Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:53])[CH2:10][CH2:11][N:12]([CH2:43][C:44]1[O:45][C:46]2[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=2[CH:48]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([C@H:22]([C:29](=[O:42])[NH:30][C:31]2[S:32][C:33]3[C:38]([N:39]=2)=[CH:37][CH:36]=[C:35]([O:40][CH3:41])[N:34]=3)[CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])C1C=CC=CC=1.[OH-].[Na+].Cl>C1COCC1.O>[O:45]1[C:46]2[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=2[CH:48]=[C:44]1[CH2:43][N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([C@H:22]([C:29](=[O:42])[NH:30][C:31]2[S:32][C:33]3[C:38]([N:39]=2)=[CH:37][CH:36]=[C:35]([O:40][CH3:41])[N:34]=3)[CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:18][CH:17]=1)(=[O:14])=[O:15])[CH2:11][CH2:10][C:9]([OH:53])=[O:8]
Reactant: COc1ccc2nc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(=O)(=O)N(CCC(=O)OCc4ccccc4)Cc4cc5ccccc5o4)cc3)sc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2nc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(=O)(=O)N(CCC(=O)O)Cc4cc5ccccc5o4)cc3)sc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title I compound, 3-(benzofuran-2-ylmethyl-{4-[(R)-2-cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-amino)-propionic acid benzyl ester (280 mg, 0.372 mmol) is dissolved in THF. To this is added a solution of sodium hydroxide (22 mg, 0.558 mmol) in water. The reaction is stirred at RT overnight. LC/MS indicates ˜80% reaction completion and, therefore, more sodium hydroxide (10 mg, 0.250 mmol) is added. After 2 h of stirring at RT, the reaction is acidified to pH 1 with concentrated hydrochloric acid, then concentrated to remove solvent. The residue is diluted with ethyl acetate and water. The organic layer is separated, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product as a yellow foam. Purification by preparative HPLC affords 3-(benzofuran-2-ylmethyl-{4-[(R)-2-cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-amino)-propionic acid as a white solid: 1H NMR (400 MHz, DMSO-D6) δ 1.4 (m, 2 H) 1.6 (m, 3 H) 1.7 (m, 3 H) 2.1 (m, 1H) 3.35 (m, 1 H) 3.9 (s, 3 H) 4.0 (m, 1 H) 4.6 (s, 2 H) 6.7 (s, 1 H) 6.9 (d, J=8.8 Hz, 1 H) 7.1 (m, 2 H) 7.3 (m, 2 H) 7.5 (dt, J=4.3, 2.1 Hz, 1 H) 7.6 (d, J=8.3 Hz, 2 H) 7.8 (d, J=8.6 Hz, 2 H) 8.0 (d, J=8.8 Hz, 1 H) 12.7 (s, 1 H); LC/MS 663.5 (M+1), 661.5 (M−1). EC50 in primary enzyme assay 0.22 μM.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1)#[N:2].[N:24]#CBr.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:9]([N:6]1[CH2:7][CH2:8][C:3]([C:1]#[N:2])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH2:4][CH2:5]1)#[N:24]
Reactant: CN1CCC(C#N)(c2ccccc2Sc2ccc(F)cc2)CC1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC(C#N)(c2ccccc2Sc2ccc(F)cc2)CC1

Procedure:
