Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:10]=[C:11]([C:16](=[O:18])[CH:17]=2)[C:12]([O:14]C)=[O:13])=[CH:4][CH:3]=1.C(O)(=O)C>CO.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH:10]=[C:11]([C:16](=[O:18])[CH:17]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cn(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1cn(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2)cc1=O
Yield: 83.3 %

Procedure:
In a mixed solvent of 5 ml of methanol and 5 ml of 1N aqueous sodium hydroxide solution was dissolved 0.5 g of methyl 6-(4-chlorophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinate, and they were reacted at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was adjusted to a pH of 5.5 with acetic acid, and the precipitated crystals were collected by filtration, washed with 10 ml of water and dried to obtain 0.4 g of 6-(4-chlorophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 199°-204° C.
Reaction SMILES: [CH3:1][S:2][CH:3]([S:8][CH3:9])[CH2:4][CH2:5][S:6][CH3:7].C([Li])CCC.[C:15](=[O:17])=[O:16].[OH-].[K+]>CCCCCC.C1COCC1>[CH3:1][S:2][C:3]([S:8][CH3:9])([CH2:4][CH2:5][S:6][CH3:7])[C:15]([OH:17])=[O:16]
Reactant: O=C=O
Reactant: CSCCC(SC)SC
Agent: [K+]
Agent: [Li]CCCC
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSCCC(SC)(SC)C(=O)O
Reaction time: 2 h

Procedure:
In a three-neck flask under a protective gas atmosphere, 1,1,3-tris(methylthio)propane (2) (3.65 g, 20 mmol) was dissolved in 50 ml of abs. THF. Subsequently, at −20° C., a butyllithium solution in n-hexane (14 ml, 1.6 M) was slowly added dropwise with stirring. In the course of this, the solution turned bright yellow. After stirring had been continued at this temperature for 2 h, gaseous dry CO2 was passed through via a frit at −70° C. over a period of 30 minutes. The reaction solution was thawed slowly until a temperature of 20° C. was attained, at which a 10% aqueous KOH solution (80 ml) was added. After phase separation, the organic phase was washed with 10% aqueous KOH solution (2×50 ml). The combined KOH phases were washed with diethyl ether (3×30 ml) and then adjusted cautiously to pH 1 with conc. HCl while cooling. The product was extracted with diethyl ether (3×50 ml). The combined ether phases were subsequently dried over Na2SO4 and, after filtration, concentrated on a rotary evaporator. 2,2,4-tris(methylthio)butanoic acid (4) was obtained as a yellowish oil (4.1 g, yield=90%), which crystallized slowly when left to stand. The NMR characterization gave the same data as in Example 3.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:14]1([C:20]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]3[CH:24]([CH2:25][NH:26][CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:30]1([C:20]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:28]3[CH:24]([CH2:25][N:26]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[S:2][CH3:1])[CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CSc1ccccc1CC(=O)O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.25 h
Yield: 59.5 %

Procedure:
N,N'-Carbonyldiimidazole (0.77 g) is added to a solution of 2-methylthiophenylacetic acid (0.87 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 15 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.56 g) and triethylamine (1.34 cc) in dichloromethane (30 cc) is then added. The reaction mixture is stirred at 20° C. for 3.5 hours, then washed with water (3×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.04-0.063 mm, diameter 5 cm, height 50 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting 50 cc fractions. Fractions 1 to 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is recrystallized from acetonitrile (5 cc) and the crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2-methylthiophenyl)acetyl]-4-perhydroisoindolone (1.29 g) is obtained in the form of pale yellow crystals melting at 188° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([Cl:13])[N:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][N:21]([CH3:31])[C:22]([C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1)=[O:23]>C(#N)C>[CH3:1][S:2][C:3]1[N:4]=[C:5]([Cl:13])[C:6]([N+:10]([O-:12])=[O:11])=[C:7]([O:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:22]([N:21]([CH3:31])[CH3:20])=[O:23])[CH:25]=2)[N:8]=1
Reactant: CN(C)C(=O)c1cccc(O)c1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CSc1nc(Cl)c([N+](=O)[O-])c(Oc2cccc(C(=O)N(C)C)c2)n1
Yield: 83 %

