Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=O.Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[N:18][OH:19]
Reactant: NO
Reactant: COc1ccc(C(=O)c2sccc2Br)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C(=NO)c2sccc2Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A mixture of (3-bromothien-2-yl) (4-methoxyphenyl)methanone (2.5 g) and hydroxylamine hydrochloride (1.5 g) and 15 ml of pyridine was stirred at room temperature overnight and then heated at 100°-115° C. for 4 hours. A thin layer chromatography analysis showed the reaction to be complete. The mixture was quenched with water and extracted with ether. The ether phase was washed with 3N hydrochloric acid and water and dried over anhydrous magnesium sulfate. Upon evaporation of the ether, an oil was obtained which crystallized upon standing overnight. The solid was recrystallized from ether/pentane to give a pure crystalline product (2.39 g, m.p. 110°-115° C.).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.CO>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][O:13][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[C@@H:9]([OH:10])[CH2:8]1
Reactant: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1Br
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](n3cc(Br)c(N)nc3=O)C[C@@H]2O)cc1
Reaction time: 22 h
Yield: 49.1 %

Procedure:
A solution of 3.06 g of 5-bromo-2'-deoxycytidine and 2.3 g of p-toluenesulfonyl chloride in 50 ml of pyridine was stirred at 4° C. for 24 hours. An additional 1.91 g of p-toluenesulfonyl chloride were added and stirring was continued at 4° C. for an additional 22 hours. 20 ml of methanol were added, the mixture was stirred at room temperature for 30 minutes and then evaporated. The crude product was subjected to flash chromatography on a column of silica gel using ethyl acetate/methanol (9:1) for the elution, there being obtained 2.26 g of 5-bromo-2'-deoxy-5'-O-p-toluenesulfonylcytidine in the form of a white solid of melting point 168° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:56][C:57]1[CH:58]=[C:59]2[C:64](=[CH:65][CH:66]=1)[CH:63]=[C:62]([C:67]([O:69][CH3:70])=[O:68])[CH:61]=[CH:60]2.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:70][O:69][C:67]([C:62]1[CH:61]=[CH:60][C:59]2[C:64](=[CH:65][CH:66]=[C:57]([NH:56][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:31])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]3)=[O:29])[CH:58]=2)[CH:63]=1)=[O:68]
Reactant: COC(=O)c1ccc2cc(N)ccc2c1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (233.5 mg, 0.50 mmol), HATU (190 mg, 0.50 mmol), methyl 6-amino-2-naphthoate (208 mg, 1 mmol) and DIPEA (0.2 mL) were combined with methylene chloride (10 ml) and the mixture was stirred at rt overnight.
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:17])[NH:5][C:6]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1.CCO>C(Cl)Cl>[OH:2][C:3]1[C:4](=[O:17])[NH:5][C:6]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1
Reactant: COc1cc(=O)c2cc(C)cc(C)c2[nH]c1=O
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(C)c2[nH]c(=O)c(O)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of 3-methoxy-7,9-dimethyl-1H-1-benzazepine-2,5-dione (272 mg, 1.18 mmol) in dry CH2Cl2 (3 mL, distilled from CaH2 under N2, there was added a solution of BBr3 in CH2Cl2 (3 mL, 1M, Aldrich) in one portion over 10 seconds at rt. The reaction instantaneously became homogeneous and orange, then an orange precipitate formed after a few seconds. The reaction bubbled vigorously during the addition. The reaction was allowed to stir under N2 at rt for 45 min. The reaction was added to saturated NaHCO3 (30 mL) and the resulting beige suspension was allowed to stir for 15 min to give a cloudy, yellow solution. The solution was filtered through glass wool to remove any suspended matter. The resulting solution was acidified with concd HCl (pH 2), the solid collected by filtration and washed to neutrality with water (6×5 mL). The damp filter cake was crystallized from 95% EtOH (dissolved in 20 mL, hot filtered, allowed to cool to rt) to yield yellow needles (176 mg, 69%, pure by TLC, 1H NMR and C,H,N analysis); mp 211°-213° C. (EtOH), 1H NMR (DMSO-d6) δ2.28 (s, 3H), 2.42 (s, 3H), 6.27 (s, 1H), 7.31 (s, 1H), 7.47 (s, 1H), 9.90 (s, 1H), 10.74 (bs, 1H); Anal. Calcd for C12H11NO3 : C, 66.35; H, 5.10; N, 6.45. Found: C, 66.34; H, 5.13; N, 6.48.
Reaction SMILES: FC1C=CC(OC)=CC=1C1C=CC(O[Si](C(C)C)(C(C)C)C(C)C)=CC=1[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29].[CH2:32]([O:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[C:50]([O:52][CH3:53])[CH:49]=[CH:48][C:47]=2[F:54])=[CH:42][C:41]=1[CH:55]=[O:56])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>C(OCC)C.C1COCC1>[CH2:32]([O:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[C:50]([O:52][CH3:53])[CH:49]=[CH:48][C:47]=2[F:54])=[CH:42][C:41]=1[CH:55]([OH:56])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COc1ccc(F)c(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2CC(C)(C)C)c1
Reactant: COc1ccc(F)c(-c2ccc(OCc3ccccc3)c(C=O)c2)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(OCc3ccccc3)c(C(O)CC(C)(C)C)c2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
A solution of neopentylmagnesium bromide (2.00 g) prepared in Example 2, step F, in diethyl ether (10 mL) was added dropwise to a mixed solution of 4-(benzyloxy)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-3-carbaldehyde (2.00 g) in THF (10 mL) and diethyl ether (10 mL) at room temperature, and the mixture was stirred at 40° C. for 1 hr. The reaction mixture was cooled to room temperature, 1N hydrochloric acid was added dropwise, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.90 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]([I:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(O)(=[O:15])C>O>[I:12][C:11]1[C:2](=[O:15])[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC(=O)O
Reactant: Clc1nc2ccccc2cc1I
Solvent: O
Product: O=c1[nH]c2ccccc2cc1I
Temperature: 100 °C