A mixture of 19.8 g of 4-cyano-4-[2-(4-fluorophenylthio)phenyl]-1-methylpiperidine, Example 26(e), in 200 ml of chloroform is added portionwise over a 15 minute span to a mixture of 33.4 g of 97% cyanogen bromide and 130 g of potassium carbonate in 250 ml of chloroform. After total addition, the mixture is successively refluxed for 16 hours, cooled, filtered, washed thrice with 300 ml portions of water and one 50 ml portion of a saturated sodium chloride solution and dried. The resulting residue is dissolved in benzene, decolorized with charcoal and then filtered through celite. The solution's volume is reduced and rediluted with hexane to provide 1,4-dicyano-4-[2-(4-fluorophenylthio)phenyl]piperidine.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[NH2:14][C@H:15]([C:23]([NH:25][C@H:26]([C:34]([OH:36])=[O:35])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:33])[NH2:32])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>>[C:3]([CH:2]([NH:14][C@H:15]([C:23]([NH:25][C@H:26]([C:34]([OH:36])=[O:35])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:32])[NH2:33])=[O:24])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:5])=[O:4]
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: N=C(N)NCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(CCc1ccccc1)C(=O)O)C(=O)O

Procedure:
In the manner described in example 24, one can condense 2-oxo-4-phenylbutyric acid and L-phenylalanyl-L-arginine in the presence of sodium cyanoborohydride to yield N-(1-carboxy-3-phenylpropyl)-L-phenylalanyl-L-arginine.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])/[C:3](/[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)=[CH:20][CH:19]=1)=[CH:4]\[C:5]1[NH:6][CH:7]=[C:8]([CH2:10][C:11]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12]2)[N:9]=1.[H-].[Na+].[CH3:33][N:34]([CH3:39])[S:35](Cl)(=[O:37])=[O:36]>O1CCCC1>[CH3:33][N:34]([CH3:39])[S:35]([N:6]1[CH:7]=[C:8]([CH2:10][C:11]2([C:14]([F:15])([F:16])[F:17])[CH2:12][CH2:13]2)[N:9]=[C:5]1/[CH:4]=[C:3](/[C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)=[CH:22][CH:23]=1)\[C:2]([F:1])([F:29])[F:30])(=[O:37])=[O:36]
Reactant: FC(F)(F)/C(=C\c1nc(CC2(C(F)(F)F)CC2)c[nH]1)c1ccc(-n2cccn2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC2(C(F)(F)F)CC2)nc1/C=C(/c1ccc(-n2cccn2)cc1)C(F)(F)F
Reaction time: 8 h

Procedure:
In a 250-mL round-bottom flask, a mixture of 1-{4-[(Z)-1-(trifluoromethyl)-2-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)vinyl]phenyl}-1H-pyrazole (5.05 g, 11.8 mmol) and 60 wt % sodium hydride (0.89 g, 22 mmol) were mixed with tetrahydrofuran (80 mL). After bubbling ceased, dimethylsulfamoyl chloride (2.6 mL, 24.26 mmol) was added, and the reaction mixture was stirred overnight. The reaction mixture was quenched with water and extracted with diethyl ether. The combined organic extracts were washed with brine, dried (potassium carbonate), and concentrated in vacuo to afford an orange solid. Chromatography over silica eluting with 25-40% ethyl acetate/hexanes afforded N,N-dimethyl-4-{[1-(trifluoromethyl)cyclopropyl]methyl}-2-{(1Z)-3,3,3-trifluoro-2-[4-(1H-pyrazol-1-yl)phenyl]prop-1-en-1-yl}-1H-imidazole-1-sulfonamide, as a yellow solid.
