Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[S:17][C:16]=3[C:15]([Br:23])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:24])[C:3]=1[OH:25].O[C@H:27]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:28]([O-:30])=[O:29].BrBr>C(Cl)(Cl)Cl>[Br:24][C:4]1[CH:5]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[S:17][C:16]=3[C:15]([Br:23])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:25][C@@H:27]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:28]([OH:30])=[O:29]
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O)c(Br)c3)c2c1C
Reactant: O=C([O-])[C@H](O)CCc1ccccc1
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O[C@@H](CCc4ccccc4)C(=O)O)c(Br)c3)c2c1C

Procedure:
Prepared from 2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (Example 9) and commercially available (R)-2-hydroxy-4-phenyl-butyrate, ethyl ester according to the procedure of Example 30. White solid: mp 176-177° C.; [a] 25/D=+7.58° (10.692 mg/mL, CHCl3); NMR (DMSO-d6); δ 13.0 (broad s, 1H, COOH), 8.21 (ddd, J=8, 7 ,1 Hz, 1H), 7.73 (s, 2H), 7.67 (ddd, J=8, 7, 1 Hz, 1H), 7.52 (ddd, J=8, 7 , 1 Hz, 1H), 7.46 (m, 1H), 7.32-7.28 (m, 2H), 7.24-7.18 (m,3H), 5.03 (t, J=6 Hz, 1H), 2.95 (m, 1H), 2.72 (m, 1H), 2.44 (s, 3H), 2.28 (m,2H), 1:61 (s, 3H); MS (+FAB): [M+], 3 bromine isotope pattern, 700 (30%), 702(100%), 704 (75%), 706 706(40%); Anal. Calc. for C30H23Br3O3S: C, 51.23, H3.30, N 0.00. Found: C, 51.15, H, 3.13, N, 0.00.
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2[CH:3]=[CH:2]1)[CH2:7]3.[Br:11][C:12]([F:19])([F:18])[C:13]([F:17])([F:16])[CH:14]=[CH2:15]>C1(C)C=CC=CC=1.COC1C=CC(O)=CC=1>[Br:11][C:12]([F:19])([F:18])[C:13]([F:17])([F:16])[CH:14]1[CH2:15][CH:1]2[CH2:2][CH:3]1[CH:4]1[CH:5]2[CH:6]2[CH2:7][CH:8]1[CH:9]=[CH:10]2
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=CC(F)(F)C(F)(F)Br
Agent: COc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: FC(F)(Br)C(F)(F)C1CC2CC1C1C3C=CC(C3)C21
Temperature: 170 °C
Reaction time: 5 h
Yield: 81.2 %

Procedure:
An autoclave was charged with 108.5 g of dicyclopentadiene and 322.4 g of 1-bromo-1,1,2,2-tetrafluoro-3-butene. A solution of 0.3 g of 4-methoxyphenol dissolved in 5 ml of toluene was added to the autoclave as a polymerization inhibitor and the mixture was stirred for 5 hours at 170° C. The reaction product was purified by distillation under reduced pressure at 85° C. and 0.1 mmHg to obtain 226 g of 1-bromo-1,1,2,2-tetrafluoro-2-(tetracyclo[4.4.0.12,5.17,10]dodec-3-en-8-yl)ethane as a clear liquid (hereinafter referred to as “compound (5-a)”).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].CC(C)([O-])C.[K+].C1COCC1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>CN(C=O)C>[CH2:23]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.29 h
Yield: 113.8 %