Procedure:
The 2-chloro-3-iodoquinoline (1-2, 30.0 g) was weighed into a 250 mL flask and suspended in of 50% aqueous acetic acid (125 mL). The mixture was heated to 100° C. and allowed to reflux for 16 h to completion by TLC analysis of the crude reaction mixture. The mixture was allowed to cool to ambient temperature followed by dilution with 200 mL of water. The resulting a suspension of the desired product was isolated by vacuum filtration follows by washing with water (50 mL). The water and traces of acetic acid were removed under vacuum for 5 h to afford the desired quinolinone as a tan powder (5-5); 1H NMR (500 MHz, CDCl3) δ12.13 (br s, 1H), 8.71 (s, 1H), 7.65 (d, 1H, J=7.5 Hz), 7.54 (m, 1H), 7.31 (d, 1H, J=8.0 Hz), 7.20 (m, 1H).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].N1C=CC=CC=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>CN(C=O)C>[C:18]([O:11][CH2:10][CH:7]1[CH2:8][CH2:9][CH:4]([CH2:1][C:2]#[CH:3])[CH2:5][CH2:6]1)(=[O:20])[CH3:19]
Reactant: C#CCC1CCC(CO)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C#CCC1CCC(COC(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of 960 mg (6.31 mmol) of 86 in 6 mL DMF was added 0.62 mL (7.57 mmol) pyridine and 0.78 mL (8.27 mmol) acetic anhydride. The reaction was allowed to stir overnight at room temperature. After 16 hours, starting material still remained. The reaction mixture was heated at 75° C. for 3 hours. The solvent was removed under reduced pressure to yield a yellow oil which was purified by flash chromatography, on silica gel, eluting with 1:3 ether/petroleum ether to yield 1.12 g (91%) of 87 as an oil. 1H NMR (CDCl3) δ3.87 (d, J=6.2 Hz, 2H), 2.06 (d, J=4.3 Hz, 2H), 2.03 (s, 3H), 1.98-1.93 (m, 1H), 1.92-1.83 (m, 2H), 1.83-1.74 (m, 2H), 1.63-1.36 (m, 2H), 1.12-0.90 (m, 4H); 13C NMR (CDCl3) δ 171.7, 83.7, 69.9, 69.6, 37.4, 37.3, 32.1, 29.7, 26.5, 21.4; APCI m/z (rel intensity) 195 (M+, 30), 153 (M+, 70), 135 (M+, 100).
Reaction SMILES: Cl[CH2:2][C@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C@@H:3]([CH3:13])[CH2:2][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[CH:7][CH:8]=1
Reactant: C[C@@H](CCl)COc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)COc3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-{[(2R)-3-chloro-2-methylpropyl]oxy}-4-fluorobenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 413.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:13]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:13]([C:17]1[CH:22]=[CH:21][C:20]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[Cl:1])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
A mixture of 2-chloro-1H-indole-3-carboxaldehyde (2.2 g, 12. 25 mmol), 4-t-butylphenylboronic acid (4.36 g, 24.49 mmol), copper acetate (4.45 g, 24.50 mmol), 4A molecular sieve (2.5 g), pyridine (3.0 mL) and dichloromethane (40 mL) is stirred overnight at room temperature. The reaction mixture is diluted with dichloromethane (100 mL), washed with water (50 mL), with 3N aqueous hydrochloric acid (10 mL), the precipitate removed by filtration and the dichloromethane layer is washed again with water (50 mL), aq sodium bicarbonate, with brine, dried and filtered. The filtrate is concentrated to give a solid. The crude is crystallized from dichloromethane-methanol to afford 1-(4-tert-butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde (3.09 g, 81% yield) as a yellow solid. TLC (silica gel, 20% ethyl acetate/heptane) Rf=0.50; ESI/MS 312 (M+H), RT 4.32 min; NMR: 10.12 (1H, s); 8.20 (1H, d, J=6 Hz); 7.71 (2H, d); 7.53 (2H, d); 7.38 (2H, m); 7.11 (1H, d); 1.38 (9H, s).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[NH:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:17][CH2:16][C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[NH:13][C:12]2=[O:22])[CH2:7][CH2:6]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[O:22]=[C:12]1[N:11]([CH:8]2[CH2:9][CH2:10][N:5]([C:1]([Cl:4])=[O:2])[CH2:6][CH2:7]2)[CH2:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[NH:13]1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cl)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6 g (12.1 mmol) phosgene (20 percent by weight in toluene) were added to a solution of 2.5 g (10.2 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 2.6 mL (14.9 mmol) ethyldiisopropylamine in 75 mL DCM cooled to 0° C. and the reaction mixture was stirred for 30 min at this temperature. The mixture was allowed to warm up to RT, evaporated down i.vac. to approx. 50 mL and filtered through silica gel, this was washed with 200 mL DCM/EtOAc (1:1) and the combined organic filtrates were again evaporated down i.vac. The residue was stirred with DIPE, suction filtered and dried i.vac.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([O:10]CC)=O)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C1COCC1>[N:1]12[CH2:7][C:4]([C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[OH:10])([CH2:3][CH2:2]1)[CH2:5][CH2:6]2
Reactant: CCOC(=O)C12CCN(CC1)C2
Reactant: [Li]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Temperature: -30 °C
Reaction time: 16 h
Yield: 55.9 %