Reaction SMILES: [Cl:1][N:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([NH:9][C:10]2[CH:11]=[C:12](S(O)(=O)=O)[C:13]([CH:16]=[CH:17][C:18]3[C:19](S(O)(=O)=O)=[CH:20][C:21]([NH:24][C:25]4[NH:30][N:29]([Cl:31])[N:28]=[C:27](Cl)[CH:26]=4)=[CH:22][CH:23]=3)=[CH:14][CH:15]=2)[NH:3]1.[NH2:41][C:42]1[C:51]([S:52]([OH:55])(=[O:54])=[O:53])=[CH:50][C:49]2[C:44](=[C:45]([S:60]([OH:63])(=[O:62])=[O:61])[CH:46]=[C:47]([S:56]([OH:59])(=[O:58])=[O:57])[CH:48]=2)[CH:43]=1>>[Cl:1][N:2]1[N:7]=[C:6]([NH:41][C:42]2[C:51]([S:52]([OH:55])(=[O:54])=[O:53])=[CH:50][C:49]3[C:44](=[C:45]([S:60]([OH:63])(=[O:62])=[O:61])[CH:46]=[C:47]([S:56]([OH:59])(=[O:57])=[O:58])[CH:48]=3)[CH:43]=2)[CH:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]([CH:16]=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]4[NH:30][N:29]([Cl:31])[N:28]=[C:27]([NH:41][C:42]5[C:51]([S:52]([OH:55])(=[O:54])=[O:53])=[CH:50][C:49]6[C:44](=[C:45]([S:60]([OH:63])(=[O:62])=[O:61])[CH:46]=[C:47]([S:56]([OH:59])(=[O:57])=[O:58])[CH:48]=6)[CH:43]=5)[CH:26]=4)=[CH:20][CH:19]=3)[C:12]([S:56]([OH:59])(=[O:58])=[O:57])([S:52]([OH:55])(=[O:54])=[O:53])[CH:11]=2)[NH:3]1
Reactant: Nc1cc2c(S(=O)(=O)O)cc(S(=O)(=O)O)cc2cc1S(=O)(=O)O
Reactant: O=S(=O)(O)c1cc(NC2=CC(Cl)=NN(Cl)N2)ccc1C=Cc1ccc(NC2=CC(Cl)=NN(Cl)N2)cc1S(=O)(=O)O
Product: O=S(=O)(O)c1cc(S(=O)(=O)O)c2cc(NC3=NN(Cl)NC(NC4=CC(S(=O)(=O)O)(S(=O)(=O)O)C(C=Cc5ccc(NC6=CC(Nc7cc8c(S(=O)(=O)O)cc(S(=O)(=O)O)cc8cc7S(=O)(=O)O)=NN(Cl)N6)cc5)C=C4)=C3)c(S(=O)(=O)O)cc2c1

Procedure:
4,4′-Bis-(2,4-dichlorotriazin-6-ylamino)-stilbene-2,2′-disulfonic acid was reacted with 2-aminonaphthalene-3,6,8-trisulfonic acid in a similar manner to Example 5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O.O.CCCCCC>[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: Brc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
A solution of 4-bromophenol (17.3 g) in dimethylformamide (200 mL) was treated with potassium carbonate (15.2 g) followed by benzyl bromide (17.1 g 11.9 mL). After stirring for 16 hours at ambient temperature, the reaction mixture was diluted with water and hexane. The aqueous layer was extracted with hexane:ether (5:1). The organic extracts were washed (water, 1N sodium hydroxide, brine), dried and evaporated to give the bromobenzene as a white solid (23.4 g); NMR (CDCl3): 5.03 (s, 2), 6.85 (dd, 2, J1 =5, J2 =2), 7.3-7.4 (m, 7); MS: m/z=263(M+1). This material was used in the next step without further purification.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([O:22]COCC[Si](C)(C)C)[C:16]=1[C:31]#[C:32][CH3:33]>CC(O)=O>[Cl:21][C:19]1[CH:18]=[C:17]([OH:22])[C:16]2[N:15]([N:14]=[C:32]([CH3:33])[CH:31]=2)[CH:20]=1
Reactant: CC#Cc1c(OCOCC[Si](C)(C)C)cc(Cl)c[n+]1N
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: CC(=O)O
Product: Cc1cc2c(O)cc(Cl)cn2n1
Reaction time: 8 h

Procedure:
AcOH (5 mL) was added to 1-amino-5-chloro-2-(prop-1-yn-1-yl)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridin-1-ium 2,4,6-trimethylbenzenesulfonate. After stirring overnight, the AcOH was removed under vaco., the residue was treated with 2 M solution of LiOH (5 mL) at rt., and extracted with ethyl acetate. Combined organics were washed with brine, dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to provide of 6-chloro-2-methylpyrazolo[1,5-a]pyridin-4-ol 6.59. LCMS [M+H]+: 183.09. 1H NMR (400 MHz, CDCl3) ppm: δ 8.028 (s, 1H), 6.419 (d, J=6.8 Hz, 1H), 6.398 (d, J=6.8 Hz, 1H), 2.395 (s, 3H).
