Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].Cl>[OH-].[Na+]>[C:25]1([CH2:24][O:23][C:21]([NH:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:9][CH2:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:22])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccccc1CCc1ccccc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1ccccc1CCc1ccccc1C(=O)O)OCc1ccccc1
Yield: 53.3 %

Procedure:
A suspension of 2-[2-(2-aminophenyl)ethyl]benzoic acid hydrochloride (339 mg, 1 mmol) in aqueous sodium hydroxide (1N, 2 mL) was stirred vigorously and treated simultaneously with benzyl chloroformate (170 mg, 1 mmol) and aqueous sodium hydroxide (1N, 1 mL). The reaction mixture was stirred for 16 h, acidified with dilute hydrochloric acid and filtered. The solid was washed with water and hexane, dissolved with methylene chloride, and the organic phase was washed with water, dried with magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was triturated with ether to give 2-[2-(2-(phenylmethoxy-carbonylamino)phenyl)ethyl]benzoic acid (0.2 g, 53%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12](I)[S:13][C:6]=12.[CH:22]([C:24]1[O:28][C:27](B(O)O)=[CH:26][CH:25]=1)=[O:23].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:27]3[O:28][C:24]([CH:22]=[O:23])=[CH:25][CH:26]=3)[S:13][C:6]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: O=Cc1ccc(B(O)O)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)o1
Temperature: 65 °C
Yield: 84.2 %

Procedure:
A stirred suspension of 7-(2-fluoro-4-nitrophenoxy)-2-iodothieno[3,2-b]pyridine (24) [US 2006/0287343 A1] (5.00 g, 12.01 mmol, scheme 4)], 5-formyl-2-furanboronic acid (2.19 g, 15.19 mmol), Pd(PPh3)2Cl2 (422 mg, 0.6 mmol), Na2CO3 (8.53 g, 80.50 mmol) in a mixture of DME/ethanol/water (60 mL/40 mL/40 mL) was degassed with nitrogen for 15 min, and heated at 65° C. for five hours under nitrogen. The reaction mixture was allowed to cool to room temperature, and filtered. The cake was successively washed with water and AcOEt. The filtrate and washings were combined, extracted with AcOEt. The extract was successively washed with water, saturated solution of ammonium chloride, water and brine, and concentrated. The residue was combined with the cake, absorbed on silica gel and subjected to flash column chromatography on silica gel (eluents AcOEt/DCM: 10/90 to 20/90, then MeOH/DCM: 5/95) followed by trituration with AcOEt, to afford aldehyde 107 (3.886 g, 84% yield) as a pale clay solid. MS (m/z): 385.0 (M+H).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:13]COC)[CH:5]=1)([CH3:3])[CH3:2].[C:17](Cl)(=O)C.Cl.C[Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO.CCCCCC>[CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:17])=[O:9])=[C:6]([OH:13])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COCOc1cc(C(C)C)ccc1C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(C(C)C)cc1O
Reaction time: 2 h

