Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20](C(OCC3C=CC=CC=3)=O)[CH3:21])[C:12]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][NH:20][CH3:21])[C:12]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Agent: Cl
Solvent: CCO
Product: CNCCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.6 %

Procedure:
2.71 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are dissolved in 30 ml of ethanol, and the solution is saturated with gaseous hydrogen chloride under ice-cooling. The saturated solution is stirred at room temperature for 20 hours. The solution is evaporated under reduced pressure at a temperature below 35° C. to remove solvent. The residue is dissolved in benzene, and the solution is extracted with conc. HCl-H2O. The aqueous layer is collected, washed with benzene, alkalized with potassium carbonate and then extracted with chloroform. The extract is washed with water, dried and then evaporated to remove solvent. Isopropyl ether is added to the residue, and crystalline precipitates are collected by filtration. 1.83 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH2:15])[C:8]=2[N:16]=1)[CH3:2].[N:25]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:17][CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([C:31]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:32])[CH2:23][CH2:24]2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH2:15])[C:8]=2[N:16]=1)[CH3:2]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCNCC1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCN(C(=O)N2CCOCC2)CC1
Yield: 61.3 %

Procedure:
Using the general method of Example 11 Part H, 2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amine (0.304 g, 0.917 mmol) was reacted with 4-morpholinecarbonyl chloride (0.107 mL, 0.917 mmol) to provide 0.250 g of 2-(ethoxymethyl)-6,7-dimethyl-1-{2-[1-(morpholin-4-ylcarbonyl)piperidin-4-yl]ethyl}-1H-imidazo[4,5-c]pyridin-4-amine as an yellow orange solid, m.p. 158.1-160.5° C.
Reaction SMILES: CS([C:5]1[O:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[C:14]=3[CH:29]=2)=[N:8][N:9]=1)(=O)=O.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:26][C:25]([F:28])([F:27])[O:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[C:14]3[CH:29]=[C:10]([C:7]4[O:6][C:5]([N:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[N:9][N:8]=4)[CH:11]=[CH:12][C:13]=3[O:17][CH:16]=2)=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)c1nnc(-c2ccc3occ(-c4ccc(OC(F)(F)F)cc4)c3c2)o1
Reactant: C1CNCCN1
Product: FC(F)(F)Oc1ccc(-c2coc3ccc(-c4nnc(N5CCNCC5)o4)cc23)cc1
Yield: 20 %

Procedure:
In the same manner as in Example 110 and using 2-(methylsulfonyl)-5-[3-[4-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole instead of 2-(2,3-dihydro-1-benzofuran-5-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole and using piperazine instead of 3-fluorobenzylalcohol, the title compound (yield 20%) was obtained as colorless crystals.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:13][C:14]1[C:18]([CH2:19]Cl)=[CH:17][O:16][CH:15]=1>CN(C)C=O>[C:1]([N:9]1[CH2:13][C:14]2=[CH:15][O:16][CH:17]=[C:18]2[CH2:19]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1cocc1CCl
Reactant: NC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1Cc2cocc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of benzamide (1.38 g) in N,N-dimethylformamide (40 mL) at 0° C., sodium hydride (1.37 g, 60%) was added. The mixture was stirred at ambient temperature for 10 min followed by addition of 3,4-bis(chloromethyl)furan (1.88 g). The resulting mixture was stirred for two days, diluted with ice-water (50 mL) and extracted with ethyl acetate (3×20 mL). The combine organic layers were dried over anhydrous sodium sulfate, filtered and evaporated and purified on a Biotage Horizon® system (silica, ethyl acetate/hexane 40/60) to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH:30]1[O:32][CH2:31]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CO>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH:30]([OH:32])[CH2:31][S:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)CSc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 77 %

