Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9](=S)[NH:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)=[O:7])=[CH:4][CH:3]=1.[F:22][C:23]([F:31])([F:30])[C:24]1[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=1.CN(C)CCCN=C=NCC>CC(OC)(C)C.[Cl-].[Na+]>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]=[C:9]([NH:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)[NH:29][C:26]2[CH:25]=[C:24]([C:23]([F:31])([F:30])[F:22])[NH:28][N:27]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1cc(C(F)(F)F)[nH]n1
Reactant: O=C(NC(=S)Nc1cc(F)cc(Cl)c1)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: O=C(N=C(Nc1cc(F)cc(Cl)c1)Nc1cc(C(F)(F)F)[nH]n1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
A suspension of 4-chloro-N-((3-chloro-5-fluorophenyl)carbamothioyl)benzamide (20.5 g, 59.7 mmol) in TBME (500 mL) was heated to 50° C. 5-(Trifluoromethyl)-1H-pyrazol-3-amine (10.8 g, 71.7 mmol, 1.20 equiv) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) (17.6 g, 89.6 mmol, 1.50 equiv) were added. The resulting reaction mixture was stirred at 40° C. for 3 hr and then diluted with a saturated aqueous sodium chloride solution (0.5 L). The organic layer of the resulting mixture was isolated, dried (Na2SO4), filtered, and concentrated. The resulting residue was diluted with EtOAc (20 mL), and this mixture was warmed to 50° C., then diluted with heptane (20 mL). Next, the heat source was removed and the mixture was allowed to cool to room temperature, then an ice/water bath was applied to the reaction vessel to affect precipitation. The resulting solids were collected by filtration, rinsed with EtOAc/heptane (1/1 mixture by volume, 20 mL) and air dried at room temperature. Then, the solids were dissolved in EtOH (80 mL) and the resulting mixture warmed to 40° C. EtOH/water (1/1 mixture by volume, 80 mL) was added to the mixture slowly over 40 minutes. Then, the heat source was removed from the reaction vessel and the reaction mixture was allowed to stir at room temperature for 2 days. Then, the reaction mixture was filtered, collected solids were rinsed with EtOH/water (1/1 mixture by volume, 15 mL), and dried (60° C./10 Torr) to afford the title compound (15.2. g, 57% yield). 1H NMR (DMSO-d6) of the title compound: δ 13.3 (s, 1H), 10.7 (s, 1H), 10.0 (s, 1H), 7.90 (s, 1H), 7.90 (d, 2H, J=8.4), 7.72 (d, 1H, J=11.5), 7.63 (m, 3H), 7.07 (d, 1H, J=8.5), 6.00 (s, 1H). HPLC: 98.6% purity at 26.02 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]=2[CH:14]=1)#[N:2].O[CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:17]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:17]3)=[O:12])=[CH:8][C:7]=2[CH:14]=1)#[N:2]
Reactant: CCOC(=O)CCN1CCC(O)CC1
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Product: CCOC(=O)CCN1CCC(OC(=O)c2cc3cc(C#N)ccc3o2)CC1
Yield: 37.1 %