Procedure:
The 4-isopropyl-2-methoxymethoxybenzoic acid (5.3 g, 23.6 mmol) was dissolved in methylene chloride (75 mL) and MeOH (75 mL). Acetyl chloride (1 mL) was added to generate HCl. The reaction mixture was stirred for 2 h. The reaction was washed with water (2×150 mL), dried (MgSO4), and concentrated under vacuum. The crude product was dissolved in methylene chloride (100 mL) and MeOH (30 mL) and to this solution a 2 M hexane solution of (trimethylsilyl)diazomethane (11.8 mL, 23.6 mmol) was added dropwise. After 1 h, the solvent was removed under vacuum, giving the title compound as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:45])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH2:41][CH:42](C)C)[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:41]([C:37]1[CH:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:45])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:21])([F:23])[F:22])[C:12]([O:14][CH2:15][C:16]([F:17])([F:19])[F:18])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[CH:40]=[CH:39][N:38]=1)[CH3:42]
Reactant: CC(C)Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from [2-{3-[3-(2-isobutyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M243) (0.31 g, 0.47 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (140 mg, 55%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[CH:27]([O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)([CH3:29])[CH3:28].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:27]([O:30][C:31]1[CH:36]=[C:35]([N:3]2[C:4](=[O:26])[C:5]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]2[CH3:1])[CH:34]=[CH:33][CH:32]=1)([CH3:29])[CH3:28]
Reactant: CC(C)Oc1cccc(B(O)O)c1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2cccc(OC(C)C)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (3-isopropoxyphenyl)boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) in methylene chloride (10 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.24 g, 89%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[N:8][OH:9])[CH2:3][CH2:2]1.ClN1C(=O)CCC1=O.[C:18]([O:23][CH2:24][CH3:25])(=[O:22])[C:19]#[C:20][CH3:21].C(N(CC)CC)C>CN(C=O)C.C(OC)(C)(C)C>[CH2:24]([O:23][C:18]([C:19]1[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:8][O:9][C:20]=1[CH3:21])=[O:22])[CH3:25]
Reactant: CC#CC(=O)OCC
Reactant: ON=CC1CCOCC1
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C2CCOCC2)noc1C
Temperature: 25 °C
Yield: 35.1 %

Procedure:
To a solution of tetrahydro-pyran-4-carbaldehyde oxime (6.5 g, 50 mmol) in DMF (47 mL) was added N-chlorosuccinimide (6.95 g, 50 mmol) at room temperature and the after 3 h the mixture was extracted with tert-butylmethylether (100 mL). The organic extract was then added dropwise over 2 h to a solution of ethyl 2-butynoate (61.2 mL, 52.5 mmol) and triethylamine (8.4 mL, 60 mmol) in tert-butylmethylether (47 mL) heated under reflux and the resulting mixture heated overnight. The reaction mixture was then cooled to room temperature and extracted with tert-butylmethylether and washed with aqueous hydrochloric acid solution (1 N). The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (4.2 g, 35%) as a light yellow solid. MS: m/e=240.2 [M+H]+.
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)[CH2:18][CH2:17]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=3)[CH2:20][CH2:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(OCCCN2CCC(O)CC2)cc1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: O=[N+]([O-])c1ccc(OCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
The procedure of Example 1 (a) was repeated except for using diphenylmethyl bromide and 4-hydroxy-1-[3-(4-nitrophenoxy)propyl]piperidine instead of diphenylmethyl bromide and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-diphenylmethoxy-1-[3-(4-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [Br:1][C:2]1[S:14][C:5]2=[N:6][C:7]([Cl:13])=[C:8]([C:10](=[O:12])[CH3:11])[CH:9]=[C:4]2[CH:3]=1>C1COCC1>[Br:1][C:2]1[S:14][C:5]2=[N:6][C:7]([Cl:13])=[C:8]([C@H:10]([OH:12])[CH3:11])[CH:9]=[C:4]2[CH:3]=1
Reactant: CC(=O)c1cc2cc(Br)sc2nc1Cl
Solvent: C1CCOC1
Product: C[C@@H](O)c1cc2cc(Br)sc2nc1Cl
Temperature: -55 °C
Reaction time: 1 h

Procedure:
In 30 mL of THF was dissolved (+)-dip-chloride(tm) (3.3 g, 10.2 mmol, 2.2 eq) and the resulting solution was cooled to −55° C. To this solution was added 1-(2-bromo-6-chlorothieno[2,3-b]pyridin-5-yl)ethanone in 10 mL of THF via cannula, followed by a rinse with 10 mL of THF. The reaction was allowed to warm to RT slowly overnight and then quenched with 5 mL of acetone and 50% sat. Na2CO3. After stirring for 1 h, the reaction was diluted with ethyl acetate (100 mL) and transferred to a reparatory funnel. The organic layer was washed with 2×50 mL of 50% sat. Na2CO3, 2×50 mL of water, and 2×50 mL of brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification of the crude was achieved by slurrying in 20 mL water and 50 mL hexanes. The resulting solid was filtered and dried overnight to afford a pure white powder, (R)-1-(2-bromo-6-chlorothieno[2,3-b]pyridin-5-yl)ethanol. Chiral HPLC (Chiralcel-AD, 30% isopropanol/hexanes)=92% ee. 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.31 (s, 1H), 5.32 (dq, J=5.9, 3.5 Hz, 1H), 2.17 (d, J=3.5 Hz, 1H), 1.56 (d, J=6.3 Hz, 3H) ppm.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[CH:5]=[C:4]1[CH2:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21](=[O:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:2].Cl.[NH2:31][OH:32].C(=O)([O-])[O-].[Na+].[Na+].O>CO>[OH:32][N:31]=[N:13][CH2:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([CH2:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:3]2[CH2:1][CH3:2])=[CH:7][CH:8]=1
Reactant: CCn1c(CC[C@@H]2CCCN2C(=O)Cc2ccccc2)cc2ccc(C#N)cc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCn1c(CC[C@@H]2CCCN2C(=O)Cc2ccccc2)cc2ccc(CN=NO)cc21
Yield: 5.3 %

