Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)C=1.[CH3:12][O:13][CH:14]([O:23][CH3:24])[C:15]1[CH:20]=[CH:19][C:18](SC)=[CH:17][CH:16]=1.C(=O)([O-])O.[Na+].[S:30]([O-:33])([O-])=[O:31].[Na+].[Na+]>ClCCl>[CH3:24][O:23][CH:14]([O:13][CH3:12])[C:15]1[CH:16]=[CH:17][C:18]([S:30]([CH3:2])(=[O:33])=[O:31])=[CH:19][CH:20]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])[O-]
Reactant: COC(OC)c1ccc(SC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(OC)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
m-Chloroperbenzoic acid (115.0 g, 0.567 mol) was added to a suspension of the 4-(methylthio)benzaldehyde dimethyl acetal (50.0 g, 0.252 mol) prepared in Preparative Example 1 and sodium hydrogencarbonate (73.1 g) in dichloromethane (1.00 l) at 0° to 10° C. in portions (over a period of about one hour and 20 minutes). The obtained suspension was stirred at room temperature for 18 hours and poured into an aqueous solution (1 l) of sodium sulfite (100.0 g) under cooling to decompose excess peracid. The resulting solution was extracted with dichloromethane and the organic layer was washed with a saturated aqueous solution of common salt, dried over magnesium sulfate and concentrated in a vacuum. The obtained solid residue was recrystallized from hexane/isopropyl ether/ethyl acetate to give the title compound as a colorless crystal (53.9 g, yield: 93%).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:10]([OH:16])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][C:28]=1[CH2:29]Br.O>C1COCC1>[CH2:1]([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:10]([O:16][CH2:29][C:28]1[CH:31]=[C:32]([O:35][C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:34][C:27]=1[O:26][CH3:25])[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(OC(F)(F)F)cc1CBr
Reactant: O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(OC(F)(F)F)cc1CO[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Reaction time: 0.17 h

Procedure:
(1R*,2R*,5R*)-8-Benzyl-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 9; 348 mg, 1.19 mmol) was dissolved in THF then sodium hydride (71 mg, 60% in oil, 1.79 mmol) added and the reaction mixture stirred for 10 minutes. 2-methoxy-5-trifluoromethoxybenzyl bromide was added and the reaction mixture stirred at 50° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (×3), dried (MgSO4) and concentrated in vacuo to give a yellow oil. This was purified by flash column chromatography [5%-15% ethyl acetate in iso-hexane] to give the title compound. (205 mg, 35%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:22]1([CH2:25]Br)[CH2:24][CH2:23]1>CN(C=O)C>[CH:22]1([CH2:25][O:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:14][CH:13]=2)[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(OCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.1 %

Procedure:
To a stirred solution of 4-[N-(tert-butoxycarbonyl)amino]phenol (5.0 g, 23.89 mmol) in DMF (140 mL) was added cesium carbonate (19.5 g, 59.73 mmol). The reaction mixture was stirred at r.t. for 20 minutes, and then cyclopropylmethyl bromide (2.3 mL, 23.89 mmol) was added. The reaction mixture was stirred at r.t. for 2 days, cooled to r.t., filtered and partitioned between Et2O (2×25 mL) and water (100 mL). The layers were separated, and the aqueous fraction was further extracted with Et2O (3×50 mL). The combined organic fractions were washed with water (3×150 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (5.1 g, 81%) as a light pink solid that was used without further purification. δH (DMSO-d6) 8.82 (1H, br. s), 7.09-7.06 (2H, m), 6.59-6.54 (2H, m), 3.50 (2H, d, J 6.9 Hz), 1.22 (9H, s), 0.97-0.90 (1H, m), 0.34-0.28 (2H, m), 0.08-0.03 (2H, m). LCMS (ES+) 207.0 ((M−tBu)+H)+, RT 3.20 minutes (Method 3).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][CH:18]([CH3:21])[C:19]#[CH:20]>CN(C=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:17][CH:18]([CH3:21])[C:19]#[C:20][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1
Reactant: OCc1ccc(I)cc1
Reactant: C#CC(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C#Cc1ccc(CO)cc1
Reaction time: 0.17 h