Procedure:
In the same manner as in Example 75 (2), 5-cyano-2-benzofurancarboxylic acid (1.00 g, 5.34 mmol) was converted a corresponding acid chloride and reacted with ethyl 3-(4-hydroxypiperidino)propionate (1.08 g, 5.77 mmol). The reaction mixture was purified by silica gel column chromatography (chloroform) to give 733 mg of ethyl 3-[4-[(5-cyano-2-benzofuranyl)carbonyloxy]piperidino]propionate as a colorless solid (33%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[S:18][CH:19]=[C:20]([C:22]([OH:24])=O)[N:21]=2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].CC[N:27]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O-])=O.[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[S:18][CH:19]=[C:20]([C:22]([NH2:27])=[O:24])[N:21]=2)[CH2:13][CH2:12]1)(=[O:10])=[O:9]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1csc(N2CCN(S(=O)(=O)c3ccccc3Cl)CC2)n1
Agent: O=C[O-]
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)c1csc(N2CCN(S(=O)(=O)c3ccccc3Cl)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
2-(4-(2-chlorophenylsulfonyl)piperazin-1-yl)thiazole-4-carboxylic acid (77 mg, 0.02 mmole), EDCI (39 mg, 0.02 mmole), HOBt (31 mg, 0.02 mmole) and ammonium formate (13 mg, 0.02 mmole) were combined in 1 ml of dry DMF. The mixture was treated with 1 equivalent of TEA and stirred at room temperature overnight. The title compound was obtained in yield of 37% after purification on preparative HPLC. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 3.41 (s, 1 H), 3.42-3.44 (m, 3 H), 3.53-3.56 (m, 3 H), 3.57 (s, 1 H), 6.02 (s, 1 H), 6.95 (s, 1 H), 7.38-7.44 (m, 2 H), 7.50-7.53 (m, 2 H), 8.02-8.07 (m, 1 H); ESI-MS: m/z 387.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl:13]N1C(=O)CCC1=O>C(#N)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[C:4]([Cl:13])=[CH:3]1
Reactant: Cn1ccc2cc(C=O)ccc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Cn1cc(Cl)c2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
N-Methylindol-5-carbaldehyde (400 mg, 2.5 mmol) was dissolved in dry acetonitrile (10 mL) and treated with N-chlorosuccinimide (400 mg, 3.02 mmol), whereupon the solution turned red. The reaction mixture was stirred at room temperature for 20 h. The solvent was removed in vacuum and the residue was purified by column chromatography (silica gel 60). Yield: 300 mg (1.55 mmol, 62%); colorless solid of mp 109° C.; Rf=0.27 (ethyl acetate/n-hexane 1:4); νmax (ATR)/cm−1 3103, 2845, 2751, 1680, 1602, 1454, 1414, 1362, 1343, 1274, 1238, 1196, 1160, 1134, 1111, 981, 894, 796, 717; 1H NMR (300 MHz, CDCl3) δ 3.75 (3H, s), 7.07 (1H, s), 7.32 (1H, d, J=8.6 Hz), 7.76 (1H, dd, J=8.6 Hz, J=1.5 Hz), 8.07 (1H, d, J=1.5 Hz), 10.01 (1H, s); 13C NMR (75.5 MHz, CDCl3) δ 32.9, 106.3, 109.9, 122.0, 123.3, 125.2, 126.9, 129.2, 138.5, 191.7; m/z (EI) 193 (100) [M+], 164 (57), 128 (43), 101 (48), 87 (28).
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[F:15][C:16]([F:30])([F:29])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([N:4]1[CH2:5][CH:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:25]([C:22]3[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][C:16]([F:15])([F:29])[F:30])=[CH:24][CH:23]=3)(=[O:27])=[O:26])=[CH:12][CH:13]=2)[CH2:7]1)[CH2:2][CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(CCC(F)(F)F)cc1
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(CCC(F)(F)F)cc3)cc2)C1
Yield: 11.7 %

Procedure:
Following the same procedure as described in example 55, 4-(1-propyl-azetidin-3-yl)phenylamine (100 mg, 0.52 mmol) in CH2Cl2/pyridine 9:1 (12 ml) was treated with 4-(3,3,3-trifluoro-propyl)-benzenesulfonyl chloride (214 mg, 0.78 mmol). Purification of the crude product by flash column chromatography (CH2Cl2:methanol, 95:5) provided the title compound (26 mg, 11%) as a colourless gum.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]([CH3:31])([C:19]([O:21][CH:22]3[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=CC=4)[CH2:23]3)=[O:20])[CH3:18])=[CH:10][CH:9]=2)[C:6](=[O:32])[CH:5]=[CH:4][C:3]=1[C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=1[F:41].CC(C(OC1CC2CC1CC2)=O)(C)N>>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][NH:16][C:17]([CH3:18])([C:19]([O:21][CH:22]3[CH2:23][CH:24]4[CH2:29][CH:30]3[CH2:26][CH2:25]4)=[O:20])[CH3:31])=[CH:12][CH:13]=2)[C:6](=[O:32])[CH:5]=[CH:4][C:3]=1[C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=1[F:41]
Reactant: CC(C)(NCCc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)cc1)C(=O)OC1Cc2ccccc2C1
Agent: CC(C)(N)C(=O)OC1CC2CCC1C2
Product: CC(C)(NCCc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)cc1)C(=O)OC1CC2CCC1C2