Procedure:
190 mg of 1-ethyl-2-[2-[(S)-1-(2-phenylacetyl)pyrrolidin-2-yl]ethyl]indole-6-carbonitrile obtained in Example 14-a) was dissolved in methanol. 103 mg of hydroxylamine hydrochloride and 210 mg of sodium carbonate were added and the reaction solution was refluxed overnight with stirring. After water was added, the reaction solution was extracted two times with dichloromethane. The extract was dried over MgSO4 and distilled under reduced pressure. The residue was purified with silica gel column chromatography [eluent: dichloromethane/methanol (20:1)] to obtain 11 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[C:11]([NH2:24])=[N:12][C:13]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:14][CH:15]=1.C(N(CC)CC)C.[C:32](Cl)(Cl)=[O:33].O>O1CCCC1>[CH2:17]([S:16][C:13]1[N:12]=[C:11]2[NH:24][C:32](=[O:33])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:9][C:10]2=[CH:15][N:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1nc(SCc2ccccc2)ncc1CNc1ccccc1Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1Nc2nc(SCc3ccccc3)ncc2CN1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a stirred solution, cooled to −10° C., of 4.3 g (12.1 mmol) of 5-(2-chlorophenyl) aminomethyl-4-amino-2-benzylthiopyrimidine in 100 mL of tetrahydrofuran was added 3.1 mL (22.2 mmol) of triethylamine. This solution was then treated dropwise with a solution of 6.15 mL of phosgene (20% solution in toluene; 11.8 mmol) After stirring for 30 minutes, an additional 1.0 mL of triethylamine (7.1 mmol) was added followed by 2.0 mL of phosgene (20% solution in toluene; 3.8 mmol). The reaction was warmed to room temperature, treated with 0.5 mL H2O and stirred for 30 minutes. The reaction was then filtered and the mother liquor was concentrated and stirred with dichloromethane. The product was then collected by vacuum filtration and dried in vacuo to give 3.83 g of 7-benzylthio-3-(2-chlorophenyl)-3,4-dihydropyrimido[4,5-d]-pyrimidin-2(1H)-one as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br)#[N:2].[CH2:11]([O:13][C:14](=[O:31])[C:15]1[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH:16]=1)[CH3:12]>CN(C=O)C>[CH2:11]([O:13][C:14](=[O:31])[C:15]1[CH:16]=[C:17]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH:18]=[C:19]([O:21][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:20]=1)[CH3:12]
Reactant: CCOC(=O)c1cc(O)cc(Oc2ccc(C#N)cc2)c1
Reactant: N#Cc1cccc(CBr)c1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCc2cccc(C#N)c2)cc(Oc2ccc(C#N)cc2)c1
Reaction time: 8 h
Yield: 81 %