Procedure:
Dissolve isatin (7.36 g, 50 mmol) in anhydrous DMF (100 mL) under nitrogen and cool in an ice bath. Treat with 1M potassium tert-butoxide in THF (53 mL, 53 mmol) stir 15-20 min. Add benzyl bromide (6.2 mL, 52.5 mmol) and after 10 min remove bath and allow to warm to room temperature over 16 h. Pour into 1N HCl and wash with ethyl acetate (500 mL). Wash ethyl acetate with 1N HCl (150 mL) and then wash combined acidic portions with more ethyl acetate (150 mL). Wash the combined organic portions with brine (2×150 ml), dry (MgSO4), filter and concentrate in vacuo to give 13.5 g of an orange solid. Triturate in diethyl ether and filter to give 10.0 g (84%) of the title compound. MS (ES): m/z=238 (M+1); 1H NMR(CDCl3): δ7.64 (dd, J=7.6 Hz, J=1 Hz, 1H), 7.5 (dt, J=7.8 Hz, J=1.3 Hz, 1H), 7.37 (m, 5H), 7.12 (t, J=7.6 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 4.97 (s, 2H).
Reaction SMILES: C(OC[CH2:12][N:13](C)[CH3:14])(=O)CCCCCCC.[C:16]([O:33][CH2:34][CH2:35][CH2:36]Br)(=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].CNC.C(Cl)(Cl)Cl.CO>C(#N)C>[C:16]([O:33][CH2:34][CH2:35][CH2:36][N:13]([CH3:14])[CH3:12])(=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCC(=O)OCCCBr
Reactant: CCCCCCCC(=O)OCCN(C)C
Agent: CNC
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC#N
Product: CCCCCCCCCCCCCCCC(=O)OCCCN(C)C
Yield: 72 %

Procedure:
This intermediate was prepared in a manner analogous to that of 2-(dimethylamino)ethyl octanoate from 3-bromopropyl hexadecanoate (3 g, 7.95 mmol) and 40% aqueous dimethylamine (15 mL, 119 mmol) in acetonitrile (20 mL). The resulting material was applied to a silica gel column (discontinuous gradient of chloroform/methanol 95:5, 8:2 as eluent) affording 1.3 g pure product. Yield 72%; mp 49°-50° C.; 1H NMR (CDCl3) 0.85-0.95 (t, CH3 (CH2)12), 1.20-1.40 (m, CH3 (CH2)12), 1.55-1.70 (m, CH2 CH2 CO), 1.88-2.00 (m, O CH2 CH2 CH2 N), 2.27-2.35 (t, CH2 CH2 CO), 2.37-2.45 (s, (CH3)2 N) 2.50-2.62 (t, O CH2 CH2 CH2 N), 4.10-4.18 (t, O CH2 CH2 CH2 N).
Reaction SMILES: [I-].C(OC([NH:9][C@H:10]([C:25]([NH:27][CH2:28][CH2:29][CH2:30][N+:31]([CH3:34])([CH3:33])[CH3:32])=[O:26])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH2:22][CH2:23][Cl:24])[CH2:19][CH2:20][Cl:21])=[CH:14][CH:13]=1)=O)(C)(C)C.C(O)C>CO>[ClH:21].[Cl:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][Cl:24])[C:15]1[CH:14]=[CH:13][C:12]([CH2:11][C@@H:10]([C:25]([NH:27][CH2:28][CH2:29][CH2:30][N+:31]([CH3:33])([CH3:32])[CH3:34])=[O:26])[NH2:9])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(N(CCCl)CCCl)cc1)C(=O)NCCC[N+](C)(C)C
Agent: [I-]
Solvent: CO
Solvent: CCO
Product: C[N+](C)(C)CCCNC(=O)[C@@H](N)Cc1ccc(N(CCCl)CCCl)cc1
Product: Cl

