Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].C(O[CH2:20][C:21]([F:33])=[CH:22][C:23]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)([CH3:25])[CH3:24])(=O)C>O1CCCC1>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]([CH3:25])([CH3:24])[CH:22]=[C:21]([F:33])[CH2:20][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=2)=[CH:31][CH:30]=1
Reactant: CC(=O)OCC(F)=CC(C)(C)c1ccc(Cl)cc1
Reactant: Brc1cccc(Oc2ccccc2)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C=C(F)Cc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Yield: 22.5 %

Procedure:
The method of Example 16 was repeated using a Grignard reagent, prepared from 3-phenoxyphenyl bromide (0.19 g), tetrahydrofuran (2 ml) and magnesium (22 g), and 4-(4-chlorophenyl)-2-fluoro-4-methylpent-2-enyl acetate (Example 13) (0.12 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: C18; solvent: methanol; flow rate: 3 ml/min; to give the title compound (38 mg, 22%).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:23][C:24]([CH3:42])([C:26]2[N:30]([CH3:31])[C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]([F:41])([F:40])[F:39])=[N:28][N:27]=2)[CH3:25])=[C:18]([CH:22]=1)[C:19](O)=[O:20].[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>C1COCC1.C1COCC1.O>[ClH:13].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:23][C:24]([CH3:42])([C:26]2[N:30]([CH3:31])[C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]([F:39])([F:41])[F:40])=[N:28][N:27]=2)[CH3:25])=[C:18]([CH2:19][OH:20])[CH:22]=1
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 116.1 %

Procedure:
CDI (144 mg) was added to a solution of 5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzoic acid (300 mg) in THF (3 ml), followed by stirring at room temperature for 1.5 hours. The reaction solution was added dropwise at 0° C. to a mixed solution of sodium borohydride in THF/water (6 ml, 1:1) under a nitrogen atmosphere, followed by stirring at room temperature for one hour. 1M hydrochloric acid was added to the reaction solution to cease the reaction and then neutralized with saturated aqueous sodium bicarbonate. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=95:5), the resulting solid (190 mg) was dissolved in ethyl acetate, and 4M hydrogen chloride-ethyl acetate was added thereto, followed by stirred for 30 minutes. The solution was concentrated under reduced pressure and powdered with diisopropylether to obtain [5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]methanol monohydrochloride (183 mg) as a white powder.
Reaction SMILES: CC([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([Br:11])[CH:5]=1)=O.ClC1C=CC=[C:15]([C:19]([O:21]O)=[O:20])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(OCC)C>[C:19]([O:21][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([Br:11])[CH:5]=1)(=[O:20])[CH3:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1ccc(F)c(Br)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
A solution of 1.09 gm (5 mMol) 3-bromo-4-fluoroacetophenone and 3.45 gm (20 mMol) m-chloroperbenzoic acid (70%) in 15 mL dichloromethane was heated at reflux for 18 hours. An additional 3.45 gm m-chloroperbenzoic acid were added and reflux continued for about 12 hours. At this point an additional 1.4 gm m-chloroperbenzoic acid were added and reflux continued for 18 hours. The reaction mixture was cooled to room temperature and was then diluted with 50 mL diethyl ether. The resulting mixture was cooled to 0° C. and was then treated with 15 mL 20% aqueous sodium thiosulfate. The resulting slurry was stirred for about 1 hour and then the phases separated. The organic phase was washed sequentially with 3×20 mL 20% aqueous sodium thiosulfate followed by 3×20 mL saturated aqueous sodium chloride. The organic phase was then dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 10:1 hexane:diethyl ether. Fractions containing product were combined and concentrated under reduced pressure to provide 68% of the desired compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:3]([OH:20])[CH:4]([NH:12]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>O1CCOCC1>[NH2:1][CH:2]([CH:3]([OH:20])[CH:4]([NH2:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
The resultant compound of Example 11 (18 mg, 0.049 mmol) was treated with 1 ml of 4M HCl in dioxane, stirred for 0.5 h at ambient temperature, and concentrated in vacuo. The residue was partitioned between chloroform and aqueous NaHCO3, dried over Na2SO4 and concentrated to provide the desired compound (Rf 0.12, 10% methanol in chloroform) as a white solid, m.p. 106°-107° C. 1H NMR (CDCl3) δ 2.51 (dd, J=13, 10 Hz, 1H), 2.67 (dd, J=13, 9 Hz, 1H), 2.85-3.0 (m, 2H), 3.19 (m, 1H), 3.38 (m, 2H), 7.15-7.35 (m, 10H). Mass spectrum: (M+H)+ =271.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH:14]=1)([O-])=O.[H][H]>CO.[Pd]>[N:15]12[CH2:16][CH2:17][CH:18]([CH2:19][CH2:20]1)[CH:13]([C:7]1[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([NH2:1])[CH:5]=3)[NH:9][CH:8]=1)[CH2:14]2
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2[nH]cc(C3=CN4CCC3CC4)c2c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2[nH]cc(C3CN4CCC3CC4)c2c1