Reaction SMILES: C1(CC(Cl)=O)C=CC=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[C:33]1([CH2:39][C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.C(O)C>[C:33]1([CH2:39][C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:43]([NH:42][C:40](=[O:41])[CH2:39][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[S:44])=[CH:28][CH:27]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cc1ccccc1)N=C=S
Agent: O=C(Cl)Cc1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
2-Phenylethanoyl isothiocyanate was prepared using commercially available 2-phenylethanoyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-phenylethanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (38 mg, yield 48%).
Reaction SMILES: FC(F)(F)C1C=C(C=CC=1)OC([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)C#N.C(NCCO)(=O)C.Cl.Cl.[F:31][C:32]([F:59])([F:58])[C:33]1[CH:34]=[C:35]([CH:55]=[CH:56][CH:57]=1)[O:36][C:37](=NC1C=CC(Cl)=CC=1)[C:38]([O:40][CH2:41][CH2:42][NH:43][C:44](=[O:46])[CH3:45])=[O:39]>CN(C)C=O.O.C(Cl)Cl>[F:59][C:32]([F:31])([F:58])[C:33]1[CH:34]=[C:35]([CH:55]=[CH:56][CH:57]=1)[O:36][CH:37]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:38]([O:40][CH2:41][CH2:42][NH:43][C:44](=[O:46])[CH3:45])=[O:39]
Reactant: N#CC(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Reactant: CC(=O)NCCOC(=O)C(=Nc1ccc(Cl)cc1)Oc1cccc(C(F)(F)F)c1
Agent: CC(=O)NCCO
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC(=O)NCCOC(=O)C(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Reaction time: 5 h
Yield: 25 %

Procedure:
(3-Trifluoromethylphenoxy)(4-chlorophenyl)acetonitrile is added to a solution of 2-acetamidoethanol (20.6 g., 0.2 mole) in anhydrous dimethylformamide (25 ml.). The reaction mixture is cooled to -10°C. and saturated with hydrogen chloride (50 g., 1.37 mole) and stirred for 5 hours at -10° to 0°C. To this reaction mixture containing 2-acetamidoethyl (3-trifluoromethylphenoxy)(4-chlorophenyl)iminoacetate hydrochloride is added methylene chloride (200 ml.) and then water (100 ml.). The organic layer is collected, washed with water (2 × 100 ml.) and then dried over magnesium sulfate. The dried solution is decolorized with carbon, filtered and then slowly diluted with hexane (1 liter) to afford 10.7 g. (25% yield) of 2-acetamidoethyl (3-trifluoromethylphenoxy)(4-chlorophenyl)acetate, m.p. 93°-95°C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([CH3:10])[C:3]=1[O:11][C:12](=[O:23])[CH2:13][NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:44]>ClCCl>[Br:44][CH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([O:11][C:12](=[O:23])[CH2:13][NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:4]([CH3:10])[CH:5]=1
Reactant: Cc1cc(CO)cc(C)c1OC(=O)CNCC(=O)OC(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(CBr)cc(C)c1OC(=O)CNCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A mixture of 2.88 g of 4-(tert-butoxycarbonylmethylamino)acetoxy-3,5-dimethylbenzaldehyde and 0.34 g of sodium borohydride in 25 ml of tetrahydrofuran was stirred for 2 h at room temperature. The mixture was diluted with ethyl acetate and was washed with 0.25N HCl. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain (tert-butoxycarbonylmethylamino)acetic acid 2,6-dimethyl-4-hydroxymethylphenyl ester (2.9 g) as a colourless syrup. To a solution of 2.8 g of (tert-butoxycarbonylmethylamino)acetic acid 2,6-dimethyl-4-hydroxymethylphenyl ester and 2.73 g of triphenylphosphine in 30 ml of dichloromethane, 3.44 g of carbon tetrabromide was added and the mixture was stirred for 1 h at room temperature. The mixture was concentrated and the residue was chromatographed on silica gel (Wakogel C-200, solvent: CH2Cl2)to obtain (tert-butoxycarbonylmethylamino)acetic acid 4-bromomethyl-2,6-dimethylphenyl ester (2.97 g, 89% ) as a colourless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:8]=2[C:9](OCC)=[O:10])=[CH:3][N:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:8]=2[CH2:9][OH:10])=[CH:3][N:2]=1