Procedure:
0.148 mmol of the product obtained in Step B is treated at ambient temperature for two ours with 10 ml of 2N hydrochloric ethanol. The solution is then evaporated under reduced pressure. The residue obtained is dissolved in 50 ml of methanol and passed over resin for a few minutes. The methanolic fractions are evaporated off under reduced pressure. The residue obtained is taken up in the minimum amount of methanol and poured into an ethereal solution. The expected product is isolated in the form of a very hydroscopic white-beige solid by means of filtration, washing with ether and drying.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:22]1(/[CH:28]=[CH:29]/[CH2:30]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:30]/[CH:29]=[CH:28]/[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: ClC/C=C/c1ccccc1
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(C/C=C/c3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 3-phenyl-2-[trans]propenylchloride as described for compound 78. Purified by chromatography (dichloromethane). Crystallized from diethyl ether at -20° C. M.p. 76°-79° C.
Reaction SMILES: [C:1]1(=[O:10])[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[CH:4]=[CH:3][NH:2]1.[H-].[Na+].[CH3:13]I>CN(C=O)C>[CH3:13][N:2]1[CH:3]=[CH:4][C:5]2[CH2:9][CH2:8][CH2:7][C:6]=2[C:1]1=[O:10]
Reactant: CI
Reactant: O=c1[nH]ccc2c1CCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2c(c1=O)CCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
The title compound of step 5 (260 mg, 1.93 mmol) was dissolved in DMF (5 mL) and cooled to 0° C. NaH (94 mg, 2.31 mmol) was added and the mixture was stirred for 30 min. Methyl iodide (146 μL, 2.31 mmol) was added and the mixture stirred at rt for 2 h. The volatile components were removed under vacuum and silica gel chromatography (PE/EtOAc=1:1) gave the title compound (192.6 mg, 67%) as a brown oil. 1H NMR (CD3Cl, 300 MHz): δ 7.13 (d, J=6.6 Hz, 1H), 6.13 (d, J=6.6 Hz, 1H), 3.53 (s, 3H), 2.79-2.85 (m, 4H), 2.01-2.11 (m, 2H). LCMS: 150 (M+1)+
Reaction SMILES: [Cl-].[Ca+2:2].[Cl-].[O-:4][P:5]([O:8][P:9]([O-:12])([O-:11])=[O:10])(=[O:7])[O-:6].[Na+:13].[Na+].[Na+].[Na+]>>[OH2:4].[OH2:4].[OH2:4].[OH2:4].[O-:6][P:5]([O:8][P:9]([OH:12])([O-:11])=[O:10])(=[O:4])[O-:7].[Na+:13].[Ca+2:2]
Reactant: O=P([O-])([O-])OP(=O)([O-])[O-]
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Product: O
Product: O=P([O-])([O-])OP(=O)([O-])O

Procedure:
A 25 weight percent aqueous solution of calcium chloride is added to a 15 weight percent aqueous solution of tetrasodium pyrophosphate in a suitable vessel until the pH reaches 7. The acicular crystals of calcium sodium pyrophosphate tetrahydrate are formed. The crystals are filtered, washed thoroughly, and dried at 60° C. The calcium sodium pyrophosphate tetrahydrate is then heated at a temperature within the range of 175° to 200° C for a period of 60 minutes until 3.2 moles of water of hydration is removed. The dehydrated solids were then ground. The structure of the material is now amorphous as determined by X-ray diffraction.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:25](CC)CC)[CH3:24].ClCC#N>CC(C)=O>[C:17]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:24][C:23]#[N:25])=[O:15])=[N:12][CH:13]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(C(c2ccccc2)c2ccccc2)cn1
Agent: N#CCCl
Solvent: CC(C)=O
Product: N#CCOC(=O)c1ccc(C(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Suspend 4.3 g. (0.015 mole) of 5-(diphenylmethyl)-picolinic acid in 100 ml. of acetone with stirring and add 2.3 g. (0.023 mole) of triethylamine. To the resulting solution add dropwise 1.7 g. (0.023 mole) of chloroacetonitrile. Stir the reaction mixture at room temperature (25° C.) for 15 minutes, then reflux for 4 hours. Cool and filter the reaction mixture. Concentrate the filtrate to a residue in vacuo and triturate the residue with hot isopropyl ether to yield the product of this example, yield 3.5 g., m.p. 95°-98° C.
Reaction SMILES: C[NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5](NC)[CH:4]=1.C(O[C:15](=[O:17])[CH3:16])(=O)C.C([O:20][CH2:21][CH3:22])C>>[CH3:22][C:21]([N:2]([C:15]([CH3:16])=[O:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:20]
Reactant: CC(=O)OC(C)=O
Reactant: CCOCC
Reactant: CNc1cccc(NC)c1
Product: CC(=O)N(C(C)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N,N'-dimethyl-1,3-benzenediamine (27.2 g, 0.20 mol) in ethyl ether (300 ml) is added acetic anhydride (44.8 g, 0.44 mol) over 20 minutes at room temperature. The mixture is stirred at room temperature for 2 hours. The solution is diluted with ether (300 ml) and washed with saturated sodium carbonate solution and water, dried over magnesium sulfate,.and concentrated to a solid. The solid is recrystallized from ethyl acetate-hexane to give the pure diacetanilide.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]OS(C1C=CC(C)=CC=1)(=O)=O.[CH-:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.[Na+]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][C:16]1[CH2:20][CH:19]=[CH:18][CH:17]=1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: c1cc[cH-]c1
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCC1=CC=CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
To a solution of 19.7 g(85.7 mmol) 2-methoxyethyltosylate as prepared in step (a) in 200 ml THF cooled to 0° C. was added 55 ml of 2.0M (110 mmol) sodium cyclopentadienylide in THF. The reaction mixture was allowed to warm to room temperature and was stirred for 16 h. 100 ml concentrated aqueous saline solution was added and the product extracted with diethyl ether (3×75 ml). The combined organic fractions were dried over sodium sulphate for 16 hrs, filtered and the solvents removed under reduced pressure using a rotary evaporator to yield a brown oil. The crude product was distilled under reduced pressure (b.p. 40-°44° C. at 2-3 mm Hg) to give 4.5 g of a colourless oil (37.7 mmol, 44.0%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[N:4]=1.C([O-])([O-])=[O:11].[K+].[K+]>O>[F:9][C:5]1[N:4]=[C:3]([CH2:2][OH:11])[CH:8]=[CH:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cccc(CCl)n1
Agent: [K+]
Solvent: O
Product: OCc1cccc(F)n1
Reaction time: 8 h
Yield: 41.5 %

