Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:24][C:25]([CH2:31][CH3:32])([CH2:29][CH3:30])[C:26]([OH:28])=[O:27])=[CH:4][CH:3]=1.[F:35][C:36]1([F:42])[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]1>>[F:35][C:36]1([F:42])[CH2:41][CH2:40][CH2:39][N:38]([C:2]2[CH:34]=[CH:33][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[C:13]([O:16][CH2:17][C:18]5[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=5)[CH:14]=[CH:15][C:10]=4[N:9]=[C:8]3[CH2:24][C:25]([CH2:31][CH3:32])([CH2:29][CH3:30])[C:26]([OH:28])=[O:27])=[CH:4][CH:3]=2)[CH2:37]1
Reactant: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(Br)cc1)C(=O)O
Reactant: FC1(F)CCCNC1
Product: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(N2CCCC(F)(F)C2)cc1)C(=O)O

Procedure:
The title compound was prepared using analogous conditions described in Example 152 using 2-((1-(4-bromobenzyl)-6-((1-methyl-1H-pyrazol-3-yl)methoxy)-1H-benzo[d]imidazol-2-yl)methyl)-2-ethylbutanoic acid and 3,3-difluoropiperidine. MS (ESI): mass calcd. for C31H37F2N5O3, 565.2; m/z found, 566.3 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 7.69 (d, J=9.0, 1H), 7.57-7.51 (m, 1H), 7.34 (d, J=2.1, 1H), 7.25 (dd, J=9.1, 2.3, 1H), 7.13 (d, J=8.7, 2H), 6.96 (d, J=8.8, 2H), 6.28 (d, J=2.2, 1H), 6.25 (d, J=2.2, OH), 5.65 (s, 2H), 5.07 (s, 2H), 3.84 (s, 3H), 3.40 (t, J=5.7, 4H), 3.27-3.23 (m, 2H), 2.08-1.96 (m, 2H), 1.89-1.68 (m, 6H), 0.90-0.83 (m, 6H).
Reaction SMILES: CC([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[F:12])=O.[OH-].[Na+]>C(O)C.O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([NH2:4])=[C:6]([F:12])[CH:7]=1
Reactant: CC(=O)Nc1ccc(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Cl)cc1F
Temperature: 80 °C
Yield: 59.5 %

Procedure:
Under a nitrogen atmosphere, a suspension of 718 g (3.8 moles) of 4-chloro-2-fluoroacetanilide in 2653 mL of ethanol was stirred as a solution of 304 g (7.6 moles) of sodium hydroxide in 1075 mL of water was added. Upon completion of addition the reaction mixture was warmed to 80° C. during a 2.3 hour period. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to a volume of approximately 2000 mL. The concentrate was dissolved in 2000 mL of ethyl acetate and washed with 500 mL of water. The organic layer was concentrated under reduced pressure to a residual oil. The oil was filtered to remove a solid, then distilled under reduced pressure to yield 329 g of 4-chloro-2-fluoroaniline; b.p. 93°-100° C./16-20 mm.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14](=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl[Si:28]([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[CH3:29][Si:28]([CH3:31])([CH3:30])[O:26][C:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH2:13]
Reactant: C[Si](C)(C)Cl
Reactant: CCCCCCCCCCCC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=C(CCCCCCCCCCC)O[Si](C)(C)C
Temperature: 10 °C
Yield: 99.1 %

Procedure:
A solution of n-butyllithium (12.6 mL, 27.7 mmol, 2.2 M in hexane) was added dropwise via syringe to a cooled (-78° C.) solution of diisopropylamine (4.1 mL, 29 mmol) in dry THF (200 mL). The resulting solution was stirred (15 minutes -78° C.), then a solution of 2-tridecanone (5.0 g, 25 mmol) in dry THF (50 mL) was added dropwise via a drop-in funnel. The resulting mixture was stirred (30 minutes, -78° C.), then a solution of chlorotrimethylsilane (3.5 mL, 28 mmol) in dry THF (40 mL) was added in one portion. The dry ice bath was removed and the resulting mixture was warmed to 10° C., then quenched with saturated sodium bicarbonate (100 mL). Dichloromethane (400 mL) and water (80 mL) were added and the layers were separated. The organic layer was washed with brine (1×200 mL), dried (MgSO4), and concentrated in vacuo to yield 6.7 g (98%) of the title compound as a milky oil which was used without further purification.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH3:23])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)[CH2:22][CH3:23]
Reactant: CCCOc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCOc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 7.2 %

