Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:20])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:5]1.[H-].[Na+].[CH3:23][N:24]1[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[N:26]=[C:25]1S(C)(=O)=O.O>CN(C=O)C>[F:20][CH:2]([F:1])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:25]3[N:24]([CH3:23])[C:28]4=[N:29][CH:30]=[CH:31][CH:32]=[C:27]4[N:26]=3)=[CH:15][CH:14]=2)=[N:5]1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: Oc1ccc(-c2nn(CC(F)F)c3cccnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(Oc2ccc(-c3nn(CC(F)F)c4cccnc34)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
To a stirred solution of 4-[1-(2,2-difluoroethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl]phenol (142 mg) in DMF (4 mL) was added NaH (60% in oil, 20.63 mg) at room temperature. The mixture was stirred at room temperature for 30 min and then 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (109 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane). The product was crystallized from AcOEt/hexane to give the title compound (90 mg)
Reaction SMILES: N(C(N(C)C)=O)=NC(N(C)C)=O.C(OC([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32][CH2:33][CH2:34][OH:35])=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.[N:36]1([C:42]2[CH:43]=[C:44](O)[CH:45]=[CH:46][CH:47]=2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:23]1([C:26]2[C:27]([O:32][CH2:33][CH2:34][O:35][C:46]3[CH:45]=[CH:44][CH:43]=[C:42]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)[CH:47]=3)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: Oc1cccc(N2CCOCC2)c1
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCOc2nccnc2N2CCNCC2)cc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 10.5 %

Procedure:
1,1′-Azobis(N,N-dimethylformamide) (TMAD; 256 mg, 1.50 mmol) was added to a solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (400 mg. 1.24 mmol; prepared in Example 52, Step 2), 3-(4-morpholinyl)phenol (441 mg, 1 23 mmol) and triphenylphosphine (646 mg, 2.46 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature for 2.5 h and then concentrated. The residue was purified by repeated chromatography on silica gel using toluene and toluene/EtOAc (8.2) as eluents Solvents were evaporated and the residue was treated with CH2Cl2/TFA/H2O (1:0.9:0. 1; 5 mL) at room temperature for 0.5 h. After concentration. 5 M NaOH was added followed by extraction with CH2Cl2. The organic phase was dried (K2CO3), filtered, and concentrated The residue was purified by chromatography on silica gel using CHCl3/MeOH (9 1) as eluent to give 50 mg (10%) of the title product as on oil. HRMS m/z calcd for C20H27N5O3 (M)+ 385.2114, found 385 2100.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:16]1[CH:35]=[CH:34][CH:33]=[CH:32][C:17]=1[O:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.[F:36][C:37]([F:42])([F:41])[CH2:38][CH2:39][OH:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:36][C:37]([F:42])([F:41])[CH2:38][CH2:39][O:40][C:34]1[CH:35]=[CH:16][C:17]([O:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:23][CH2:24]2)=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2O)CC1
Reactant: OCCC(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCCC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.7 %

Procedure:
Diisopropyl azodicarboxylate (0.97 mL) was added to a solution of tert-butyl 4-(hydroxyphenoxy)piperidine-1-carboxylate (1.2 g), 3,3,3-trifluoro-1-propanol (0.56 g) and triphenylphosphine (1.5 g) in dichloromethane (15 mL). The reaction mixture was stirred at ambient temperature for 18 hours and then concentrated at reduced pressure. This resulting mixture was purified by silica column chromatography, eluting with a gradient of 0 to 15% ethyl acetate in hexane to give tert-butyl 4-[4-(3,3,3-trifluoropropoxy)phenoxy]piperidine-1-carboxylate as a white solid (0.6 g); NMR Spectrum: (CDCl3) 1.47 (s, 9H), 1.66-1.77 (m, 2H), 1.83-1.94 (m, 2H), 2.52-2.66 (m, 2H), 3.24-3.34 (m, 2H), 3.65-3.75 (m, 2H), 4.11 (t, 2H), 4.27-4.37 (m, 1H), 6.78-6.89 (m, 4H); Mass Spectrum: M+H+ 390 and (M-tBuOCO)+H+ 290.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1
Reactant: Nc1ccccc1
Reactant: Clc1nc(Cl)c2ncn(C3CCOC3)c2n1
Solvent: CCCCO
Product: Clc1nc(Nc2ccccc2)c2ncn(C3CCOC3)c2n1
Yield: 87.4 %