Procedure:
To a solution of 2-chloromethyl-6-fluoro-pyridine I-3c (1.43 g, 9.84 mmol) in H2O (22 mL) was added K2CO3 (1.77 g, 12.8 mmol). The reaction mixture was stirred overnight at reflux. The cooled aqueous mixture was first extracted with heptane (2×20 mL)and then ethyl acetate (2×50 mL). The ethyl acetate layers were combined, washed with brine, dried (Na2SO4), and concentrated to dryness. The crude residue was chromatographed over silica gel (15 g) using 2% methanol/methylene chloride with 0.5% NH4OH as the eluant to yield 518.7 mg of the title compound (I-3d) as a yellow oil.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:23])[CH:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:35])[C@@H:27]([NH2:34])[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C.ON1C(=O)C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.NC(N)=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:24][O:25][C:26](=[O:35])[C@@H:27]([NH:34][C:11](=[O:12])[CH:10]([C:9](=[O:23])[NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)[CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: COC(=O)[C@@H](N)C1CCCCC1
Reactant: N#Cc1ccc(CC(C(=O)O)C(=O)NCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(N)=O
Agent: O=c1c2ccccc2nnn1O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C#N)cc1)C(=O)NCc1ccccc1)C1CCCCC1
Yield: 66.3 %

Procedure:
A solution of N-benzyl-2-(R,S)-(4-cyano-benzyl)-malonamic acid (10 g, 32.4 mmol), (S)-amino-cyclohexyl-acetic acid methyl ester (5.94 g, 34.7 mmol), diisopropylethyl-amine (6.45 ml, 37.9 mmol), 3-hydroxy-3H-benzo[d][1,2,3]triazin-4-one (1.32 g, 8.1 mmol), and dimethylformamide (100 ml) was cooled to 10° C. A solution of dicyclohexyl-carbodiimide (7.83 g, 37.9 mmol) in toluene (10 ml) was added dropwise and the reaction mixture stand over night. The precipitated urea was sucked off, the filtrate was evaporated in vacuo, solved in ethyl acetate, washed with saturated sodium hydrogen carbonate-solution and brine, dried, and evaporated in vacuo. Crystallization from n-heptane/isopropanol gave 9.91 g (66%) of the desired product. mp.: 170-174° C., MS m/z: 462 (M+H)+.
Reaction SMILES: [CH3:1][C:2](/[CH:4]=[N:5]/O)=O.[CH3:7][C:8]([CH2:10][C:11]([C:13]([F:16])([F:15])[F:14])=[O:12])=O.C(O)(=O)C.[OH-].[Na+]>[Zn].O>[CH3:7][C:8]1[NH:5][CH:4]=[C:2]([CH3:1])[C:10]=1[C:11](=[O:12])[C:13]([F:16])([F:15])[F:14]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: CC(=O)/C=N/O
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c[nH]c(C)c1C(=O)C(F)(F)F
Temperature: 25 °C
Yield: 14.6 %

