Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C@H:2]1[C@@H:10]2[C@@H:6]([CH2:7][N:8](C(Cl)=O)[CH2:9]2)[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][CH2:3]1.Cl>O1CCCC1>[ClH:1].[Cl:1][C@H:2]1[C@@H:10]2[C@@H:6]([CH2:7][NH:8][CH2:9]2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)N1C[C@@H]2[C@H](Cl)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Agent: Cl
Solvent: C1CCOC1
Product: Cl[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Temperature: 80 °C
Reaction time: 9 h
Yield: 188.1 %

Procedure:
A solution of 0.4 g of (3aR, 7R,7aR)-7-chloro-2-chlorocarbonyl-4,4-diphenylperhydroisoindole in 6 cm3 of a 1N aqueous solution of hydrochloric acid and 14 cm3 of tetrahydrofuran is heated with stirring at 80° C. for 9 hours. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). 0.35 g of (3aR, 7R,7aR)-7-chloro-4,4-diphenylperhydroisoindole hydrochloride is obtained in the form of a white solid.
Reaction SMILES: CS(O)(=O)=O.C([O:13][C:14]1[CH:15]=[C:16](/[C:29](/[CH3:33])=[N:30]/[O:31][CH3:32])[C:17]2[S:21][C:20]([NH:22][C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[N:19][C:18]=2[CH:28]=1)C1C=CC=CC=1>C(Cl)Cl>[CH2:26]([NH:25][C:23]([NH:22][C:20]1[S:21][C:17]2[C:16](/[C:29](/[CH3:33])=[N:30]/[O:31][CH3:32])=[CH:15][C:14]([OH:13])=[CH:28][C:18]=2[N:19]=1)=[O:24])[CH3:27]
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(/C(C)=N/OC)c2s1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(O)cc(/C(C)=N/OC)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A solution of methanesulfonic acid (6.5 mL) in DCM (32 mL) was added to 1-[5-benzyloxy-7-[(E)-N-methoxy-C-methyl-carbonimidoyl]-1,3-benzothiazol-2-yl]-3-ethyl-urea (718 mg, 1.8 mmol) and the reaction stirred at ambient temperature for 2 h after which time LCMS indicated clean conversion to the desired product. The reaction was diluted with DCM, washed with water and the aqueous layer neutralized with saturated aqueous Na2CO3 solution and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and the solvent was removed in vacuo. The crude material obtained was purified by flash chromatography on silica gel using MeOH:DCM 3:97 as the eluent to give the desired compound as an off white solid, 300 mg, 54% yield.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]([C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:8])([CH3:6])[CH3:5].[CH2:16](Br)[CH:17]=[CH2:18].O>CS(C)=O>[OH:3][C:4]([C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:18][CH:17]=[CH2:16])=[CH:13][CH:14]=1)=[O:8])([CH3:5])[CH3:6]
Reactant: CC(C)(O)C(=O)c1ccc(O)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCOc1ccc(C(=O)C(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6.6 g (0.22 mol) of sodium hydride (80% strength in paraffin oil) are addedin portions to 36.0 g (0.2 mol) of 4-hydroxyphenyl 2-hydroxy-2-propyl ketone in 450 ml of dimethyl sulfoxide under an inert gas and the mixture is stirred for 15 minutes at room temperature. 26.8 g (0.22 mol) of allyl bromide in 40 ml of dimethyl sulfoxide are then added dropwise at 30°-40° C., and the mixture is stirred for 15 minutes. The reaction mixture is poured into 2 l of water and then extracted with methyl t-butyl ether. By removing the solvent, 41.5 g of compound IIh are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][CH:5]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:8]=2[C:7]([C:18]2[CH:23]=[CH:22][C:21]([NH:24]C(=O)OC(C)(C)C)=[CH:20][CH:19]=2)=[N:6]1.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl.O>[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:7]2[C:8]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[CH:5]([CH2:4][C:3]3[CH:32]=[CH:33][CH:34]=[CH:35][C:2]=3[Br:1])[N:6]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2=NC(Cc3ccccc3Br)C(=O)Nc3ccc(Cl)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1ccc(C2=NC(Cc3ccccc3Br)C(=O)Nc3ccc(Cl)cc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of (Z)-tert-butyl 4-(3-(2-bromobenzyl)-7-chloro-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)phenylcarbamate (3.3 g, 5.94 mmol) in dichloromethane (45 mL) was added dropwise at 0° C. trifluoroacetic acid (15 mL). After completion of the addition, the reaction mixture was stirred at 0° C. for 1 h then the temperature was raised to room temperature and kept at room temperature for 4 h. The reaction mixture was cooled down to 0° C. and treated with a solution of 10% NaOH in water until a pH >10 was obtained. The two layers were separated. The aqueous layer was extracted with dichloromethane (2×50 mL). The combined extracts were washed with brine (100 mL), dried (MgSO4) and evaporated in vacuo. The crude material was purified by flash column chromatography (eluted with 40% EtOAc in Hexane) to give (Z)-5-(4-aminophenyl)-3-(2-bromobenzyl)-7-chloro-1H-benzo[e][1,4]diazepin-2(3H)-one (2.35 g, 87%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 3.45 (d, 2H), 3.71 (t, 1H), 5.62 (s, 2H), 6.53 (d, 2H), 7.10-7.17 (m, 3H), 7.22-7.25 (m, 2H), 7.33 (t, 1H), 7.46-7.61 (m, 3H), 10.64 (s, 1H). MS, m/z 455.19 [M+1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](C=O)=[C:5]([O:11][CH3:12])[C:4]=1[O:13][CH3:14].[OH:15]S(O)(=O)=O.OO.CCOC(C)=O>CO>[CH3:12][O:11][C:5]1[C:4]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:10]=[CH:9][C:6]=1[OH:15]
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(O)c(OC)c1OC
Yield: 98 %