Procedure:
0.2 g of Pd/C (10%) is added to a suspension of 7.4 mmol of 3-(5-nitro-1H-indol-3-yl)-1-azabicyclo[2.2.2]oct-2-ene in 50 ml of methanol, and the mixture is stirred at room temperature for 12 hours in a hydrogen atmosphere at atmospheric pressure. The mixture is filtered, and the filter residue is subjected to conventional work-up, giving 3-(1-azabicyclo[2.2.2]-oct-3-yl)-1H-indol-5-ylamine.
Reaction SMILES: [F:1][CH2:2][CH:3]([N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17])[CH:4]=[CH:5][CH3:6].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:1][CH2:2][CH:3]([N:7]1[C:8](=[O:17])[C:9]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:10]2[C:11]1=[O:12])[CH:4]=[CH:5][CH2:6][Br:18]
Reactant: CC=CC(CF)N1C(=O)c2ccccc2C1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1C(C=CCBr)CF

Procedure:
A mixture of 1-fluoro-2-phthalimido-3-pentene (800 mg, 3.4 mmoles) prepared as in Step C above, N-bromosuccinimide (612 mg. 3.4 mmoles), carbon tetrachloride (30 mL) and a few mg of benzoyl peroxide is heated under strong reflux during irradiation with a lamp (325 W) during one hour. After washing with water the organic phase is dried over magnesium sulfate and then concentrated under reduced pressure to yield 1-fluoro-2-phthalimido-5-bromo-3-pentene as a slightly yellow oil (1.06 g, quantitative yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.BrC1C=CC(/C=C\C2C=CC=CC=2)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(C=Cc2ccccc2)cc1
Agent: Brc1ccc(/C=C\c2ccccc2)cc1
Product: Brc1ccc(/C=C/c2ccccc2)cc1

Procedure:
First, a synthesis method of 4-bromostilbene is described. 25.3 g (49.5 mmol) of (4-bromobenzyl)triphenylphosphoniumbromide and 5.25 g (49.5 mmol) of benzaldehyde were put into a 500 mL three-necked flask and the air in the flask was replaced with nitrogen. 250 mL of tetrahydrofuran (THF) was added to the mixture. Then, a suspension in which 6.10 g (54.4 mmol) of potassium tert-butoxide was dissolved in 60 mL of THF was dropped to this mixture. After the dropping, the reaction mixture was stirred for 24 hours at room temperature. After the reaction, the reaction mixture was washed with water and the product was extracted with ethyl acetate from the water which was used for the washing. The obtained extraction solution and the organic layer, which was washed with water, were mixed and dried with magnesium sulfate. After the drying, the mixture was suction filtrated, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (developing solution: toluene). The obtained compound was washed with methanol and the solid was collected by suction filtration to give 3.75 g or a white powdered solid of (E)-4-bromostilbene (yield: 29.2%). A synthesis scheme (h-1) of 4-bromostilbene is shown below. Note that (Z)-4-bromostilbene was also observed in this reaction, but only (E)-4-bromostilbene was isolated and purified.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C@@H:13]([CH3:20])[CH2:14][O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=O)=O)=CC=1.[CH2:22]([Mg]Br)[CH:23]([CH3:25])[CH3:24]>>[C:16]([O:15][CH2:14][C@H:13]([CH3:20])[CH2:12][CH2:11][CH2:22][CH:23]([CH3:25])[CH3:24])([CH3:17])([CH3:18])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H](C)COC(C)(C)C)cc1
Reactant: CC(C)C[Mg]Br
Product: CC(C)CCC[C@@H](C)COC(C)(C)C
Yield: 76 %

