirred solution of 7-chloro-3-(4-methoxyphenyl)-1-propyl-1H-indazole (0.218 g, 0.73 mmol) in anhydrous degassed dimethoxyethane (3 mL) was added morpholine (0.076 mL, 0.84 mmol) and sodium t-butoxide (0.098 g, 1.02 mmol). Tris(dibenzylidene-acetone)dipalladium(0) (0.010 g, 0.011 mmol) and 2-dicyclohexyl phosphino-2′-(N,N-dimethylamino)biphenyl (0.09 g, 0.23 mmol) were added and the reaction refluxed for 90 minutes. The reaction was cooled to room temperature and water added. The mixture was extracted with ethyl acetate and the organic layer washed with water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the organic phase was filtered and the filtrate evaporated in vacuo to yield crude title compound. The oil was purified by silica gel column chromatography eluting with hexane/ethyl acetate (5/1 to 3/1) to provide the title compound as a white solid (0.157 g, 0.45 mmol, 63%). An analytical sample was crystallized from hexane.
Reaction SMILES: C1COCC1.[BH4-].[Na+].[C:8]([NH:11][C@H:12]([C@H:18]([OH:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:13](OCC)=[O:14])(=[O:10])[CH3:9].C(OCC)(=O)C>O>[C:8]([NH:11][C@H:12]([C@H:18]([OH:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:13][OH:14])(=[O:10])[CH3:9]
Reactant: CCCCCCCCCCCCCCC[C@@H](O)[C@@H](NC(C)=O)C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O
Temperature: 60 °C
Reaction time: 5.5 h
Yield: 84 %

Procedure:
A THF suspension (0.3 mL) containing sodium borohydride (38.2 mg, 0.93 mmol) was heated to 60° C., and a THF solution (2.5 mL) of ethyl (2R,3R)-2-acetylamino-3-hydroxyoctadecanoate (250.1 mg. 0.62 mmol) synthesized in the same manner as Example 14 was added thereto dropwise for 5.5 hours. After completion of the dropwise addition, the mixture was further stirred at 60° C. for 17 hours. After ethyl acetate and water were added thereto, the reaction mixture was stirred at 60° C. for 1 hour. After the organic layer was separated, the organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was removed in reduced pressure. It was confirmed that 178.7 mg of the title compound was contained (yield: 84%). HPLC analysis was carried out to find that the optical purity of the anti-form was 99% ee.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][SiH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][CH2:3]1.[Mg].P(OCC)(OCC)(OCC)=O.Br[CH2:26][CH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>[Cu]I.C1COCC1>[CH2:8]([Si@H:5]1[CH2:6][CH2:7][C@H:2]([CH2:26][CH2:27][C@H:28]2[CH2:33][CH2:32][C@H:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=4)=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:3][CH2:4]1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC[SiH]1CCC(Br)CC1
Reactant: Fc1ccc(-c2ccc([C@H]3CC[C@H](CCBr)CC3)cc2)cc1
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOP(=O)(OCC)OCC
Product: CCCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(F)cc4)cc3)CC2)CC1

Procedure:
24.9 g (0.1 mol) of 1-bromo-4-n-pentyl-4-silacyclohexane was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 36.1 g (0.1 mol) of 4-(trans-4-(2-bromoethyl)cyclohexyl)-4'-fluorobiphenyl. After a conventional after treatment, 4-(trans-4-(2-(trans-4-n-pentyl-4-silacyclohexyl)ethyl)cyclohexyl)-4'-fluorobiphenyl was obtained. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 30.5 g (yield 67.6%) of the trans isomer.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:31])[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([N:42]=[C:43]=[O:44])=[O:41])=[CH:35][CH:34]=1>O1CCCC1>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:43]([NH:42][C:40](=[O:41])[CH2:39][C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)=[O:44])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ccn3)CC2)CC1
Solvent: C1CCOC1
Product: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccc(F)cc5)cc4F)ccn3)CC2)CC1
Reaction time: 72 h
Yield: 8.5 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(1-methylpiperidin-4-yl)piperazin-1-yl]carbonylamino}pyridine (81.2 mg) in tetrahydrofuran (2.0 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 1.9 ml) at room temperature, followed by stirring for 3 days. The reaction mixture was concentrated under reduced pressure. The resultant residue was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=97:3 to 95:5) to provide the titled compound (9.7 mg, 8.5%) as white powder.
Reaction SMILES: [C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[C:11](C(O)=O)[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(C(=O)c2ccccc2)n2c1C(C(=O)O)CC2
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1)c1ccc2n1CCC2C(=O)O