Procedure:
According to the literature procedure (Chiswell, B. Inorganica Chimica Acta. 1972, 629), a mixture of anti-pyruvic aldehyde 1-oxime (1.3 g, 15 mmol), 1,1,1-trifluoro-2,4-pentadione (1.85 mL, 15 mmol), glacial acetic acid (12 mL) and H2O (3.0 mL) was stirred vigorously at room temperature. To this flask, zinc dust (3 g) was added slowly keeping the temperature below 60° C. After addition, the resulting brown solution was heated under reflux condition for 2 hours. After cooling down to room temperature, the reaction mixture was basified by an addition of 2 M aqueous NaOH, then filtered. The filtrate was extracted with CH2Cl2 (20 mL×3), the combined organic layer dried over MgSO4, and concentrated iii vacito. The residue was purified by flash chromatography (1-3:1 CH2Cl2-Hexane) to afford the subtitle compound (0.42 g, 15% yield) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]34[CH2:20][CH2:19][C:16]([C:21]5O[C:23]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=6[C:32]([F:35])([F:34])[F:33])=[N:24][N:25]=5)([CH2:17][CH2:18]3)[CH2:15][CH2:14]4)[O:10][N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH3:43][NH2:44]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]34[CH2:14][CH2:15][C:16]([C:21]5[N:44]([CH3:43])[C:23]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=6[C:32]([F:34])([F:35])[F:33])=[N:24][N:25]=5)([CH2:19][CH2:20]3)[CH2:17][CH2:18]4)[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2noc(C34CCC(c5nnc(-c6ccccc6C(F)(F)F)o5)(CC3)CC4)n2)cc1
Reactant: CN
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(c3nc(-c4ccc(F)cc4)no3)(CC1)CC2

