Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:15](=[O:16])[CH2:14][C:13](=[O:17])[N:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[C:11]1=[O:27].C(N(C(C)C)CC)(C)C.[N:37]([CH2:40][C:41]([O:43]CC)=[O:42])=[C:38]=[O:39]>ClCCl>[OH:17][C:13]1[N:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[C:11](=[O:27])[N:10]([CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:15](=[O:16])[C:14]=1[C:38]([NH:37][CH2:40][C:41]([OH:43])=[O:42])=[O:39]
Reactant: COc1ccccc1CN1C(=O)CC(=O)N(Cc2ccccc2OC)C1=O
Reactant: CCOC(=O)CN=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1Cn1c(O)c(C(=O)NCC(=O)O)c(=O)n(Cc2ccccc2OC)c1=O
Reaction time: 5 h

Procedure:
N-[(6-hydroxy-1,3-bis{[2-(methyloxy)phenyl]methyl}-2,4-dioxo-1,2,34-tetrahydro-5-pyrimidinyl)carbonyl]glycine. A mixture of 1,3-bis{[2-(methyloxy)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione (1.64 g, 4.45 mmoles) and diisopropylethylamine (1.56 mL, 8.94 mmoles) was stirred in dichloromethane (30 mL) and treated with ethyl isocyanatoacetate (500 uL, 4.45 mmoles). The mixture was stirred for 5 hours, washed with 1 molar hydrochloric acid (×2), evaporated, taken up in ethanol-6 molar sodium hydroxide and stirred overnight. The mixture was acidified and extracted into ethyl acetate (×2). The extracts were washed with 1 molar hydrochloric acid evaporated, dried and evaporated. The title compound was recrystallized from acetic acid (1.0 g, 48%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.51 (br. s., 1 H), 10.11 (t, J=4.93 Hz, 1 H), 7.20-7.28 (m, 2 H), 7.00 (d, J=7.83 Hz, 2 H), 6.86-6.96 (m, 4 H), 5.00 (s, 4 H), 4.10-4.18 (m, 2 H), 3.82 (s, 6 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([CH:13]2[CH2:15][CH2:14]2)O)=[CH:5][CH:4]=1.P(Br)(Br)[Br:17].[Br-].[Li+]>[Br-].[Zn+2].[Br-]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]=[CH:13][CH2:14][CH2:15][Br:17])=[CH:5][CH:4]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc(CCC(O)C2CC2)cc1
Agent: [Br-]
Agent: [Li+]
Agent: [Zn+2]
Product: COc1ccc(CCC=CCCBr)cc1

Procedure:
6-(4-Methoxyphenyl)-3-hexenyl bromide [V; Ar is 4-CH3OC6H4, R is H] was prepared from 38.2 g. of 2-(4-methoxyphenyl)ethyl cyclopropyl carbinol (Preparation B5), 42.5 g. of phosphorus tribromide, 35 g. of lithium bromide and 40 g. of zinc bromide according to the procedure given above in Preparation C1, affording 48 g. of product as an oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:30]=[CH:29][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=O)[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=3)[CH:12]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[NH2:31][NH:32][C:33]([NH2:35])=[S:34].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH:1]([O:4][C:5]1[CH:30]=[CH:29][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[N:31][NH:32][C:33]([NH2:35])=[S:34])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=3)[CH:12]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(C(=O)c2cccc(C(=O)c3ccc(OC(C)C)cc3)c2)cc1
Reactant: NNC(N)=S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(C)Oc1ccc(C(=O)c2cccc(C(=NNC(N)=S)c3ccc(OC(C)C)cc3)c2)cc1
Yield: 26.9 %

Procedure:
1,3-bis-(4-isopropoxybenzoyl)benzene 21 (0.14 g, 0.39 mmol) was dissolved in anhydrous methanol (20 mL). The solution was heated at reflux for 15 min, and thiosemicarbazide (0.043 g, 0.47 mmol) and a catalytic amount of p-toluenesulfonic acid were added. After 10 h at reflux, the solvent was removed under vacuum and the resulting solid was further purified using flash chromatography (silica gel, hexanes:ethyl acetate, 50:50) to afford the desired 1,3-bis-(4-isopropoxybenzoyl)benzene thiosemicarbazone 22 as a white solid (0.05 g, 0.105 mmol, 27% yield); HRMS (ESI) calculated for C27H29N3O3SH+ (M+H) 476.2002, found 476.2005; HPLC retention time 18.440, 18.767 min.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][C:13](=[O:15])[O:12][C:11](=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[NH4+:18].N>O1CCOCC1>[Si:1]([O:8][CH:9]1[CH2:14][C:13](=[O:15])[NH:18][C:11](=[O:12])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)[Si](C)(C)OC1CC(=O)OC(=O)C1
Agent: N
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OC1CC(=O)NC(=O)C1
Temperature: 100 °C