Procedure:
4-Iodobenzyl alcohol (1.00 g) was dissolved in DMF (17 mL), added with copper (1) iodide (97.7 mg), triethylamine (0.89 mL), and 3-methyl-1-butyne (1.27 mL), and stirred for 10 minutes in argon atmosphere. Subsequently, it was added with bis(triphenylphosphine)palladium (II) chloride (300 mg) and stirred for 4.3 hours at room temperature in argon atmosphere. After filtration through Celite, it was washed with ethyl acetate and the solvent was evaporated under reduced pressure. The residues were purified by silica gel column chromatography (6 to 40% ethyl acetate/hexane) to obtain the title compound as a yellow oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][NH2:11].Cl>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[C:18]([O:17][C:15]([NH:8][C@@H:9]([CH2:10][NH:11][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])[C:12]([OH:14])=[O:13])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)CCCCl)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
4-Chlorobutanoyl chloride (12.1 g, 86 mmol) was added to a solution of Boc-L-Dap (16.0 g, 78 mmol) in dioxane (160 mL) and 10% aqueous Na2CO3 (180 mL) at 0° C. dropwise. The reaction mixture was stirred at 0° C. for 1 h and then allowed to warm to ambient temperature and stirred overnight. The mixture was acidified with 1N aqueous hydrochloric acid to pH=3 and extracted with EtOAc (300 mL×3). The combined organic phases were washed with 1N aqueous hydrochloric acid (300 mL×3) and brine (300 mL×1), dried over anhydrous sodium sulfate, and concentrated to afford (S)-2-(tert-butoxycarbonylamino)-3-(4-chlorobutanamido)propanoic acid (15.5 g, 64% yield), which was used directly without further purification.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2([OH:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]2=[O:25])=[CH:11][C:10]=1[CH3:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:28][C:29]([F:41])([F:40])[O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][C:9]1[C:10]([CH3:27])=[CH:11][C:12]([C:16]2([OH:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][C:29]([F:28])([F:40])[F:41])[CH:32]=3)[C:17]2=[O:25])=[CH:13][C:14]=1[CH3:15])([CH3:6])([CH3:5])[CH3:7]
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: Cc1cc(C2(O)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C2(O)C(=O)N(c3cccc(OC(F)(F)F)c3)c3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Temperature: 32 °C
Yield: 80.2 %

Procedure:
Using a method similar to Preparation 38, with 3-[4-(tert-Butyl-dimethylsilanyloxy)-3,5-dimethyl-phenyl]-3-hydroxy-1,3-dihydro-indol-2-one (15.34 g, 40 mmol), 3-(trifluoromethoxy)phenylboronic acid (16.47 g, 80 mmol), copper (II) acetate (7.27 g, 40 mmol), pyridine (6.5 ml, 80 mmol) and powdered 4A sieves (25 g) in dichloromethane (130 mL) and heat at 32° C. for 1 day stirring mechanically. Add more 3-(trifluoromethoxy)phenylboronic acid (8.24 g, 40 mmol), copper (II) acetate (3.64 g, 20 mmol), pyridine (6.5 ml, 80 mmol) and powdered 4A sieves (25 g) and continue heating for 1 day. Dilute with ethyl acetate (150 mL) and filter slowly through a pads of Celite and silica gel. After the filtration is complete stir the pads in additional ethyl acetate and refilter. Evaporate the organics in vacuo and apply the resulting residue to a silica pad with dichloromethane/acetone. Elute with 2% ethyl acetate/dichloromethane and concentrate in vacuo to obtain 17.45 g of a yellow solid. Titurate the solid in diethyl ether, filter, and dry to obtain 9.47 g (44%) of a white solid. MS (ES): m/z=526 (M+1−H2O); 1H NMR (DMSO-d6): δ7.71 (t, 1H), 7.58-7.52 (m, 3H), 7.32-7.25 (m, 2H), 7.13 (t, 1H), 7.01 (s, 2H), 6.87 (d, 1H), 6.76 (s, 1H), 2.14 (s, 6H), 0.99 (s, 9H), 0.17 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[CH3:11][C:12]([CH:15]=O)([CH3:14])[CH3:13].[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:17]1([CH:15]([NH:7][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[C:12]([CH3:13])([CH3:14])[CH3:11])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: NC(=O)c1cccc(F)c1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)C(NC(=O)c1cccc(F)c1)n1nnc2ccccc21

