Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9](F)([C:17]([F:20])([F:19])[F:18])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH:6]=[C:5]([CH3:22])[C:4]=1[NH2:23])[CH3:2].[OH-:24].[K+]>C(#N)C.O>[NH2:23][C:4]1[C:5]([CH3:22])=[CH:6][C:7]([C:9]([OH:24])([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:3]=1[CH2:1][CH3:2]
Reactant: [OH-]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1N
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCc1cc(C(O)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1N
Temperature: 70 °C
Reaction time: 48 h
Yield: 59.8 %

Procedure:
To a solution of 2-ethyl-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-6-methyl-phenylamine (prepared as descriebed in WO 2008/074427) (3.88 g, 11 mmol) in a mixture of acetonitrile (320 ml) and water (80 ml) was added potassium hydroxide (46.2 g, 827 mmol). The reaction mixture was stirred at 70° C. for 2 days. The reaction mixture was diluted with water (200 ml) and the mixture extracted three times with ethyl acetate (200 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:3) to give 2-(4-amino-3-ethyl-5-methylphenyl)-1,1,1,3,3,4,4,4-octafluorobutan-2-ol (2.31 g, 60% yield). LC-MS (Method 1): RT=1.87, [M−H]−=352.
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][CH2:11][C:6]21[O:10][CH2:9][CH2:8][O:7]2)([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH2:1][CH2:4][CH:5]1[C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:12][CH2:11][C:6]21[O:7][CH2:8][CH2:9][O:10]2
Reactant: O=[N+]([O-])CC1C2(CCCC1(c1ccccc1)c1ccccc1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC1C2(CCCC1(c1ccccc1)c1ccccc1)OCCO2
Yield: 28.6 %

Procedure:
A solution of (RS)-6-nitromethyl-7,7-diphenyl-1,4-dioxaspiro[4.5]decane (63 g) in anhydrous tetrahydrofuran (300 cc) is added dropwise in the course of 1 hour to a suspension, cooled to +5° C., of lithium aluminium hydride (8.13 g) in anhydrous tetrahydrofuran (250 cc) while the temperature of the reaction mixture is maintained at +5° C., and the mixture is then brought to reflux for 2 hours. The reaction mixture is then cooled to +5° C., treated with distilled water (8.93 cc), then with 5N aqueous sodium hydroxide solution (8 cc) and then with distilled water (25 cc), filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel with a slight excess pressure of nitrogen (0.04-0.063 mm, diameter 6.5 cm, height 45 cm), eluting with a mixture of dichloromethane and methanol (90:10) by volume) and collecting 120-cc fractions. Fractions 10 to 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa). (RS)-6-Aminomethyl-7,7-diphenyl-1,4-dioxaspiro[4.5]decane (16.5 g) is obtained in the form of an orange-colored oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][N:43]1[C:47]([CH3:48])=[C:46]([S:49](Cl)(=[O:51])=[O:50])[C:45]([CH3:53])=[N:44]1>C(#N)C>[CH3:42][N:43]1[C:47]([CH3:48])=[C:46]([S:49]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:50])=[O:51])[C:45]([CH3:53])=[N:44]1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: Cc1nn(C)c(C)c1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nn(C)c(C)c1S(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 27.2 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0316 g, 0.0685 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 1,3,5-trimethyl-1H-pyrazol-4-sulfonyl chloride (0.0407 g, 0.195 mmol) to obtain 4-(1,3,5-trimethyl-1H-pyrazol-4-ylsulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0118 g, yield 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[OH:28])=[CH:11][CH:10]=1.[CH2:33](Br)[CH:34]=[CH2:35]>>[CH2:35]([O:28][CH:16]1[CH:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]3[CH:29]=[CH:30][CH:31]=[CH:32][C:2]=3[Cl:1])=[CH:14][CH:13]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1)[CH:34]=[CH2:33]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccccc3Cl)cc2)C(O)C1
Reactant: C=CCBr
Product: C=CCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOc2ccccc2Cl)cc1

