Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:18](O)([CH3:20])[CH3:19])[CH:14]=[CH:15][C:16]=1[CH3:17])[CH3:9].P(Cl)(Cl)(Cl)=O.O.[OH-].[Na+]>N1C=CC=CC=1>[CH3:1][C:2]([CH3:23])([CH3:22])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:18]([CH3:20])=[CH2:19])[CH:14]=[CH:15][C:16]=1[CH3:17])[CH3:9]
Reactant: Cc1ccc(C(C)(C)O)cc1CN(C)C/C=C/C#CC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: C=C(C)c1ccc(C)c(CN(C)C/C=C/C#CC(C)(C)C)c1
Temperature: 135 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
Compound 33 (520 mg; 1.66 mmol) was dissolved in pyridine (6 ml), and phosphorus oxychloride (1.27 g; 8.3 mmol) was added thereto. The mixture was stirred for 1 hour at 130-140° C., and then cooled. The reaction mixture was poured into water, and alkalinized with sodium hydroxide pellet. The mixture was extracted with ether (120 ml), and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1), to thereby yield 420 mg of the target compound (yield: 85.7%).
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH3:8][O:9][C:10]1[C:11](OC)=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:24][O:25]C1C=CC(C=O)=CC=1>ClCCl.O>[CH3:17][O:16][C:12]1[CH:13]=[C:14]([O:25][CH3:24])[CH:15]=[C:10]([O:9][CH3:8])[C:11]=1[C@@H:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[OH:7]
Reactant: COc1ccc(C=O)cc1
Reactant: COc1cccc(OC)c1OC
Reactant: C1CCC2OC2C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(OC)c([C@@H]2CCCC[C@H]2O)c(OC)c1
Temperature: -78 °C
Reaction time: 0.83 h

Procedure:
Cyclohexene oxide (90.2 ml; 0.89 mol) was added dropwise to a mechanically stirred mixture of trimethoxybenzene (I, 100 g; 0.594 mol) and aluminum chloride (118.82 g; 0.89 mol) in dichloromethane (500 ml) cooled at -78° C. The addition was done over a period of 50 min. The reaction mixture was allowed to stir at that temperature and the progress of the reaction monitored by TLC (tlc system 25% ethyl acetate-pet ether; anisaldehyde spray; pdt. Rf-value 0.35). The reaction mixture was worked up after 3 hours by adding cold-water (400 ml) and extracting with ethyl acetate (4×400 ml). The combined organic layers were washed with water, brine, and dried over sodium sulphate. The solvents were removed in-vacuo at a rotary evaporator. The oily residue was crystallized from pet ether (400 ml) to get the crystals of the title compound (62 g). The mother liquor, on evaporation of the solvents followed by chromatography over silica gel (column diam. 9.5 cm; silica gel 800 g; eluent 10, 25 and 40% ethyl acetate-pet ether), gave 28 g of the title compound. In total, 90 g (yield 57%; mp. 125-27° C.) of the title compound was isolated.
Reaction SMILES: [C:1]([N:9]1[CH2:19][CH2:18][C:12]2[N:13]=[N:14][C:15](Cl)=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:21][NH2:22]>>[C:1]([N:9]1[CH2:19][CH2:18][C:12]2[N:13]=[N:14][C:15]([NH:21][NH2:22])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCc2nnc(Cl)cc2C1
Reactant: NN
Solvent: O
Product: NNc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2