Procedure:
A suspension of 3-fluorobenzamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 1C to provide the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH2:25])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11].[F:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1.N1C=CC=CC=1CCNC(C1C(C2C=CC=CC=2C(S(C2C=CC=C(F)C=2)(=O)=O)N)=CC=CC=1)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH:25][S:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([F:26])[CH:28]=2)(=[O:35])=[O:34])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccn1
Agent: NC(c1ccccc1-c1ccccc1C(=O)NCCc1ccccn1)S(=O)(=O)c1cccc(F)c1
Product: O=C(NCCc1ccccn1)c1ccccc1-c1ccccc1CNS(=O)(=O)c1cccc(F)c1

Procedure:
From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)-ethylamide (precursor 5d) and 3-fluorophenylsulfonyl chloride, according to the general working procedure 102 mg of 2′-(3-fluorophenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide were obtained; m.p. 123° C. MS (ES+): m/e=490 (M+1).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:21]([OH:23])=O)[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:57]1[C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH:60]=[CH:59][C:58]=1[NH:67][C:68](=[O:86])[CH2:69][N:70](C(OC(C)(C)C)=O)[CH2:71][CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:57]1[C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH:60]=[CH:59][C:58]=1[NH:67][C:68](=[O:86])[CH2:69][N:70]([C:21](=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:71][CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccccc1)CC(=O)Nc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CCc1ccccc1)CC(=O)Nc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution (0° C.) of Nα,Nδ-bis-Boc-D-ornithine (130 mg, 0.39 mmol), diisopropylethylamine (1.6 mmol) and methylene chloride (10 mL) was treated with PyBroP (275 mg, 0.59 mmol) and kept at 0° C. for 30 min. In another reaction, a solution of Boc-N-(phenethyl)glycine 2-naphthylamide (240 mg, 0.59 mmol) (made by coupling of N-Boc-N-(phenethyl)glycine and 2-naphthylamine) and trifluoroacetic acid (3 mL) was stored at 24° C. for 1 hr and then concentrated in vacuo. The residue was coevaporated twice with methylene chloride and the resultant solid resuspended in methylene chloride (10 mL) and treated with diisopropylethylamine (1.2 mmol). The two solutions were mixed and stirred at 25° C. for 1 hr at which time the mixture was washed with 1M hydrochloric acid (2×25 mL), sat. sodium bicarbonate (25 mL), and brine (25 mL). The organic layer was dried over anhydrous sodium sulfate and adsorbed onto silica gel (500 mg) and applied to a column prepacked with silica gel. The column was eluted with ethyl acetate:hexane (50:50, v:v) to afford the titled compound.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH:17]([C:20]1[CH:21]=[CH:22][C:23]([S:26](Cl)(=[O:28])=[O:27])=[N:24][CH:25]=1)([CH3:19])[CH3:18].Cl>N1C=CC=CC=1>[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH:16][S:26]([C:23]3[CH:22]=[CH:21][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:25][N:24]=3)(=[O:27])=[O:28])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)nc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)c1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrochloride with 0.46 g of 5-isopropyl-pyridine-2-sulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 25 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 30 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 40 ml of ethanol and 20 ml of ethyl acetate yielded 0.31 g of 5-isopropyl-pyridine-2-sulfonic acid [4-(3-nitro-phenyl)-thiazol-2-yl]-amide as yellowish crystals.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[Br:7][C:8]1[C:9]([CH3:17])=[N:10][N:11]([CH2:14]SC)[C:12]=1[CH3:13].[CH3:18]O.O>>[Br:7][C:8]1[C:9]([CH3:17])=[N:10][N:11]([CH2:14][S:3]([CH3:18])(=[O:5])=[O:2])[C:12]=1[CH3:13]
Reactant: O=S([O-])OO
Reactant: CO
Reactant: CSCn1nc(C)c(Br)c1C
Agent: [K+]
Solvent: O
Product: Cc1nn(CS(C)(=O)=O)c(C)c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
Oxone (9.25 g, 14 mmol) was added portion-wise to a solution of 4-bromo-3,5-dimethyl-1-(methylthiomethyl)-1H-pyrazole of preparation 91 (2.56 g, 10.9 mmol) in methanol/water at 0° C. The reaction solution was stirred at 0° C. for 30 min, then slowly warmed to room temperature overnight. The reaction was thick with white precipitate, which was concentrated to roughly 20 mL, poured into water and filtered the white solid. The solid was washed with water and air dried to give the title compound as a white solid (1.2 g, 41% yield)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18]C)=[CH:17][C:12]=3[S:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br>C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:12]=3[S:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc2c(CCc3ccccc3)csc2c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Product: Oc1ccc2c(CCc3ccccc3)csc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred, -10° C. solution of the product from Step D (5.483 grams; dry methylene chloride; 60 mL) was treated with 1M boron tribromide solution (methylene chloride; 20.81 mL). After 2 hours, the reaction was momentarily warmed to ambient temperature. It was partitioned between isopropyl acetate and aqueous sodium bicarbonate, washed once with water and dried over magnesium sulfate. Filtration and evaporation produced a semi-solid. Chromatography over silica gel (2.5:1 hex/ethyl acetate) resulted in the isolation of the title compound, a pale yellow solid.
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH2:27][CH2:28][NH2:29]>C(Cl)Cl>[C:1]1([O:7][C:8](=[O:9])[NH:29][CH2:28][CH2:27][C:21]2[C:20]3[C:24](=[CH:25][CH:26]=[C:18]([F:17])[CH:19]=3)[NH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1c[nH]c2ccc(F)cc12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(F)cc12)Oc1ccccc1
Reaction time: 24 h

