Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)=CCC[N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:26])[C:14]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)([OH:20])[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[CH2:8][CH2:7]1.Cl.Cl.NC1CCN([CH2:37][CH:38]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)CC1>>[CH:38]1([CH2:37][N:6]2[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:26])[C:14]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)([OH:20])[C:15]3[S:16][CH:17]=[CH:18][N:19]=3)[CH2:8][CH2:7]2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: NC1CCN(CC2CCCCCC2)CC1
Reactant: CC(C)=CCCN1CCC(NC(=O)C(O)(c2nccs2)C2CCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CC2CCCCCC2)CC1)C(O)(c1nccs1)C1CCCC1

Procedure:
The title compound was prepared in the same manner as described in Step 4 of Example 22 using 2-cyclopentyl-2-hydroxyl-2-(2-thiazolyl)acetic acid obtained in Example 51 and 4-amino-1-(cycloheptylmethyl)piperidine dihydrochloride.
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3]C1.[C:6]([OH:14])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9]C=1.Cl[CH2:16]Cl>>[C:12]1(=[CH:7][C:6]([O:14][C:4]([CH3:3])([CH3:1])[CH3:16])=[O:13])[CH2:11][CH2:10][CH2:9]1
Reactant: ClCCl
Reactant: O=C1CCC1
Reactant: O=C(O)c1ccccc1
Product: CC(C)(C)OC(=O)C=C1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon and at room temperature, 3.0 g (42.8 mmol) of cyclobutanone were dissolved in 160 ml of dichloromethane, and 20.95 g (55.64 mmol) of tert-butyl (triphenyl-λ5-phosphanylidene) acetate and 0.68 g (5.56 mmol) of benzoic acid were then added. The reaction mixture was stirred at room temperature overnight and then concentrated to dryness. The residue was triturated with 25 ml of diethyl ether, and the mixture was stored at 4° C. for 12 h. The precipitated triphenylphosphane oxide was filtered off and the filtrate was concentrated to dryness. The crude product obtained was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 9.3 g (99% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH2:23]([OH:26])[CH2:24][OH:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:25][CH2:24][CH2:23][OH:26])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: OCCO
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(OCCO)c(Br)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 44.2, 400 mg, 1.011 mmol), ethane-1,2-diol (1 mL, 17.88 mmol), K2CO3 (210 mg, 1.517 mmol) and DMF (2 mL) was stirred at 50° C. overnight. The solvent was evaporated off under reduced pressure and the residue was treated with water and extracted with DCM. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to afford the title compound which was used directly. UPLC-MS (Condition 2) tR=1.04 min, m/z=421.3/423.3 [M+H]+.
Reaction SMILES: C(O)(C(F)(F)F)=O.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=1>CC(O)C>[N+:27]([C:22]1[CH:21]=[C:20]([NH:19][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:25]=[CH:24][C:23]=1[OH:26])([O-:29])=[O:28]
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Reactant: Clc1ccnc2ccccc12
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cc(Nc2ccnc3ccccc23)ccc1O
Temperature: 130 °C