Procedure:
A solution of ethyl 1-azabicyclo[2.2.1]heptane-4-carboxylate (4 g, 23 mmol) in THF (60 mL) was added dropwise to a solution of phenyllithium (1.5 M in 70% cyclohexane/30% diethyl ether, 63.1 mL, 94.6 mmol) pre-cooled to −30° C. under Ar. The reaction was warmed to RT and stirred for 16 h. The reaction was treated with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Trituration (diethyl ether) afforded the title compound (3.595 g, 54%). EI-MS m/z 280 (MH)+ Rt (1.56 min).
Reaction SMILES: Cl.[CH3:2][O:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5]1=[O:15].C(N(CC)CC)C.[CH3:23][N:24]=[C:25]=[O:26]>O>[CH3:2][O:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]2([CH2:14][CH2:13][N:12]([C:25](=[O:26])[NH:24][CH3:23])[CH2:11][CH2:10]2)[C:5]1=[O:15]
Reactant: CON1C(=O)CC2(CCNCC2)C1=O
Reactant: CN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CNC(=O)N1CCC2(CC1)CC(=O)N(OC)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methoxy-2,8-diazaspiro[4,5]decane-1,3-dione hydrochloride (1.5 g) in water (20 ml) was added triethylamine (1 ml), followed by methyl isocyanate (1 ml), and this was followed by stirring at room temperature for 30 minutes. The water was then evaporated off under reduced pressure. The residue was directly subjected to silica gel column chromatography (eluent; chloroform-acetone-methanol=10:3:2 (v/v)), and the solvent for the solution containing the desired product was evaporated off under reduced pressure to obtain 1.4 g of a colorless oily compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:42])=[C:5]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]2C(=O)C3=CC=CC=C3C2=O)=[O:23])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].O.NN>C(O)C>[CH3:42][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[C:5]=1[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])=[O:23]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCN2C(=O)c3ccccc3C2=O)C1c1cccc(C(F)(F)F)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCN)C1c1cccc(C(F)(F)F)c1
Yield: 29.9 %