Procedure:
Chloroformic acid phenyl ester (310 μl, 2.45 mmole) and pyridine (415 μl, 5.13 mmole) were added to a solution of 2-(5-fluoro-1H-indol-3-yl)-ethylamine (0.5 g, 2.33 mmole) in abs. DCM (10 ml). Stirring was then performed for 24 h at RT. Working up was performed by extracting the batch with water (2×20 ml), with 1M HCl (2×20 ml) and with 1M NaOH (2×20 ml). The organic phase was dried with Na2SO4 and evaporated. [2-(5-Fluoro-1H-indol-3-yl)-ethyl]-carbamic acid phenyl ester was obtained as a colorless solid in a yield of 0.69 g (100%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: OCc1ccccc1
Reactant: O=C(O)CCCCCBr
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CCCCCBr)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
6-Bromohexanoic acid (10.0 g, 0.051 mol), benzyl alcohol (6.1 g, 0.056 mol) and DMAP (dimethylaminopyridine, 0.63 g, 0.005 mol) were dissolved in 100 mL CH2Cl2, then cooled to 0° C. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 10.8 g, 0.056 mol) was added and the reaction stirred overnight at room temperature. The organics were diluted with CH2Cl2 and washed with water, aq. NaHCO3, and brine. The organic phase was dried (Na2SO4), filtered, and solvent was removed. Intermediate 12 was obtained as a colorless oil (11.6 g, 0.04 mol). MS(MH+): m/z=286.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:25])[CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][C:10]=1[O:26][CH3:27])C1C=CC=CC=1.N.CCCCCC>Br.C(O)(=O)C.CCOCC>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:25])[CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:11][C:10]=1[O:26][CH3:27]
Reactant: COc1cc(C(=O)CCCc2ccccc2)ccc1OCc1ccccc1
Agent: Br
Agent: N
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COc1cc(C(=O)CCCc2ccccc2)ccc1O
Temperature: 0 °C