Procedure:
Coupling of (R)-(+)-4-tert. butoxy-3-methyl-1-butanol p-toluene-sulfonate with isobutylmagnesium bromide was carried out using the procedure of Example 47. (R)-(+)-1-tert. Butoxy-2,6-dimethylheptane was obtained in 76% yield as a colorless liquid.
Reaction SMILES: [CH2:1]([C:13]1[CH:14]=[C:15]([C:18]2[NH:19][C:20](=[O:44])[C:21]3[C:25]=2[C:24](=[O:26])[NH:23][C:22]=3[C:27]2[S:28][CH:29]=[C:30]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:31]=2)[S:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Br[CH2:46][CH:47]([CH2:50][CH2:51][CH2:52][CH3:53])[CH2:48][CH3:49].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:32]([C:30]1[CH:31]=[C:27]([C:22]2[N:23]([CH2:17][CH:13]([CH2:14][CH3:15])[CH2:1][CH2:2][CH2:3][CH3:4])[C:24](=[O:26])[C:25]3[C:21]=2[C:20](=[O:44])[N:19]([CH2:46][CH:47]([CH2:48][CH3:49])[CH2:50][CH2:51][CH2:52][CH3:53])[C:18]=3[C:15]2[S:16][CH:17]=[C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:14]=2)[S:28][CH:29]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCCCCCc1csc(C2=C3C(=O)NC(c4cc(CCCCCCCCCCCC)cs4)=C3C(=O)N2)c1
Reactant: CCCCC(CC)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCCCCCCCCCCCc1csc(C2=C3C(=O)N(CC(CC)CCCC)C(c4cc(CCCCCCCCCCCC)cs4)=C3C(=O)N2CC(CC)CCCC)c1
Temperature: 60 °C
Yield: 21.3 %

Procedure:
A 100 mL flask was charged with 3,6-bis-(4-dodecyl-thiophen-2-yl)-2,5-dihydro-pyrrolo[3,4-c]pyrrole-1,4-dione 4 (1.91 g, 3.0 mmol), 3-bromomethyl-heptane (1.54 g, 8.0 mmol), Cs2CO3 (2.93 g, 9.0 mmol) and then purged with argon for 10 minutes before 100 mL of dimethylformamide (DMF) was added. The mixture was heated at 60° C. overnight and then cooled to room temperature. Dichloromethane (50 mL) was added. The organic layer was washed with water (50 mL for 3 times) and then dried over anhydrous Na2SO4. Black solids were obtained after removal of the solvent and precipitation from methanol. The product was purified by column with dichloromethane/hexane (v/v: 2/1) as the eluent and weighed 0.55 g (overall yield: 21.3% from 4-dodecyl-thiophene-2-carbonitrile 3) after being dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: CCCCCCCCCCCCO
Reactant: COc1cscn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCOc1cscn1
Temperature: 130 °C
Yield: 55.1 %