Procedure:
A solution of 11.2 g of methyl 6-phthalimidohexyl 2,6-dimethyl-4-(m-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 10.1 g of hydrazine monohydrate in 330 ml of 95% ethanol (containing water of 5%) was refluxed for 4 hours under heating. After cooling the reaction solution, the solution was concentrated under reduced pressure. The residue was extracted with chloroform, and the extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated. Crude crystal were recrystallized from chloroform-ether to provide 2.6 g of 6-aminohexyl methyl 2,6-dimethyl-4-(m-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:26])[CH:6]=C(C1C=CC([N+]([O-])=O)=CC=1)[O:8]2.B(Br)(Br)Br>C(Cl)Cl>[OH:8][C:9]1[C:4]([C:5](=[O:26])[CH3:6])=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=1
Reactant: COc1cc2oc(-c3ccc([N+](=O)[O-])cc3)cc(=O)c2c(OC)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1cc(O)c(C(C)=O)c(OC)c1OC
Temperature: -20 °C
Reaction time: 5 h
Yield: 66.3 %

Procedure:
To a solution of 8 (71 mg, 0.2 mmol) in CH2Cl2 (5 mL) was added a 1M solution of boron tribromide (0.4 mL, 0.4 mmol) in CH2Cl2 at −78° C. The solution was stirred for an additional 2 h and at −20° C. for 5 h then quenched with water (10 mL). The precipitate was collected by filtration and recrystallized from CH2Cl2 to afford crude product 5 (30 mg, 46%). 1H NMR (400 MHz, DMSO) δ 3.93 (s, 3H), 7.01 (s, 1H), 7.21 (s, 1H), 8.38-8.39 (m, 4H).
Reaction SMILES: [O:1]1[C:5]2([CH2:9][CH2:8][NH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:10]12[O:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]2>O>[O:1]1[C:5]2([CH2:9][CH2:8][N:7]([C@H:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]3[OH:16])[CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C1CC2(CN1)OCCO2
Reactant: C1CCC2OC2C1
Solvent: O
Product: O[C@H]1CCCC[C@@H]1N1CCC2(C1)OCCO2
Temperature: 80 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
A mixture of 1,4-dioxa-7-azaspiro[4.4]nonane (23.54 g, step iv, no more than 182 mmol), cyclohexene oxide (22.6 mL, 98%, 219 mmol) and water (7.8 mL) was heated at 80° C. for 2 hours. The reaction mixture was then partitioned between 40% sodium hydroxide aqueous solution (60 mL) and diethyl ether (120 mL). The basic aqueous layer was extracted twice more with diethyl ether (2×120 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. The residue was then pumped under high vacuum at 50° C. for 1 hour under stirring (to remove the excess of cyclohexene oxide) to yield 32.79 g of the crude title compound (yield 79.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][N+:7]3[CH2:20][CH2:19][C:18]4[C:13](=[CH:14][C:15]5[O:23][CH2:22][O:21][C:16]=5[CH:17]=4)[C:8]=3[CH:9]=2)[C:4]=1[O:24][CH3:25].[Cl-].[C:27]1([Mg]Cl)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)C>[CH3:25][O:24][C:4]1[C:5]2[CH:6]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:7]3[CH2:20][CH2:19][C:18]4[C:13]([C:8]3=[CH:9][C:10]=2[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])=[CH:14][C:15]1[O:23][CH2:22][O:21][C:16]=1[CH:17]=4
Reactant: Cl[Mg]c1ccccc1
Reactant: COc1ccc2cc3[n+](cc2c1OC)CCc1cc2c(cc1-3)OCO2
Agent: [Cl-]
Solvent: CCOCC
Product: COc1ccc2c(c1OC)C(c1ccccc1)N1CCc3cc4c(cc3C1=C2)OCO4
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67.2 %