Procedure:
A solution of 7.0 g of 4'-(benzyloxy)-3'-methoxy-4-phenylbutyrophenone in 40 ml of 33 percent hydrobromic acid in glacial acetic acid is stirred at room temperature for 5 hours and subsequently poured into 500 ml of ice-water. The solution is adjusted to pH 6.0 by the addition of conc. ammonia and extracted three times with 250 ml of ethyl acetate each time. The organic phase is washed three times with 50 ml of water each time, dried over sodium sulfate and evaporated. The oil obtained is dissolved in 20 ml of ether, whereupon the solution is treated with hexane until it becomes turbid and is left to crystallize out. There is obtained colorless 4'-hydroxy-3'-methoxy-4-phenylbutyrophenone of m.p. 91°-92°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-])=O.[C:17](Cl)(=O)[C:18](Cl)=O>C(Cl)Cl.CN(C=O)C>[CH2:17]([O:9][C:7]([C:6]1[CH:5]=[C:4]([CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=1)[NH2:1])=[O:8])[CH3:18]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(N)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of 3-nitro-5-trifluoromethylbenzoic acid (0.36 g, 1.53 mmol) in CH2Cl2 (20 mL) was added oxalyl chloride (0.58 g, 4.60 mmol) followed by DMF (3 drops). An immediate evolution of gas occurred and the reaction was stirred for 18 h. The solvent was removed under reduced pressure, the resulting oil was dissolved in THF (80 mL) and cooled to 0° C. To the cooled solution was added EtOH (5 mL) in THF (15 mL) and the mixture was stirred for 18 h at room temperature. The mixture was concentrated to remove the THF and the resulting precipitate was filtered and dried. The solid was dissolved in EtOH (25 mL) and 10% Pd/C (0.12 g) was added and the suspension was stirred for 15 h under a blanket of H2. The reaction was filtered through celite and the filtrate evaporated to dryness to provide 3-ethoxycarbonyl-5-trifluoromethylaniline as a yellow oil. This compound was then coupled to 2-chloro-4-trifluoromethyl pyrimidine-5-carbonyl chloride as described above to provide the title compound in a 12% yield; m.p. 67°-71° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=O)=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[C:4]([O:14][CH3:15])[C:3]=1[O:16][CH3:17].CC1[C:24](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:23](OC)[C:22](OC)=C(OC)C=1OC>>[CH3:1][C:2]1[C:7](/[CH:8]=[C:26](\[CH2:25][CH2:24][CH2:23][CH3:22])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[C:4]([O:14][CH3:15])[C:3]=1[O:16][CH3:17]
Reactant: CCOC(=O)/C=C/c1c(C)c(OC)c(OC)c(OC)c1OC
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Product: CCCC/C(=C\c1c(C)c(OC)c(OC)c(OC)c1OC)C(=O)OCC

Procedure:
Compound 8e was prepared from 7 (0.650 g, 2.71 mmol) as described above for 8a to give 0.484 g (1.32 mmol, 49%) of the product as a yellow oil following flash chromatography (1:9 EtOAc:hexanes).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH:10]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH3:13])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(C(N[C@H](C)c2ccc(F)c(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(N[C@H](C)c2ccc(F)c(F)c2)c2cccc(N)c2)cc1

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(3-nitrophenyl)-(4-methoxyphenyl)methyl]-[(R)-1-(3,4-difluorophenyl)ethyl]amine (1.27 g) [prepared as described in step (a) above] in methanol (50 ml), nickel chloride hexahydrate (1.52 g) and sodium borohydride (510 mg) were reacted, and the reaction mixture was purified by chromatography through a silica gel column using a 1:8 by volume mixture of ethynyl acetate and toluene as the eluant, to afford isomer A (235 mg,) as a yellow oil and isomer B (240 mg) as a pale yellow oil of the title compound.