Procedure:
A suspension of 21.6 g of 6-benzoyl-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 80 cc of hydrazine hydrate is boiled at reflux at an oil bath temperature of 110° for 1 hour. After a reaction time of approximately 15 minutes the material dissolves completely. The crude title compound resulting after cooling the mixture, is washed with a small amount of absolute ethanol and dissolved in 60 cc of dimethyl formamide. 60 cc of absolute ethanol are added to the solution, whereupon the title compound crystallizes.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:11][C:12]1[CH:35]=[CH:34][C:15]([O:16][CH:17]2[CH2:20][N:19](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:18]2)=[CH:14][CH:13]=1>C(Cl)Cl>[Cl:11][C:12]1[CH:35]=[CH:34][C:15]([O:16][CH:17]2[CH2:18][N:19]([C:1]([Cl:4])=[O:2])[CH2:20]2)=[CH:14][CH:13]=1
Reactant: Clc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: O=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Cl)N1CC(Oc2ccc(Cl)cc2)C1
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A solution of 32.34 g (0.33 mole) of phosgene in 200 ml of methylene chloride cooled with a tap water bath was treated with 45.5 g (0.33 mole) of potassium carbonate and stirred for 30 min. Then 105 g (0.3 mole) of 3-(4-chlorophenoxy)-1-(diphenylmethyl)azetidine in 600 ml of methylene chloride was added dropwise. After stirring for an additional 18 h, the reaction mixture was filtered to remove the inorganic salts then concentrated in vacuo to a oily residue, 127.7 g. A solid formed upon standing which was triturated with boiling petroleum ether 3 times to remove the diphenylmethyl chloride. The residue, 33 g of dark brown crystalline material, was mainly starting material. Upon standing a white crystalline material separated from the petroleum ether triturates (4.4 g, mp 78°-80° C., sent for elemental analysis). The triturates were concentrated in vacuo yielding 31 g of pale yellow tacky crystals. Trituration of these crystals with 2-propyl ether yielded 21.9 g (36%) of pale yellow crystalline product.
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:53](Cl)(OC1C=CC=CC=1)[O:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C(OCC)(=O)C.O>[CH3:40][O:39][C:8]1[CH:9]=[C:10]([CH:37]=[CH:38][C:7]=1[NH:6][C:4]([C:3]1[C:2]2[N:1]=[C:53]([O:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[NH:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)=[O:5])[C:11]([N:13]([CH3:36])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:28])=[O:12]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Reactant: ClC(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(Oc3ccccc3)nc12
Reaction time: 5 h
Yield: 11 %

Procedure:
To a mixture of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (140 mg) and sodium carbonate (14 mg) in ethyl acetate (1.5 ml) was added dropwise a solution of 1,1-dichloro-1,1-diphenoxymethane (67 mg) in ethyl acetate (1 ml) in water bath and the mixture was stirred at same temperature for 5 hours. The reaction mixture was evaporated in vacuo and dissolved in chloroform. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-(2-phenoxy-1H-benzimidazol-4-yl)carbonylaminobenzamide (18 mg).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[I:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.O>CN(C=O)C>[I:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][C:8]1[S:9][CH:10]=[CH:11][N:12]=1
Reactant: Brc1nccs1
Reactant: Oc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Ic1cccc(Oc2nccs2)c1
Temperature: 135 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
Cesium carbonate (4.52 g, 13.87 mmol) was added to 2-bromo-1,3-thiazole (1.90 g, 11.6 mmol) and 3-iodophenol (2.54 g, 11.5 mmol) in anhydrous DMF (30 mL). The reaction was heated to 135° C. and stirred at this temperature overnight. The reaction was allowed to cool, then was poured into water (100 mL), and extracted with EtOAc (3×100 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered, and concentrated. The crude product was purified via flash chromatography using a Varian SF15-24 g column and an eluent of EtOAc in hexanes (0-10%) to afford the title compound as a yellow oil (2.52 g, 71.8%). MS (LCMS) m/z 304.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:15][C:6]2[N:7]=[C:8]([NH:10][C:11]([NH:13][CH3:14])=S)[S:9][C:5]=2[CH:4]([CH3:16])[CH2:3]1.[CH2:18]1[O:23][CH2:22]OCO1.[OH-:24].[Na+]>O>[CH3:1][C:2]1([CH3:17])[CH2:15][C:6]2[N:7]=[C:8]([N:10]3[C:11](=[O:24])[N:13]([CH3:14])[CH2:22][O:23][CH2:18]3)[S:9][C:5]=2[CH:4]([CH3:16])[CH2:3]1
Reactant: C1OCOCO1
Reactant: [OH-]
Reactant: CNC(=S)Nc1nc2c(s1)C(C)CC(C)(C)C2
Agent: [Na+]
Solvent: O
Product: CC1CC(C)(C)Cc2nc(N3COCN(C)C3=O)sc21
Temperature: 5 °C
Reaction time: 16 h