Procedure:
4-Nitrothiophenol (1.21 g) and triethylamine (0.91 ml) were added to (2S)-1-(t-butoxycarbonyl)-2-(1,2-epoxyethyl)-pyrrolidine (1.39 g) as obtained in Example 1-A) in methanol (50 ml), and the mixture was stirred for 2 hours under reflux. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluate : hexane-ethyl acetate) to give 1.85 g of the title compound. B) (2S)-1-(N-Benzyloxycarbonyl-L-prolyl)-2-[1-hydroxy-2-(4-nitrophenylthio)ethyl]pyrrolidine
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[CH2:43][CH2:44][N:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1>C1COCC1>[N:45]1([CH2:44][CH2:43][O:10][C:3]2[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=2)[CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: OCCN1CCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCCN2CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
A solution of 10 g of p-nitrophenol (72 mmol) in 100 mL dry THF was treated with 28.28 g (108 mmol) of triphenyl phosphine. The solution was cooled to 0° C. then treated with 18.78 g (108 mmol) diethyl azodicarboxylate. After stirring for 30 min at 0° C., 12.4 g (108 mmol) 1-(2-hydroxyethyl)pyrrolidine was added. The cooling bath was removed and the reaction allowed to stir overnight at ambient temperature. EtOAc was added (300 mL) and the mixture was extracted twice with 200 mL 1 N H2SO4. The combined extracts were washed twice with 200 mL EtOAc, made basic with 5 N NaOH and extracted three times with 150 mL EtOAc. The extracts were dried over MgSO4 and concentrated under vacuum to an oil which was purified by chromatography (SiO2 ; 1% MeOH in CHCl3) to recover 7.56 g (32 mmol, 44%) of the desired compound as a solid.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([N+:35]([O-])=O)[CH:31]=3)[N:26]([CH3:38])[C:25]2=[O:39])[CH2:20][CH2:19]1>[Fe].O>[NH2:35][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH3:38])[C:25](=[O:39])[N:24]([CH:21]1[CH2:20][CH2:19][N:18]([C:9]3[C:8]4[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([O:5][CH3:4])[CH:7]=4)[N:12]=[CH:11][N:10]=3)[CH2:23][CH2:22]1)[C:33]2=[O:34]
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)c5cc([N+](=O)[O-])ccc5n(C)c4=O)CC3)c2cc1OC
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc(N)ccc5n(C)c4=O)CC3)c2cc1OC
Yield: 58.3 %

Procedure:
In a solvent mixture of 15 ml of ethanol and 5 ml of water was dissolved 500 mg (1.02 mmol) of Compound 1 obtained in Example 1, and 500 mg of iron and a catalytic amount of ferric chloride were added thereto, followed by heating under reflux for 1 hour. The reaction mixture was filtered while hot by using a filter aid, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was washed and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=50/1) and recrystallized from ether to give 275.2 mg (yield: 63%) of Compound 14 as pale yellow crystals.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:5]=1)(=O)[CH3:2].Cl.[CH3:27][O:28][NH2:29].N1C=CC=CC=1>O1CCOCC1>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[S:8][C:4]([C:1](=[N:29][O:28][CH3:27])[CH3:2])=[CH:5][C:6]=2[C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)=[CH:10][CH:11]=1
Reactant: CC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CON=C(C)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
A mixture of 5-acetyl-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (1.35 g), methoxyamine hydrochloride (0.45 g) and pyridine (0.44 ml) in dioxane (17 ml) was stirred at ambient temperature for 1 hour. The mixture was concentrated, and the residue was triturated with water, filtered, washed with water and dried. The crude crystals were recrystallized from ethyl acetate to give pure crystals of 2-(4-fluorophenyl)-5-[-1-(methoxyimino)ethyl]-3-[4-(methylsulfonyl)phenyl]thiophene (0.68 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[C:4](/[CH3:28])=[CH:5]/[C:6]1[CH:27]=[CH:26][C:9]2[C:10]3[N:14]([CH2:15][CH2:16][O:17][C:8]=2[CH:7]=1)[CH:13]=[C:12]([C:18]1[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=1)[N:11]=3>[Pd]>[CH3:1][O:2][C:3](=[O:29])[CH:4]([CH3:28])[CH2:5][C:6]1[CH:27]=[CH:26][C:9]2[C:10]3[N:14]([CH2:15][CH2:16][O:17][C:8]=2[CH:7]=1)[CH:13]=[C:12]([C:18]1[N:19]([CH:23]([CH3:24])[CH3:25])[N:20]=[CH:21][N:22]=1)[N:11]=3
Reactant: COC(=O)/C(C)=C/c1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Agent: [Pd]
Product: COC(=O)C(C)Cc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.5 %