Procedure:
Following a modified procedure by Tremblay et al.,17 2,3,4-trimethoxybenzaldehyde (16, 6.075 g, 31.0 mmol) was dissolved in MeOH (60.0 mL), and then H2SO4 (0.6 mL) and 35% aq. H2O2 (4.0 mL, ˜40 mmol) was added at room temperature. The reaction was then heated to reflux for 2 hrs and monitored by TLC (1:4 EtOAc:hexanes) for completion. When the reaction was complete the solution was cooled and extracted with ethyl acetate. The layers are separated and the organic layer was washed with brine, dried over MgSO4, and filtered. Flash chromatography (1:4 EtOAc:hexanes) provides 17 (5.564 g, 30.2 mmol, 98%) as a light red oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][CH:8]=[CH:7]2)[CH3:2].[CH2:14](Br)[C:15]#[CH:16].[I-:18].[Na+]>C(#N)C>[I-:18].[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N+:9]([CH2:16][C:15]#[CH:14])[CH:8]=[CH:7]2)[CH3:2]
Reactant: CCOc1ccc2cnccc2c1
Reactant: C#CCBr
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: C#CC[n+]1ccc2cc(OCC)ccc2c1

Procedure:
6-Ethoxyisoquinoline (500 mg.), propargyl bromide (500 mg.) and sodium iodide (300 mg.) were heated under reflux in acetonitrile (30 ml) for 5 hrs. The mixture was evaporated to dryness, the residue taken up in hot water (5 ml) and a saturated aqueous solution (5 ml) of sodium iodide added to the cooled filtrate. The solid that precipitated was recrystallised from isopropanol/ether, m.p. 121°-123°.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:20]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34]O)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1.[Br:41]Br>C(#N)C.C(OCC)C.CC#N.CCOCC>[Si:20]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][Br:41])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1CO
Reactant: BrBr
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1CBr