Procedure:
Sulfuric acid, 85% concentration, (40 grams) is charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and is cooled to about 5° C. N-(5,5,7-trimethyl-4,5,6,7-tetrahydrobenzothiazol-2-yl)-N'-methylthiourea (0.015 mole) and s-trioxane (0.015 mole) are added portionwise, with stirring to the cold surfuric acid. Stirring is continued for a period of about 16 hours at room temperature. The reaction mixture is then diluted 1:1 with water and neutralized with aqueous 40% sodium hydroxide. The neutralized mixture is filtered and the filtered-off solid is washed with 3-100 ml portions of water and air dried to yield the desired product 3-(5,5,7-trimethyl-4,5,6,7-tetrahydrobenzothizol-2-yl)-5-methyltetrahydro-1,3,5-oxidiazin-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.[H-].[Na+].Cl[CH2:25][CH2:26][S:27](Cl)(=[O:29])=[O:28].O>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:4](=[N:8][S:27](=[O:29])(=[O:28])[CH2:26][CH2:25]2)[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1
Reactant: Nc1nccc(Cl)c1-c1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: O=S1(=O)CCN2C=CC(Cl)=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-chloro-3-(4-phenoxyphenyl)pyridin-2-amine (124 mg) in THF (dry) (5 mL) was added to a suspension of NaH (60%, 84.0 mg) and 2-chloroethanesulfonyl chloride (0.131 mL) in THF (dry) (5 mL) at 0° C. The mixture was stirred at room temperature overnight. Water and hexane were added to give a white precipitate. The precipitate was collected by filtration and washed with water and EtOAc, and then crystallized from THF-IPE to give the title compound (60.0 mg) as a white solid.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].Cl.Cl.[CH2:8]([NH:15][NH2:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C1(C)C(C)=CC=CC=1>[CH2:8]([N:15]1[C:8]2[C:9](=[CH:10][CH:11]=[C:1]([OH:4])[CH:2]=2)[C:14]([CH2:13][CH3:12])=[N:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)[O-]
Reactant: NNCc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCc1nn(Cc2ccccc2)c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
1-(2-Fluoro-4-hydroxyphenyl)propan-1-one (5.37 g) that can be produced by the method described in Reference Example 9 or the like, sodium acetate (12.75 g; manufactured by Wako Pure Chemical Industries, Ltd.) and benzylhydrazine dihydrochioride (9.452 g; manufactured by Sigma-Aldrich Co.) were suspended in xylene (76 mL). The suspension was stirred overnight at reflux using a Dean-Stark apparatus. The reaction solution was cooled to room temperature, subsequently water was added thereto, and the mixture was extracted two times with ethyl acetate. The organic layer was washed two times with water and with brine, and was dried over anhydrous sodium sulfate. Subsequently, the solvent was evaporated under reduced pressure. Before completely evaporating the solvent, precipitates were filtered, and the solids were washed with n-hexane. Thus, the title compound (4.76 g) was obtained. Furthermore, the filtrate was concentrated under reduced pressure, and the solids precipitating in the middle of the concentrating process were also filtered. Thus, the title compound (3.44 g) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]1[N:19]=[N:20][N:21]=[C:14]1[C:13]([N+:22]([O-])=O)=[C:12]2[NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(#N)C.[Pt]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]1[N:19]=[N:20][N:21]=[C:14]1[C:13]([NH2:22])=[C:12]2[NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC(C)CNc1c([N+](=O)[O-])c2nnnn2c2ccc(OCc3ccccc3)cc12
Agent: [Pt]
Solvent: CC#N
Product: CC(C)CNc1c(N)c2nnnn2c2ccc(OCc3ccccc3)cc12
Reaction time: 5 h
Yield: 82.6 %

Procedure:
7-(Benzyloxy)-N-(2-methylpropyl)-4-nitrotetraazolo[1,5-α]quinolin-5-amine (10 g, 25.4 mmol) was shaken in 200 mL of acetonitrile with 5% platinum on carbon (1 g) under 50 psi (3.45×105 Pa) of hydrogen. After 5 hours, the mixture was filtered through CELITE filter agent. Some product was isolated as a solid on the top of the filter cake. This solid was collected, dissolved in warm DMF, and filtered again through fresh CELITE filter agent. The combined filtrates were cooled and allowed to sit overnight. The resulting precipitate was collected in 2 crops to yield 7.6 g of 7-(benzyloxy)-N5-(2-methylpropyl)tetraazolo[1,5-α]quinoline-4,5-diamine as a brown solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:6][CH:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[CH3:8].Cl>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:13]([C:12]1[CH:16]=[CH:17][C:9]([CH:7]([Cl:6])[CH3:8])=[CH:10][CH:11]=1)=[O:14]
Reactant: c1ccsc1
Reactant: CC(Cl)c1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: CC(Cl)c1ccc(C(=O)c2cccs2)cc1