Procedure:
To a solution of (E)-3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-2-methyl-acrylic acid methyl ester (181 mg, 0.46 mmol) in IMS (10 mL) was added palladium on carbon (200 mg, 10%). The reaction was stirred at RT under an atmosphere of hydrogen for 16 h. More palladium on carbon (200 mg, 10%) was added and the reaction stirred at RT under an atmosphere of hydrogen for a further 16 h. The reaction mixture was filtered and the filtrate concentrated in vacuo to give 3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-2-methyl-propionic acid methyl ester as a yellow oil (150 mg, 82%). LCMS: RT=3.40 min, [M+H]+=396.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10](S(C3C=CC=CC=3)(=O)=O)[CH:9]=2)[CH:5]=[C:4]([Cl:26])[N:3]=1.[F:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:29]=1[C:30]([NH2:32])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:26][C:4]1[N:3]=[C:2]([NH:32][C:30](=[O:31])[C:29]2[C:28]([F:27])=[CH:36][CH:35]=[CH:34][C:33]=2[F:37])[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:5]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(Cl)c2)c2cccnc21
Reactant: NC(=O)c1c(F)cccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1)c1c(F)cccc1F
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 8.9 %

Procedure:
A mixture of Example 7a (0.100 g, 0.247 mmol), 2,6-difluorobenzamide (0.066 g, 0.421 mmol), cesium carbonate (0.105 g, 0.322 mmol), palladium (II) acetate (2.78 mg, 0.012 mmol), and Xantphos (10.73 mg, 0.019 mmol) in dioxane (3 mL) and DMF (0.1 mL) was heated at 150° C. for 30 minutes in a Biotage microwave reactor. The mixture was concentrated. The solid was suspended in dioxane (3 mL), treated with NaOH (20%, 0.10 mL), and heated at 50° C. for 3 hours. The reaction mixture was concentrated. The residue was stirred in water for 15 minutes, filtered, and purified by reverse-phase HPLC as described in Example 56 to give the title compound (8.5 mg) as trifluoroacetic acid salts. 1H NMR (500 MHz, DMSO-d6) ppm 7.24 (t, J=8.24 Hz, 2H), 7.30 (dd, J=8.09, 4.73 Hz, 1H), 7.52-7.65 (m, 2H), 7.70 (s, 1H), 8.34-8.41 (m, 3H), 8.65 (s, 1H), 11.66 (s, 1H), 12.41 (s, 1H). MS (ESI+) m/z 384.9 (M+H)+.
Reaction SMILES: [CH2:1]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C:14]4[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[CH:18][C:19]=4[CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])[CH2:2][CH2:3][CH3:4].[Li].N.C(O)C>O1CCCC1.CCOCC.O>[CH2:1]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C:14]4[CH2:15][CH:16]=[C:17]([O:22][CH3:23])[CH2:18][C:19]=4[CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCCC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(OC)=CC4

Procedure:
Add 13β-n-butyl-3-methoxy-gona-1,3,5(10)-trien-17β-ol (0.5 g.) in a mixture of tetrahydrofuran (5 cc.) and ether (15 cc.) dropwise to a stirred solution of lithium (0.5 g.) in liquid ammonia (60 cc.). After 5 minutes beyond completion of addition, add ethanol (8 cc.) dropwise and when the blue color is discharged, add water and extract the mixture with ether. Work up in the usual way to give 13β-n-butyl-3-methoxy-gona-2,5(10)-dien17β-ol as a crystalline solid, m.p. 135°-9°; infrared absorption peaks at 2.97, 6.25, 6.38 and 8.16 μ.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:13])[CH3:12])=[O:4].[CH3:20][C:21]1[CH2:26][O:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH:22]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N(Cl)C(=O)C1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][C:9]=1[N:10]([CH:11]([CH3:13])[CH3:12])[C:27]([CH:24]1[CH2:23][CH:22]=[C:21]([CH3:20])[CH2:26][O:25]1)=[O:28])=[O:4]
Reactant: CC1=CCC(C(=O)O)OC1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)C
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CC=C(C)CO1)C(C)C
Yield: 65.3 %