Procedure:
To 2-methylthio-4,6-dichloro-5-nitropyrimidine, a compound of formula (A), (5.0 g, 20.8 mmol) in 200 mL acetonitrile at 0° C. was added cesium carbonate (8.82 g, 27.1 mmol) followed by the addition of 3-(dimethylaminocarbonyl)phenol (3.44 g, 20.8 mmol), a compound of formula (B), and the reaction mixture was stirred for 16 hours. The volatiles were evaporated and the residue chromatographed on silica gel (CH2 Cl2 /ethyl acetate, 7:12) to afford 6.3 g (83% yield) of 2-methylthio-4-chloro-5-nitro-6-(3-(dimethylaminocarbonyl)phenoxy)pyrimidine, a compound of formula (C).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br[CH2:13][CH2:14][CH2:15][CH2:16][Cl:17].[H-].[Na+]>CN(C=O)C>[Cl:17][CH2:16][CH2:15][CH2:14][CH2:13][C:2]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:3][CH2:4][CH2:5][CH2:6][S:1]1
Reactant: CCOC(=O)C1SCCCS1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CCCCCl)SCCCS1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
Step AS (1): To a solution of ethyl 1,3-dithiane-2-carboxylate (500 mg, 2.60 mmol) and 1-bromo-4-chlorobutane (1337 mg, 7.80 mmol) in DMF (10 mL) was added 60% NaH (dispersion in mineral oil, 125 mg, 3.12 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (3×100 mL) and concentrated in vacuo. The residue was purified using silica gel column chromatography (10% EtOAc/hexanes) to give ethyl 2-(4-chlorobutyl)-1,3-dithiane-2-carboxylate (550 mg, 75% yield). LC-MS (M+H)+ 283.0.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[C:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[C:18]2[CH2:19][C:20]([CH3:27])([CH3:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH2:23]2)[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(C#N)cc2)cc1
Agent: BrB(Br)Br
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(C#N)cc2)CC(C)(C)C1
Yield: 52 %

Procedure:
The demethylation protocol described for 208 was used. 4-[[4-(methyloxy)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]benzonitrile (209) (0.700 g, 1.95 mmol) was treated with BBr3 to afford 0.350 g (52%) of compound 210 as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.58 (d, J=8.1 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 6.79 (d, J=8.7 Hz, 2H), 2.01 (s, 2H), 1.94 (s, 2H), 1.33 (s, 2H), 0.96 (s, 6H), 0.95 (s, 6H). LCMS (ESI): m/z 344 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[Br:9]Br.O>C(Cl)(Cl)Cl>[Br:9][C:5]1[S:4][C:3]([CH:7]=[O:8])=[C:2]([CH3:1])[CH:6]=1
Reactant: Cc1ccsc1C=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(Br)sc1C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 3-methylthiophene-2-carbaldehyde (5.7 g) in chloroform (40 mL) was added dropwise bromine (2.5 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was and stirred at 0° C. for 30 min, and then at room temperature for 1 hr, and then under reflux overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate/hexane to give the title compound (8.1 g, 88%) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][C:14]([NH:16][CH3:17])=O)=[CH:9][CH:10]=2)[NH:5][N:4]=1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:14][NH:16][CH3:17])=[CH:9][CH:10]=2)[NH:5][N:4]=1
Reactant: CNC(=O)C=C(c1ccccc1)c1ccc2c(OC)n[nH]c2c1
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNCCC(c1ccccc1)c1ccc2c(OC)n[nH]c2c1

