Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([O:14][C:15]3[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=3[F:25])(=[O:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH3:26])[CH:3]=1.[CH3:27][N:28]1[C:32]([C:33]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=2B(O)O)=[CH:31][CH:30]=[N:29]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[CH3:26][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([S:11]([O:14][C:15]3[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=3[F:25])(=[O:13])=[O:12])[CH:6]=2)[C:2]([C:34]2[CH:35]=[CH:36][C:37]([C:39]([F:42])([F:40])[F:41])=[CH:38][C:33]=2[C:32]2[N:28]([CH3:27])[N:29]=[CH:30][CH:31]=2)=[CH:3]1
Reactant: Cn1cc(Br)c2ccc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)cc21
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cn(C)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Temperature: 90 °C
Yield: 364.9 %

Procedure:
The following reaction was conducted in two separate vials, and the reaction mixtures were combined before purification: A vial was charged with perfluorophenyl 3-bromo-1-methyl-1H-indole-6-sulfonate (52.1 mg, 0.114 mmol), (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid (Intermediate G) (40.1 mg, 0.148 mmol), potassium phosphate (72.7 mg, 0.343 mmol), Pd(AmPhos)2Cl2 (4.04 mg, 5.71 μmol), 1,4-dioxane (428 μl), and water (143 μl). The vial was flushed with Ar, sealed, and heated in a microwave reactor to 90° C. for 30 min. A separate vial was charged with perfluorophenyl 3-bromo-1-methyl-1H-indole-6-sulfonate (180 mg, 0.395 mmol), (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid (139 mg, 0.513 mmol), potassium phosphate (251 mg, 1.184 mmol), Pd(AmPhos)2Cl2 (13.97 mg, 0.020 mmol), 1,4-dioxane (1480 μl), and water (493 μl). The vial was flushed with Ar, sealed, and heated in a reactor to 90° C. for 30 min. The reaction mixtures from both vials were combined, and the combined mixture was diluted with water and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (10 to 60% EtOAc/Heptane) to give perfluorophenyl 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonate (250.0 mg, 0.416 mmol, 82% yield) as a pink foam. 1H NMR (400 MHz, CDCl3) δ=8.09-8.01 (m, 1 H), 7.91-7.81 (m, 3 H), 7.76-7.67 (m, 2 H), 7.53 (d, J=2.0 Hz, 1 H), 6.79 (s, 1 H), 6.38 (d, J=1.9 Hz, 1 H), 3.81 (s, 3 H), 3.23 (s, 3 H). m/z (ESI) 602.0 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:3]([CH3:19])[C:4]([N:6]1[C@H:10]([CH3:11])[C@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][C:7]1=[O:18])=[O:5].[CH3:32]N(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.F[B-](F)(F)F.C[O+](C)C>ClCCl>[CH3:32][O:1][C@@H:2]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[C@@H:3]([CH3:19])[C:4]([N:6]1[C@H:10]([CH3:11])[C@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][C:7]1=[O:18])=[O:5]
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)[C@H](C)[C@@H](O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CO[C@H]([C@@H](C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.6 %

Procedure:
Following a literature method (Diem, M. J.; Burow, D. F.; Fry, J. L. Journal of Organic Chemistry 42(10), 1977, 1801-1802), to a solution of tert-butyl (2S)-2-{(1R,2R)-1-hydroxy-2-methyl-3-[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]-3-oxopropyl}pyrrolidine-1-carboxylate (0.70 g, 1.6 mmol, from Reference Example 5) in anhydrous dichloromethane (5 mL) is added N,N,N′,N′-tetramethyl-1,8-naphthalenediamine (0.62 g, 2.9 mmol), followed by trimethyloxonium tetrafluoroborate (0.35 g, 2.4 mmol). The resulting reaction mixture is stirred for 24 hours at room temperature, quenched by the addition of ice water (25 mL), and then filtered through a diatomaceous earth pad. The filtrate is evaporated under reduced pressure and then partitioned between diethyl ether and water. The aqueous phase is extracted thrice with diethyl ether. The combined organic extracts are washed with 1 M aqueous potassium bisulfate solution, water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 0.69 g (97%) of tert-butyl (2S)-2-{(1R,2R)-1-methoxy-2-methyl-3-[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]-3-oxopropyl}pyrrolidine-1-carboxylate as a foam.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:15][CH:16]=2)[CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:15][CH:16]=2)[CH:3]=1
Reactant: Oc1cc(-c2cccc(C(F)(F)F)c2)nc2ccnn12
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cccc(-c2cc(Cl)n3nccc3n2)c1