Procedure:
To a stirred and cooled (0° C) mixture of 4.2 parts of thiophene, 13 parts of stannic chloride and 40 parts of methylene chloride is added dropwise a solution of 10.2 parts of p-(1-chloroethyl)benzoyl chloride in 20 parts of methylene chloride (exothermic reaction with gaseous hydrogen chloride evolution). After stirring for 2h.30 the reaction mixture is poured onto a mixture of crushed ice and hydrochloric acid solution. The product is extracted with methylene chloride. The organic layer is separated, washed with alkaline water, dried and evaporated. The solid residue is triturated with hot petroleum-ether. The product is filtered off and crytallized from ethanol, yielding p-(1-chloroethyl)phenyl 2-thienyl ketone.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[C:5]([NH:16][CH2:17][CH3:18])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.[CH:19]([C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[CH:25]=[C:24]([OH:36])[N:23]=1)([CH3:21])[CH3:20].[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:2].[ClH:1].[CH2:17]([NH:16][C:5]1[C:4]([CH2:3][C:25]2[C:26]3[C:31](=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=3)[C:22]([CH:19]([CH3:20])[CH3:21])=[N:23][C:24]=2[OH:36])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[N:6]=1)[CH3:18]
Reactant: COc1cc2cc(O)nc(C(C)C)c2cc1OC
Reactant: CCNc1nc2ccc(OC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNc1nc2ccc(OC)cc2cc1Cc1c(O)nc(C(C)C)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 5 %

Procedure:
To a stirred solution of 3-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amine hydrochloride (250 mg, 0.87 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 1-isopropyl-6,7-dimethoxyisoquinolin-3-ol SIL 32164 (215 mg, 0.87 mmol) followed by a 2 N aq. LiOH solution (0.87 mL, 1.74 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 0:100) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided, after evaporation and drying, 38 mg of 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-1-isopropyl-6,7-dimethoxyisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.70 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-1-isopropyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 47 as a yellow solid (24 mg, 5% yield).
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:5]([OH:24])[CH2:6][NH:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[O:11][C:10]([CH3:23])([C:19]([F:22])([F:21])[F:20])[CH2:9]1.N1([C:37](=[O:39])[CH3:38])C=CN=C1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[Br:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[O:11][C@:10]([CH3:23])([C:19]([F:22])([F:21])[F:20])[CH2:9][C@@H:8]2[NH:7][CH2:6][C@@H:5]([OH:24])[C@@H:4]([NH:3][C:37](=[O:39])[CH3:38])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC1(C(F)(F)F)C[C@H](NC[C@@H](O)[C@@H](N)Cc2ccccc2)c2cc(Br)ccc2O1
Reactant: CC(=O)n1ccnc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN[C@H]1C[C@@](C)(C(F)(F)F)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
To a solution of (2R,3S)-3-amino-1-((4S)-6-bromo-2-methyl-2-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-ylamino)-4-phenylbutan-2-ol dihydrochloride (160 mg, 338 mmol) in DMF was added 1-(1H-imidazol-1-yl)ethanone (37.2 mg, 338 μmol) followed by DIPEA (177 μl, 1014 μmol). The reaction was stirred at RT for 30 min, then diluted with MeOH and purified on Shimadzu HPLC to afford 43.0 mg of the title compounds as a mixture. MS m/z: 515, 517.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Si:4]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]>CS(C)=O>[Si:4]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:1]#[N:2])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCC#N
Temperature: 90 °C