Procedure:
From Intermediate 2 and Intermediate 14.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1([CH2:18][OH:19])[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH2:9]1>C(Cl)Cl.[O-2].[Cr+4].[O-2]>[CH3:7][C:8]1([CH:18]=[O:19])[CH2:17][CH2:16][C:11]2([O:12][CH2:13][CH2:14][O:15]2)[CH2:10][CH2:9]1
Reactant: CC1(CO)CCC2(CC1)OCCO2
Agent: [Cr+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C=O)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
Under a nitrogen atmosphere, solid chromium (IV) oxide (84.7 mmol, 8.47 g, 6.6 eq.) was added to a stirred solution of extra dry pyridine (171 mmol, 14.53 mL, 13.3 eq.) in dry methylene chloride (123 mL) cooled to 0° C. in an ice bath. The resulting solution was stirred at room temperature for 15 minutes. To this mixture was then added a solution of 4 (12.83 mmol, 2.28 g) in dry methylene chloride (19 mL) and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was then decanted into a seperatory funnel and the residue was washed with ethyl ether (40 mL and 50 mL). The washings were combined and the organic layer was washed with 5% aqueous sodium hydroxide solution (2×40 mL), 5% aqueous hydrochloric acid solution (3×40 mL), saturated aqueous sodium bicarbonate solution (3×40 mL) and brine (3×40 mL), then dried over magnesium sulfate, filtered, and concentrated in vacuo to give 5 (12.24 mmol, 2.35 g, 95%) as an amorphous solid. The product was used in the next reaction without further purification: 1H NMR (CDCl3) δ 9.47 (1H, s), 3.95 (4H, s), 2.00-1.96 (2H, m), 1.71-1.67 (2H, m), 1.61-1.53 (4H, m), 1.05 (s, 3H); 13C NMR (CDCl3) δ 205.9, 108.4, 64.4, 64.4, 45.7, 31.4, 29.9, 21.2.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:15]1([N:21]=[C:22]=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:22]([NH:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:23])[CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(I)cc(N)cc1C(C)(C)C
Reactant: O=C=Nc1ccccc1
Product: COc1c(I)cc(NC(=O)Nc2ccccc2)cc1C(C)(C)C

Procedure:
3-tert-Butyl-5-iodo-4-methoxyaniline (305 mg, 1 mmol) and phenyl isocyanate (0.109 mL, 1.000 mmol) were reacted in the same manner as Example 15 Part A to give the title compound.
Reaction SMILES: FC1C(O[C:9](=[O:27])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[C:11]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=C(F)C(F)=C(F)C=1F.[Cl-].[OH:33][CH:34]1[CH2:38][O:37][NH2+:36][CH2:35]1.CN1CCOCC1.C(OCC)(=O)C>CN(C)C=O>[F:17][C:12]1[C:11]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:10]([C:9]([N:36]2[CH2:35][CH:34]([OH:33])[CH2:38][O:37]2)=[O:27])[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: OC1C[NH2+]OC1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
To a stirring solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid pentafluorophenyl ester (171 mg, 0.306 mmol) and 4-hydroxytetrahydroisoxazol-2-ium chloride (BIONET, 58 mg, 0.46 mmol) in dimethylformamide (2 mL) was added 4-methylmorpholine (0.1 mL, 0.91 mmol). The resultant reaction mixture was stirred at ambient temperature for 3 h. Ethyl acetate (50 mL) was added the mixture was washed with water (3×10 mL) and saturated brine solution (10 mL). The extracts were dried over magnesium sulfate and concentrated in vacuo. Chromatography (10% methanol-dichloromethane) afforded a tan-colored oil that solidified upon standing. Recrystallization from acetone-ether afforded [3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]-(4-hydroxy-isoxazolidin-2-yl)-methanone (61 mg, 43% yield) as a white powder: m.p. 122-124° C.; 1H NMR (400 MHz, Acetone-d6) δ 7.97 (br s, 1H), 7.51-7.45 (m, 2H), 7.38 (ddd, J=8.6, 1.7, 1.2 Hz, 1H), 7.12 (m, 1H), 6.68 (td, J=8.8, 5.2 Hz, 1H), 4.82 (m, 1H), 4.71 (br d, J=4.2 Hz, OH), 3.98 (dd, J=8.8, 4.2 Hz, 1H), 3.96-3.88 (m, 2H), 3.75 (dd, J=11.8, 0.9 Hz, 1H); 19F-NMR (376 MHz, Acetone-d6) δ −30.5, −135.4, −144.4. Anal Calcd/Found C16H12F3IN2O3: C, 41.40/41.52; H, 2.61/2.53; N, 6.03/6.05.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([N:24]2[CH:28]=[N:27][N:26]=[CH:25]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([N:24]2[CH:25]=[N:26][N:27]=[CH:28]2)[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([Br:23])=[CH:21][CH:22]=2)=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(N(Cc2ccc(Br)cc2)n2cnnc2)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(N(Cc2ccc(Br)cc2)n2cnnc2)cc1