Procedure:
A mixture of 1.75 g. of 7-hydroxy-5-(α,α,α-trifluoro-m-tolyl) pyrazolo[1,5-a]pyrimidine and 15 ml. of phosphorus oxychloride is refluxed for 2 hours. After evaporation at reduced pressure, ice is added to the residue and the desired compound is extracted with methylene chloride. After washing the organic layer with a saturated saline solution and drying with solid anhydrous sodium sulfate, evaporation gives the desired compound, m.p. 137°-139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([CH:15]([CH3:18])[CH2:16][CH3:17])=[C:11]([Cl:19])[NH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-:21].[K+].[K+].ClC1C=CC=C(C(OO)=O)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([OH:21])([CH:15]([CH3:18])[CH2:16][CH3:17])[C:11]([Cl:19])=[N:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCC(C)c1c(Cl)[nH]n(-c2cc(Cl)cc(Cl)c2)c1=O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Product: CCC(C)C1(O)C(=O)N(c2cc(Cl)cc(Cl)c2)N=C1Cl
Yield: 46.3 %

Procedure:
0.7 g of 1-(3,5-dichlorophenyl)-3-chloro-4-(1-methylpropyl)-5-pyrazolone and 0.7 g of potassium carbonate were cooled to -20° C. and 0.7 g of 75% m-chloroperbenzoic acid were added all at once. The procedure of Example 46 was followed to obtain 0.34 g of 1-(3,5-dichlorophenyl)-3-chloro-4-hydroxy-4-(1-methylpropyl)-5-pyrazolone used as is for the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]([C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][N:21]=2)=[O:19])[C:12]=1[F:27])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+:30]>CN1C(=O)CCC1.[Cu-]=O>[C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([NH2:30])=[CH:22][N:21]=2)=[O:19])[C:12]=1[F:27])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(Br)cn2)c1F
Agent: O=[Cu-]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(N)cn2)c1F
Temperature: 80 °C
Yield: 70 %

Procedure:
Step 2 To a solution of {(R)-1-[3-(5-bromo-pyridine-2-carbonyl)-4-chloro-2-fluoro-phenyl]-propyl}-carbamic acid tert-butyl ester (371 mg, 0.79 mmol) in NMP (2 mL) was added copper (I) oxide (23 mg, 0.16 mmol, 0.2 eq.) and ammonium hydroxide (˜29% in water, 2 mL) in a Reacti-vial and the mixture heated at 80° C. for 4 h. The mixture was partitioned between EtOAc (20 mL) and water (20 mL) and the organic phase extracted with further EtOAc (10 mL). Combined organic phase was washed with water (3×20 mL) and brine (10 mL) before it was dried (MgSO4), filtered and concentrated. Purified by silica column, 25 M, eluting 25-80% EtOAc in petrol to give {(R)-1-[3-(5-amino-pyridine-2-carbonyl)-4-chloro-2-fluoro-phenyl]-propyl}-carbamic acid tert-butyl ester (226 mg, 0.55 mmol, 70%). [M+H]+ 408
Reaction SMILES: [C:1]([C:5]1(O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:15].[Na+].[Na+].S(=O)(=O)(O)O>CCOCC.O>[C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CC(C)(C)C1(O)CCCCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)C1CCCCC1=O
Temperature: 25 °C

Procedure:
A solution of 31.25 g. (0.20 mole) t-butylcyclohexanol in 80 ml. of ethyl ether was cooled to 10° C. To this was added dropwise, with stirring, a solution of 21.0 g. (0.07 mole) sodium dichromate dihydrate and 15.75 ml. (0.30 mole) concentrated sulfuric acid in 100 ml. water while maintaining the reaction mixture below 25° C. The mixture was then warmed to room temperature, stirred for two hours, poured onto ice-water, ether layer separated, the aqueous phase extracted again with ether and the combined extracts washed with water, sodium bicarbonate and dried (MgSO4). Evaporation of the ether afforded 30.6 g. (99%) of the desired ketone.
Reaction SMILES: [C:1]([C:3]1[CH:42]=[CH:41][C:6]([C:7]([N:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@@H:11]([CH2:20][N:21]([C@@H:29]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)[CH3:30])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10]2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[N-:43]=[N+:44]=[N-:45].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[C:31]1([C@H:29]([N:21]([CH2:20][C@@H:11]2[C@@H:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:13][N:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([C:1]4[NH:45][N:44]=[N:43][N:2]=4)=[CH:42][CH:41]=3)[CH2:10]2)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:30])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)c2ccc(C#N)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)c2ccc(-c3nnn[nH]3)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 87.7 %