Procedure:
The coupling of 3-isopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (63.3 mg, 0.23 mmol) and 5-methyl-3,6-dihydro-2H-pyran-2-carboxylic acid (40 mg, 0.28 mmol) using PPh3 (78.6 mg, 0.3 mmol) and NCS (39.9 mg, 0.3 mmol) furnished 3-[isopropyl-(5-methyl-3,6-dihydro-2H-pyran-2-carbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (60 mg, 65.3% yield). NMR 1H (CDCl3, 400 MHz, for major rotamer): 7.68-7.62 (m, 2H), 7.4-7.5 (m, 3H), 7.22 (s, 1H), 5.46 (m, 1H), 3.86 (s, 3H), 1.48 (s, 3H), 1.24 (d, 3H), 1.0 (d, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=2[CH3:29])[CH2:19][CH2:18]1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([CH3:12])[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=3[CH3:29])[CH2:19][CH2:18]2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: C[C@@H](C(=O)O)c1ccc(Cl)cc1
Solvent: CO
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)[C@H](C)c2ccc(Cl)cc2)CC1

Procedure:
Example 167 was prepared from (2R)-2-(4-chlorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12; [α]D=−9.3° (C=1.65, MeOH): 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1 H), 7.36–7.24 (m, 4 H), 7.22–7.12 (m, 2 H), 7.08 (d, 1 H, J=8.0 Hz), 6.92 (s, 1 H), 3.53 (q, 1 H, J=7.2 Hz), 3.42–3.23 (m, 2 H), 2.95 (ABq, 2 H), 2.73–2.59 (m, 1 H), 2.57–2.43 (m, 1 H), 2.42–2.33 (m, 2 H), 2.28 (s, 3 H), 2.08–1.92 (m, 2 H), 1.86–1.56 (m, 6 H), 1.51 (d, 3 H, J=7.2 Hz), 1.24 (d, 6 H, J=6.8 Hz); ESMS m/e: 484.3 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].C(N(CC)CC)C.Cl[C:41]([O:43][C:44]1[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=1)=[O:42].O>ClCCl.C1(C)C=CC=CC=1>[C:15]([C:14]1[C@@H:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[S:29]([CH3:32])(=[O:31])=[O:30])[N:10]([C:41]([O:43][C:44]2[CH:45]=[CH:46][C:47]([N+:50]([O-:52])=[O:51])=[CH:48][CH:49]=2)=[O:42])[C:11](=[O:28])[N:12]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:13]=1[CH3:17])#[N:16]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (1.00 g, 2.17 mmol; Example 6) and triethylamine (659 mg, 6.52 mmol) were, together with a spatula tip of 4-N,N-dimethylaminopyridine, suspended in dichloromethane (8.3 ml). 4-Nitrophenyl chloroformate (875 mg, 4.34 mmol) was then added. The resulting solution was stirred at room temperature for 5 min, and water (1 ml) was then added. Furthermore, toluene (7 ml) was added to the contents of the flask, and the mixture was concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (mobile phase: dichloromethane). The concentrated product fractions were triturated with ethanol (20 ml), and the resulting solid was filtered off with suction. This gave the target compound (559 mg, 39% of theory).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7](=O)[CH2:8][C@@H:9]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][C:20]=2[S:29]([C:32]([F:35])([F:34])[F:33])(=[O:31])=[O:30])[CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3][CH2:2]1.B.C1COCC1.Cl.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.CO>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C@@H:9]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:26])=[O:27])=[CH:21][C:20]=2[S:29]([C:32]([F:35])([F:33])[F:34])(=[O:31])=[O:30])[CH2:10][S:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)N2CCOCC2)c(S(=O)(=O)C(F)(F)F)c1
Agent: B
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
(R)-4-(4-morpholino-4-oxo-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 68, 2.01 g, 3.5 mmol) was dissolved in a solution of borane-THF complex (1M in THF, 8.0 ml, 8.0 mmol) and the resulting solution was stirred at room temperature overnight. The flask was opened to atmosphere and cautiously treated with MeOH (4.0 ml) followed by concentrated HCl (1.55 ml). The resulting mixture was heated at reflux for 3 hours and was then allowed to cool to room temperature. The pH of the mixture was adjusted to approximately 10 by the addition of aqueous solution of Na2CO3 (2 M) resulting in a precipitate. The mixture was dissolved in EtOAc (250 ml) and washed with water (125 ml), brine (125 ml), and dried (Na2SO4). Evaporation of the volatiles under reduced pressure afforded a concentrate, which was purified by column chromatography (ISCO, 80 g silica gel column, eluting with 0→100% EtOAc/hexanes) to provide the title product (1.33 g, yield: 68%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH:8]([NH2:10])[CH3:9])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[C:17]([O:21]C(=O)N[C@@H](C)COC1C=CC(F)=CC=1C(F)(F)F)(C)(C)[CH3:18].[ClH:40]>CO>[ClH:40].[F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C@@H:8]([NH:10][CH2:18][CH2:17][OH:21])[CH3:9])=[C:4]([C:13]([F:14])([F:15])[F:16])[CH:3]=1
Reactant: CC(N)COc1ccc(F)cc1C(F)(F)F
Reactant: C[C@@H](COc1ccc(F)cc1C(F)(F)F)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: C[C@@H](COc1ccc(F)cc1C(F)(F)F)NCCO
Reaction time: 4 h