Procedure:
TFA (0.57 mL) was added to a suspension of 4-chloroquinoline (0.48 mg, 2.9 mmol) and 4-amino-2-nitrophenol (0.45 g, 2.9 mmol) in i-PrOH (4 mL) was added at RT. The reaction was heated to 130° C. in a sealed tube for 2 h. A solid precipitated upon cooling. The solid was filtered out and washed with i-PrOH to give 2-nitro-4-(quinolin-4-ylamino)-phenol.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)=[O:4].[C:10]([O:14][C:15]([NH:17][CH:18]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:19]([O:21][C@@H:22]1[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1)=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].CCOCC>C(OCC)(=O)C>[Br-:1].[C:10]([O:14][C:15]([NH:17][CH:18]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:19]([O:21][C@@H:22]1[CH:27]2[CH2:28][CH2:29][N+:24]([CH2:2][C:3](=[O:4])[C:5]3[CH:9]=[CH:8][S:7][CH:6]=3)([CH2:25][CH2:26]2)[CH2:23]1)=[O:20])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: O=C(CBr)c1ccsc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1C[N+]2(CC(=O)c3ccsc3)CCC1CC2)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
2-Bromo-1-(thiophen-3-yl)ethanone (39.8 mg, 0.19 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-phenylacetate (C1) (70.0 mg, 0.19 mmol) in ethyl acetate (2 ml). The reaction was stirred at RT overnight. Et2O (1 ml) was added, and the solid was collected by suction filtration. The compound was further purified by flash chromatography (DCM/MeOH=95/5) to obtain (3R)-3-(2-(tert-butoxycarbonylamino)-2-phenylacetoxy)-1-(2-oxo-2-(thiophen-3-yl)ethyl)-1-azoniabicyclo[2.2.2]octane bromide (55.6 mg; 51% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([CH:23]2[CH2:28][CH2:27]CN[CH2:24]2)[CH:20]=[CH:21][CH:22]=1.[CH:31]([N:34](C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:34]2[CH2:31][CH2:24][CH:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:29])[F:30])[CH:18]=3)[CH2:28][CH2:27]2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1
Reactant: CCN(C(C)C)C(C)C
Reactant: FC(F)(F)c1cccc(C2CCCNC2)c1
Reactant: ClCCCCn1nnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1cccc(C2CCN(CCCCn3nnc4ccccc43)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (0.06 mol) was dissolved into 150 ml of acetonitrile, 4-(3-(3-trifluoromethylphenyl) piperidine (0.05 mol), diisopropylethylamine (0.2 mol) and potassium iodide (0.05 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, purified, eluted with dichloromethane/methanol mixture to produce 13.6 g N-(4-(1H-benzotriazole-1-yl)butyl)-4-(3-trifluoromethylphenyl)piperidine (I-110) with a yield of 67.8%. ESI-MS [M+H]+: m/z 403.2.
Reaction SMILES: [CH3:1][C:2]([C@H:5]([NH2:8])[CH2:6][OH:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:8][C@H:5]([CH2:6][OH:7])[C:2]([CH3:4])([CH3:3])[CH3:1])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)[C@H](N)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 16 h

Procedure:
To a solution of S-tert-leucinol (0.20 g, 1.70 mmol), triethylamine (0.19 g, 1.87 mmol) and methylene chloride (10 mL) at 0° C., was added a solution of 4-chloro benzenesulfonyl chloride (0.36 g, 1.70 mmol) in CH2Cl2 (5 mL). After 15 minutes the ice bath was removed and the reaction allowed to reach 25° C. After 16 hours, the reaction was quenched by pouring into saturated sodium bicarbonate solution (20 mL) and additional-methylene chloride (15 mL). The organic phase was separated and washed sequentially with 1N HCl solution (20 mL), distilled water and brine, dried over MgSO4 and evaporated to give the desired product as a white solid, mp 128-130° C. (0.46 g, 94%). MS (+APCI) 292.06 ([M+H]+). Anal. Calc'd for C12H18ClNO3S: C, 49.39; H, 6.22; N, 4.80; Found: C, 49.40; H, 6.17; N, 4.79.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH3:32])=[CH:26]2>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][C:27]([CH3:32])=[CH:26]4)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCc1ccccc1
Yield: 91.2 %

Procedure:
Using an analogous procedure to that described in Example 32, 7-benzyloxy-4-chloro-6-methoxyquinazoline (1 g, 3.33 mmol), (prepared as described for the starting material in Example 1), was reacted with 5-hydroxy-2-methylindole (0.59 g, 4 mmol) to give 7-benzyloxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (1.25 g, 91%).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:15])[CH:4]=[CH:5][C:6]=1[S:7]([NH:10]C(C)(C)C)(=[O:9])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[N:3]([CH3:15])[CH:4]=[CH:5][C:6]=1[S:7]([NH2:10])(=[O:8])=[O:9]
Reactant: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc(S(N)(=O)=O)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.4 %

Procedure:
To a solution of 7.11 g (24 mmol) of 2-bromo-N-(1,1-dimethylethyl)-1-methyl-1H-pyrrole-3-sulfonamide in 50 mL methylene chloride under a nitrogen atmosphere was added 50 mL of TFA. The reaction mixture was allowed to stir at room temperature overnight ca. 16 hours. The reaction mixture was concentrated in vacuo. Three portions of diethyl ether were added to the crude residue and was removed by evaporation to remove residual TFA, which yielded 1.23 g of the title compound as a light brown solid. 1H NMR (Acetone-d6, 200 MHz.) δ: 7.36(d,1H), 6.49(d,1H), 6.3(bs,2H) 3.68(s,3H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[C:16]1([NH:15][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.2 %