Procedure:
A 1.5 ml DMF solution of 72 mg of tert-butyl {[(3R,4S)-1-(4-cyanobenzoyl)-4-phenylpyrrolidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate was mixed with 153 mg of sodium azide and 304 mg of triethylamine hydrochloride and stirred at 120° C. for 2Hours. By post-treating and purifying this in the standard method, 68 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]({(3R,4S)-4-phenyl-1-[4-(1H-tetrazol-5-yl)benzoyl]pyrrolidin-3-yl}methyl)carbamate was obtained as a yellow amorphous substance. EN: 601
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.C([N-]C(C)C)(C)C.[Li+].CON(C)[C:20](=[O:24])[CH:21]([CH3:23])[CH3:22]>C1COCC1>[CH3:22][CH:21]([CH3:23])[C:20]([C:2]1[S:1][CH:5]=[CH:4][C:3]=1[C:6]([OH:8])=[O:7])=[O:24]
Reactant: O=C(O)c1ccsc1
Reactant: CON(C)C(=O)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C(=O)c1sccc1C(=O)O
Temperature: 25 °C
Yield: 94.4 %

Procedure:
To a solution of thiophene-3-carboxylic acid (26.65 g) in THF (300 ml) was added 2M lithium diisopropylamide (229 ml) dropwise at 0–5° C. with stirring under nitrogen, and the resulting mixture stirred for 15 min. A solution of N-methoxy-N,2-dimethylpropanamide (30 g) in THF (150 ml) was added dropwise over a period of 1 hr. When the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 2 hr. It was poured onto water, the layers separated and the aqueous washed with ether. The aqueous was acidified with conc. hydrochloric acid and extracted with ethyl acetate, the organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the sub-title compound as a solid (38.91 g).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@@:10]21[C:51]1[S:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][C:48]=3[CH2:52][C:53]3[CH:58]=[CH:57][C:56]([CH2:59][CH3:60])=[CH:55][CH:54]=3)[C:43]=1[CH2:42][CH2:41][O:40]2)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[CH2:59]([C:56]1[CH:55]=[CH:54][C:53]([CH2:52][C:48]2[CH:47]=[CH:46][CH:45]=[C:44]3[C:49]=2[S:50][C:51]2[C@@:10]4([C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]4)[O:40][CH2:41][CH2:42][C:43]3=2)=[CH:58][CH:57]=1)[CH3:60]
Reactant: CCc1ccc(Cc2cccc3c4c(sc23)[C@@]2(OCC4)O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1ccc(Cc2cccc3c4c(sc23)[C@@]2(OCC4)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 81.4 %

Procedure:
To a solution of (1S,3′R,4′S,5′S,6′R)-3′,4′,5′-tris-benzyloxy-6′-benzyloxymethyl-8-[(4-ethylphenyl)methyl]-3,3′,4,4′,5′,6′-hexahydro-spiro[2-oxa-9-thia-fluorene-1,2′-[2H]pyran] (23 mg, 0.028 mmol) in methanol (1 mL) and ethyl acetate (1 mL) was added 10% palladium on carbon (10 mg). The resultant mixture was stirred under a hydrogen atmosphere for 1 hour at room temperature, and the catalyst was then filtered off. Solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solution=dichloromethane:methanol (10:1)), to thereby obtain the titled compound (10.4 mg, 81%).
Reaction SMILES: Cl.OC(COC1C=CC=CC=1OC)CN1CCC([N:11]2[CH2:15][CH2:14][N:13](C3C=CC(OC)=CC=3)C2=O)CC1.[CH3:35][O:36][C:37]1[CH:43]=[CH:42][C:40](N)=[CH:39][CH:38]=1.Br.BrCCN>C(C(C)=O)C>[CH3:35][O:36][C:37]1[CH:43]=[CH:42][C:40]([CH:14]([NH2:13])[CH2:15][NH2:11])=[CH:39][CH:38]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1ccc(N2CCN(C3CCN(CC(O)COc4ccccc4OC)CC3)C2=O)cc1
Agent: Br
Agent: Cl
Agent: NCCBr
Solvent: CCC(C)=O
Product: COc1ccc(C(N)CN)cc1