Procedure:
A mixture of methyl thiosalicylate (0.24 g, 1.4 mmol), 2-cyano-6-propoxypyridine (0.23 g, 1.4 mmol), triethylamine (0.30 ml, 2.1 mmol) and toluene (20 ml) was refluxed for 48 hrs as described in Example 1. The reaction mixture was concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography, eluted with hexane-ethyl acetate (5:1, v/v) and recrystallized from hexane-ethyl acetate to give the titled compound (0.03 g, 7%) as crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:21][CH:22]=[N:23][N:24]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25].O1CCOC[CH2:27]1>>[ClH:25].[CH3:27][C:22]1[O:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:15][CH:16]=2)=[N:24][N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nnco3)cc2)CC1
Reactant: C1COCCO1
Agent: Cl
Product: Cc1nnc(-c2ccc(N3CCNCC3)cc2)o1

Procedure:
Prepared in analogy to example 4.4(b) from 4-(4-[1,3,4]Oxadiazol-2-yl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and hydrochloric acid in dioxane. MS (m/e): 245.3 (MH+, 100%)
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[C:21]([CH2:23]O)[CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1>ClCCl>[Cl:3][CH2:23][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([Cl:10])[CH:12]=2)[N:22]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(-c2cccc(Cl)c2)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: ClCc1cccc(-c2cccc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
433 mg (0.264 ml, 3.64 mmol) thionyl chloride were added drop by drop at 0° C. to a solution of 0.2 ml N,N-dimethylformamide (DMF) and 400 mg (1.82 mmol) [6-(3-Chloro-phenyl)-pyridin-2-yl]-methanol in 25 ml dichloromethane and stirred for 3 h at 0° C. The mixture was poured on ice/sodium bicarbonate solution and the organic phase separated. The water phase is extracted with dichloromethane. The combined organic phases were washed with water, dried (sodium sulphate), evaporated and the obtained material (409 mg, 94%) used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Br:15])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl-].[F:17][CH:18]([F:24])[C:19](OCC)=[O:20].[Cl-].[NH4+]>O1CCCC1.CO>[Br:15][C:13]1[CH:12]=[C:4]([CH:3]=[C:2]([CH:19]([OH:20])[CH:18]([F:24])[F:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CCOC(=O)C(F)F
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)c1cc(Br)cc(C(O)C(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
To a solution of tert-butyl 3,5-dibromobenzoate (18.43 g, 54.9 mmol) in tetrahydrofuran (137 mL) at 0° C. was added isopropylmagnessium chloride (2.0 M in THF; 46.6 mL, 93 mmol). The reaction mixture was warmed to ambient temperature. The reaction was monitor by LC-MS for disappearance of tert-butyl 3,5-dibromobenzoate. The mixture was cooled back to 0° C. and ethyl difluoroacetate (13.7 mL, 137 mmol) was added. The mixture was stirred at 0° C. for 1 h, then warmed to ambient temperature. After 18 h, methanol and saturated ammonium chloride were added and the mixture was concentrated to remove organic solvents. Water was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→75% hexanes/ethyl acetate) gave the title compound (4.04 g).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=O)[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:6][CH:7]=2)[N:12]=1
Reactant: CCCCc1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCc1ccc(-c2cc3ccccc3c(Cl)n2)cc1