Procedure:
To a solution of Boc-4-piperidone (4.0 g, 20 mmol), aniline (1.9 ml, 20 mmol), and acetic acid, glacial (1.4 ml, 24 mmol) in dichloroethane (60 mL) was added sodium triacetoxyborohydride (6.0 g, 28 mmol) portionwise at RT. The suspension was stirred at RT for 24 h, diluted with water and extracted with dichloromethane. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by ISCO using 0-30% EtOAc in Hexanes to give tert-butyl 4-(phenylamino)piperidine-1-carboxylate (2.5 g, 45% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[CH:8]1[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH2:15][CH2:16][N:7]1[CH2:6]2.[OH-:22].[K+].C.C[OH:26]>CN(C)C=O>[OH:22][C:8]12[C:17]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:19]([O:20][CH3:21])[CH:18]=3)[C:6](=[O:26])[N:7]1[CH2:16][CH2:15][C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12
Reactant: CO
Reactant: [OH-]
Reactant: COc1cc2c(cc1OC)C1c3ccccc3CCN1C2
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C1(O)c3ccccc3CCN1C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10,11-Dimethoxy-5,6,8,12b-tetrahydro-isoindolo-[1,2-a]isoquinoline (109.65 g) and potassium hydroxide in pellet form (23.2 g) are dissolved in methanol (1100 cc). Air is bubbled into the reaction mixture, which is heated under reflux for 3 hours and then maintained at 25° C. for 48 hours. After concentration to 500 cc, the addition of distilled water (5000 cc) and stirring for 2 hours, a precipitate appears which is filtered off, washed three times with distilled water (total 500 cc) and dried under reduced pressure (20 mm Hg) at 40° C. A crude product (104.65 g), melting at 219° C., is obtained. A solution of a portion of this product (30 g) in dimethylformamide (200 cc) at 120° C. is treated with decolourising charcoal (1 g), filtered whilst hot, and cooled at about 5° C. for 16 hours. The resulting crystals are filtered off, washed three times with diisopropyl ether (total 30 cc) and dried under reduced pressure (1 mm Hg) at 60° C. for 6 hours. 12b-Hydroxy-10,11-dimethoxy-5,6,8,12b-tetrahydro-isoindolo[1,2-a]isoquinol-8-one (16.70 g), melting at 220° C., is thus obtained.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:8]([C:16]([CH3:21])([CH3:20])[C:17]([O-:19])=O)=[N:9][C:10]([CH3:15])([CH3:14])[C:11]([O-:13])=O.C[O-].[Na+].O>CO.CCCCCC>[N:9]([C:10]([CH3:14])([CH3:15])[C:11]([NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:13])=[N:8][C:16]([CH3:21])([CH3:20])[C:17]([NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:19]
Reactant: CC(C)(N=NC(C)(C)C(=O)[O-])C(=O)[O-]
Reactant: CCCCCCN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCCCCC
Product: CCCCCCNC(=O)C(C)(C)N=NC(C)(C)C(=O)NCCCCCC
Reaction time: 8 h
Yield: 95 %

Procedure:
28.2 Grams of n-hexylamine is mixed with 50 g of 2,2'-azobis (2-methyl propionate), and 20 g of 28% sodium methoxide solution in methanol and 10 ml of methanol are added thereto with stirring followed by conducting a reaction at room temperature with stirring for 6 hours and keeping standing overnight. 100 Milliliter of water is added to the reaction solution and extraction with 100 ml of n-hexane is conducted. The hexane layer is washed with water and dried over anhydrous sodium sulfate. The solvent is removed by distillation to give 76.3 g (yield 95%) of 2,2'-azobis (N-hexyl-2-methyl propionamide) as pale yellow sintering crystal. The solubility is shown in Table 1.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.O.O.[Sn](Cl)Cl>CCO>[CH3:1][C:2]1[C:6]2[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Cc1noc2cccc(Oc3ccc([N+](=O)[O-])cc3)c12
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cc1noc2cccc(Oc3ccc(N)cc3)c12
Temperature: 90 °C
Reaction time: 5 h
Yield: 33.7 %