Procedure:
The acidic decarboxylation is conducted under mild conditions. For example, 5-benzoyl-7-hydroxycarbonyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-caboxylic acid is treated with refluxing trifluoroacetic acid to afford 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid. Other acids may also be used. For example, those listed below in Table I.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][NH:9][C:8]2=[O:17])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:27][O:28][C:29]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:27][O:28][C:29]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:30]=1[C:31]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][NH:9][C:8]2=[O:17])[CH2:5][CH2:6]1)=[O:32]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: O=C1NCc2ccccc2N1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCC(N3C(=O)NCc4ccccc43)CC2)c(OC)c1
Reaction time: 2 h

Procedure:
To a solution of 1-(4-piperidinyl)-3,4-dihydroquinazolin-2(1H)-one (680 mg, 1.40 mmol) from Step 5 in DCM (15 mL) was added DIEA (0.366 mL, 2.1 mmol) followed by 2,4-dimethoxybenzoyl chloride (309 mg, 1.54 mmol). The reaction was stirred for 2 h and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with 5% aqueous citric acid (50 mL) and saturated aqueous NaHCO3 (2×50 mL). The EtOAc layer was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography eluting first with 95:5 EtOAc:CHCl3 and then with 95:3:2 EtOAc:CHCl3 :MeOH. The title compound was obtained as a white solid (77% yield).
Reaction SMILES: C(OC([NH:8][CH:9]([CH:14]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1)[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH:9]([CH:14]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1)[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)C(Sc1cccc(OC)c1)c1cccc(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(N)C(Sc1cccc(OC)c1)c1cccc(OC)c1

Procedure:
A solution of 0.110 g (0.25 mmol) of (R,S; R,S)-2-tert-butoxycarbonylamino-3-(3-methoxyphenyl)-3-(3-methoxyphenyl-sulfanyl) propionic acid, methyl ester of Example 31 and 0.75 mL of trifluoroacetic acid in 2 mL of methylene chloride is stirred at room temperature for 30 minutes. The solvent is evaporated ant the residue is dissolved in 100 mL of ethyl acetate. The solution is washed with 2×80 mL of 1N sodium hydroxide and 80 mL of brine and then dried (magnesium sulfate) and evaporated to give the product as a mixture of diastereomers which is used in the next step without further purification; wt 0.084 g (94%); tlc (ethyl acetate/silica gel) one spot Rf 0.4;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][O:26][C:27]1[CH:41]=[CH:40][C:30]([CH2:31][N:32]2[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][C:33]2=[O:39])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CNCCNC>[Cu]I.O.O1CCOCC1>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[C:35]([CH3:38])([CH3:37])[CH2:36][N:32]([CH2:31][C:30]5[CH:40]=[CH:41][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)[C:33]4=[O:39])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: COc1ccc(CN2CC(C)(C)NC2=O)cc1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN2CC(C)(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)c(F)c3)C2=O)cc1

Procedure:
To a mixture of (4-bromo-2-fluorophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (157 mg) described in Preparation Example 114, 1-(4-methoxybenzyl)-4,4-dimethylimidazolidin-2-one (112 mg) described in Preparation Example 54, cesium carbonate (261 mg) and copper(I) iodide (38 mg) were added 1,4-dioxane (10 mL) and N,N′-dimethylethylenediamine (43 μL), and the mixture was stirred with heating under reflux for 32 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-1-(4-methoxybenzyl)-4,4-dimethylimidazolidin-2-one. The obtained 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-1-(4-methoxybenzyl)-4,4-dimethylimidazolidin-2-one was dissolved in dichloromethane (5 mL), trifluoromethanesulfonic acid (75 μL) was added, and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added 5% aqueous sodium hydrogen carbonate solution, and the solvent was evaporated, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution, and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol) to give the title compound (30 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][N:5]([CH:7]([CH3:32])[CH:8](N)[O:9][C:10](=[O:30])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:6]=1.[Cl:33][CH2:34][CH2:35][CH2:36][S:37]([NH:40]CC(OC)CSCCCCCCCCCCCCCCCC)(=[O:39])=[O:38]>>[Cl:33][CH2:34][CH2:35][CH2:36][S:37]([NH:40][CH2:32][CH:7]([N:5]1[N:4]=[N:3][C:2]([CH3:1])=[N:6]1)[CH2:8][O:9][C:10](=[O:30])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:39])=[O:38]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OC(N)C(C)n1nnc(C)n1
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)n1nnc(C)n1