Procedure:
Dissolve 4.1 mmol of 4-(tert-butyldimethylsilyloxy)dihydro-2H-pyran-2,6(3H)-dione (Nagao Y et al., Chem. Lett. 1990 9: 1503) in 10 mL of dioxane in a pressure tube. Cool in an ice/water bath, add 15 mL of saturated ammonium hydroxide and treat with gaseous ammonia via bubbler for about 10 min. Cap the pressure tube and heat in a 100° C. oil bath for 17 h. Cool the mixture and concentrate in vacuo. Purify the residue by silica gel chromatography using ethyl acetate/hexanes eluant to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]([C:18](=[N:22][OH:23])[CH:19]([CH3:21])[CH3:20])=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1.C[Si]([N:28]=[C:29]=[O:30])(C)C.N1C=CC=CC=1>C1COCC1>[C:29]([O:23][N:22]=[C:18]([C:17]1[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12)[CH:19]([CH3:20])[CH3:21])(=[O:30])[NH2:28]
Reactant: COc1ccc(-c2nn3ccccc3c2C(=NO)C(C)C)cc1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(-c2nn3ccccc3c2C(=NOC(N)=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 29.8 %

Procedure:
To a solution of 775 mg (2.5 mmol) of 1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime in 5 ml of anhydrous THF was added 2 ml of trimethylsilyl isocyanate (85%) dropwise at 0° C. over 30 minutes. The mixture was stirred at room temperature over 48 hours, followed by addition of 500 μl pyridine. After stirring for another 4 hours the solvent was removed, and the residue was extracted with ethyl acetate three times. The combined organic layers were washed with 10% citric acid twice and dried over MgSO4. After evaporation of the solvent, 900 mg of crude product was obtained, which was purified on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant to yield 263 mg (29.8%) of 1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one O-carbamoyl oxime. Compound 1023.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.S(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH2:8][C:9]([Cl:15])=[O:10])[CH:7]=1
Reactant: Cc1ccc(Br)cc1CC(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1ccc(Br)cc1CC(=O)Cl
Temperature: 80 °C
Reaction time: 2 h

Procedure:
6.00 g (26.19 mmol) of (5-bromo-2-methylphenyl)acetic acid (EP 1791816 A1 and US 2006/29799 A1) were dissolved in 31.20 g (261.92 mmol) of thionyl chloride. The reaction mixture was stirred at 80° C. for two hours and then concentrated under reduced pressure. Drying under fine vacuum gave 6.29 g (97% of theory) of the title compound as a brownish oil.
Reaction SMILES: [CH3:1][C:2]1([CH2:14][OH:15])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]1=[O:13].[CH:16]1[CH:21]=[C:20]2[C:22]([O:24][S:25](=[O:27])(=[O:26])[C:19]2=[CH:18][CH:17]=1)=[O:23]>C(#N)C>[S:25]([C:19]1[CH:18]=[CH:17][CH:16]=[CH:21][C:20]=1[C:22]([O:15][CH2:14][C:2]1([CH3:1])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]1=[O:13])=[O:23])([OH:27])(=[O:26])=[O:24]
Reactant: O=C1OS(=O)(=O)c2ccccc21
Reactant: CC1(CO)CN(c2ccccc2)NC1=O
Solvent: CC#N
Product: CC1(COC(=O)c2ccccc2S(=O)(=O)O)CN(c2ccccc2)NC1=O
Reaction time: 24 h

Procedure:
To a suspension of 4-methyl-4-hydroxymethyl-1-phenyl-3-pyrazolidinone (dimezone-S) (10 g, 48.5 mmol) in dry acetonitrile (200 ml), was added 2-sulfobenzoic acid cyclic anhydride (8.9 g, 48.5 mmol) in a single portion at room temperature with stirring. The reaction mixture was heated to reflux under nitrogen until complete dissolution was observed. The reflux was continued for 24 hours and the mixture was cooled in an ice/water bath for 2 hours. A solid precipitate was obtained which was recovered by filtration and washed with ice cooled acetonitrile. After drying under vacuum, 17.9 g (95%) of 4-methyl-3-oxo-1-phenyl-pyrazolidin-4-yl)methyl 2-sulfobenzoate (Compound II) were isolated as an off-white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2Cl)[CH3:2].[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOCC>[CH2:1]([C:3]1[CH2:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: CCC1=Cc2cccc(Cl)c2C1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: CCC1=Cc2cccc(-c3ccccc3)c2C1
Yield: 80 %