Procedure:
Potassium carbonate K2CO3 0.44 g (3.18 mmol) followed by 3-cyano benzylbromide 0.31 g (1.58 mmol) in 2 ml of DMF were added to a solution of 3-(4-cyano phenoxy)-5-hydroxy benzoic acid ethyl ester 0.45 g (1.58 mmol) in 7 ml of DMF at 20° C. The reaction mixture was allowed to attain RT and stirred overnight. The reaction mixture was quenched with ice cold water, extracted with ethyl acetate. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated to afford 0.51 g of a thick oily liquid. 1H NMR (CDCl3): δ 1.3 (3H, t), 4.3 (2H, q), 5.25 (2H, s), 6.88 (1H, s), 7.02 (2H, d), 7.34 (1H, s), 7.5 (2H, m), 7.66 (4H, m), 7.78 (1H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:13]=1[NH2:14]>>[CH3:20][O:19][C:17]1[CH:16]=[CH:15][C:13]([NH:14][C:2]2[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)=[C:12]([C:11]([F:10])([F:21])[F:22])[CH:18]=1
Reactant: COc1ccc(N)c(C(F)(F)F)c1
Reactant: N#Cc1ccc(Br)cn1
Product: COc1ccc(Nc2ccc(C#N)nc2)c(C(F)(F)F)c1
Yield: 97.4 %

Procedure:
Analogously to Example 1a) 5-bromo-pyridine-2-carbonitrile was reacted with 2-trifluoromethyl-4-methoxy-aniline. After chromatographic purification through silica gel (petroleum ether with 10 to 30% ethyl acetate) the 4-(4-methoxy-2-trifluoromethyl-phenyl-amino)-benzonitrile was obtained in a yield of 97.4% of theory.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC=CC=1>[CH2:11]1[CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3][CH:2]1[NH:1][C:23]([NH:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:24]
Reactant: O=C=Nc1ccccc1
Reactant: NC1CCN2CCc3ccccc3C2C1
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1)NC1CCN2CCc3ccccc3C2C1
Reaction time: 18 h

Procedure:
To 2-amino-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine (0.436 g) stirred at room temperature in benzene (50 ml) was added phenyl isocyanate (0.290 g, 5% excess) in benzene (25 ml). After stirring for 18 hours, the title compound was filtered off as a white solid (0.621 g) which was converted in ethanolic hydrogen chloride to the hydrochloride (0.654 g), m.p. 210.1° C. C20H23N3O.HCl.H2O requires C, 63.90; H, 6.97; N, 11.18% Found: C, 63.72; H, 6.87; N, 11.10%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:15]([O:17][C@H:18]4[C@H:22]5[O:23][CH2:24][C@@H:25]([OH:26])[C@H:21]5[O:20][CH2:19]4)=[N:16][C:11]3=[CH:10][C:9]=2[Cl:35])=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:43](=[O:51])[O:44][CH:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[CH2:38][CH2:37]1>>[Cl:35][C:9]1[CH:10]=[C:11]2[N:16]=[C:15]([O:17][C@@H:18]3[CH2:19][O:20][C@@H:21]4[C@H:25]([OH:26])[CH2:24][O:23][C@H:22]34)[N:14]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:12]2=[N:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([N:36]2[CH2:41][CH2:40][CH:39]([NH:42][C:43](=[O:51])[O:44][CH:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[CH2:38][CH2:37]2)=[CH:3][CH:4]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(Br)cc3)nc21
Reactant: O=C(NC1CCNCC1)OC1CCOCC1
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(N4CCC(NC(=O)OC5CCOCC5)CC4)cc3)nc21

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(5-(4-bromophenyl)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and tetrahydro-2H-pyran-4-yl piperidin-4-ylcarbamate following a procedure analogous to that described for Intermediate 23. LC (method 1): tR=0.99 min; Mass spectrum (ESI+): m/z=730 [M+H]+.
Reaction SMILES: [C:1](Br)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:47]([F:50])([F:49])[F:48])=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[S:32](=[O:42])(=[O:41])[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:22][CH:21]=3)[C:15]([CH2:43][CH2:44][CH2:45][CH3:46])=[N:14]2)[CH:12]=1>>[C:37]([O:36][C:34]([NH:33][S:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:16]2[C:15]([CH2:43][CH2:44][CH2:45][CH3:46])=[N:14][N:13]([C:11]3[CH:12]=[C:7]([NH:6][C:1](=[O:4])[CH2:2][CH3:3])[CH:8]=[CH:9][C:10]=3[C:47]([F:49])([F:48])[F:50])[C:17]2=[O:18])=[CH:21][CH:22]=1)(=[O:41])=[O:42])=[O:35])([CH3:38])([CH3:39])[CH3:40]
Reactant: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Reactant: CCC(=O)Br
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Yield: 52 %