Procedure:
Sodium cyanide (1.2 g) dissolved in dimethylsulphoxide was heated at 90° C. for 30 min. Solid 1-t-butyldimethylsilyloxy-6-bromohexane (5.8 g, compound X1) prepared according to the method previously described (ref. 37), then was added into the sodium cyanide solution. After heating at 120-130° C. for 20-180 min, the reaction mixture was poured into ice-cold water and the aqueous layer was extracted with ether, washed with brine, dried and concentrated. The product was distilled at 0.5 Torr and 107° C. to give a colorless oil. High resolution mass spectrometer for C12 H24 O N Si: calculated 226.1627, found 226.1624.
Reaction SMILES: Cl.Cl.C([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][O:20][C:19]2=[O:23])[CH2:12][CH2:11]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[N:13]1([CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][O:20][C:19]2=[O:23])[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]1
Reactant: O=C1OCCN1CCN1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C1OCCN1CCN1CCNCC1

Procedure:
291 g of 3-[2-(4-benzyl-1-piperazinyl)-ethyl]-2-oxazolidinone dihydrochloride in 7 litres of methanol are hydrogenated in the presence of 70 g of palladium/carbon (5%) at 50° C and 10 atmospheres of hydrogen. The mixture is filtered and concentrated under reduced pressure. The residue is treated with sodium hydroxide, extracted with chloroform, filtered through diatomaceous earth and concentrated. There is obtained 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone as a yellow oil. The dihydrochloride of melting point 203° C (decomposition) is obtained by treatment with an excess of hydrochloric acid in methanol/ether.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:6]=1.[I:13]N1C(=O)CCC1=O>C(#N)C>[Br:1][C:2]1[S:3][C:4]([I:13])=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCCCCCc1csc(Br)n1
Solvent: CC#N
Product: CCCCCCc1nc(Br)sc1I
Yield: 78.3 %

Procedure:
4.07 g (16.4 mmol) of 2-bromo-4-hexylthiazole was dissolved in 8 mL of acetonitrile, and 32 mL of acetonitrile solution of 4.41 g (19.7 mmol) of N-iodosuccinimide was added under an argon gas atmosphere, and refluxed for 18 hours. Next, the resultant reaction mixed liquid was washed with a Na2S203 aqueous solution, and the aqueous layer was extracted with chloroform and added to the organic layer. The organic layer was concentrated, and subjected to silica gel column chromatography (development solvent:chloroform/hexane=1/1 (volumetric ratio)) to take out red transparent liquid. Since a peak of a molecular weight of 373 containing one bromine atom was observed in the mass spectrum, it could be confirmed that the above-described red transparent liquid was the intended 2-bromo-4-hexyl-5-iodothiazole. The amount obtained was 4.80 g, and the yield was 78.3%.
Reaction SMILES: [F:1][C:2]1([C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH:3]1[O:7][CH3:8].[C:12](O)([CH3:15])([CH3:14])[CH3:13].C1(N=C=NC2CCCCC2)CCCCC1>CCOCC.CNC1(NC)C=CN=CC1>[C:12]([O:10][C:9]([C:2]1([F:1])[CH2:6][CH2:5][CH2:4][CH:3]1[O:7][CH3:8])=[O:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)O
Reactant: COC1CCCC1(F)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CNC1(NC)C=CN=CC1
Solvent: CCOCC
Product: COC1CCCC1(F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
The 1-fluoro-2-hydroxy 1-cyclopentanecarboxylic acid methyl ester in cis form (compound number 2a) synthesized in Example 1 was methylated in the same manner as in Example 10 and further hydrolyzed in the same manner as in Example 11 to obtain 1-fluoro-2-methoxy-1-cyclopentanecarboxylic acid in cis form (compound number 12a). 0.4 g (2.7 mmol) of this carboxylic acid, 0.20 g (2.7 mmol) of tertiary butyl alcohol, 0.56 g (3.7 mmol) of dicyclohexylcarbodiimide and 15 mg of 4,4-dimethylaminopyridine were mixed in 5 ml of ether and stirred at room temperature for 2 hours. The reaction solution was filtered, ether was added to the filtrate, and the mixture was successively washed with a diluted hydrochloric acid solution, saturated saline, a saturated aqueous sodium bicarbonate solution and saturated saline. The ether layer was dried over anhydrous magnesium sulfate, and the solvent was distilled away to obtain 0.31 g (yield: 56%) of the objective 2-methoxy-1-fluoro-1-cyclopentanecarboxylic acid tertiary butyl ester in cis form (compound number 20a).