Procedure:
Analogously to Method D, 2.01 g of tert-butyl 4-{4-[3-(2-chlorophenoxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.74 ml of allylbromide are reacted. The title compound is obtained as a colourless oil. Rf=0.80 (1:1 EtOAc-heptane); Rt=6.13.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH2:14]([N:21]=[C:22]=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[CH2:14]([NH:21][C:22]([N:6]1[CH:7]=[C:2]([F:1])[C:3](/[N:9]=[CH:10]/[N:11]([CH3:13])[CH3:12])=[N:4][C:5]1=[O:8])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C=NCc1ccccc1
Reactant: CN(C)C=Nc1nc(O)ncc1F
Solvent: ClCCl
Product: CN(C)/C=N/c1nc(=O)n(C(=O)NCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a suspension of N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (0.25 g, 1.35 mmol) in CH2Cl2 (5 mL) was added benzyl isocyanate (0.187 mL, 1.49 mmol) forming a solution that was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 (100 mL) and was washed with brine (2×50 mL). The combined aqueous layers were extracted with CH2Cl2 (2×25 mL). The organic extracts were dried over sodium sulfate (Na2SO4), filtered and concentrated. The residue was purified by normal phase chromatography (gradient, methanol/CH2Cl2) and then by reverse phase chromatography (gradient, acetonitrile (CH3CN) in water (H2O)). The resulting solution was concentrated under reduced pressure forming a precipitate. The mixture was extracted with CH2Cl2 (4×100 mL), dried (Na2SO4), filtered and concentrated to yield (E)-N-benzyl-4-((dimethylamino)methyleneamino)-5-fluoro-2-oxopyrimidine-1(2H)-carboxamide (0.268 g, 62%) as a white solid: mp 147-150° C.; 1H NMR (300 MHz, CDCl3) δ 10.83 (t, J=4.94 Hz, 1H), 8.81 (s, 1H), 8.44 (d, J=6.59 Hz, 1H), 7.32-7.22 (m, 5H), 4.56 (d, J=5.93 Hz, 2H), 3.21 (s, 3H), 3.20 (s, 3H); ESIMS m/z 318.2 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:18])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].CC1C=CC(S(O[CH2:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[C:3]([CH3:18])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Reactant: Cc1cc(O)c(F)c(C)c1-c1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCCCS(C)(=O)=O)c(F)c(C)c1-c1cccc(C=O)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
To a solution of 3′-fluoro-4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (2.44 g, 10.0 mmol) and 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (3.51 g, 12.0 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.80 g, 13.0 mmol), and the mixture was stirred at 90° C. for 24 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=40:60-80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (3.45 g, yield 95%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH:11]=[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([OH:22])=[CH:7][CH:8]=2)[O:3]1.[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:28]1[CH2:27][CH:26]1[CH2:24][O:22][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)=[CH:11][C:2]([CH3:23])([CH3:1])[O:3]2)=[CH:8][CH:7]=1
Reactant: CC1(C)C=C(c2cccc3ccccc23)c2ccc(O)cc2O1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)C=C(c2cccc3ccccc23)c2ccc(OCC3CO3)cc2O1
Yield: 86 %

Procedure:
2,2-Dimethyl-4-(1-naphthyl)-2H-chromen-7-ol (7.92g, 0.026 moles) and epichlorohydrin (28.5ml) were dissolved in acetone (50ml). Potassium carbonate (6.3g) was added and the mixture refluxed for 6 hours, allowed to cool and filtered. The acetone was removed in vacuo and the residue dissolved in ether, washed with water and dried. Removal of solvent gave the title product as an orange oil (8.1g, 86%) which was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C:39](O)=[O:40])=[N:36][CH:37]=1>>[Si:22]([O:21][CH2:20][C:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:39](=[O:40])[CH2:38][C:35]3[CH:34]=[CH:33][C:32]([F:31])=[CH:37][N:36]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: O=C(O)Cc1ccc(F)cn1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cnccc21
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(F)cn3)c2)c2cnccc21

Procedure:
Prepared according to Method Z (Preparation 8) using (5-Amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 28) and (5-fluoropyridin-2-yl)acetic acid (Preparation 82).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[C:17]([O:25][CH3:26])[CH:16]=2)[O:4][CH2:3]1.[H-].[Na+].[CH3:31]I>CN(C)C=O>[CH3:1][C:2]1([CH3:28])[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:13]([CH3:31])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[C:17]([O:25][CH3:26])[CH:16]=2)[O:4][CH2:3]1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccccc2C2=NC(C)(C)CO2)cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)N(C)c2ccccc2C2=NC(C)(C)CO2)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-[2-(4,4-dimethyl(2,5-oxazolinyl)]-phenyl]-3-methoxy-4-methoxycarbonylbenzamide (1.45 g) in N,N-dimethylformamide (18 ml) was added portionwise sodium hydride (167 mg) at 0° C. and the mixture was stirred at 0° C. for 30 minutes. Methyl iodide (0.283 ml) was added to the mixture and the solution was stirred at 0° C. for 1 hour. The reaction was quenched with water and then the aqueous solution was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo to give N-[2-[4,4-dimethyl-(2,5-oxazolinyl)]phenyl]-N-methyl-3-methoxy-4-methoxycarbonylbenzamide (1.5 g).
Reaction SMILES: N[C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[BrH:18]>O.[Cu]Br>[Br:18][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)c2c1OCO2
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(Br)c2c1OCO2
Reaction time: 0.25 h