Procedure:
Propionyl bromide was reacted with 2-[5-amino-2-(trifluoromethyl)phenyl]-4-[[2'-[N-(t-butoxycarbonyl)sulfamoyl]biphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step F) according to the method of Example 26. Purification by silica gel flash chromatography (gradient elution with 0.5-5% MeOH in CH2Cl2) followed by semi-preparative HPLC (Zorbax C8 reverse phase column, elution with 60:40 and then 65:35 MeCN--H2O) gave 13 mg (52%) of the title compound as a solid, mp 158°-161° C.; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 714 (M+2Li)+.
Reaction SMILES: ClC1C=CC=[C:4]([C:8]([O:10]O)=[O:9])C=1.[CH2:12]([NH:19][CH2:20][CH2:21][C:22]1[CH:37]=[CH:36][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30](C(=O)C)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl.ClCCl>[CH2:12]([NH:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:10][C:8](=[O:9])[CH3:4])=[CH:31][CH:32]=2)=[CH:36][CH:37]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
Metachloroperbenzoic acid (0.23 g) was added to a solution of 1-{4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}-ethanone (0.36 g) in chloroform (25 mL) while stirring at room temperature. Stirring was continued overnight then the reaction was diluted with dichloromethane, washed with saturated aqueous sodium thiosulfate, dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue was diluted with methanol (5 mL) and saturated aqueous sodium bicarbonate (5 mL) then stirred overnight at room temperature. The methanol was removed on a rotary evaporator and the pH of the residue was adjusted to 7-8 then extracted with dichloromethane (3×30 mL). The combined dichloromethane extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield 0.4 g of crude product, which was purified by flash column chromatography on silica gel eluting with ethanol in dichloromethane to yield Acetic acid 4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl ester (117 mg), 1H NMR (CDCl3, 300.00 MHz): 8.01-7.93 (m, 2H), 7.42-7.21 (m, 7H), 7.06-6.97 (m, 4H), 3.87 (s, 2H), 3.02-2.94 (m, 4H), 2.61 (s, 3H); m/z=361.85 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16](Br)=[C:15]([Br:18])[S:14](=[O:19])[C:13]=2[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:21]1([CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CC(C)([O-])C.[K+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([O:36][C:33]3[CH:32]=[CH:31][C:30]([O:29][CH2:28][CH2:27][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:35][CH:34]=3)=[C:15]([Br:18])[S:14](=[O:19])[C:13]=2[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(OCCN2CCCCC2)cc1
Reactant: O=S1C(Br)=C(Br)c2ccc(OCc3ccccc3)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=S1C(Br)=C(Oc2ccc(OCCN3CCCCC3)cc2)c2ccc(OCc3ccccc3)cc21
Temperature: 45 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Dissolve 6-benzyloxy-2,3-dibromo-benzo[b]thiophene 1-oxide (5.9 g, 14.2 mmol) in THF (120 mL). Add a suspension of 4-(2-piperidin-1-yl-ethoxy)-phenol (3.14 g, 14.2 mmol) and potassium tert-butoxide (1.75 g, 15.6 mmol) in THF (120 mL) and stir at 45° C. for 1 hour. Partition reaction mixture between dichloromethane (400 mL) and saturated aqueous NH4Cl (400 mL) and separate. Wash the organic layer with saturated aqueous NH4Cl (400 mL) and brine. Dry with sodium sulfate, filter, and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with methanol in dichloromethane (0 to 5%) to give 6.9 g of 1-{2-[4-(6-benzyloxy-2-bromo-1-oxo-1H-1λ4-benzo[b]thiophen-3-yloxy)-phenoxy]-ethyl}-piperidine (88%).