Procedure:
The resulting 3-[4-(n-butyl)phenyl]isoquinolin-1-one (2.44 g) was reacted with phosphorus oxychloride (20 ml) according to the method of Example 10-2, to give 1-chloro-3-[4-(n-butyl)phenyl]isoquinoline. The resulting compound was reacted, as it was, with N-ethylpiperazine (11 ml) at 100° C. overnight. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and purified water. The resulting ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 1.78 g of the free compound of the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].C([O:15][C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])C.O>C1COCC1>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16](=[O:15])[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]#[N:10]
Reactant: CCOC(=O)c1ccccc1Cl
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(C(=O)c1ccccc1Cl)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 113.7 %

Procedure:
To a solution of (4-chlorophenyl)acetonitrile (15.1 g, 100 mmol) in THF (250 ml) was added NaH (60% dispersion in oil, 8.0 g, 200 mmol) in 3 portions over 5 minutes. To this was added a solution of 2-chlorobenzoic acid ethyl ester (18.3 g, 100 mmol) in THF (50 ml), dropwise over 10 minutes. The mixture was then heated at 60° C. overnight. After cooling to room temperature, water was added (2×10 ml, bubbling observed), and the reaction was concentrated, in vacuo, to ½ volume. The mixture was diluted with water (125 ml) and methylene chloride (125 ml), adjusted to pH=7 with 3 N aqueous HCl, and the aqueous layer separated and extracted with additional methylene chloride. The combined organics were dried (MgSO4) and concentrated, in vacuo, to give a brown oil (33 g) that began to solidify on standing. After stirring the residue overnight in diisopropyl ether (250 ml), the solid product was collected by vacuum filtration to afford, after drying, in vacuo, title product I-3A-1a (15.2 g, 52%) as a tan solid: −ESI MS (M−1) 288.0; 1H NMR (400 MHz, CD2Cl2) δ 7.74 (d, J=8.30 Hz, 1H), 7.60–7.25 (m, 7H), 5.65 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].[N:13]1([CH2:18][CH2:19]O)[CH2:17][CH2:16][CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[N:13]1([CH2:18][CH2:19][O:12][C:4]2[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: OCCN1CCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc([N+](=O)[O-])cc1OCCN1CCCC1
Reaction time: 1 h
Yield: 61 %

Procedure:
A stirred solution of 2-methoxy-5-nitrophenol (1.5 g, 0.0088 mole), 1-pyrrolidineethanol (1.03 ml, 0.0088 mole) and triphenylphosphine (2.4 g, 0.0088 mole) in TBF (50 ml) at room temperature under argon was treated with diethyl azodicarboxylate (1.4 ml, 0.0088 mole). The reaction mixture was stirred for 1 h, then concentrated in vacuo and the residue treated with 2M HCl acid (50 ml) and ethyl acetate (50 ml). The mixture was shaken well, then the acid layer separated, washed with ethyl acetate (2×30 ml) and then basified by addition of potassium carbonate. The basic mixture was extracted with ethyl acetate (2×50 ml) and the combined extract dried (Na2SO4) and concentrated in vacuo to afford the title compound as a yellow oil (1.43 g, 61%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11](=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N#N.[CH2:23]([Mg]Br)[CH3:24].COC(C)(C)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH2:23][CH3:24])([OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[Mg]Br
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2=O
Agent: N#N
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCC1(O)CCN(C(=O)OC(C)(C)C)c2cc(OC)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a flame dried 250 mL round bottom flask equipped with a magnetic stir bar and a N2 gas inlet was added IV (2.23 mg, 8.05 mmol) in dry THF (100 mL). The solution was cooled to 0° C. under a blanket of N2 and a 1.0M solution of ethyl magnesium bromide (EtMgBr) in methyl-tert-butyl ether (16.1 mL, 16.1 mmol, 2 equiv) was added via syringe. The solution was stirred at 0° C. for 1 h. The reaction was quenched with NH4Cl (saturated aqueous solution) extracted with EtOAc, dried (MgSO4), and concentrated to give V as a colorless oil (1.11 g, 3.61 mmol, 45%). Spectral data matched that previously disclosed for this compound.
Reaction SMILES: [N:1]1C=CC=CC=1.[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:1])(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: c1ccncc1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccccc1Br
Reaction time: 8 h