Procedure:
3-methyl-4-[(4-nitrophenyl)oxy]-1,2-benzisoxazole (Intermediate 11, 100 mg) was dissolved under nitrogen atmosphere in 5.0 ml of EtOH. Tin(II) chloride dihydrate (417 mg, 1.85 mmol) was added. The reaction mixture was then stirred at 90° C. for 5 hours. After removal of the volatiles, water was added and the reaction mixture was extracted two times with ethyl acetate. The collected organic layers were washed with a 5% aqueous solution of NaHCO3, dried over sodium sulphate, filtered and evaporated. The crude obtained was purified by a NH column and eluted with DCM/MeOH (100/0, then a gradient from 100/0 to 90/10, then 90/10) to afford 30 mg of the title compound.
Reaction SMILES: [CH2:1]([CH:3]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][C:14]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=3)=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:31](=[O:40])[CH2:32][CH:33]([CH3:39])[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:10]=2)[CH3:2].[F:45][C:46]([F:60])([C:49]([F:59])([F:58])[C:50]([F:57])([F:56])[C:51]([F:55])([F:54])[CH2:52][OH:53])[CH2:47][OH:48].[OH-:61].[Na+]>N1C=CC=CC=1>[CH2:1]([CH:3]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][C:14]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([O:53][CH2:52][C:51]([F:54])([F:55])[C:50]([F:57])([F:56])[C:49]([F:58])([F:59])[C:46]([F:60])([F:45])[CH2:47][O:48][C:26]4[CH:27]=[CH:28][C:23]([C:22]([C:14]5[C:15]6[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=6[C:17]6[N:5]([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:41][CH2:42][CH2:43][CH3:44])[C:6]7[C:11]([C:12]=6[CH:13]=5)=[CH:10][C:9]([C:31](=[O:40])[CH2:32][CH:33]([CH3:39])[CH2:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:8][CH:7]=7)=[O:61])=[CH:24][CH:25]=4)=[CH:25][CH:24]=3)=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:31](=[O:40])[CH2:32][CH:33]([CH3:39])[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:10]=2)[CH3:2]
Reactant: [OH-]
Reactant: CCCCC(CC)Cn1c2ccc(C(=O)CC(C)CC(C)(C)C)cc2c2cc(C(=O)c3ccc(F)cc3)c3ccccc3c21
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO
Agent: [Na+]
Solvent: c1ccncc1
Product: CCCCC(CC)Cn1c2ccc(C(=O)CC(C)CC(C)(C)C)cc2c2cc(C(=O)c3ccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)COc4ccc(C(=O)c5cc6c7cc(C(=O)CC(C)CC(C)(C)C)ccc7n(CC(CC)CCCC)c6c6ccccc56)cc4)cc3)c3ccccc3c21
Temperature: 100 °C
Reaction time: 43 h

Procedure:
To 1-[11-(2-ethylhexyl)-5-(4-fluoro-benzoyl)-11H-benzo[a]carbazol-8-yl]-3,5,5-trimethyl-hexan-1-one (1.18 g; 2.00 mmol) in pyridine (5 mL) are added 2,2,3,3,4,4,5,5-octafluoro-1,6-hexanediol (0.24 g; 0.90 mmol) and sodium hydroxide (0.16 g; 4 mmol) at 80° C., and the mixture is stirred at 100° C. for 43 hours. After the reaction is completed, the reaction mixture is cooled to room temperature, and poured into ice water. The crude product is extracted with ethyl acetate, and the combined organic layer is washed with water and brine, dried over MgSO4, and concentrated to give a yellow resin. The crude is purified by column chromatography on silica gel eluting with a mixed solvent of CH2Cl2 and n-hexane (1:1) to give a yellow solid (0.40 g; 32%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 0.81-0.92 (m), 1.03 (d), 1.18-1.46 (m), 2.27-2.35 (m), 2.89-2.96 (m), 3.02-3.08 (m), 4.60 (t), 4.74 (m), 7.06 (d), 7.58 (m), 7.66 (t), 7.99 (m), 8.14 (dd), 8.33 (s), 8.43 (d), 8.61 (d), 8.68 (d); 19F-NMR spectrum (CDCl3). δ [ppm]: −123.32, −119.45.
Reaction SMILES: P(=O)(O)(O)O.C1(NC(N)=S)C=CC=CC=1.P(Cl)(Cl)([Cl:18])=O.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[CH2:27])=[CH:24][CH:23]=1.Cl[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>[Hg]>[CH3:27][CH:26]1[C:25]2[C:24](=[CH:23][C:22]([Cl:21])=[CH:29][CH:28]=2)[CH:32]([C:33]2[CH:38]=[CH:37][C:36]([Cl:18])=[CH:35][CH:34]=2)[CH2:31]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: C=Cc1ccc(Cl)cc1
Reactant: ClCCc1ccccc1
Agent: NC(=S)Nc1ccccc1
Agent: O=P(O)(O)O
Agent: [Hg]
Product: CC1CC(c2ccc(Cl)cc2)c2cc(Cl)ccc21
Yield: 80.7 %