Procedure:
The operation is carried out as in Stage 2 of Example 2 from 200 mg (0.77 mM) of the product obtained in Stage 1 of Example 2 and 3 ml of butanol and using 0.088 ml of aniline (0.96 mmole) in place of the benzylamine. In this way 213 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH3:21])[CH:4]([NH2:19])[C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:8]=[CH:7][CH:6]=1)[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.S(Cl)(Cl)(=O)=O>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:19][CH:4]([C:5]2[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[N:8]=[CH:7][CH:6]=2)[CH:3]([CH2:1][CH3:2])[CH2:20][CH3:21])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: CCC(CC)C(N)c1ccnn1Cc1ccc(OC)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: O=S(=O)(Cl)Cl
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)cc1)c1ccnn1Cc1ccc(OC)cc1
Yield: 52 %

Procedure:
The compound of example 2 was synthesized from {2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butyl}amine in a manner similar to that of example 1 but using 4-chlorobenzenesulfonyl chloride as the sulfonyl chloride in step 1 D. The product was isolated as white foam in 52% yield.
Reaction SMILES: [O:1]=[C:2]1[CH:8]([C:9]([O:11][CH3:12])=[O:10])[S:7][C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[O:4][CH2:3]1.[C:17]1([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31]Cl)[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:1]=[C:2]1[CH:8]([C:9]([O:11][CH3:12])=[O:10])[S:7][C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[O:4][CH:3]1[CH2:31][CH2:30][CH2:29][N:26]1[CH2:27][CH2:28][N:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24][CH2:25]1
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Reactant: COC(=O)C1Sc2ccccc2OCC1=O
Product: COC(=O)C1Sc2ccccc2OC(CCCN2CCN(c3ccccc3)CC2)C1=O

Procedure:
By the same procedure as described in Example 1, methyl 3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate as obtained in Reference Example 24 is allowed to undergo condensation with 3-(4-phenylpiperazin-1-yl)propyl chloride, and methyl 3-oxo-[3-(4-phenylpiperazin-1-yl)-propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate is isolated as the hydrochloride salt. Recrystallization from methanol produces white crystals, m.p. of 176°-178° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])=[N:8][CH:9]=1)([O-])=O.O.[NH4+].[Cl-]>C1COCC1.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[C:19]([F:22])([F:20])[F:21])=[N:8][CH:9]=1
Reactant: N#Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)c(C(F)(F)F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(Oc2ccc(N)cn2)c(C(F)(F)F)c1
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a solution of 4-[(5-nitro-2-pyridinyl)oxy]-3-(trifluoromethyl)benzonitrile (Intermediate 120, 83 mg) in THF (3 mL)/water (1.5 mL) was added at room temperature, iron (75 mg, 1.34 mmol) and NH4Cl (72 mg, 1.34 mmol) and the resulting reaction mixture was stirred overnight. The mixture was filtered through a small pad of celite washing with EtOAc and water. To the filtered mixture was added an aqueous NaHCO3 saturated solution and the two phases were separated. The aqueous phase was extracted with EtOAc and the combined organic phases were dried and evaporated to dryness. The crude was purified by flash chromatography (companion system, 2×12 g Si cartridge, from 100:0 to 70:30 Cyclohexane/EtOAc) to afford the title compound (72 mg).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]([CH2:14][OH:15])[CH2:12][OH:13])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)#[N:17].CC1C=CC(S(O)(=O)=O)=CC=1.O>ClCCl>[C:16]([C:18]1[CH:25]=[CH:24][C:21]([C@H:22]2[O:13][CH2:12][C@H:11]([C@H:8]3[CH2:7][CH2:6][C@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:10][CH2:9]3)[CH2:14][O:15]2)=[CH:20][CH:19]=1)#[N:17]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCCCC1CCC(C(CO)CO)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCCC[C@H]1CC[C@H]([C@H]2CO[C@H](c3ccc(C#N)cc3)OC2)CC1