Procedure:
[3-(3-Methoxy-1H-indazol-6-yl)-3-phenyl-propyl]-methyl-amine CCXL was prepared from 3-(3-methoxy-1H-indazol-6-yl)-N-methyl-3-phenyl-acrylamide using the procedure described for preparation of [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (Example 4). MS (M+H)=297.
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1)([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36](Cl)(Cl)([Cl:38])[Cl:37]>>[Cl:37][C:36]([Cl:38])=[C:11]([C:8]1[CH:7]=[N:6][C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[N:10][CH:9]=1)[C:12]([F:15])([F:14])[F:13]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ncc(C(=O)C(F)(F)F)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)c1ncc(C(=C(Cl)Cl)C(F)(F)F)cn1

Procedure:
2-(1,1-dimethylethyl-5-trifluoroacetylpyrimidine (0.9 g) was dissolved in dry carbon tetrachloride (15 cm3) containing triphenylphosphine (2.5 g). The reaction mixture was stirred under a nitrogen atmosphere and heated at the reflux temperature for 30 hours to give a deep red-brown solution. The reaction mixture was fractioned by filtering the cooled solution through a short column of silica gel and eluting with a mixture of hexane/dichloromethane (3:1 by volume). On evaporation of the solvents the product was obtained as a colourless solid (0.9 g)
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH:23]1[CH:27]=[C:26]([CH2:28][C:29]([NH:31][NH2:32])=[O:30])[N:25]=[CH:24]1.Cl>C(O)C.O1CCOCC1>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[CH:19]=[N:32]/[NH:31][C:29](=[O:30])[CH2:28][C:26]2[N:25]=[CH:24][NH:23][CH:27]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: NNC(=O)Cc1c[nH]cn1
Reactant: O=Cc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(Cc1c[nH]cn1)N/N=C/c1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-formylphenyl 4-(trifluoromethyl)benzenesulfonate (6.5 g, 19.7 mmol) in ethanol (100 ml) is added to a solution of 4-imidazoleacetic acid hydrazide (18 mmol) in ethanol (200 mL). A catalytic amount of HCl in dioxane (3 mL) is added and the mixture is stirred at room temperature overnight. The precipitate that forms is removed by filtration. The filtrate is concentrated and chromatographed on silica eluting with 5% (2M ammonia in methanol)/CH2Cl2 to give 2-((E)-{2-[2-(1H-imidazol-4-yl)acetyl]hydrazono}methyl)phenyl 4-(trifluoromethyl)benzenesulfonate as a white solid. The yield is 3.1 g, 38%. 1H NMR (400 MHz, DMSO) d 11.94 (s, 1H), 11.48 (2s, 1H), 8.02 (m, 6H), 7.21 (m, 5H), 3.64 (2 s, 2H). ESI+ for C19H15F3N4O4S, m/z 453, (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[C@:19]([OH:27])([C:20]([CH2:22][O:23]C(C)=O)=[O:21])[C@:18]2([CH3:28])[C@H:4]([C@H:5]3[C@:15]([F:30])([C@@H:16]([OH:29])[CH2:17]2)[C@:14]2([CH3:31])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[C@@H:7]([F:32])[CH2:6]3)[CH2:3]1.[OH-].[K+]>>[CH3:1][C@H:2]1[C@:19]([OH:27])([C:20]([CH2:22][OH:23])=[O:21])[C@:18]2([CH3:28])[C@H:4]([C@H:5]3[C@:15]([F:30])([C@@H:16]([OH:29])[CH2:17]2)[C@:14]2([CH3:31])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[C@@H:7]([F:32])[CH2:6]3)[CH2:3]1
Reactant: CC(=O)OCC(=O)[C@@]1(O)[C@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Agent: [K+]
Agent: [OH-]
Product: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO

Procedure:
A process according to claim 1, characterized by the fact that the flumethasone 21-acetate is reacted with methanolic potassium hydroxide in the absence of an oxidization agent to yield flumethasone.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:13]([CH2:24][O:25][CH3:26])[S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[Li+].[C:29]1(OB(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:2]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]=[C:10]([N:13]([CH2:24][O:25][CH3:26])[S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[S:11][CH:12]=2)[CH:3]=1
Reactant: COCN(c1nc(-c2cccc(Br)c2)cs1)S(=O)(=O)c1ccc(C)cc1
Reactant: OB(O)Oc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: COCN(c1nc(-c2cccc(-c3ccccc3)c2)cs1)S(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h