Procedure:
200 parts of 98 per cent strength by weight aqueous phosphoric acid containing 0.9 part of phenylthiourea are irradiated for 10 minutes at 25° with ultraviolet light (mercury vapor lamp, with 15 watt hours per kilogram of halogenostyrene III) whilst passing 2,000 parts of air through the mixture. 70 parts of phosphorus oxychloride are added followed by a mixture of 120 arts of p-chlorostyrene and 97 parts of o-chloroethylbenzene added over 3 hours. Distillation of the organic phase gives 97 parts (= 80.7% of theory) of 1-methyl-3-(p-chlorophenyl)-5-chloroindan of b.p. 148° to 156° C (0.15 mm).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14](O)=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.S(Cl)([Cl:24])=O>>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([Cl:24])=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CC(C(=O)O)c1ccc2c(c1)CCc1ccccc1C2=O
Reactant: O=S(Cl)Cl
Product: CC(C(=O)Cl)c1ccc2c(c1)CCc1ccccc1C2=O

Procedure:
2-(5-Oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionyl chloride is obtained by heating 2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionic acid (28 g.) in thionyl chloride (280 cc.) for one hour. After cooling, the thionyl chloride is evaporated at 60°C. under reduced pressure (20 mm.Hg). 2-(5-Oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionyl chloride (28.8 g.) is thus obtained in the form of an oil.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:54]([O:58][C:59](=[O:79])[CH2:60][C:61]1([C:76](O)=[O:77])[CH:65]([CH3:66])[CH2:64][N:63]([CH2:67][C:68]2[C:73]([Cl:74])=[CH:72][CH:71]=[CH:70][C:69]=2[Cl:75])[CH2:62]1)([CH3:57])([CH3:56])[CH3:55]>O.CN(C)C=O>[Cl:75][C:69]1[CH:70]=[CH:71][CH:72]=[C:73]([Cl:74])[C:68]=1[CH2:67][N:63]1[CH2:64][C@@H:65]([CH3:66])[C@@:61]([CH2:60][C:59]([O:58][C:54]([CH3:55])([CH3:57])[CH3:56])=[O:79])([C:76](=[O:77])[NH:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:12][CH2:11]2)[CH2:62]1
Reactant: CCCCCCN1CCC(N)CC1
Reactant: CC1CN(Cc2c(Cl)cccc2Cl)CC1(CC(=O)OC(C)(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCN1CCC(NC(=O)[C@@]2(CC(=O)OC(C)(C)C)CN(Cc3c(Cl)cccc3Cl)C[C@H]2C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
1-Hexylpiperidin-4-amine obtained in Example 10a (894 mg, 4.85 mmol), triethylamine (1.04 ml, 7.46 mmol), N,N-dimethylformamide (10 ml) and PyBOP (2.52 g, 4.85 mmol) were added to (3RS,4SR)-3-[2-(tert-butoxy)-2-oxoethyl]-1-[(2,6-dichlorophenyl)methyl]-4-methylpyrrolidine-3-carboxylic acid obtained in Example 10g (1.5 g, 3.73 mmol), followed by stirring at room temperature overnight. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. This was concentrated, and the crude product was purified by column chromatography (NH silica gel, elution solvent: ethyl acetate/heptane) to give a white solid (1.85 g). This was optically resolved by HPLC (CHIRALPAK IA (3 cm diameter×25 cm), elution solvent: ethanol/hexane=6/94, flow rate: 20 ml/min.) to give a chiral form corresponding to the peak with a shorter retention time (875 mg).