Procedure:
A 5 L flask was equipped as in Example 3.178 g 2-ethyl-7-chloroindene (1 mol %), 1 L ether and 10.8 g Ni(dpp) (0.02 mol, 2 mol %) added, followed by 355 mL of 3.1M phenylmagnesium bromide in either (1.1 mol, 10% excess). After quenching and work-up by the method described in Example 3, 176 g 2-ethyl-7-phenylindene (0.8 mol) was obtained by vacuum distillation at 140° C. in 80% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[CH:23]=[N:24][C:25]([O:29]C)=[C:26]([CH3:28])[CH:27]=4)[C:19]([CH3:31])=[CH:18][CH:17]=3)=[O:14])[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Si](I)(C)(C)C>C(#N)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:31])=[C:20]([C:22]4[CH:27]=[C:26]([CH3:28])[C:25](=[O:29])[NH:24][CH:23]=4)[N:21]=3)=[O:14])[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C2(C(=O)Nc3ccc(C)c(-c4cnc(OC)c(C)c4)n3)CC2)cc1Cl
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc(C2(C(=O)Nc3ccc(C)c(-c4c[nH]c(=O)c(C)c4)n3)CC2)cc1Cl
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-(3-chloro-4-methoxyphenyl)-N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (44 mg, 0.10 mmol) in acetonitrile (2 mL) was added TMS-Iodide (57.2 μL, 0.40 mmol). The reaction was stirred at 50° C. for 20 min. The reaction solution was diluted with dichloromethane and washed with saturated NaHSO3 (2×), brine, dried over MgSO4 and concentrated. The crude product was dissolved in DMSO (1 mL) and purified by reverse phase HPLC (10-99% CH3CN in water). ESI-MS m/z calc. 423.1. found 424.3 (M+1)+. Retention time 1.52 minutes.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:28])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([C:26]#[N:27])([CH3:25])[CH3:24])[CH:18]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.O>N1C=CC=CC=1>[C:26]([C:23]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([NH:1][S:36]([C:33]3[CH:34]=[CH:35][C:30]([CH3:29])=[CH:31][CH:32]=3)(=[O:38])=[O:37])=[CH:3][CH:4]=2)[CH:10]=1)=[O:28])([CH3:24])[CH3:25])#[N:27]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)nc3)c2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)cn2)cc1
Temperature: 80 °C
Yield: 98.5 %

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (2.5 g, 6.71 mmol) in pyridine (60 mL) was added 4-methylbenzenesulfonyl chloride (1.34 g, 7.05 mmol) under ice-cooling, and the mixture was stirred with heating at 80° C. for 2 days. The reaction mixture was cooled to room temperature, water (200 mL) was added thereto and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (300 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (3.48 g, 99%) as a colorless powder. The compound was used in the next reaction without further purification.
Reaction SMILES: [H-].[Na+].Cl[CH:4](Cl)[C:5]([OH:7])=[O:6].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[OH:17])=[C:12]([OH:25])[CH:11]=1.[OH-].[Na+]>O1CCOCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]2[C:16]([CH3:24])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:17][CH:4]([C:5]([OH:7])=[O:6])[O:25][C:12]=2[CH:11]=1
Reactant: CC(O)(c1ccccc1)c1ccc(Cl)cc1O
Reactant: O=C(O)C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1(c2ccccc2)OC(C(=O)O)Oc2cc(Cl)ccc21
Temperature: 95 °C
Yield: 109.4 %

Procedure:
A mixture of 9.85 g of sodium hydride as a 50% oil suspension, 100 ml of dioxane, 0.73 g of dibenzo-18-courone-6 was stirred and a solution of 11.31 g of dichloroacetic acid in 120 ml of dioxane was added thereto at room temperature with stirring. Then, a solution of 14.550 g of 4-chloro-2-hydroxy-α-methyl-α-phenyl benzene methanol in 200 ml dioxane was added thereto dropwise and the mixture was then refluxed for 6 hours at 95° C. and then returned to room temperature. The reaction mixture was poured into ice and 10 ml of 2 N sodium hydroxide were added thereto. The aqueous phase was washed with 300 ml of ether, was acidified with 20 ml of concentrated hydrochloric acid and then was extracted 3 times with 250 ml of ether. The ether extracts were washed twice with 100 ml of water and the acid of the organic phase was extracted twice with 250 ml of a 5% aqueous solution of sodium bicarbonate. The aqueous phase was washed with 100 ml of ether and was acidified again with 50 ml of concentrated hydrochloric acid. The acid was again extracted 4 times with 250 ml of ether, and the decanted organic phase was washed 3 times with 100 ml of water, dried over magnesium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure to obtain 19.5 g of 7-chloro-4-methyl-4-phenyl-[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of two racemates of diastereoisomers).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:26]=2)=[CH:21][C:20]1=[O:38])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C@H:10]([N:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[N:26]=3)=[CH:21][C:20]2=[O:38])[CH2:9][OH:8])=[CH:12][C:13]=1[F:18]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(NC3CCOCC3)n2)cc1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1[C@H](CO)c1ccc(Cl)c(F)c1