Procedure:
A solution of 0.5 g of N-[4-(3-bromo-phenyl)-thiazol-2-yl]-N-methoxymethyl-4-methyl-benzenesulfonamide in 8 ml of toluene was treated in succession with 0.1 g of anhydrous lithium chloride, 60 mg of tetrakis(triphenylphosphine)palladium, 0.23 g of phenylboric acid and 2 ml of 2N potassium carbonate solution. The mixture was boiled overnight, cooled and, after the addition of water, extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulphate and concentrated. The residue was chromatographed on 80 g of Kieselgel 60 with ethyl acetate/hexane (1:4) as the eluent. The product-containing fractions were concentrated and yielded 0.29 g of colorless, amorphous N-(4-biphenyl-3-yl-thiazol-2-yl)-N-methoxymethyl-4-methyl-benzenesulfonamide, which was processed without further purification.
Reaction SMILES: C1(CO[C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([CH2:25][OH:26])[CH2:21][CH2:22][CH2:23][CH3:24])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])C=CC=CC=1.C(N(CC)CC)C.[N:34]1(C(Cl)=O)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CO.C(Cl)Cl.[C].[Pd]>[N:34]1([C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([CH2:25][OH:26])[CH2:21][CH2:22][CH2:23][CH3:24])=[O:18])[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:10])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: CCCC[C@@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: O=C(Cl)N1CCOCC1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC[C@@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
70 mg of 10% palladium-carbon was added to a solution of 700 mg (2 mmol) of N—[N-[(phenylmethoxy)carbonyl]-L-leucyl]-L-norleucinol obtained in Reference Example 185 in 10 ml of methanol, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure. 20 ml of methylene chloride and 404 mg (4 mmol) of triethylamine were added to the residue. A solution of 299 mg (2 mmol) of 4-morpholinecarbonyl chloride in 3 ml of methylene chloride was added to the mixture solution under ice-cooling. The reaction solution was returned to room temperature and stirred overnight. After the reaction solution was washed with water and then saturated brine, it was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. Ether was added to the residue to wash it to obtain 488 mg (71%) of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:27][CH3:28])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[C@@H:20]2[O:24][C:23](=[O:25])[NH:22][C@H:21]2[CH3:26])[CH:9]=1)([CH3:3])[CH3:2].[H-].[Na+].[F:31][C:32]([F:46])([F:45])[C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:36]Br>CN(C=O)C.CCOC(C)=O.O>[F:31][C:32]([F:45])([F:46])[C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=1)[CH2:36][N:22]1[C@@H:21]([CH3:26])[C@H:20]([C:11]2[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=2[C:8]2[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=2[O:27][CH3:28])[O:24][C:23]1=[O:25]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1[C@@H]1OC(=O)N[C@H]1C
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1[C@@H]1OC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 30 mg of trans-5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one in 1 mL of DMF was added 8 mg of sodium hydride. The mixture was stirred 10 min at room temperature, and then 32 mg of 3,5-bis(trifluoromethyl)benzyl bromide was added. The mixture was stirred overnight at room temperature, then diluted with 10 mL of EtOAc and 10 mL of water. The phases were separated and the aqueous phase was extracted with 5 mL of EtOAC. The combined organics were washed with 5 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of 4% EtOAc in hexanes, followed by a linear gradient of EtOAc in hexanes from 4 to 100% over 10 CV to provide the title compound. Mass spectrum (ESI) 620.2 (M+1). 1H NMR signals are doubled because of atropoisomerism. 1H NMR (500 MHz, CDCl3): δ 7.53-7.80 (m, 5H), 7.33 (d, J=8 Hz, 1H), 7.21-7.29 (m, 1H), 7.00, 6.76 (d, J=2.5 Hz, 1H), 6.91, 6.86 (d, J=8.5 Hz, 0.4H), 5.15, 5.10 (d, J=4.5 Hz, 1H), 4.80, 4.74 (d, J=16 Hz, 1H), 4.25, 4.21 (d, 16 Hz, 1H), 3.76 (s, 2H), 3.49 (s, 1H), 3.43 (m, 0.4H), 3.18 (m, 0.5H), 2.77-2.98 (m, 1H), 1.24 (m, 3H), 1.16 (m, 3H), 0.78, 0.61 (d, J=6.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9](O)[CH:10]([N+:12]([O-:14])=[O:13])[CH3:11].CCN(S(F)(F)[F:22])CC>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:22])[CH:10]([N+:12]([O-:14])=[O:13])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C(O)c1ccc(Cl)cc1Cl)[N+](=O)[O-]
Solvent: ClCCl
Product: CC(C(F)c1ccc(Cl)cc1Cl)[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a stirred mixture of erythro 1-(2,4-dichlorophenyl)-2-nitro-propan-1-ol (2.5 g, 10.0 mmol) in dry dichloromethane (20 ml) under nitrogen atmosphere DAST (1.3 ml, 10.0 mmol) in dichloromethane (5 ml) was added dropwise under cooling to 5° C. The solution was stirred at ambient temperature for 1 hour. Dichloromethane (80 ml) was added and the organic layer was washed sequentially with saturated NaHCO3 (50 ml), 1M HCl (30 ml) and sole (30 ml). The organic layer was dried over NaSO4, filtered, and concentrated. 2.5 g of 2,4-dichloro-1-(1-fluoro-2-nitro-propyl)-benzene was obtained in the form of a brown oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=2)[C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3n2-c2cccc(C(F)(F)F)c2)CC1
Yield: 65 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone (example 21), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (65%).
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][NH:5][CH2:4]1)[CH3:2].[CH:15]([O:18][C:19]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:20]=1[C:21](O)=[O:22])([CH3:17])[CH3:16]>>[CH2:1]([CH:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][N:5]([C:21]([C:20]2[CH:24]=[C:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=[CH:27][C:19]=2[O:18][CH:15]([CH3:17])[CH3:16])=[O:22])[CH2:4]1)[CH3:2]
Reactant: CCC1CNCc2cc(OC)ccc21
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CCC1CN(C(=O)c2cc(S(C)(=O)=O)ccc2OC(C)C)Cc2cc(OC)ccc21