Reactant: CCOC(=O)c1ccc(C(F)(F)F)cc1-c1ccnnc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(C(F)(F)F)cc1-c1ccnnc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To a solution of ethyl 2-pyridazin-4-yl-4-(trifluoromethyl)benzoate (Preparation 31, 510 mg, 1.72 mmol) in tetrahydrofuran (15 mL) cooled to 0° C. was added lithium aluminium hydride (2.0 M in tetrahydrofuran, 0.86 mL, 1.72 mmol) dropwise. The reaction was stirred for 1 hour at 0° C. before warming to room temperature and stirring for a further 2 hours. The reaction was re-cooled to 0° C. before excess lithium aluminium hydride was quenched by the addition of water (65 μL), 2M aqueous solution of sodium hydroxide (130 μL) and further water (195 μL). Diethyl ether and anhydrous magnesium sulphate were added to aid the formation of a granular solid which was filtered. The organics were concentrated in vacuo and re-dissolved in dichloromethane (5 mL). The organics were purified by silica gel column chromatography (ISCO™ companion, 40 g column, eluting with 100% heptane to 100% ethyl acetate to 5% methanol in ethyl acetate). Fractions containing product were combined and concentrated in vacuo to obtain the title compound as a yellow solid (197 mg, 45%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([C@H:23]([CH2:27]C)[C:24](O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:24](=[O:25])[C@H:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:27])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: CC[C@H](C(=O)O)c1ccccc1
Product: C[C@H](C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and substituting (S)-2-phenylpropanoic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (500 MHz, CDCl3) δ ppm 7.38-7.26 (m, 8H), 7.25-7.20 (m, 2H), 5.20 (d, J=6.7, 1H), 4.03-3.91 (m, 1H), 3.60 (d, J=13.0, 1H), 3.52-3.43 (m, 2H), 2.54 (dd, J=5.7, 13.8, 2H), 2.43 (dd, J=7.1, 16.0, 1H), 2.29-2.23 (m, 1H), 2.22-2.08 (m, 2H), 1.98 (ddd, J=5.8, 11.9, 15.7, 1H), 1.74-1.60 (m, 1H), 1.50 (t, J=6.4, 3H), 1.44-1.30 (m, 2H); MS (ESI+) m/z 349 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O-:14])(=[O:13])=[O:12].[Na+:15].[CH3:16][O:17][CH2:18][CH2:19][OH:20].[OH-].[Na+]>[O-2].[O-2].[Mn+4].O>[CH3:16][O:17][CH2:18][CH2:19][O:20][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O-:14])(=[O:13])=[O:12].[Na+:15]
Reactant: COCCO
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)[O-])c1
Agent: [Mn+4]
Agent: [Na+]
Agent: [O-2]
Solvent: O
Product: COCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)[O-]
Temperature: 75 °C
Reaction time: 0.67 h

Procedure:
5.2 g of sodium 2-chloro-5-nitrobenzenesulfonate, 0.6 g of manganese dioxide, 15 ml of methyl cellosolve, 1 ml of water, and 0.95 g of sodium hydroxide were mixed and stirred at 75° C. for 40 minutes. After cooling, insolubles were filtered, and the filtrate was poured into 100 ml of isopropyl alcohol. Crystals thus formed were collected by filtration to obtain 4.8 g of sodium 2-(2-methoxyethoxy)-5-nitrobenzenesulfonate. m.p. 238° to 239° C.