Procedure:
A solution of (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one (6.00 g, 10.7 mmol) in THF (20 mL) was treated with tetrabutyl ammonium fluoride (12.9 mL, 12.9 mmol) at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was taken up with ethyl acetate and water. The organic layer was washed with water (1×). The combined organics were dried, filtered and concentrated. The crude product was purified via column chromatography, eluting with ethyl acetate to give (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-ylamino))pyrimidin-4-yl)pyridin-2(1H)-one as a solid (4.14 g, 87%; 96% enantiomeric excess (“e.e.”) by chiral HPLC (Chiral Tech, column OJ-H, 4.6 mm×250 mm, 5u, 30% ethanol/70% hexanes, 1 mL/minute)). 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J=5.0 Hz, 1H), 7.40 (m, 2H), 7.20 (m, 2H), 7.10 (d, J=8.2 Hz, 1H), 6.88 (d, J=5.0 Hz, 1H), 6.78 (m, 1H), 6.20 (m, 1H), 5.16 (d, J=8.0 Hz, 1H), 4.31 (m, 2H), 4.10 (m, 1H), 4.00 (m, 2H), 3.55 (m, 2H), 2.74 (br, s, 1H), 2.06 (m, 2H), 1.58 (m, 2H); m/z (APCI-pos) M+1=445.1, 447.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([Cl:9])=[CH:4][N:3]=1.Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Oc1cc(Cl)ncc1Cl
Reactant: Fc1ccc(CBr)cc1
Product: Fc1ccc(COc2cc(Cl)ncc2Cl)cc1

Procedure:
The title compound was synthesized in analogy to Example 12a, using 2,5-dichloro-4-pyridinol (CAN 847664-65-7) and 1-(bromomethyl)-4-fluoro-benzene (CAN 459-46-1) as starting materials and isolated (1.03 g, 62%) as white solid; LC-MS (UV peak area, m/z) 98.6%, 272.0040 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][C:10]=2[CH3:18])=[CH:5][C:4]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[CH2:29][N:30]1[C@@H:34]([CH3:35])[C@@H:33]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[O:32][C:31]1=[O:43].C(Cl)(=O)C(Cl)=O.[OH-].[NH4+].C([N:55](C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH2:55])=[O:17])=[CH:11][C:10]=2[CH3:18])=[CH:5][C:4]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][C:20]=1[CH2:29][N:30]1[C@@H:34]([CH3:35])[C@@H:33]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[O:32][C:31]1=[O:43]
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2ccnc(C)c2)[C@@H]1C
Reactant: CCN(C(C)C)C(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-c2ccc(C(N)=O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2ccnc(C)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid (15 mg, 0.025 mmol) in CH2Cl2 (2 mL), was added 2M oxalyl chloride in CH2Cl2 (0.038 mL, 0.076 mmol) and 2 drops of DMF. The mixture was stirred at room temperature under N2 for 30 min. The reaction mixture was concentrated in vacuo. The residue was re-dissolved in THF (2 mL), then ammonium hydroxide (0.035 mL, 0.254 mmol) and diisopropylethylamine (0.013 mL, 0.076 mmol) were added. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC reverse phase (C-18), eluting with MeCN/water. The fractions were collected and lyophilized to give 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxamide as a white powder. LCMS calc.=590.2; found=590.0 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 8.49 (t, J=4.3 Hz, 1H); 7.77 (br s, 1H); 7.72 (s, 0.5H); 7.66 (br s, 1.5H); 7.46-7.38 (m, 3H); 7.33-7.29 (m, 1H); 7.14 (dd, J=2.2, 7.7 Hz, 1H); 7.09 (dd, J=6.2, 8.5 Hz, 1H); 7.06 (s, 0.5H); 7.01 (s, 0.5H); 6.95 (d, J=4.3 Hz, 0.5H); 6.90 (d, J=4.4 Hz, 0.5H); 6.17 (br s, 1H); 5.79 (br s, 1H); 5.43 (d, J=8.1 Hz, 0.5H); 5.20 (d, J=8.0 Hz, 0.5H); 4.92 (d, J=15.9 Hz, 0.5H); 4.86 (d, J=15.8 Hz, 0.5H); 4.22 (d, J=15.8 Hz, 0.5H); 4.00 (d, J=15.8 Hz, 0.5H); 3.88 (s, 1.5H); 3.87 (s, 1.5H); 3.80-3.75 (m, 1H); 2.57 (s, 1.5H); 2.56 (s, 1.5H); 2.39 (s, 1.5H); 2.35 (s, 1.5H); 0.58 (d, J=6.5 Hz, 1.5H); 0.47 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].COCCOC.[CH:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)([CH3:33])[CH3:32]>>[CH:31]([C:34]1[CH:39]=[C:38]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:37]=[CH:36][CH:35]=1)([CH3:33])[CH3:32]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: CC(C)c1cccc(B(O)O)c1
Solvent: COCCOC
Product: CC(C)c1cccc(-c2ccccc2CCC(=O)N(NC(=O)c2ccccc2)C(C)C)c1
Yield: 30.5 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml) 2M Na2CO3 (225 μL, 0.45 mmol) was treated with 3-isopropyl-phenylboronic acid (32 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (17 mg, 31%). LC-MS m/e 429.39 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH2:10])[CH:4]=[C:5]([CH3:7])[N:6]=1.[CH3:11][O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH2:21][CH2:22][CH:23]=O>>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH2:21][CH2:22][CH:23]1[NH:10][CH2:9][CH2:8][N:3]2[C:2]([CH3:1])=[N:6][C:5]([CH3:7])=[C:4]12
Reactant: Cc1cn(CCN)c(C)n1
Reactant: COc1ccc(CCC=O)c(OC)c1
Product: COc1ccc(CCC2NCCn3c(C)nc(C)c32)c(OC)c1