Procedure:
1.95 g of 7-amino-benzo[1,3]dioxole-4-carboxylic acid in 25 ml of hydrobromic acid (48%) and 20 ml of water are mixed at 0° C. with a solution of 760 mg of sodium nitrite in 4.2 ml of water. It is stirred for 15 minutes and then added to a solution of 2.07 g of copper(I) bromide in 5.5 ml of hydrobromic acid (48%). It is heated for 30 minutes to 100° C., added to water and extracted with ethyl acetate. It is washed with brine, dried with sodium sulfate and concentrated by evaporation in a vacuum. 2.88 g of 7-bromo-benzo[1,3]dioxole-4-carboxylic acid is obtained as a brown solid. The latter is reacted in 50 ml of DMF at 0° C. with 4.08 g of cesium carbonate and 0.8 ml of methyl iodide. It is stirred for 4 hours at room temperature, added to water, and extracted with ethyl acetate. It is washed several times with water and brine, dried and concentrated by evaporation in a vacuum. 1.81 g of 7-bromo-benzo[1,3]dioxole-4-carboxylic acid methyl ester is obtained as a red solid. The latter is dissolved in 5 ml of ether, and 10 ml of THF is added to a solution of 5.06 ml of methylmagnesium chloride (3 M in THF) and 6 ml of ether at room temperature. After 3.5 hours, the batch is added to 1N hydrochloric acid, extracted with ethyl acetate, washed with brine, dried and concentrated by evaporation in a vacuum. 1.79 g of 2-(7-bromo-1,3-benzodioxol-4-yl)-propan-2-ol is obtained as an orange-colored oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:13])[CH:8]=2)[N:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].S(=O)(=O)(O)O.O>C(O)(=O)C>[Br:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:1][C:14](=[O:16])[CH3:15])[CH:11]=[C:10]2[OH:12]
Reactant: Nc1cc(O)c2cc(Br)ccc2n1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(O)c2cc(Br)ccc2n1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
A mixture of 2-amino-6-bromo-quinolin-4-ol (29.4 g, 0.12 mol), acetic anhydride (36.7 g, 0.36 mol) and sulphuric acid (20 ml) in glacial acetic acid (300 ml) was refluxed for 30 min. The mixture was allowed to cool to rt and then poured into water. The precipitate was isolated by filtration and dried to afford product N-(6-bromo-4-hydroxy-quinolin-2-yl)-acetamide as a brown solid (32 g, 93%). This material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH3:15]>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH2:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N
Reactant: Clc1cc(-c2ccccc2)c(Cl)nn1
Product: Nc1cc(-c2ccccc2)c(Cl)nn1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
36.5 g (162 mmol) 3,6-Dichloro-4-phenyl-pyridazine were suspended in 1000 mL aqueous ammonia solution (25%) and stirred in an autoclave for 18 hours at 100° C. The reaction mixture was transferred into a separating funnel and the phases were separated. The aqueous phase was washed twice with dichloromethane. The combined organic phases were washed twice with water, the solvent was evaporated and the crude residue (two regioisomers, 6-chloro-5-phenyl-pyridazin-3-yl-amine and 6-chloro-4-phenyl-pyridazin-3-yl-amine 20.2 g=60.6%) was used without further purification in the next step.
Reaction SMILES: [CH2:1]([C@@:4]1([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].C[NH:39][S:40]([CH:43]1[CH2:45][CH2:44]1)(=[O:42])=[O:41]>>[CH2:1]([C@@:4]1([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:35])[CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH:39][S:40]([CH:43]2[CH2:45][CH2:44]2)(=[O:42])=[O:41])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: CNS(=O)(=O)C1CC1
Reactant: C=CC[C@@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Product: C=CC[C@@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C2CC2)C1=O

Procedure:
The title compound was prepared from (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2-one (Example 414, Step B) and N-methylcyclopropanesulfonamide by a procedure similar to the one described in Example 201, Step A. The product was purified by chromatography through a RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (12 g), eluting with a gradient of 0% to 80% EtOAc in hexane, to provide the title compound as an oil. Mass Spectrum (ESI) m/z=665.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.I[CH:12]([CH3:14])[CH3:13]>C(O)(C)C.[OH-].[Na+].C(OCC)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH:12]([CH3:14])[CH3:13])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: CC(C)I
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)O
Product: Cc1cc(Br)cc(C)c1OC(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.6 %