Reaction SMILES: O[CH:2]1[CH2:7][O:6][CH:5]([C:8]([O:10]CC)=[O:9])[CH2:4][CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH:2]12[CH2:3][CH2:4][CH:5]([O:6][CH2:7]1)[C:8](=[O:9])[O:10]2
Reactant: CCOC(=O)C1CCC(O)CO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1OC2CCC1OC2
Temperature: 25 °C

Procedure:
A mixture of the cis and trans isomers of ethyl 5-hydroxytetrahydropyran-2-carboxylate (3.9 g, 0.023 mol) was dissolved in dry toluene (200 ml). p-Toluene-sulfonic acid monohydrate (0.20 g, 1.1 mmol) was added as a catalyst. The mixture was refluxed for 7 hours through a Soxhlet extractor containing molecular Type A sieves in a thimble. The mixture was cooled to room temperature, and anhydrous sodium carbonate (5 g) was added to neutralize the acid. The solution was passed through a short pad of silica gel and concentrated. A brown viscous oil was subjected to column chromatography (column, silica gel; eluent, n-hexane/ethyl acetate, 1:1 v/v). The crude product thus isolated was purified by repeated recrystallization from a mixture of ethyl ether and n-hexane (5-20:1 v/v). The lactone has a melting point of 56°-57° C.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH:7]([N:16]([CH3:28])[C:17](=[O:27])[CH:18]=[C:19]2[C:23](=O)[O:22]C(C)(C)[O:20]2)[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33]>>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH:7]([N:16]([CH3:28])[C:17](=[O:27])[CH:18]=[C:19]([OH:20])[C:23]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])=[O:22])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: CN(C(=O)C=C1OC(C)(C)OC1=O)C(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Product: CN(C(=O)C=C(O)C(=O)NS(C)(=O)=O)C(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Yield: 72.2 %

Procedure:
Reaction of N-[1-(4-chlorobenzyl)-2-(4-chlorophenyl)-ethyl]-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (0.363 g, 0.81 mmol) with methanesulfonamide (0.077 g, 0.81 mmol) as described in the preparation of compound 22 gave 0.284 g (72% yield) of the title amide as a white solid. 1H NMR (400 MHz, DMSO) δ: mixture of rotamers: 2.5-3.5 (10H, m, CH3 and CH2), 4.55 and 5.1 (1H, broad m, CH), 5.8 (1H, s, CH), 7.1-7.4 (8H, m, aromatics).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[N+](C1C=CC([O:39][C:40]([NH:42][C@@H:43]([CH2:61][CH:62]2[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]2)[C@@H:44]([O:56][Si](C)(C)C)[CH2:45][NH:46][C:47](=[O:55])[O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])=O)=CC=1)([O-])=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:40]([NH:42][C@@H:43]([CH2:61][CH:62]3[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]3)[C@@H:44]([OH:56])[CH2:45][NH:46][C:47](=[O:55])[O:48][CH2:49][CH2:50][Si:51]([CH3:52])([CH3:54])[CH3:53])=[O:39])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCNC1
Reactant: C[Si](C)(C)CCOC(=O)NC[C@H](O[Si](C)(C)C)[C@H](CC1CCCCC1)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)[C@@H](O)CNC(=O)OCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a solution of (S)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (33.0 mg, 0.10 mmol) in CH2Cl2 (2 mL), DIEA (39 mg, 0.30 mmol) was added, followed by the solution of 2-(trimethylsilyl)ethyl (2S,3S)-3-(4-nitrophenoxycarbonylamino)-4-cyclohexyl-2-(trimethylsilyloxy)butylcarbamate in CH2Cl2 (0.8 mL, 0.2 mmol) prepared in the previous step. The resulting yellow solution was stirred at rt for 30 min, and completion of reaction was confirmed by LC-MS. Solvent was removed under vacuum, and the residue was purified by preparative HPLC to give 2-(trimethylsilyl)ethyl (2S,3S)-3-((R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-4-cyclohexyl-2-hydroxybutylcarbamate (25.8 mg, 38%); MS m/z 686 (M+H+).