Procedure:
To a solution of triphenylphosphine (39.5 g, 0.15 mol), (2-((tert-butyldimethylsilyl)-oxy)phenyl)methanol (Ia) (12.23 g, 0.05 mol) and imidazole (10.5 g, 0.15 mol) in acetonitrile and diethyl ether (500 ml, CH3CN/Et2O=1:3, v/v) was added bromine (7.7 mL, 0.15 mol) dropwise at 0° C. with stirring. The reaction mixture was stirred at 0° C. for 20 minutes, during which time a white solid precipitated. The solution was carefully decanted and washed with brine (100 mL). The remaining solid was washed with diethyl ether (2×160 mL). All of the organic solutions were combined and concentrated. Hexane (200 ml) was added to the residue, and the solid was removed by filtration. The hexane solution was concentrated to provide the crude product. The product was purified by vacuum distillation (66-68° C. 0.093 Torr) reduced distillation to provide compound IIa (10.4 g, 67%) as a colorless oil.
Reaction SMILES: Cl.[NH:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([Cl:14])=[N:6][N:5]=1)[NH2:3].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+].C([O-])(=O)C.[Na+].BrBr>O.C(O)C.C(O)(=O)C>[Cl:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]2=[N:2][N:3]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:5]2[N:6]=1
Reactant: NNc1nnc(Cl)c2ccccc12
Reactant: O=Cc1ccccc1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Clc1nn2c(-c3ccccc3)nnc2c2ccccc12
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
Concentrated HCl is gradually added to a suspension of 1-hydrazino-4-chloro-phthalazine (0.1 mole) in water (900 ml) until a clear solution is obtained. Then benzaldehyde (0.1 mole) dissolved in the smallest amount of ethanol possible, is dripped into the obtained solution which is heated to 60°/70° C. and stirred for 10 minutes. The reaction mixture is then cooled, and brought to pH 8 by the addition of aqueous sodium bicarbonate. The hydrazone which forms is recovered by filtration and crystallized from isopropanol (m.p. 174°-75° C.). This hydrazone (0.1 mole) is then suspended in acetic acid (900 ml) containing anhydrous sodium acetate (0.3 mole) and to the obtained suspension a solution of bromine (0.105 mole) in acetic acid (60 ml) is added dropwise. After vigorously stirring for 60 minutes, the reaction mixture is poured into ice-water (5 1) and the solid which separates is recovered by filtration, washed first with a diluted aqueous solution of sodium metabisulfite and then with water, and finally crystallized from isopropanol yielding the compound of the title in 74% yield. M.p. 172°-74° C. Using essentially the same procedure outlined in example 1 above, a number of other 3-substituted-6-chloro-1,2,4-triazolo[3,4-a]phthalazines are prepared having the general formula ##STR17## These compounds, as well as the hydrazone intermediates of formula ##STR18## are described in Table I below.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:14][CH3:15])[CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([OH:13])=O)[CH2:6]1)[CH3:3].[NH2:16][C@@H:17]([CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19]>>[CH2:37]([O:36][CH2:35][C@H:17]([NH:16][C:11](=[O:13])[CH2:10][N:7]1[CH2:8][CH2:9][CH:5]([N:4]([CH2:2][CH3:3])[CH2:14][CH3:15])[CH2:6]1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CCN(CC)C1CCN(CC(=O)O)C1
Agent: Cl
Product: CCN(CC)C1CCN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1
Yield: 48.2 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3-(diethylamino)pyrrolidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 109, (2S)-3-(benzyloxy)-2-(2-(3-(diethylamino)pyrrolidin-1-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (21.7 mg, 48.2%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.22 (s, 1H), 7.87 (d, 1H), 7.61 (d, 2H), 7.29 (m, 5H), 7.21 (t, 2H), 7.03-6.98 (m, 4H), 4.71 (m, 1H), 4.52 (s, 2H), 3.76-3.67 (m, 2H), 3.31 (m, 1H), 3.15 (m, 1H), 3.03 (m, 1H), 2.69-2.58 (m, 3H), 2.48 (m, 5H), 1.88 (m, 1H), 1.55 (m, 1H), 0.92 (t, 6H). MS (EI) for C32H39FN4O4. found 563.7 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:26])/[CH:11]=[CH:12]\[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pt](=O)=O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:26])[CH2:11][CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C\C(=O)c2ccccc2[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccccc2N)CC1
Yield: 83.4 %