Procedure:
A mixture of above 1,2,4-oxadiazole (7-E) (115.2 mg, 0.238 mmol) and the trifluoroacetic acid salt of methylamine (1.73 g, 11.9 mmol) in a 2M solution of methylamine in methanol (4 mL) was heated at 150° C. in a sealed tube for 48 h. The mixture was then concentrated, and the residue was taken up in dichloromethane, washed with saturated sodium bicarbonate aqueous solution. The organics were concentrated and the residue was purified using reverse-phase HPLC with TFA-buffered acetonitrile/water (40-80%) as eluent. The fractions containing the product were combined, neutralized with saturated sodium bicarbonate aqueous solution and lyophilized from acetonitrile/water to provide 3-(4-fluorophenyl)-5-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole (7-F). 1HNMR (CDCl3) δ 2.25-2.35 (m, 12H), 3.53 (s, 3H), 7.21 (t, J=8.7 Hz, 2H), 7.54 (m, 1H), 7.73 (m, 2H), 7.88 (m, 1H), 8.13 (m, 2H). ESI-MS m/z (M+H) 498.2.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C([Li])CCC.[C:16]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1>[OH:21][C:16]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCCC1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2(O)CCCC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
A solution of 4-bromobenzoic acid (4.02 g, 20.0 mmol) in tetrahydrofuran (100 mL) was purged with argon for 5 min. n-Butyllithium (16.0 mL of 2.5 M in hexanes, 40 mmol) was added dropwise at −78° C., resulting in a yellow thick syrup. The mixture was stirred at −78° C. for 30 min. Cyclopentanone (3.89 mL, 44.0 mmol) was added dropwise. The reaction was quenched immediately with saturated NH4Cl and allowed to warm to room temperature. The mixture was acidified with 1 N HCl to pH ˜3 and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The solid residue was suspended in hexanes, filtered, and the solid washed with additional hexanes. The solid was re-suspended in dichloromethane followed by hexanes. The resulting precipitate was filtered, washed with hexane and air dried to yield 4-(1-hydroxycyclopentyl)benzoic acid (1.25 g, 30%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 7.88 (d, J=8.5 Hz, 2H), 7.58 (d, J=8.5 Hz, 2H), 4.93 (s, 1H), 1.93-1.71 (m, 8H).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]2[CH:6](O)[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH3:19][N:20]1[CH:27]=[CH:26][C:24](=[O:25])[NH:23][C:21]1=[O:22]>FC(F)(F)C(O)=O.O>[CH3:15][C:12]1[CH:13]=[CH:14][C:7]2[CH:6]([C:26]3[C:24](=[O:25])[NH:23][C:21](=[O:22])[N:20]([CH3:19])[CH:27]=3)[C:5]3[CH:17]=[CH:18][C:2]([CH3:1])=[CH:3][C:4]=3[CH:10]=[CH:9][C:8]=2[CH:11]=1
Reactant: Cc1ccc2c(c1)CCc1cc(C)ccc1C2O
Reactant: Cn1ccc(=O)[nH]c1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of step (i) (0.094 g) in trifluoroacetic acid (4 ml) under a nitrogen atmosphere was added 1-methyluracil (0.01 g), and the mixture stirred at room temperature for 1 hour. Evaporation of solvent afforded an orange oil which was azeotroped once with acetonitrile (5 ml). The crude product was redissolved in acetonitrile (2 ml), and stirred at room temperature for 0.5 h, giving a white precipitate. The reaction mixture was diluted with water (10 ml) and the white precipitate isolated by filtration. Yield: 0.085 g
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:11]2[CH2:16][CH2:15][C:14]([CH2:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(O)[CH2:13][CH2:12]2)[CH3:10])=[CH:5][CH:4]=1.O=S(Cl)[Cl:29]>ClCCl>[ClH:29].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:11]2[CH2:16][CH2:15][C:14]([CH2:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([Cl:29])[CH2:13][CH2:12]2)[CH3:10])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(C)N2CCC(O)(CC(=O)c3ccccc3)CC2)cc1
Solvent: ClCCl
Product: COc1ccc(C(C)N2CCC(Cl)(CC(=O)c3ccccc3)CC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
N-(1-(4-methoxyphenyl)ethyl)-4-benzoylmethyl-4-piperidinol (III-19) is firstly prepared according to the method of synthesis and post-treatment in Example 19. 1.41 g (4.0 mmol) of N-(1-(4-methoxyphenyl)ethyl)-4-benzoylmethyl-4-piperidinol is dissolved into 20 ml of anhydrous dichloromethane and cooled in an ice-water bath with temperature controlled at below 0° C. The reaction solution is added dropwise a dichloromethane solution (8 mol, 25 ml) of SOCl2. After completion of addition, the temperature is raised slowly to room temperature and reacting for 1 hour. Then operating according to the post-treatment method in General Method seven obtains 0.68 g of white crystal, with yield of 39.9%.
Reaction SMILES: [Br-:1].O1CCO[CH:3]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N+:8]=1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Br-]>Br>[Br-:1].[CH:12]1[C:7]2[CH:3]=[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]3=[CH:13][N+:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(C[n+]2ccccc2C2OCCO2)cc1
Agent: Br
Agent: [Br-]
Product: c1ccc2c[n+]3ccccc3cc2c1
Yield: 87.6 %

Procedure:
A mixture of 1526.8 g (4.74 mol) of 2-(1,3-dioxolan-2-yl)-1-benzylpyridinium bromide in 9 L of 48% HBr solution was heated on a steam-bath until the bromide dissolved. The mixture was heated (heating mantle) in vacuo (aspirator) to remove HBr solution. The dry residue was suspended in 800 mL of HBr solution, cooled, and 4 L of THF was slowly added. The reaction mixture was filtered to afford 1080 g (87%) of benzo[b]quinolizinium bromide as a green solid. Benzo[b]quinolizinium bromide (586 g) was dissolved in 2.4 L of hot water and filtered to remove an insoluble dark material. The filtrate was cooled in ice-water for 4 h, filtered, and the residue was washed with water, dried in vacuo at room temperature for 9 days to afford 508.8 g (86.8%) of benzo[b]quinolizinium bromide (Formula II: R1 =R2 =R7 =H; X- --=Br-).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])C(F)(F)F)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[OH-:17].[K+].Cl>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:16])=[O:17])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: O=C(O)c1c[nH]c2cc(Cl)ccc12
Yield: 96 %

Procedure:
A solution of 21.6 g (87.2 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in 110 ml of a 4 M aqueous solution of potassium hydroxide was heated at reflux for 2 h. After cooling to 0° C. neutralisation with 36.7 ml of a concentrated aqueous hydrochloric acid solution a white solid precipitated from the solution. The solid was collected by filtration and washed with water. Drying in high vacuo at 80° C. gave 16.4 g (96%) of the title compound as a light yellow solid.