Procedure:
The resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) followed by 2-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Temperature: 82.5 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 1.15 g (7.14 mmol) of 3-bromo-1-chloropropane (purity: 98 wt. %), 0.85 g (6.04 mmol) of potassium carbonate (purity: 98 wt. %), and 30 mL of acetonitrile. The resulting mixture was refluxed under stirring at 80-85° C. for 8 hours in an argon gas atmosphere. After the reaction was complete, the reaction mixture was filtered and concentrated under reduced pressure. To the concentrate was added n-heptane, to precipitate a crystalline product. The crystalline product was collected by filtration and dried under reduced pressure, to obtain 1.34 g (isolated yield: 97.8%, purity: 98% in terms of area percentage determined by high performance liquid chromatography) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate as a white crystalline product.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:15]([O:17][CH3:18])=[O:16])[CH:2]=[CH2:3].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CC#N>[CH2:1]([C:4]1[C:13]([O:14][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:15]([O:17][CH3:18])=[O:16])[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)cc(C(=O)OC)cc1C(=O)OC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: C=CCc1c(OCc2ccccc2)cc(C(=O)OC)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 94.6 %

Procedure:
To a mixture of dimethyl 4-allyl-5-hydroxyisophthalate (376b) (5.05 g, 20.18 mmol) and Cs2CO3 (13 g, 40.1 mmol) in CH3CN (30 mL) was added benzyl bromide (3.6 mL, 30.27 mmol). The mixture was stirred at room temperature for 14 hours. The solution was treated with water, and extracted with EtOAc (2×). The organic layer was dried over sodium sulfate, filtered and evaporated to provide the desired product as white solid (6.5 g, 98% yield). The crude product was used without purification. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.85 (t, J=6.78 Hz, 2 H) 3.89-3.93 (m, 3 H) 3.93 (s, 3 H) 4.93-4.99 (m, 1 H) 4.99-5.07 (m, 1 H) 5.16 (s, 2 H) 5.87-6.11 (m, 1 H) 7.30-7.38 (m, 1 H) 7.39-7.55 (m, 4 H) 7.74 (d, J=1.51 Hz, 1 H) 8.12 (d, J=1.70 Hz, 1 H); MS (ESI, pos):341.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[CH:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:16]=[CH:15]2)[OH:11].C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:16]=[CH:15]2)=[O:11]
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)c1ccc2c(cnn2-c2ccccc2)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C(=O)c1ccc2c(cnn2-c2ccccc2)c1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.2 %

Procedure:
To a solution of 2-(2,4-dichloro-phenyl)-1-(1-phenyl-1H-indazol-5-yl)-propan-1-ol (180 mg) in dichloromethane (5 ml) was added powdered molecular sieve 3A (1 g). Tetrapropylammonium perruthenate (16 mg) and 4-methylmorpholine-4-oxide (106 mg) were added. The mixture was stirred at room temperature for 1.5 h. The mixture was filtered and the filtrate was concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>1:3) to give the title compound (149 mg) as an off-white solid. MS (m/e)=394.9 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[S:30][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])=[N:32][N:33]=1>C(#N)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:28][C:29]3[S:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])=[N:32][N:33]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccccc1-c1nnc(CBr)s1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CO
Product: O=c1n(Cc2nnc(-c3ccccc3Cl)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
30 mg (0.10 mmol) of the compound from Example 5A were dissolved in 3 ml of acetonitrile, and 48 mg (0.15 mmol) of cesium carbonate and 28 mg (0.10 mmol) of the compound from Example 86A were added. The mixture was stirred at 70° C. for 8 h. For work-up, the mixture was cooled to RT, diluted with 5 ml of methanol and filtered. The filtrate was concentrated under reduced pressure and the crude product was then purified chromatographically [Method 19]. This gave 11 mg (22% of theory) of the target compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[Cl:11].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:11][C:5]1[C:6]([Cl:10])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:2][NH:1][C:21](=[O:22])[O:23][CH2:24][CH3:25]
Reactant: CC(C)(C)OC(=O)NC(CN)c1cccc(Cl)c1Cl
Reactant: CCOC(=O)Cl
Product: CCOC(=O)NCC(NC(=O)OC(C)(C)C)c1cccc(Cl)c1Cl