Procedure:
The compound prepared in Example 301 (1.30 g) was suspended in ethyl acetate (4.0 mL) and platinum (IV) oxide (81.9 mg, 0.361 mmol) added. The reaction mixture was stirred at room temperature under a balloon of hydrogen for 18 hours and then concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 10% ethyl acetate/hexane) to furnish the title compound (1.00 g) with the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:10][C:9](C(OCC)=O)=[C:8]([OH:16])[C:5]2=[N:6][CH:7]=1.Cl.C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[O:10][CH2:9][C:8](=[O:16])[C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)c1oc2cc(Cl)cnc2c1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1COc2cc(Cl)cnc21
Temperature: 110 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
A mixture of ethyl 6-chloro-3-hydroxyfuro[3,2-b]pyridine-2-carboxylate (154 mg, 637 μmol) and 10% hydrochloric acid (4.65 g, 3.87 ml, 127 mmol) was stirred at 110° C. for 3 hours. To the cooled brown solution was added some ice and neutralized with sat NaHCO3 to pH=8. Then the aqueous layer was extracted thrice with dichloromethane, the combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give a brown oil. The residue was purified by silica gel flash chromatography with dichloromethane toster) with CH2Cl2 to give the 6-chloro-furo[3,2-b]pyridin-3-one (79 mg, 466 μmol, 73.1% yield) as a light brown solid. MS (ISP): m/z=170.0 [(M+H)+] and 172.0 [(M+2+H)+].
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:12][Mg]Cl>O1CCCC1>[OH:3][C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)([CH3:12])[CH3:2]
Reactant: C[Mg]Cl
Reactant: CC(=O)c1ccc(C#N)cc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C#N)cc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a stirred solution of p-acetylbenzonitrile (3.0 g, 20.0 mmol) in tetrahydrofuran at −78° C. was added drop-wise a solution of 3.0 M methyl magnesium chloride in tetrahydrofuran (7.6, 23.0 mmol). The reaction mixture was stirred at −78° C. for 3 hours and then quenched with methanol added drop-wise. The reaction mixture was thereafter poured into water (200 ml), acidified with oxalic acid added portion-wise, and then extracted with diethyl ether (2×200 ml). The organic extracts were combined, washed with water (1×40 ml), brine (1×40 ml), dried over magnesium sulfate (MgSO4), and then concentrated to give an oil. The oil product was purified using chromatography on silica gel, eluting with ethyl acetate/hexane (1:5), to give 1.4 g of 4-(1-Hydroxy-1-methyl-ethyl)-benzonitrile as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH:9]([CH3:12])[C:8](=O)[NH:7][C:6]=2[CH:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH:9]([CH3:12])[C:8](=[S:24])[NH:7][C:6]=2[CH:14]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1CNc2ccc(F)cc2NC1=O
Solvent: C1CCOC1
Product: CC1CNc2ccc(F)cc2NC1=S

Procedure:
A solution of 8-fluoro-3-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (6.2 g, 32 mmol) and Lawesson's reagent (25.9 g, 64 mmol) in tetrahydrofuran (300 mL) was heated at 80° C. for 1 hour. The mixture was concentrated in vacuo, and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1-2:1) to afford 8-fluoro-3-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione as a pale green solid (10.0 g, crude).
Reaction SMILES: [C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[O:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[H-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].O>CN(C=O)C>[C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:20]3=[O:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: O=c1[nH]c2ccccc2n1C1CCN([C@@H]2Cc3cccc4cccc2c34)CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c(=O)n(C2CCN([C@@H]3Cc4cccc5cccc3c45)CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
(R)-1-[1-(Acenaphthen-1-yl)piperidin-4-yl]-1,3-dihydro-2H-benzoimidazol-2-one (2.3 g, 6 mmol) was dissolved in DMF (20 ml) and sodium hydride (300 mg, 60%) was added. The suspension was stirred at 50° C. for 30 min. After cooling to room temperature, ethyl bromoacetate (1.17 g, 7 mmol) was added and the mixture was stirred for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (2.6 g) as pale-yellow crystals.
Reaction SMILES: [CH2:1]1O[C:4]([N:8]2[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][C:12](=[O:17])[CH2:13]3)[CH2:9]2)([O:5]CC)[O:3][CH2:2]1>OS(O)(=O)=O>[O:17]=[C:12]1[CH2:11][CH:10]2[CH2:16][CH:14]([CH2:15][N:8]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:9]2)[CH2:13]1
Reactant: CCOC1(N2CC3CC(=O)CC(C3)C2)OCCO1
Agent: O=S(=O)(O)O
Product: CCOC(=O)N1CC2CC(=O)CC(C2)C1
Reaction time: 4 h
Yield: 88.1 %