Procedure:
0.28 Milliliter of acetic anhydride was added to ml of a pyridine solution containing 0.35 g of 4-[N-(4-aminophenyl)-N-(4-bromobenzyl)amino]-4H-1,2,4-triazole at room temperature and the mixture was stirred for about minutes. After reaction, the solvent was removed by distillation under reduced pressure, and a proper amount of an aqueous sodium hydrogen carbonate solution was added to the resulting residue, which was then extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography to obtain 0.33 g of 4-[N-(4-acetylaminophenyl)-N-(4-bromobenzyl)amino]-4H-1,2,4-triazole from the chloroform/methanol (50/1) eluate.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][O:8][CH2:9][N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH2:19])C(=O)C2=CC=CC=C12.O.NN.C(O)C>COCCO>[NH2:5][CH2:6][CH2:7][O:8][CH2:9][N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][CH:13]=[N:14][C:15]=2[NH2:19]
Reactant: Nc1ncnc2c1ncn2COCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: COCCO
Solvent: O
Product: NCCOCn1cnc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.1 %

Procedure:
A mixture of 9-(2-phthalimidoethoxymethyl)adenine (3.38 g), hydrazine hydrate (1.0 ml of an 85% aqueous solution) and ethanol (150 ml) was heated at reflux for 2 hours. 2-Methoxyethanol (50 ml) was added and refluxing continued for an additional 2 hours. The solvent was removed under reduced pressure and 1 N hydrochloric acid (50 ml) added. The mixture was stirred at ambient temperature for 30 minutes and allowed to stand at 0° C. overnight. The solution was filtered and the filtrate diluted with water (100 ml) and stirred with excess basic ion exchange resin {Rexyn 201(OH)} until a negative silver nitrate test was obtained. It was then filtered and most of the water removed under reduced pressure. The aqueous solution was cooled and the resulting solid removed by filtration. This was recrystallized from isopropanol to give 9-(2-aminoethoxymethyl)adenine (1.0 g), m.p. 170°-171° C.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([F:11])=[CH:7][CH:8]=2)/[C:3]/1=[CH:12]/[C:13]([NH2:15])=[O:14].C(COC)[O:17]C>O.[N+]([O-])([O-])=O.[Ag+]>[F:11][C:6]1[CH:5]=[C:4]2[C:9]([CH2:10][CH:2]([OH:17])/[C:3]/2=[CH:12]\[C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1
Reactant: COCCOC
Reactant: NC(=O)/C=C1/c2cc(F)ccc2CC1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: NC(=O)/C=C1/c2cc(F)ccc2CC1O
Yield: 28 %

Procedure:
A mixture of (Z)-2-(2-bromo-6-fluoro-1-indanylidene)acetamide (5.30 g, 19.25 mmoles) and silver nitrate (10.40 g, 61.18 mmoles, Aldrich) in dimethoxyethane (265 mL) and water (100 mL) was refluxed for 18 hours. The mixture was filtered, and the filtrate was diluted with water (700 mL) and extracted with ethyl acetate (6×100 mL). The combined extracts were washed with water (200 mL) and brine (200 mL), dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with hexane ethyl acetate (2:1), gradually increasing the polarity to hexane:ethyl acetate (1:1). The fractions containing the compound with Rf=0.18 were combined and evaporated in vacuo to give 1.13 g (28%) of crude (Z)-2-(6-fluoro-2-hydroxy-1-indanylidene)acetamide as an orange solid. Recrystallization from ethyl acetate:hexane mixtures gave 0.49 g (12%) of (Z)-2-(6-fluoro-2-hydroxy-1-indanylidene)acetamide as an off-white solid, mp 201-202° C.;
Reaction SMILES: [ClH:1].Cl.CN[C@@H]1CCCN(C2CCCCC2(C(C2C=CC=C(OC(F)(F)F)C=2)C)O)C1.[OH:31][C:32]1([CH:38]([C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([O:61][C:62]([F:65])([F:64])[F:63])[CH:56]=2)[C:39]([N:41]2[CH2:46][CH2:45][CH2:44][C@@H:43]([NH:47][C:48](=O)OC(C)(C)C)[CH2:42]2)=O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[ClH:1].[ClH:1].[CH3:48][NH:47][C@@H:43]1[CH2:44][CH2:45][CH2:46][N:41]([CH2:39][CH:38]([C:32]2([OH:31])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)[C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([O:61][C:62]([F:63])([F:64])[F:65])[CH:56]=2)[CH2:42]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(C(=O)C(c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)C1
Agent: CN[C@@H]1CCCN(C2CCCCC2(O)C(C)c2cccc(OC(F)(F)F)c2)C1
Agent: Cl
Product: CN[C@@H]1CCCN(CC(c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)C1