Procedure:
Synthesis of (2S)-1-[(4-fluoro-2-(trifluoromethyl)phenoxy]propan-2-amine (C7). To a solution of tert-butyl{(2S)-1-[4-fluoro-2-(trifluoromethyl)phenoxy]propan-2-yl}carbamate (C6) (1.87 g, 5.54 mmol) in methanol (10 mL) was added a solution of hydrogen chloride (4 N in 1,4-dioxane, 5 mL). After 4 hours, the reaction mixture was concentrated in vacuo. The resulting residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution and water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0 to 20% methanol in ethyl acetate) afforded the title compound as a yellow liquid. Yield: 785 mg, 3.31 mmol, 60%. LCMS m/z 238.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.19 (d, J=6.5 Hz, 3H), 3.35-3.44 (m, 1H), 3.74 (dd, J=8.4, 7.4 Hz, 1H), 3.94 (dd, J=8.5, 4.0 Hz, 1H), 6.93 (dd, J=9.1, 4.2 Hz, 1H), 7.18 (br ddd, J=9, 8, 3 Hz, 1H), 7.30 (dd, J=8.4, 3.1 Hz, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2(O)[CH:11]3[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]3)[CH2:7]2)=[CH:2]1.C([SiH](CC)CC)C.[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(#N)C>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]2[CH:11]3[CH2:10][CH2:9][N:8]([CH2:13][CH2:12]3)[CH2:7]2)=[CH:2]1
Reactant: OC1(c2ccoc2)CN2CCC1CC2
Agent: CC[SiH](CC)CC
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC#N
Product: c1cc(C2CN3CCC2CC3)co1
Temperature: -30 °C
Yield: 13.6 %

Procedure:
A stirred solution of (±) 3-(fur-3-yl)-3-hydroxy-1-azabicyclo[2.2.2]octane (D20) (1.20 g, 0.0062 mole) in an acetonitrile (20 ml)/dichloromethane (10 ml) mixture was treated with triethylsilane (5.9 ml, 0.037 mole) and cooled to -30° C. under nitrogen. The solution was treated dropwise over 5 minutes with tin (IV) chloride (1.6 ml, 0.0136 mole) and then allowed to warm to room temperature over 0.5 h, before pouring into excess potassium carbonate solution and extracting with ethyl acetate (2×60 ml). The combined extracts were dried (Na2SO4), concentrated in vacuo and the residue eluted through a short basic alumina column with ether. The yellow oil obtained was then chromatographed on silica gel eluting with 0 to 20% methanol/chloroform to give the title compound (E10) as a pale yellow oil (150 mg, 10%). This was converted into its hydrochloride salt and recrystallised from methanol/ether m.p. 179°-182° C.