Procedure:
To a suspension of berberine hydrochloride (400 mg, 1.08 mmol) in anhydrous diethyl ether (50 mL) at 0° C. was added phenylmagnesium chloride solution (2.8 mL, 2.7 mmol) dropwise. After stirring at 0° C. for 10 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 9,10-dimethoxy-8-phenyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (300 mg, 67%). LC/MS m/e calcd for C26H23NO4 (M+H)+: 414.48, observed: 414.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.67-2.90 (m, 3 H) 3.35-3.41 (m, 1 H) 3.49 (s, 3 H) 3.74 (s, 3 H) 5.70 (s, 1 H) 5.99 (d, J=1.52 Hz, 2 H) 5.98 (s, 1 H) 6.72 (s, 1 H) 6.80 (m, 1 H) 6.88 (m, 1 H) 7.16-7.28 (m, 4 H) 7.35 (d, J=7.07 Hz, 2 H).
Reaction SMILES: N([O-])=O.[Na+].O.[CH2:6]([C:8]1[CH:14]=[CH:13][C:11](N)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])[CH3:7].[ClH:18]>[Cu]Cl>[Cl:18][C:11]1[CH:13]=[CH:14][C:8]([CH2:6][CH3:7])=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: Cl
Reactant: CCc1ccc(N)cc1[N+](=O)[O-]
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 56 %

Procedure:
A solution of sodium nitrite in water (4.2 g, 60 mmol, 5 M, 12 mL) was added dropwise to a cooled (0° C.) solution of 4-ethyl-3-nitroaniline (10 g, 60 mmol) in HCl (conc., 200 mL) and the reaction mixture was stirred at the same temperature for 1.5 h. Copper(I) chloride (9.5 g, 96 mmol) was then added and the solution was stirred at r.t. for 1 h and then at 80° C. for an additional hour. After cooling down the reaction mixture was extracted with DCM (3×100 mL) and the combined organic layers were dried over sodium sulfate. The crude was then purified by flash chromatography (hexane:AcOEt 9:1) to obtain the title compound as a yellow oil (6.28 g, 56%).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[CH:18][S:17][C:16]=2[CH:20]=[CH:21][C:22]2[CH:40]=[CH:39][C:25]([N:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][CH:23]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:41]N1C(=O)CCC1=O.Cl>CN(C=O)C>[Br:41][C:18]1[S:17][C:16]([CH:20]=[CH:21][C:22]2[CH:23]=[CH:24][C:25]([N:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:39][CH:40]=2)=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=2)[CH:19]=1
Reactant: CCCCCCCCc1ccc(-c2ccsc2C=Cc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(-c2cc(Br)sc2C=Cc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Reaction time: 2 h
Yield: 64.6 %

Procedure:
In a three necked flask under argon, 1.00 g (1.85 mmol, 1 eq.) of YKP70 in 20 mL of DMF are cooled to −10° C. 328 mg (1.85 mmol, 1 eq.) of N-bromosuccinimide are solubilised in 10 mL of mixture [DMF/MeOH:1/1]. This solution of NBS (protected from light) is then added drop by drop (30 min) into the reaction medium. The temperature of the medium is then left to rise to ambient temperature over 2 h. The medium is hydrolysed with a 1 mol·L−1 HCl solution and extracted with ethyl ether. The combined organic phases are washed with a saturated NaCl solution then dried on anhydrous Na2SO4. After drying on Na2SO4, filtration and evaporation of the solvent, the purification is carried out on neutral alumina column with the eluent [hexane/CHCl3: 100/1]. 742 mg of final compound YKP69 are obtained in the form of a translucent oil (yield of 64.6%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:26]=[C:27]1[NH:31][C@H:30]([CH2:32][O:33]C(=O)C2C=CC=CC=2)[CH2:29][O:28]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:31]5[C@H:30]([CH2:32][OH:33])[CH2:29][O:28][C:27]5=[O:26])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)nc2)CC1
Yield: 63.3 %

Procedure:
By reaction and treatment in the same manner as in Example 19 and using (6-bromopyridin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (500 mg) described in Preparation Example 106 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (426 mg), the title compound (345 mg) was obtained.