Procedure:
In an analogous manner to Example 13, step 2 1-{2-[(3R)-3-(methylamino)piperidin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethylcyclohexanol dihydrochloride was prepared from tert-butyl ((3R)-1-{(1-hydroxycyclohexyl)[3-(trifluoromethoxy)phenyl]acetyl}piperidin-3-yl)carbamate. MS m/z 401; HRMS: calcd for C21H31F3N2O2+H, 401.24159; found (ESI, [M+H]+), 401.2406.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[N:27]([CH2:35][CH2:36][OH:37])[C:28](=O)[O:29]C(C)(C)C)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[CH:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[N:27]3[CH2:35][CH2:36][O:37][C:28]3=[O:29])[N:14]=2)=[CH:4][C:3]=1[C:1]#[N:2])([CH3:12])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N(CCO)C(=O)OC(C)(C)C)no2)cc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N3CCOC3=O)no2)cc1C#N
Reaction time: 20 h
Yield: 29 %

Procedure:
To a stirred solution of (R)-tert-butyl (4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)(2-hydroxyethyl)carbamate INT-22 in DMF (1 mL) was added NaH (6 mg, 0.15 mmol, of a 60% solution in mineral oil). After stirring for 20 h, the reaction mixture was diluted with EA and washed with NaHCO3. The combined aqueous extracts were back-extracted with EA. The combined organic extracts were dried over Na2SO4, concentrated, and purified by column chromatography (EA/hexanes) to provide 11.9 mg (29%) of (R)-2-isopropoxy-5-(3-(1-(2-oxooxazolidin-3-yl)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile 154. LCMS-ESI (m/z) calculated for C22H22N4O4: 430.5; found 431.1 [M+H]+, tR=3.72 min. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=2.2 Hz, 1H), 8.34 (dd, J=8.9, 2.2 Hz, 1H), 8.14 (t, J=4.4 Hz, 1H), 7.42 (m, 2H), 7.13 (d, J=9.0 Hz, 1H), 5.72-5.57 (m, 1H), 4.80 (dt, J=12.2, 6.1 Hz, 1H), 4.35 (qt, J=15.7, 7.8 Hz, 2H), 3.56-3.39 (m, 2H), 3.25 (dtd, J=24.4, 8.6, 7.1 Hz, 2H), 2.65-2.48 (m, 1H), 2.10 (ddt, J=13.7, 9.0, 7.1 Hz, 1H), 1.48 (d, J=6.1 Hz, 6H). Compound 155 was made in an analogous fashion.
Reaction SMILES: C[Al](C)C.[O:5]1[C@H:9]2[O:10][CH2:11][CH2:12][C@H:8]2[C:7](=[O:13])[CH2:6]1.[Si](C=[N+]=[N-])(C)(C)[CH3:15].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl.C1COCC1.CC(O)=O>[O:10]1[C@@H:9]2[O:5][CH2:6][C:7](=[O:13])[CH2:15][C@@H:8]2[CH2:12][CH2:11]1
Reactant: O=C1CO[C@H]2OCC[C@@H]12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Al](C)C
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1CO[C@H]2OCC[C@H]2C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63.3 %