Procedure:
From 192 mg (629 μmol) of the compound from Example 40A and 72 μl (755 μmol) of ethyl chloroformate, in the same way as for Example 123A, 184 mg (78% of theory) of the title compound were prepared.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[I:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[CH:23]([CH2:31][CH2:32]OS(C)(=O)=O)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:16][CH:15]=1>CN(C)C=O>[O:6]=[C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[O:11])[N:5]1[CH2:32][CH2:31][CH:23]([CH:22]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1)[CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([I:13])=[CH:15][CH:16]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(COC(CCc2ccc(I)cc2)C(CCOS(C)(=O)=O)C(=O)OC(C)(C)C)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(COC(CCc2ccc(I)cc2)C(CCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Yield: 20.9 %

Procedure:
Potassium phthalimide (0.33 g, 2.2 mmol) was added in one portion to a stirred solution of 1,1-dimethylethyl 5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)-2-{2-[(methylsulfonyl)oxy]ethyl}pentanoate (1.15 g, 1.86 mmol) in dimethylformamide (6 mL) at room temperature under nitrogen. The resulting solution was heated at 80° C. for 1 h 45 min then cooled to room temperature. The volatiles were evaporated and the residue partitioned between dichloromethane (50 mL) and water (50 mL). The layers were separated and the organic phase evaporated to dryness. The residue was chromatographed on silica gel (50% ethyl acetate: cyclohexane) to give the title compound (0.26 g, 21%) as a yellow oil which was a mixture of diastereoisomers. LC/MS: 4.29 min; z/e 687, calcd (M+18) 687. 1H NMR (400 MHz: CDCl3): 7.85 (2H), 7.70 (2H), 7.55-7.20 (4H), 6.90-6.75 (4H), 4.55-4.30 (2H), 3.80 (3H), 3.75 (1H), 3.65 (2H), 2.80-2.45 (3H), 2.10-1.50 (4H), 1.40 (9H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]3[C:19]([NH2:23])=[N:20][CH:21]=[CH:22][C:17]=3[S:16][CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:31])C(=O)C1.O>COCCOC>[I:31][C:22]1[C:17]2[S:16][CH:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:13][CH:12]=3)[C:18]=2[C:19]([NH2:23])=[N:20][CH:21]=1
Reactant: Nc1nccc2scc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: O=C1CCC(=O)N1I
Solvent: COCCOC
Solvent: O
Product: Nc1ncc(I)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.6 %

Procedure:
A solution of Example 10A (1.69 g, 5.3 mmol) in DME (20 mL) was treated with NIS (1.26 g, 5.6 mmol), stirred at room temperature for 3 hours, poured into water, and filtered. The filter cake was purified by flash column chromatography on silica gel with 15% ethyl acetate/hexanes to provide 1.64 g (70% yield) of the desired product. MS (ESI(+)) m/e 444.8 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12]O)=[CH:2]1.[Br:14]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1CCCCC1>O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][Br:14])=[CH:2]1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCCc1c[nH]c2ccccc12
Solvent: C1COCCO1
Solvent: C1CCCCC1
Product: BrCCCc1c[nH]c2ccccc12
Reaction time: 18 h
Yield: 99.4 %

Procedure:
To a solution of 2 g (11.41 mmol) of 3-(1H-indol-3-yl)propanol in 40 ml of dioxane was added at room temperature 5.3 g (12.55 mmol) of dibromotriphenylphosphorane and the resulting solution was stirred during 18 h. An excess of cyclohexane was added and the resulting precipitate was filtered and discarded. The solvent was evaporated to dryness to give 2.7 g (99%) of product as an oil which was used in the subsequent step without further purification.