Procedure:
A mixture of 17.9 g of 1-(4-methoxy-phenyl)-3-(4-piperidyl)-2-imidazolidinone and 11.7 g of 1-(2-methoxyphenyloxy)-2,3-epoxypropane in 200 ml of isopropyl alcohol is refluxed for 6 hours. The mixture is thereafter acidified with 5 N methanolic hydrochloric acid and concentrated under reduced pressure. The residue is freed from moisture still adhering to it by treatment with toluene. Recrystallisation of the residue from methanol with the addition of activated charcoal yields the 1-{1-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-4-piperidyl}-3-(4-methoxy-phenyl)-imidazolidin-2-one-hydrochloride as a white crystalline substance with a melting point of 214°-215° C. The 1-(4-methoxy-phenyl)-3-(4-piperidyl)-2-imidazolidinone used as starting material can be prepared as follows: A mixture of 61.5 g of 4-methoxy-aniline and 51.3 g of 2-bromoethylamine-hydrobromide in 125 ml of methyl ethyl ketone is refluxed for 5 hours with stirring. The viscous suspension is thereafter evaporated to dryness under reduced pressure. The residue is suspended in 150 ml of isopropanol and then collected by filtration. The filter cake is washed with three 50 ml portions of isopropanol and with two 50 ml portions of diethyl ether. The crystalline product is made alkaline with a concentrated aqueous ammonia solution and extracted with five 50 ml portions of chloroform. The extracts are dried over sodium sulphate and concentrated under reduced pressure. The oily residue crystallises after trituration to give the 1-(4-methoxyphenyl)-ethylenediamine with a melting point of 64° C.
Reaction SMILES: N[CH2:2]C(C1(O)CCCCC1)C1C=CC=CC=1.[NH2:17][CH2:18][CH:19]([C:28]1([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.Cl.C1(O)CCCCC1>>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH:19]([C:28]2([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:18][NH:17][CH3:2])=[CH:25][CH:24]=1
Reactant: NCC(c1ccccc1)C1(O)CCCCC1
Reactant: COc1ccc(C(CN)C2(O)CCCCC2)cc1
Agent: Cl
Solvent: OC1CCCCC1
Product: CNCC(c1ccc(OC)cc1)C1(O)CCCCC1

Procedure:
By replacing 1-[α-(aminomethyl)benzyl]cyclohexanol with a molar equivalent amount of 1-[2-amino-1-(p-methoxyphenyl)ethyl]cyclohexanol in Example 7, 1-[1-(4-methoxyphenyl)-2-methylamino)ethyl]cyclohexanol hydrochloride (m.p. 164°-166° C.) was obtained.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:35][C@H:36]([C:41](O)=[O:42])[CH2:37][C:38](=[O:40])[NH2:39])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:35][C@H:36]([C:41]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([N:5]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:1][CH:2]([CH3:3])[CH3:4])[C:12]([OH:14])=[O:13])=[O:42])[CH2:37][C:38]([NH2:39])=[O:40])(=[O:33])=[O:34])=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CC(N)=O)C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N[C@@H](CC(N)=O)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using Nα-(4-methylbenzenesulfonyl)-L-asparagine (90 mg, 0.3 mmol) which was prepared in step A of example 47. The final product was triturated with ether to yield 95 mg (15%) of the desired material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:16]([N:19]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:20]2[CH:21]=[CH:22][C:23]3[N:24]([CH2:33][CH3:34])[C:25]4[C:30]([C:31]=3[CH:32]=2)=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:18])=[O:17])[CH:5]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:7]=1.[CH3:43][Si:44]([C:47]#[CH:48])([CH3:46])[CH3:45].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[C:39]([O:38][C:36](=[O:37])[CH2:35][N:19]([S:16]([C:4]1[CH:5]=[C:6]([C:48]#[C:47][Si:44]([CH3:46])([CH3:45])[CH3:43])[CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:17])=[O:18])[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([CH2:33][CH3:34])[C:25]3[C:30]([C:31]=2[CH:32]=1)=[CH:29][CH:28]=[CH:27][CH:26]=3)([CH3:41])([CH3:40])[CH3:42]
Reactant: CCn1c2ccccc2c2cc(N(CC(=O)OC(C)(C)C)S(=O)(=O)c3cc(Cl)cc(OS(=O)(=O)C(F)(F)F)c3)ccc21
Reactant: C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(N(CC(=O)OC(C)(C)C)S(=O)(=O)c3cc(Cl)cc(C#C[Si](C)(C)C)c3)ccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
320 mg tert-butyl [(3-chloro-5-trifluoromethylsulphonyloxy-phenylsulphonyl)-(9-ethyl-9H-carbazol-3-yl)-amino]-acetate are dissolved in 4 ml dimethylformamide. 20 mg copper-1-iodide, 40 mg bis-triphenylphosphine-palladium-dichloride and 210 μl trimethylsilylacetylene are added under argon. Then the mixture is heated to 60° C. for 6 hours and then stirred overnight at ambient temperature. The mixture is then divided between saturated potassium carbonate solution and ethyl acetate. The organic phase is dried on magnesium sulphate and the solvents are eliminated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 100:0 to 95:5).
Reaction SMILES: BrC[CH2:3][C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([O:19][CH3:20])=[O:18])=[O:9])=[CH:6][CH:5]=1.[P:23]([O:30]CC)([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26]>>[CH2:25]([O:24][P:23]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([O:19][CH3:20])=[O:18])=[O:9])=[CH:21][CH:22]=1)([O:27][CH2:28][CH3:29])=[O:30])[CH3:26]
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc(CCBr)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(C(=O)Nc2ccccc2C(=O)OC)cc1)OCC