Procedure:
AlMe3 (25% w/w hexanes, 250 μL, 0.6 mmol) was diluted in dry CH2Cl2 (5 mL) under argon and the solution was cooled to −78° C. A solution of ketone 28 (64 mg, 0.5 mmol) in dry CH2Cl2 (5 mL) was slowly added dropwise. After 10 min, TMSCHN2 (2 M solution in Et2O, 275 μL, 0.55 mmol) was added. The reaction was stirred for 2 h while warmed to −30° C. Saturated Rochelle's salts solution (5 mL) was added and the mixture was stirred for 1 h. The phases were separated, the aqueous phase extracted with CH2Cl2, and the combined organic phase was dried (MgSO4). The solution was filtered on a small silica gel pad, flushing with Et2O, and the collected organic phase evaporated. A crude mixture of the desired ketone along with α-silylated derivatives and isomers was then obtained. The mixture was re-dissolved in THF (5 mL). AcOH (6 drops) and TBAF (0.5 mL, 0.5 mmol) were successively added. The resulting mixture was stirred at 23° C. for 3 h and evaporated to dryness. The residue was purified by flash column chromatography on silica gel using hexanes/EtOAc (5:1) as the eluent to give ketone 29 (45 mg, 63%). TLC: Rf=0.35 (hexanes/EtOAc=2:1); 1H NMR (CDCl3, 400 MHz) δ 5.49 (d, J=6.8 Hz, 1H), 4.11 (d, J=18.2 Hz, 1H), 4.10 (m, 1H), 3.92 (d, J=18.2 Hz, 1H), 3.74 (dt, J=6.5, 8.9 Hz, 1H), 2.85 (m, 1H), 2.71 (d, J=6.3, 15.6 Hz, 1H), 2.48 (d, J=3.9, 15.6 Hz, 1H), 2.15 (m, 1H), 1.55 (ddt, J=7.7, 8.9, 12.7 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 210.7, 100.9, 67.5, 67.1, 39.2, 36.2, 31.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](Cl)=[O:13])[CH:6]=[CH:5]2.[Si]([CH:19]=[N+:20]=[N-:21])(C)(C)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](=[O:13])[CH:19]=[N+:20]=[N-:21])[CH:6]=[CH:5]2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(Cl)c1ccc2cc(Br)ccc2c1
Solvent: ClCCl
Product: [N-]=[N+]=CC(=O)c1ccc2cc(Br)ccc2c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
6-Bromonaphthalene-2-carbonyl chloride (27.0 g, crude) was dissolved in dichloromethane (330 mL) and cooled to 0° C. TMS diazomethane solution (100 mL, 2 M in DCM) was added, and ice bath was removed. Reaction mixture was stirred for 16 hours and evaporated under vacuum, giving 1-(6-bromonaphthalen-2-yl)-2-diazoethanone (34.7 g, crude) as an orange solid.
Reaction SMILES: [N:1]([CH:4]([C:11]1([CH3:15])[CH2:14][O:13][CH2:12]1)[C:5]1[O:6][C:7]([CH3:10])=[CH:8][CH:9]=1)=[N+]=[N-].[H][H]>C(O)C.[Pd]>[CH3:10][C:7]1[O:6][C:5]([CH:4]([NH2:1])[C:11]2([CH3:15])[CH2:12][O:13][CH2:14]2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(C(N=[N+]=[N-])C2(C)COC2)o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(N)C2(C)COC2)o1
Yield: 97.9 %

Procedure:
A solution of 1.68 g (8 mmol, 1 eq) of 2-[azido-(3-methyloxetan-3-yl)methyl]-5-methylfuran in 30 ml of ethanol in the presence of 252 mg (15% by weight) of palladium on carbon at 10% was stirred at hydrogen atmospheric pressure for 3 hours. The reaction medium was filtered and the filtrate was evaporated. 1.42 g of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine were obtained in the form of a greenish oil. Yield=98%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[NH:16]1[C:20]([C:21]2[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=2)=[N:19][N:18]=[N:17]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]4[NH:19][N:18]=[N:17][N:16]=4)[CH:22]=3)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Br)cc12
Product: Cc1c(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)sc2ccc(Br)cc12
Yield: 47.6 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 5-bromo-3-methylbenzothiophene-2-sulfonyl chloride (Intermediate 10) (510 mg, 1.57 mmol) and [3-(1H-tetrazol-5-yl)phenyl]amine (230 mg, 1.4 mmol) giving 300 mg (27%) of the title compound. MS (ESI+) calcd for C16H12BrN5O2S2 448.961579, found 448.961839.