Procedure:
In dichloromethane, 4.6 g (0.02 mol) of 2-(4'-butylcyclohexyl) propane-1,3-diol, 3.2 g (0.024 mol) of 4-cyanobenzaldehyde, and 0.1 g of TsOH were refluxed for three hours over a hot water bath fitted with a Dean-Stark trap and the water formed was continuously removed from the reaction system. The reaction solution was washed with water and the dichloromethane was distilled off. The distillation residue was recrystallized from a solvent mixture of acetone and methanol to yield 1.1 g (0.004 mol) of trans-2-(4'-cyanophenyl)-5-(trans-4'-butylcyclohexyl)-1,3-dioxane. The phase transition points of this compound, measured by DSC, were: ##STR53##
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[F:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[O:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[F:20][C:21]1[CH:30]=[CH:29][C:24]2[N:25]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[C:26](=[O:28])[O:27][C:23]=2[CH:22]=1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: O=c1[nH]c2ccc(F)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(F)ccc43)CC2)ccc1Cl

Procedure:
In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (59 mg, 0.20 mmol, 1.0 equiv), 6-fluoro-3H-benzooxazol-2-one (30 mg, 0.20 mmol, 1.00 equiv), K2CO3 (110 mg, 0.80 mmol, 4.0 equiv) and 800 μL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 6-fluoro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (18): HPLC retention time, 2.35 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 419.8, found, 419.9.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.[Cl:9][C:10]1[CH:11]=[C:12]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]1[CH:17]([NH2:23])[CH2:16][CH2:15][CH2:14][C:13]2=1>>[Cl:9][C:10]1[CH:11]=[C:12]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]1[CH:17]([NH:23][C:6]([C:4]3[N:3]=[CH:2][NH:1][CH:5]=3)=[O:8])[CH2:16][CH2:15][CH2:14][C:13]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Reactant: O=C(O)c1c[nH]cn1
Product: O=C(NC1CCCc2c1[nH]c1ccc(Cl)cc21)c1c[nH]cn1

Procedure:
N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1H-imidazole-4-carboxamide was prepared from 4-imidazole carboxylic acid and 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine in a similar manner as described above to give a white solid (4% yield). 1H-NMR (CDCl3): δ 9.19 (s, 1H), 7.62 (s, 1H), 7.57 (s, 1H), 7.41 (s, 1H), 7.37 (d, 1H), 7.17 (d, 1H), 7.05 (dd, 1H), 6.60 (d, 1H), 5.25 (m, 1H), 2.62 (m, 2H), 2.21 (m, 1H), 1.91 (m, 3H); MS m/z 313 (M−1).
Reaction SMILES: CC([O-])(C)C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.[Br:23][C:24]1[CH:25]=[CH:26][C:27](F)=[C:28]([CH:31]=1)[C:29]#[N:30]>CS(C)=O.ClCCl>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)=[O:15])=[CH:12][CH:13]=2)=[C:28]([CH:31]=1)[C:29]#[N:30]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CN1CCN(C(=O)c2ccc(N)cc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(Nc3ccc(Br)cc3C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19.8 %

Procedure:
KOtBu (2.81 g, 25.08 mmol) was dissolved in 20 ml DMSO in a round bottom flask. (4-aminophenyl)(4-methylpiperazin-1-yl)methanone (5.0 g, 22.80 mmol) in 30 ml DMSO was added and the resulting mixture was stirred for 15 minutes at r.t. The mixture was cooled in an iced bath for 5 minutes. 5-bromo-2-fluorobenzonitrile (4.6 g, 23.00 mmol) in 20 ml DMSO was added. The ice bath was removed and the mixture stirred for 5 hours while warming to room temperature. Additional KOtBu (2 g, 17.82 mmol) was added and the mixture stirred at room temperature overnight. The mixture was diluted with dichloromethane, extracted twice with water, once with brine, then dried over MgSO4, filtered and concentrated. 8.8 g crude brown oil were isolated. The crude product was recrystallized from dichloromethane+ethyl acetate+hexanes. 5.012 g pale yellow crystals were collected by filtration. The mother liquor was concentrated and purified by chromatography on silica, using a gradient from 100% Solvent A to 50% Solvent A+50% Solvent B. Solvent A: 99% dichloromethane+1% Triethylamine, Solvent B: 99% Ethylacetate+1% Triethylamine. Evaporation of product containing fractions gave additional 1.8 g product of ˜70% purity. MS (ESI) m/z 399/401(M+H). 1H NMR (CDCl3) δ ppm 7.63 (s, 1H), 7.48 (d, 1H, J=9.2), 7.42 (d, 2H, J=7.9), 7.18-7.14 (m, 3H), 6.41 (s, 1H), 3.80-3.40 (bm, 4H), 2.42 (bs, 4H), 2.32 (s, 3H).
Reaction SMILES: [CH:1]1([S:7][C:8]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)[C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>>[NH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]([S:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:9]#[N:10]
Reactant: COc1ccc(C(C#N)(CCCCCN2C(=O)c3ccccc3C2=O)SC2CCCCC2)cc1OC
Agent: NN
Solvent: O
Product: COc1ccc(C(C#N)(CCCCCN)SC2CCCCC2)cc1OC
Yield: 88.8 %