Procedure:
Prepared in analogy to example 1.1 from 4-ethyl-7-methoxy-1,2,3,4-tetrahydro-isoquinoline and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:8]1[CH:17]=[CH:16][C:15]2[C:14]([C:18]([NH:20][CH2:21][C@:22]3([OH:29])[CH2:27][CH2:26][CH2:25][C@H:24]([CH3:28])[CH2:23]3)=[O:19])=[C:13]([Cl:30])[CH:12]=[CH:11][C:10]=2[N:9]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:30][C:13]1[CH:12]=[CH:11][C:10]2[N:9]=[C:8]([N:4]3[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]3)[CH:17]=[CH:16][C:15]=2[C:14]=1[C:18]([NH:20][CH2:21][C@:22]1([OH:29])[CH2:27][CH2:26][CH2:25][C@H:24]([CH3:28])[CH2:23]1)=[O:19]
Reactant: O[C@H]1CCNC1
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@H](O)C4)ccc23)C1
Temperature: 120 °C

Procedure:
(S)-3-hydroxypyrrolidine (80 mg) was added to a suspension of the product of step d) (0.2 g) and diisopropylethylamine (300 μl) in acetonitrile (3 ml). The reaction mixture was heated in a microwave (100 W) for 30 minutes at 120° C. before being concentrated in vacuo. Water (15 ml) was added and the suspension sonicated for 10 minutes. The solid was filtered and dried in vacuo overnight to afford the title compound as a cream solid (180 mg). m.p. 222° C. (acetonitrile).