Procedure:
2-(5-Methyl-2H-tetrazol-2-yl)-1-octadecylcarbamoyloxypropylamine IVh2 is allowed to react and worked up by the same procedure as described in (4). m.p. 70°-70.5° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[IH:7].[CH3:8][N:9]1[CH2:13][CH2:12][N:11]=[C:10]1[NH:14][NH2:15]>N1C=CC=CC=1>[IH:7].[CH2:5]([O:4][C:2]([NH:15][NH:14][C:10]1[N:9]([CH3:8])[CH2:13][CH2:12][N:11]=1)=[O:3])[CH3:6]
Reactant: CN1CCN=C1NN
Reactant: CCOC(=O)Cl
Agent: I
Solvent: c1ccncc1
Product: CCOC(=O)NNC1=NCCN1C

Procedure:
Ethyl chloroformate (0.95 ml) was added dropwise to a mixture of (1-methyl-4,5-dihydro-1H-imidazol-2-yl)-hydrazine hydroiodide (CAS 49541-82-4) (2 g) and pyridine (40 ml) while stirring, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off and the residue was purified by silica gel column chromatography. The obtained compound was washed with diethyl ether to obtain the title compound (1.14 g).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([OH:9])[C:6](=[O:8])[CH:7]=1.Cl.CC(C)=O.CC1(C)OC2C=C3OC(C)(C)OC3=CC=2O1>O.[Fe]>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([OH:9])=[CH:4][C:3]=1[OH:10]
Reactant: O=C1C=C(O)C(=O)C=C1O
Agent: [Fe]
Agent: CC1(C)Oc2cc3c(cc2O1)OC(C)(C)O3
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: Oc1cc(O)c(O)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,5-Dihydroxy-1,4-benzoquinone (10.00 g, 71.43 mmol) was suspended in water (200 ml, distilled) followed by HCl (6 mL, 142-86 mmol, conc.). Iron (4.00 g, 71.43 mmol, powder) was added and the mixture was stirred 30 minutes at room temperature. The solution was filtered and the solution evaporated to dryness. The product was isolated as a grey brown powder containing some iron complexes. Yield 14.80 g. The product is used as such in the reaction with acetone and P2O5 (Example 5) with no negative effects.
Reaction SMILES: [C:1]1([C:7](=[O:15])[CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([O:15][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:8][C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cc1ccncc1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(OC(=Cc1ccncc1)c1ccccc1)c1ccccc1
Yield: 62 %

Procedure:
Following a similar procedure to that described in reference example 4, but using 1-phenyl-2-(4-pyridyl)ethanone (obtained in reference example 3) instead of 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone and benzoyl chloride instead of 4-fluorobenzoyl chloride, the title compound was obtained (yield: 62%).
Reaction SMILES: C([O:5][C:6](=[O:24])[CH2:7][CH2:8][C:9]1[CH:22]=[CH:21][C:20]2[C:11](=[C:12]([NH2:23])[C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=1)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>ClCCl.C(OCC)C>[NH2:23][C:12]1[C:13]2[C:18]([N:19]=[C:20]3[C:11]=1[CH:10]=[C:9]([CH2:8][CH2:7][C:6]([OH:24])=[O:5])[CH:22]=[CH:21]3)=[CH:17][CH:16]=[CH:15][CH:14]=2.[C:27]([OH:29])([C:26]([F:31])([F:30])[F:25])=[O:28]
Reactant: CC(C)(C)OC(=O)CCc1ccc2nc3ccccc3c(N)c2c1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1c2ccccc2nc2ccc(CCC(=O)O)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(9-Amino-acridin-2-yl)-propionic acid tert-butyl ester 7 (55 mg, 0.17 mmol) was dissolved in anhydrous dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was carefully added. The mixture was stirred at room temperature overnight before evaporation of the solvent. Co-evaporation with diethyl ether (3 times) afforded a yellow solid, which was slurried in diethyl ether, filtered and washed with diethyl ether. Pure 3-(9-amino-acridin-2-yl)-propionic acid (Target 1) was isolated as a yellow TFA salt (49 mg, 76%). 1H NMR and LCMS analyses conformed to structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[H-].[Na+].[CH2:14]([O:16]C(=O)OCC)C.Cl>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8]([OH:10])=[CH:9][C:14](=[O:16])[O:11]2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=c1cc(O)c2ccc(F)cc2o1
Temperature: 115 °C
Reaction time: 6 h