Procedure:
The procedure of Example 25 is repeated using 2.0 g of α-(cyclohexylthio)-α-(3,4-dimethoxyphenyl)-1,3-dioxo-2H-isoindole-2-heptanenitrile and 3.0 mL of hydrazine hydrate. This affords 1.32 g of the desired product as a light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.N#N>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)CC1
Agent: [Pd]
Agent: N#N
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2ccccc2)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Yield: 37 %

Procedure:
A solution of the above amine (500 mg, 1.72 mmol), 1-iodo-4-nitrobenzene (408 mg, 1.64 mmol), Pd2(dba)3, (±)BINAP and toluene was purged with N2 and then heated to 100° C. for 24 h to afford 4-[benzyl-(4-nitro-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a yellow foam (250 mg, 37%) following aqueous work-up and purification.
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.CCOCC>[CH2:13]([O:9][CH:6]1[CH2:7][O:8][CH:3]([O:2][CH3:1])[CH2:4][CH2:5]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC1CCC(O)CO1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC1CCC(OCc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C. to a solution of 6-methoxytetrahydro-2H-pyran-3-ol (222 mg, 1.680 mmol) in DMF (2 mL) was added 60% NaH (81 mg, 2.02 mmol) and the mixture was allowed to warm to rt and stirred at rt for 30 min. A solution of (bromomethyl)benzene (345 mg, 2.016 mmol) in DMF (1 ml) was added and the mixture was stirred at rt for 18 h. The reaction mixture was diluted with ether and quenched with water. The crude product was purified by silica gel FCC (20% EtOAc in hexanes) to afford 5-(benzyloxy)-2-methoxytetrahydro-2H-pyran. 1H NMR (400 MHz, CDCl3) δ ppm 7.29-7.41 (5H, m), 4.53-4.64 (3H, m), 3.90 (1H, dd, J=12.05, 2.51 Hz), 3.56-3.65 (1H, m), 3.46-3.53 (1H, m), 3.43 (3H, s), 1.97-2.14 (2H, m), 1.69-1.81 (1H, m), 1.48-1.60 (1H, m).
Reaction SMILES: Br.[C:2]1([CH2:8][C:9](=[NH:13])OCC)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[C:22]1([C:28]2([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:36]3[CH:32]([CH2:33][NH:34][CH2:35]3)[C:31](=[O:37])[CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[NH:13]=[C:9]([N:34]1[CH2:33][CH:32]2[CH:36]([C:28]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:29][CH2:30][C:31]2=[O:37])[CH2:35]1)[CH2:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: CCOC(=N)Cc1ccccc1
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: N=C(Cc1ccccc1)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 20 h
Yield: 45.1 %

Procedure:
Ethyl phenylacetimidate hydrobromide (1.2 g) and triethylamine (1.4 cc) are added to a stirred suspension of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.6 g) in 1,2-dichloroethane (40 cc). Stirring of the reaction mixture is continued for 20 hours at ambient temperature and then for 6 hours under reflux. After the temperature has returned to ambient temperature, the reaction mixture is treated with a saturated aqueous solution (50 cc) of potassium carbonate; the organic phase is dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from acetonitrile (20 cc). The crystals obtained are drained and dried. (3aRS,7aRS)-2-(α-iminophenethyl)-7,7-diphenyl-4-perhydroisoindolone (0.9 g) melting at 195° C. is obtained.
Reaction SMILES: [ClH:1].[S:2](=[O:6])(=O)([OH:4])[OH:3].[O-2].[Al+3:8].[O-2].[O-2].[Al+3]>O>[S:2]([Cl:1])([O-:4])(=[O:6])=[O:3].[Al+3:8].[S:2]([Cl:1])([O-:4])(=[O:6])=[O:3].[S:2]([Cl:1])([O-:4])(=[O:6])=[O:3]
Reactant: Cl
Reactant: O=S(=O)(O)O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Product: O=S(=O)([O-])Cl