Procedure:
A mixture of 4.0 g (34.7 mmol) of 4-methoxythiazole (9), 12.8 g (68.7 mmol) of dodecanol, 0.7 g (3.7 mmol) of p-toluenesulfonic acid monohydrate, and 75 mL of toluene was heated at 130° C. for 24 hours. The mixture was cooled to room temperature and purified by flash chromatography (silica gel, 5.5×30 cm, methylene chloride). The resulting oily solid was recrystallized from 20 mL of cold pentane to give 5.15 g (55% yield) of 4-dodecyloxythiazole (10) as a colorless solid. 1H NMR (500 MHz) δ 8.58 (d, 1H, J=2.3 Hz), 6.13 (d, 1H, J=2.3 Hz), 4.13 (t, 2H, J=6.6 Hz), 1.83 (m, 2H), 1.49-1.28 (m, 18H), 0.90 (t, 3H, J=7.0).
Reaction SMILES: [I:1][C:2]1[C:3]([C:7]2[S:8][CH:9]=[C:10]([Cl:12])[CH:11]=2)=[N:4][NH:5][CH:6]=1.[H-].[Na+].I[CH:16]([CH2:18][CH3:19])[CH3:17].C(N1C=C(I)C(C2SC=C(Cl)C=2)=N1)(CC)C>CN(C)C=O.CC(OC)(C)C.O>[CH:16]([N:4]1[C:3]([C:7]2[S:8][CH:9]=[C:10]([Cl:12])[CH:11]=2)=[C:2]([I:1])[CH:6]=[N:5]1)([CH2:18][CH3:19])[CH3:17]
Reactant: Clc1csc(-c2n[nH]cc2I)c1
Reactant: CCC(C)I
Agent: CCC(C)n1cc(I)c(-c2cc(Cl)cs2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Solvent: O
Product: CCC(C)n1ncc(I)c1-c1cc(Cl)cs1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a solution of 4-iodo-3-(4-chloro-2-thienyl)-1H-pyrazole (3.3 mmol) in 10 mL dry N,N-dimethylformamide under argon atmosphere was added sodium hydride (3.9 mmol, 60% dispersion in mineral oil) in portions. The reaction mixture was stirred at room temperature for 15 min, then 2-iodobutane (4.9 mmol) was added dropwise. After 2 days at room temperature, water and MTBE were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated to afford 1.2 g of a mixture of 1-sec-butyl-3-(4-chloro-2-thienyl)-4-iodo-1H-pyrazole and 1-sec-butyl-5-(4-chloro-2-thienyl)-4-iodo-1H-pyrazole (88:12; 100% yield). The mixture was purified by chromatography on silica gel (toluene:ethyl acetate 100:0 to 0:100) to afford 923 mg 1-sec-butyl-3-(4-chloro-2-thienyl)-4-iodo-1H-pyrazole (74% yield) and 150 mg of 1-sec-butyl-5-(4-chloro-2-thienyl)-4-iodo-1H-pyrazole (11% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:14].[CH:15]1([CH2:18][NH:19][C:20](=[O:37])[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:22]=2)[CH2:17]C1>CN(C=O)C>[CH:18]1([NH:19][C:20]([C:21]2[CH:22]=[C:23]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[N:12]=[C:11]([CH3:13])[O:10][N:9]=4)=[CH:4][C:3]=3[CH3:14])[C:24]([CH3:27])=[CH:25][CH:26]=2)=[O:37])[CH2:15][CH2:17]1
Reactant: Cc1nc(-c2ccc(Br)c(C)c2)no1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)c(C)c2)no1

Procedure:
Example 29 was prepared using 3-(4-bromo-3-methylphenyl)-5-methyl-[1,2,4]oxadiazole and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 17) using DMF as the solvent.
Reaction SMILES: [C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C.[OH-].[Na+]>[C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1ccc(N(c2ccccc2)c2ccccc2)cc1
Yield: 92 %

Procedure:
The compound (1) obtained in Example 1-1, that is, 4-(diphenylamino)benzaldehyde, (4.2 g) was dissolved in 50 mL of ethanol and a solution prepared by dissolving 0.29 g of NaBH4 in 0.1 M aqueous solution of NaOH (15 mL) was slowly added thereto. The reactant solution was reacted at room temperature for 4 hours. An organic layer was separated from the reactant solution using methylene chloride and recrystallized in a methylene chloride/hexane solvent, yielding 92% of a white solid. Data of NMR spectra confirmed that the product had the same structure as the compound (2) in the reaction scheme 2.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:14]N1C(=O)C2=CC=CC=C2C1=O.O=O>C(#N)C1C=CC=CC=1>[C:1]1(=[O:14])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Solvent: N#Cc1ccccc1
Product: O=C1C=CC=C2C1=Cc1ccccc12
Yield: 30 %

Procedure:
Ten (10) millimoles of fluorene, 1 millimole of N-hydroxyphthalimide and 0.05 millimole of acetylacetonatomanganese Mn(AA)2 were added to 25 milliliters of benzonitrile. The resultant mixture was stirred in an oxygen atmosphere at a temperature of 100° C. for six hours. A product in the reaction mixture was analyzed by means of gas chromatography, and fluorene was transformed into fluorenone (yield 30%) with a transformation rate of 38 percent.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:12])=[CH:10][S:11][C:5]2=[N:4][C:3]=1[CH:13](Br)[CH3:14].[N-:16]=[N+:17]=[N-:18].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[N:16]([CH:13]([C:3]1[N:4]=[C:5]2[S:11][CH:10]=[C:9]([CH3:12])[N:6]2[C:7](=[O:8])[C:2]=1[Br:1])[CH3:14])=[N+:17]=[N-:18]
Reactant: Cc1csc2nc(C(C)Br)c(Br)c(=O)n12
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Reaction time: 0.12 h
Yield: 97.5 %