Procedure:
A solution of 1-(4-fluoro-2-hydroxyphenyl)ethanone (50 g, 0.33 mol) in toluene was added over 30 min to a suspension of NaH (60% oil, 65 g, 1.63 mol) in toluene. Then diethylcarbonate (59 mL, 0.49 mol) was added over 15 min and the reaction mixture was stirred at 115° C. for 6 h. The mixture was cooled to rt followed by the addition of HCl 2N and diluted with EtOAc. The organic phase was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by trituration in hexane and Et2O to give the title compound.
Reaction SMILES: [C:1]([O:5][C@H:6]1[CH2:15][CH2:14][CH2:13][C:12]2[C@:7]1([CH3:17])[CH2:8][CH2:9][C:10](=[O:16])[CH:11]=2)([CH3:4])([CH3:3])[CH3:2].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[OH-].[Na+].OO>O1CCCC1.O>[C:1]([O:5][C@H:6]1[CH2:15][CH2:14][CH2:13][C:12]2[C@:7]1([CH3:17])[CH2:8][CH2:9][C@H:10]([OH:16])[CH:11]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)O[C@H]1CCCC2=CC(=O)CC[C@@]21C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)O[C@H]1CCCC2=C[C@@H](O)CC[C@@]21C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 96.8 %

Procedure:
A solution of 30.1 g (0.13 mole) (4aS,5S)-5-tert-butoxy-4a-methyl-4,4a, 5,6,7,8-hexahydro-2(3H)-naphtalenone in 600 ml tetrahydrofurane was cooled under stirring and Argon atmosphere to -78° C. After dropwise addition of 140 ml (0.14 mole) of L-selectride (1 molar in tetrahydrofurane),the reaction mixture was kept at -78° C. for an additional hour, then warmed to room temperature and kept at this temperature for 4.5 hours. After cooling to -15° C., 12 ml of H2O, 90 ml of 4N NaOH and 100 ml of H2O2 (30%) were added sequentially and dropwise by keeping the temperature between -10° C. to -15° C. After completed addition the reaction mixture was warmed to room temperature, poured onto water and extracted three times with ethylacetate. The combined organic layers were dried with sodium sulfate and evaporated after filtration to yield 30 g of crude (2S,4aS,5S)-5-tert-butoxy-4a-methyl-2,3,4,4a,5,6,7,8-octahydro-naphtalen-2-ol as an amorphous product shown by thin layer chromatography and NMR to be sufficiently pure for further transformations.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CC(O)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[BH3-]C#N.[Na+]>C1COCC1>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([CH2:19][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2nc3ccc(C=O)cc3s2)CC1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)N1CCN(c2nc3ccc(CN4CCOCC4)cc3s2)CC1
Temperature: 63 °C
Yield: 20.8 %

Procedure:
To a solution of 2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carboxaldehyde (0.5 g, 1.73 mmol) and AcOH (11 mg, 0.173 mmol) in THF (5 mL), morpholine (0.31 mL, 3.46 mmol) and NaCNBH3 (132 mg, 2.08 mmol) were added in turn. The reaction mixture was heated at 63° C. for 12 hours. The solvent was removed and the residue was extracted with ethyl acetate, washed with water and brine and dried (MgSO4). The volatiles were evaporated and the residue was purified by preparative HPLC to yield 130 mg (21%) of 2-(4-isopropylpiperazin-1-yl)-6-(morpholin-4-ylmethyl)benzothiazole as a trifluoroacetate salt.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:12]1([CH2:18]Br)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>[O-]CC.[Na+]>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH2:18][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: BrCC1CCCCC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(CC1CCCCC1)C(=O)OCC
Yield: 66.4 %

Procedure:
Diethyl malonate (16.0 g) was added to a freshly prepared solution of sodium ethoxide (from 2.3 g of sodium in 150 ml of absolute ethanol), followed by 17.7 g of cyclohexylmethyl bromide. The mixture was heated under reflux for four hours and evaporated to dryness. The resulting mixture was treated with water, extracted with ethyl acetate and the extracts washed with water, brine and dried (MgSO4). Evaporation gave an oil which was distilled in vacuo to give 17 g of diethyl(cyclohexylmethyl)malonate (b.p. 104°-107° C. at 0.2 mm Hg).