Procedure:
A suspension of 1.07 g of 4-bromoethyl-N-(2-methoxycarbonylphenyl)benzamide in 5 ml of triethyl phosphite was stirred under heating at 140° to 150° C. for 30 minutes. After excess triethyl phosphite had been distilled off in vacuo, the residue was subjected to silica gel column chromatography (eluent; chloroform:methanol=1:1) to give 4-diethoxyphosphinylmethyl-N-(2-methoxycarbonylphenyl)benzamide. It was recrystallized from a benzene-n-hexane mixture to give 1.20 g of colorless needles.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[CH3:11])([CH3:3])[CH3:2].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][CH:14]2[CH2:15][O:16]2)=[CH:6][C:5]=1[CH3:11])([CH3:3])[CH3:2]
Reactant: Cc1cc(O)ccc1C(C)C
Reactant: ClCC1CO1
Product: Cc1cc(OCC2CO2)ccc1C(C)C

Procedure:
The title compound was prepared from 4-isopropyl-3-methyl-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:11][C:10]=2[C:27]([F:30])([F:29])[F:28])[CH:7]=1.[OH:31]OS([O-])=O.[K+]>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:20]=[CH:21][C:22]([S:25]([CH3:26])=[O:31])=[CH:23][CH:24]=3)(=[O:17])=[O:18])=[CH:11][C:10]=2[C:27]([F:28])([F:30])[F:29])[CH:7]=1
Reactant: O=S([O-])OO
Reactant: CSc1ccc(S(=O)(=O)Nc2ccc(Oc3cncc(Cl)c3)c(C(F)(F)F)c2)cc1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CS(=O)c1ccc(S(=O)(=O)Nc2ccc(Oc3cncc(Cl)c3)c(C(F)(F)F)c2)cc1
Reaction time: 5 h

Procedure:
To a solution of 2-(3-chloro-5-pyridyloxy)-5-(4-methylthiobenzenesulfonamido)benzotrifluoride (0.21 g) in acetone (5 mL) was added Oxone™ (0.136 g) in water (1 mL). After 5 hr, the reaction mixture is filtered, and the filtrate is diluted in methylene chloride and extracted with water. The solids from the organic extract were purified by silica chromatography. Trituration with hexane gave the title sulfoxide (0.144 g) as a white solid. mp 156-159° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:14][CH2:13][CH2:12]2)[C:3]=1[C:4]#[N:5].[C:15]([N:23]=[C:24]=[O:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1.CCOC(C)=O>[C:4]([C:3]1[C:6]([O:10][CH:11]2[CH2:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:24]([NH:23][C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:25])#[N:5]
Reactant: N#Cc1c(N)cccc1OC1CCC1
Reactant: O=C=NC(=O)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1c(NC(=O)NC(=O)c2ccccc2)cccc1OC1CCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 70.8 %

Procedure:
To a solution of 2-amino-6-cyclobutoxybenzonitrile (example 162b) (30 mg, 0.16 mmol) in 1,4-dioxane (2 mL) was added benzoyl isocyanate (23 mg, 0.16 mmol). The reaction was stirred at rt under N2 for 19 hours. Upon completion, the reaction was diluted with EtOAc, washed with saturated NaHCO3 (2×), water, brine, dried over MgSO4, filtered and concentrated to provide N-(2-cyano-3-cyclobutoxyphenylcarbamoyl)benzamide (38 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ 1.64 (m, 1H), 1.81 (m, 2H), 2.05 (m, 1H), 2.42 (m, 2H), 4.71 (pent, J=7.1 Hz, 1H), 6.05 (d, J=8.2 Hz, 1H), 6.33 (d, J=8.3 Hz, 1H), 7.15 (t, J=8.5 Hz, 1H), 7.45 (m, 1H), 7.56 (m, 2H), 7.87 (m, 1H), 8.05 (m, 1H), 11.35 (s, 1H).