Procedure:
To a suspension of 6-bromo-7-(1-bromoethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (6.85 g, 19.4 mmol) in N,N-dimethylformamide (30.1 mL) was added sodium azide (1.45 g, 22.4 mmol). The mixture slowly turned clear after 5-10 min. After 50 min, a solution of sodium bicarbonate (4.7 g, 56 mmol) in water (90 mL) was added dropwise with stirring. The mixture was stirred at room temperature for 1 h and the solid precipitates were filtered off. The solid was then washed with water (30 mL×3), and dried to give 7-(1-azidoethyl)-6-bromo-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one as an off-white solid (5.94 g, 97.2%). LCMS calculated for C9H9BrN5OS (M+H)+: m/z 313.96, 315.96. Found: 313.75, 315.75. 1H NMR (400 MHz, DMSO-d6) δ 7.15 (q, J=1.3 Hz, 1H), 4.83 (q, J=6.8 Hz, 1H), 2.67 (d, J=1.4 Hz, 3H), 1.48 (d, J=6.8 Hz, 3H).
Reaction SMILES: [BH4-].[Na+].[CH:3]([CH2:5][CH2:6][C:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)([C:10]#[N:11])[C:8]#[N:9])=[O:4].O>C(O)C>[OH:4][CH2:3][CH2:5][CH2:6][C:7]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=1)([C:10]#[N:11])[C:8]#[N:9]
Reactant: N#CC(C#N)(CCC=O)Cc1ccc(C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CC(C#N)(CCCO)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.9 %

Procedure:
First, 0.01 g of sodium borohydride was added to the solution of 0.30 g of 2-(2-formylethyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the intermediate (19)) in ethanol at 0° C., followed by stirring for 5 hours at room temperature. Then, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.19 g of 2-(3-hydroxypropyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the intermediate (20)).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH3:36])[C:30]([N:32]([O:34][CH3:35])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH3:36])[C:30]([N:32]([O:34][CH3:35])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CON(C)C(=O)[C@H](C)N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](C)C(=O)N(C)OC)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.21 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 254-2 (4.31 mmol, crude form) as starting materials, respectively 946 mg (Isomer A, colorless amorphous) and 686 mg (Isomer B, colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]([CH3:18])[CH:4]=1)#[N:2].[Cl:19][C:20]1[CH:21]=[C:22]([SH:29])[C:23](=[CH:27][CH:28]=1)[C:24](O)=[O:25]>N1C=CC=CC=1>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]2[C:24](=[O:25])[N:2]=[C:1]([C:3]3[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH:6]=[C:5]([CH3:18])[CH:4]=3)[S:29][C:22]=2[CH:21]=1
Reactant: Cc1cc(C#N)nc(CCC(=O)OC(C)(C)C)c1
Reactant: O=C(O)c1ccc(Cl)cc1S
Solvent: c1ccncc1
Product: Cc1cc(CCC(=O)OC(C)(C)C)nc(-c2nc(=O)c3ccc(Cl)cc3s2)c1
Yield: 28.3 %

Procedure:
tert-Butyl 3-(6-cyano-4-methyl-2-pyridyl)propanoate (0.69 g, 2.8 mmol) and 4-chlorothiosalicylic acid (1.05 g, 5.7 mmol) were dissolved in pyridine (10 ml). The mixture was refluxed for 22 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (0.33 g, 28%) as white crystals.
Reaction SMILES: [C:1]1([C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+].Cl>O1CCCC1.CO.O>[C:27]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)[CH2:14][CH2:15]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of EXAMPLE 1C (10.00 g, 23.4 mmol) in tetrahydrofuran/methanol (100/50 mL) was added solution of lithium hydroxide monohydrate (2.59 g, 70 mmol) in water (30 mL). The reaction mixture was stirred at 60° C. for 16 hours, then was cooled to room temperature and the organic solvents were concentrated. The white solid residue was dissolved in hot water and then the product was neutralized with HCl (3 equivalents). After cooling to room temperature, the precipitate was filtered off, washed with water and dried in a vacuum oven overnight at 40° C.