Procedure:
Prepared according to the previously described general procedure (GP11) by reaction of 2-(2,4-dimethyl-imidazol-1-yl)-ethylamine with 3-(2,4-dimethoxy-phenyl)-propionaldehyde. LC-MS: tR=0.59 min.; [M+H]+=316 g/mol.
Reaction SMILES: [H-].[Na+:2].[CH3:3][C:4]([CH3:33])([CH3:32])[C:5]#[C:6][C:7]1[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([CH:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)[C:16]([CH:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]2)=[O:17])[CH:8]=1.Cl[C:35]1[CH:40]=[C:39]([C:41]([N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[O:42])[CH:38]=[CH:37][N:36]=1.[OH-].[Na+]>C1COCC1.C(OCC)C>[CH3:33][C:4]([CH3:32])([CH3:3])[C:5]#[C:6][C:7]1[S:11][C:10]([C:12]([O-:14])=[O:13])=[C:9]([N:15]([CH:25]2[CH2:30][CH2:29][CH:28]([O:31][C:37]3[CH:38]=[C:39]([C:41]([N:43]4[CH2:47][CH2:46][CH2:45][CH2:44]4)=[O:42])[CH:40]=[CH:35][N:36]=3)[CH2:27][CH2:26]2)[C:16]([CH:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]2)=[O:17])[CH:8]=1.[Na+:2]
Reactant: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C2CCC(O)CC2)CC1
Reactant: O=C(c1ccnc(Cl)c1)N1CCCC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)[O-])C2CCC(Oc3cc(C(=O)N4CCCC4)ccn3)CC2)CC1
Temperature: 25 °C
Yield: 16 %

Procedure:
NaH (50 mg of a 60% oil dispersion, 1.14 mmol) was added in portions to a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (128 mg, 0.287 mmol) and (2-chloro-pyridin-4-yl)-pyrrolidin-1-yl-methanone from the previous step (300 mg, 1.42 mmol) in THF (5.0 mL) at 0° C. After 5 min the reaction was warmed to room temperature and then heated at 85° C. overnight. The reaction was cooled, aqueous NaOH (0.5 mL of a 1.0 N solution) was added and the reaction evaporated to dryness to give a solid residue. The solid was suspended in ethyl ether and sonicated for several minutes. The ether layer was removed to give an orange solid that was dried under vacuum and purified by column chromatography on reverse phase C18 silica gel (100% water to 20% acetonitrile/water). Fractions containing product were pooled and lyophilized to give the desired product as a colorless solid (30 mg, 16%). MS (m/z): 618.0 [M−H]−; HPLC retention time: 6.43 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>>[CH:10]1([NH:13][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: NC1CC1
Reactant: O=Cc1ccc(F)cc1
Product: Fc1ccc(CNC2CC2)cc1

Procedure:
Synthesized according to typical procedure J from 4fluorobenzaldehyde and cyclopropylamine.