Procedure:
Ethyl 7-oxo-3-azabicyclo[3.3.1]nonane-3-carboxylate ethylene ketal (4.40 g, 17.2 mmol) was combined with 2% aqueous H2SO4 (50 ml) and stirred for 4 h. Then the reaction mixture was extracted with ethyl acetate (4×30 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation to yield a light yellow oil (3.20 g, 88.1%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[C:26](#[N:28])[CH3:27].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[CH3:8][C:7]1[C:6]([CH3:9])=[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)[N:4]=[N:3][C:2]=1[CH2:27][C:26]#[N:28]
Reactant: Cc1c(Cl)nnc(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1C
Reactant: CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Product: Cc1c(CC#N)nnc(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
3-Chloro-4,5-dimethyl-6-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyridazine (1.0 g, 2.64 mmol), acetonitrile (0.225 mL, 4.22 mmol), and toluene (5 mL) are combined and cooled to 0° C. LiHMDS (8.4 mL, 1.0 M, 8.4 mmol) is added dropwise over 5 min. The reaction is stirred at 0° C. for 1 h, then warmed to room temperature and stirred an additional 16 h. The reaction is quenched by the addition of saturated aq. NH4Cl, and the organics are extracted with EtOAc. The combined organic layers are dried over MgSO4 and concentrated. The residue is purified by flash chromatography on silica gel (0-100% EtOAc in heptanes) to afford the title compound as an orange solid (500 mg, 50%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([Cl:16])[CH:10]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+]>>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([Cl:16])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CON=C(C(=O)OC)c1ccc(O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Product: CON=C(C(=O)O)c1ccc(O)c(Cl)c1
Yield: 97.9 %

Procedure:
Methyl 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetate (syn isomer) (2.6 g.) and a 2N aqueous solution of sodium hydroxide (10.6 ml.) were treated according to a similar manner to that of Preparation 5-(3)(c) to give 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (2.4 g.), mp 147° to 150° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:3]=1[NH:4][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 51.7 %

Procedure:
To a solution of 2-bromo-5-trifluoromethylaniline (3.18 g, 13.25 mmol) in pyridine (18 ml) was added methanesulfonyl chloride (1.03 ml, 13.25 mmol) and the mixture was stirred for 6 hours at room temperature. The solvent was removed in vacuo and the residue was diluted with chloroform. The organic layer was washed with water, 1N hydrochloric acid, a saturated sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by recrystallization to give the subject compound (2.18 g, 52%).
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[C:13]1([C:19]2[N:20]=[C:21]([CH2:38][CH2:39][C:40]([N:42]([CH2:44][CH2:45][C@:46]3([OH:60])[CH2:51][C@H:50]4[CH2:52][CH2:53][C@@H:47]3[CH:48]=[C:49]4[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH3:43])=O)[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:13]1([C:19]2[N:20]=[C:21]([CH2:38][CH2:39][CH2:40][N:42]([CH3:43])[CH2:44][CH2:45][C:46]3([OH:60])[CH2:51][CH:50]4[CH2:52][CH2:53][CH:47]3[CH:48]=[C:49]4[C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(CC[C@]1(O)C[C@H]2CC[C@@H]1C=C2c1ccccc1)C(=O)CCc1nc(-c2ccccc2)c(-c2ccccc2)n1COCC[Si](C)(C)C
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN(CCCc1nc(-c2ccccc2)c(-c2ccccc2)n1COCC[Si](C)(C)C)CCC1(O)CC2CCC1C=C2c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
0.241 mL of a Red-Al solution (65% in toluene) was added dropwise at 0° C. to a solution of 131 mg of rac-3-[4,5-diphenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-N-[2-((1R*,2R*,4R*)-2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-ethyl]-N-methyl-propionamide in toluene (0.23 mL). The reaction mixture was stirred for 30 min at 0° C. and for 2 h at room temperature. The mixture was carefully poured onto a mixture of 1M-NaOH (1.75 mL) and ice. The mixture was stirred for 5 min until rt and extracted with toluene. The aq. phase was extracted with toluene. The combined toluene phases were washed with 1M-NaOH and brine, dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using EtOAc/MeOH/NEt3 as eluant from 100/0/1 to 95/5/1 to yield 125 mg of rac-(1R*,2R*,4R*)-2-[2-({3-[4,5-diphenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-propyl}-methyl-amino)-ethyl]-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol as a colorless oil.