Procedure:
15,903 kg of 31.5% hydrochloric acid, 1,352 kg of water and 1,761 kg of 93.5% sulfuric acid are added to a 10,000 gallon (37,850 liter) brick-lined, rubber coated steel reactor equipped with an agitator and fume scrubber. While the solution is being agitated, 9,869 kg of aluminum oxide wet filtercake (59% Al2O3) is added such that a slurry is maintained. The mixture is recycled through a heat exchanger to raise it temperature to 60 degrees centigrade. Although the application of external heat is stopped at this point, the exothermic reaction forming aluminum chlorosulfate continues to raise the batch temperature. An additional 15,903 kg of 31.5% hydrochloric acid is then added to the batch such that the temperature does not exceed 90 degrees centigrade or fall below 60 degrees centigrade. If the temperature is allowed to exceed 90 degrees at this time, there is a risk of the batch boiling out of the reactor. If the temperature falls below 60 degrees, the batch may require additional heating to continue the reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:30])[CH:16]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[CH3:29])[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.Cl>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:30])[CH:16]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[CH3:29])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(C(=O)c1cccc(OCc2ccccc2)c1)c1ccncc1C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnccc1C(CCC(=O)O)C(=O)c1cccc(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
A mixture of methyl (RS)-5-(3-benzyloxy-phenyl)-4-(3-methylpyrid-4-yl)-5-oxopentanoate (3.26 g), dioxan (50 mL), water (9 mL) and concentrated hydrochloric acid (6 mL) is stirred at 60° C. for 1 hour and then evaporated to dryness under reduced pressure. The residue is treated with saturated aqueous sodium bicarbonate solution to give a solution of pH 7 and extracted with ethyl acetate. Evaporation, followed by crystallisation from a mixture of ethyl acetate and pentane affords (RS)-5-(3-benzyloxyphenyl)-4-(3-methylpyrid-4-yl)-5-oxopentanoic acid (1.56 g) in the form of a cream coloured solid, m.p. 55-57° C. [Elemental analysis:- C,73.7;H,5.92; N,3.41%. Calculated:- C,74.0;H,5.95;N,3.60%].
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[CH:13][CH:14]=3)[C:9]([S:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:8]2[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33]C)=[O:32])=[CH:4][CH:3]=1.C1COCC1.[Li+].[OH-]>CO>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[CH:13][CH:14]=3)[C:9]([S:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:8]2[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([OH:33])=[O:32])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccccn3)ccc2n1Cc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)Sc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccccn3)cc12

Procedure:
A solution of methyl 3-[1-(4-chlorobenzyl)-3-(1,1-dimethylethylthio)-5-(pyrid-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropionate (8.8 g; 16 mmol), prepared as in step 5, in 100 mL 1:2:1 THF, methanol, 1N aqueous LiOH was heated at reflux for 3 hours. The reaction mixture was concentrated, diluted with water, and acidified to pH 5-6 with solid citric acid. The mixture was extracted with ethyl acetate. The extracts were dried over magnesium sulfate and the solvent was evaporated. The product was recrystallized from ethyl acetate/hexane to give 3-[1-(4-chlorobenzyl)-3-(1,1-dimethylethylthio)-5-(pyrid-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropionic acid as a white solid. m.p. 189°-190° C. 1H NMR (300 MHz, DMSO-d6) δ1.09 (s, 6H), 1.10 (s, 9H), 3.18 (bs, 2H), 5.20 (s, 2H), 5.47 (s, 2H), 6.85 (m, 3H), 7.09 (d, J=3 Hz, 1H), 7.32 (m, 4H), 7.49 (d, J=8 Hz, 1H), 7.79 (m, 1H), 8.57 (m, 1H). MS (DCI/NH3) 537 (M+H)+. Analysis calcd for C30H33ClN2O3S; C, 67.08; H, 6.19; N, 5.22. Found: C, 67.30; H, 6.21; N, 5.18.