Procedure:
A mixture of 4-bromo-2,6-dimethylphenol (4.69 g, 23.3 mmol), 2-iodo-propane (15.81 g, 93.0 mmol) in isopropanol (200 mL) and 1 N aq. NaOH (50 mL) is stirred at rt for 24 h. The mixture is diluted with diethyl ether, washed with 1 N aq. HCl and 1 N aq. NaOH, dried over Na2SO4, filtered and concentrated to give crude 5-bromo-2-isopropoxy-1,3-dimethyl-benzene (4.62 g) as an orange oil; LC-MS: tR=1.07 min. The arylbromide is dissolved in THF (100 mL) and cooled to −78° C. BuLi (15 mL of a 1.6 N solution in hexane) is slowly added (30 min) and the mixture is stirred at −78° C. for 30 min. The mixture is transferred via needle to a cooled (0° C.) solution of dimethylcarbonate (10.7 g, 118.8 mmol) in THF (50 mL). The mixture is stirred for 15 h, quenched with 3 N aq. LiOH (100 mL) and stirred at 60° C. for 24 h. The mixture is diluted with ether (200 mL) and 1M aq. NaOH (100 mL), the phases separated and the org. phase re-extracted with NaOH (50 mL). The aq. phases are washed with diethyl ether (2×50 mL), carefully acidified to pH 3 with 25% HCl. The org. phases are discarded. The aq. phase is extracted with DCM (5×75 mL). The org. extracts are dried over Na2SO4, filtered and evaporated to give 4-isopropoxy-3,5-dimethyl-benzoic acid (2.23 g) as a beige solid; LC-MS: tR=0.91 min, [M+1]+=209.07, 1H NMR (CDCl3): δ 1.34 (d, J=6.3 Hz, 6H), 2.34 (s, 6H), 4.32 (hept, J=6.0 Hz, 1H), 7.81 (s, 2H).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][CH2:13][N:14]=2)=[CH:6][CH:5]=1>O.CO>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH2:12][CH2:13][NH:14]2)=[CH:8][CH:9]=1
Reactant: Brc1ccc(C2=NCCC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Brc1ccc(C2CCCN2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
NaBH4 (1.52 g, 40 mmol) was added to a solution of 5-(4-bromophenyl)-3,4-dihydro-2H-pyrrole (4.48 g, 20 mmol) in H2O/MeOH (30 mL, v/v 1:4) at −41° C. After stirred for 4 hrs, the solution was allowed to warm to room temperature. Once the reaction was deemed complete by TLC, the unreacted NaBH4 was quenched by the addition of 2 N HCl. The solution was then diluted with water and ether, and separated two layers. The aqueous layer was washed with an additional portion of ether, basified with 4 M NaOH (pH 12-13) and washed with ethyl acetate. The combined organic extracts were washed with brine, and then dried over Na2SO4. Evaporation of the solvent afforded the title crude product as a yellow oil (3.8 g, yield 84%), which was used directly in the next step. LC-MS (ESI) m/z: 226 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@@H:27]([C:32](O)=[O:33])[C@@H:28]([CH2:30][CH3:31])[CH3:29])=[O:25])[CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14](=[O:16])[OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([C@H:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:36].O.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH2:35]([C@H:37]([NH:44][C:32](=[O:33])[C@@H:27]([C@@H:28]([CH2:30][CH3:31])[CH3:29])[NH:26][C:24](=[O:25])[C@H:12]([CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:36]
Reactant: CC[C@H](N)c1ccccc1
Reactant: CC[C@@H](C)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC[C@H](NC(=O)[C@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)[C@H](C)CC)c1ccccc1
Reaction time: 1 h
Yield: 33.1 %

Procedure:
To a solution of 6.69 g (14.2 mmols) of N-benzyloxycarbonyl-β-benzyl-L-aspartyl-D-isoleucine and 2.04 g (15.1 mmols) of (S)-α-ethylbenzylamine in 200 ml of methylene chloride were added 2.73 g (14.2 mmols) of water-soluble carbodiimide hydrochloride and 1.92 g (14.2 mmols) of HOBt under cooling and stirred for one hour under cooling and then overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and 150 ml of ethyl acetate was added. The resulting residue was washed two times each with 70 ml of aqueous 5% citric acid, once with 70 ml of water, two times each with 70 ml of aqueous 5% sodium hydrogencarbonate and once with 70 ml of brine in that order. The resulting organic layer was dried with anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration, and the resulting filtrate was concentrated under reduced pressure. The resulting residue was dissolved in chloroform and concentrated under reduced pressure. The resulting solid residue was washed with ethyl acetate and dried to obtain 2.81 g (4.7 mmols) of N-benzyloxycarbonyl-β-benzyl-L-aspartyl-D-isoleucine (S)-α-ethylbenzylamide.
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:10]2[S:25][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:27][C:9]1=2)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH:19]1([C:11]2[C:10]3[S:25][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:27][C:9]=3[N:8]([CH2:7][C:6]([OH:32])=[O:5])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccccc1)n2CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccccc1)n2CC(=O)O
Yield: 100 %

Procedure:
A solution (0.1 M) of methyl 4-(2-tert-butoxy-2-oxoethyl)-6-cyclohexyl-5-phenyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in DCM/TFA (1:1) was stirred at RT for 4 h. Evaporation of the solvent gave the title compound (100%) as a solid.