Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][C:29]([CH3:31])=[N:28][C:27]=2[C:32](O)=[O:33])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:32]([C:27]3[N:28]=[C:29]([CH3:31])[O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:33])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)o1
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(F)c3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[Br:38][C:39]1[CH:40]=[C:41]([C@H:49](O)[CH3:50])[CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1.CN(C1C=CC=CN=1)C>C1(C)C=CC=CC=1.ClCCl>[C:17]1([C:11]2([C:14]([O:16][C@@H:49]([C:41]3[CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=[C:39]([Br:38])[CH:40]=3)[CH3:50])=[O:15])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@@H](O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@@H](OC(=O)C1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1-(tert-butoxycarbonyl)-4-phenylpiperidine-4-carboxylic acid (3.8 g, 10.3 mmol) in a dichloromethane (5 mL) and toluene (30 mL) mixture was treated with 1,3-dicyclohexylcarbodiimide (2.96 g, 14.4 mmol) and stirred for 30 min. The suspension was cooled to 0° C. and treated with (R)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethanol (2.79 g, 10.3 mmol) and dimethylaminopyridine (1.26 g, 10.3 mmol). The ice bath was removed and the suspension stirred at room temperature for 60 h. The reaction mixture was poured into pentane, filtered, and the solids washed several times with pentane. The filtrate was washed with 1 N hydrochloric acid (1×), water (2×), then 1 N sodium hydroxide, then brine (2×), dried over sodium sulfate, and concentrated. Flash chromatography on silica gel (12% ethyl acetate/hexanes) gave 4.8 g (84%) as a light yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 7.58 (s, 1H), 7.23-7.33 (m, 6H), 7.19 (s, 1H), 5.80 (q, J=6.6 Hz, 1H), 3.82-3.97 (m, 2H), 2.97-3.09 (m, 2H), 2.44-2.53 (m, 2H), 1.76-2.01 (m, 2H), 1.42 (s, 9H), 1.40 (m, 3H). Mass spec.: 558.06 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[CH:24]1([N:29]2[CH2:32][CH2:31][CH:30]2[C:33]([O-])=[O:34])[CH2:28][CH2:27][CH2:26][CH2:25]1.[Li+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:33]([CH:30]2[CH2:31][CH2:32][N:29]2[CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:34])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=C([O-])C1CCN1C1CCCC1
Agent: [Li+]
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2CCN2C2CCCC2)CC1

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H and lithium 1-cyclopentylazetidine-2-carboxylate 201 carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-cyclopentylazetidine-2-carbonyl)pyrrolidine-2-carboxamide 1:1 epimers as a light brown solid (quant.). MS ISP (m/e): 505.2 (100) [(M+H)]]+.
Reaction SMILES: [C:1]([C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=1[C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13][N:12]=1)([O:3][CH3:4])=[O:2].[H-].[Na+].[CH3:24]I>O1CCCC1>[CH3:24][N:13]1[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:15][C:11]([C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=2[C:1]([O:3][CH3:4])=[O:2])=[N:12]1
Reactant: COC(=O)C1=C(c2cc(-c3ccccc3)[nH]n2)CCCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2cc(-c3ccccc3)n(C)n2)CCCC1

Procedure:
A mixture of 3.0 g 3-(2-carbomethoxy-1-cyclohexen-1-yl)-5-phenylpyrazole, 0.3 g of 50% sodium hydride-mineral oil slurry, and 1.0 g of methyl iodide in 50 ml of anhydrous tetrahydrofuran is stirred and refluxed overnite. The reaction mixture is filtered, and the solvent is evaporated from the filtrate to give 1-methyl-3-(2-carbomethoxy-1-cyclohexen-1-yl)-5-phenylpyrazole.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.O[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([O:9][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)[nH]cc2Cl)CC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 58.4 %

Procedure:
A 500 mL round bottom flask was charged with 5-chloro-4-hydroxypyridin-2(1H)-one (10 g, 68.7 mmol), t-butyl 4-hydroxypiperidine-1-carboxylate (16.59 g, 82 mmol), triphenylphosphine (27.0 g, 103 mmol) and DMF (200 ml). This mixture was stirred for 40 minutes to form a clear and homogeneous solution. The solution was then cooled to 0° C. and diisopropyl azodicarboxylate (16.23 mL, 82 mmol) was added drop-wise while maintaining the temperature below 20° C. during the addition. After the addition, the reaction mixture was allowed to warm to room temperature overnight. The reaction was then heated to 60° C. for 0.5 hours. After cooling the reaction mixture to room temperature, the DMF was distilled from the reaction under vacuum at 50° C. to yield brownish, viscous oil. The oil was dissolved in 300 mL of chloroform and then was washed with dilute sodium bicarbonate (pH 8-10) (3×50 mL). The chloroform layer was directly concentrated to afford a light yellow viscous oil, which was partitioned between 250 mL of diethyl ether and 70 mL of 1 N NaOH. The aqueous phase was extracted thoroughly with diethyl ether until LC/MS showed no triphenylphosphine oxide or other impurities in the aqueous layer. The aqueous layer was purged with nitrogen to remove residual ether and then acidified slowly with 1 N HCl (˜70 mL) to pH 5 followed by cooling to 0° C. for 2 hours. The precipitates were collected by filtration, washed with ice water (2×20 mL), and air dried overnight. The light yellow solid was further vacuum dried at 40° C. to a constant weight to yield t-butyl 4-(5-chloro-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (13.2 g, 40.1 mmol, 58.4% yield) as a light yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 12.5 (br, s, 1H), 7.19 (s, 1H), 5.75 (s, 1H), 4.34-4.41 (m, 1H), 3.40-3.48 (m, 2H), 3.26-3.37 (m, 2H), 1.71-1.83 (m, 2H), 1.60-1.71 (m, 2H), 1.32 (s, 9H); MS m/e 329 (M+H+), 273 (M+H+-t-butyl).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[OH:8].[H-].[Na+].Cl[C:12]1[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([O:24][CH3:25])=[O:23])=[CH:14][N:13]=1.O>O1CCCC1.[Cl-].[Na+].O>[CH:4]12[CH2:7][CH:1]([CH2:2][CH2:3]1)[CH2:6][CH:25]2[O:24][C:22]([C:15]1[C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]([O:8][C@@H:2]2[CH2:3][C@@H:4]3[CH2:7][C@H:1]2[CH2:6][CH2:5]3)=[N:13][CH:14]=1)=[O:23]
Reactant: OC1CC2CCC1C2
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OC1CC2CCC1C2)c1cnc(O[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.3 %

Procedure:
To a solution of rac-(1R,2R,4S)-bicyclo[2.2.1]heptan-2-ol (1.12 g) in tetrahydrofuran (10 mL) was added 60% sodium hydride (400 mg) under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was further stirred at an external temperature of 60° C. for 30 minutes, and then ice-cooled, and a mixture of methyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (481 mg) and tetrahydrofuran (2 mL) was added thereto, followed by stirring at room temperature for 3 hours. To the reaction mixture were added water and saturated brine, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=100:0 to 97:3) to obtain a mixture (351 mg) of rac-(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yloxy]-4-(trifluoromethyl)pyrimidine-5-carboxylate and rac-(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl2-[(1S,2S,4R)-bicyclo[2.2.1]hept-2-yloxy]-4-(trifluoromethyl)pyrimidine-5-carboxylate as a colorless oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]([C:13]([NH2:15])=[O:14])[C:10]([NH2:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>[Pd].C(OCC)(=O)C.C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([C:10]([NH2:12])=[O:11])[C:13]([NH2:15])=[O:14])=[CH:16][CH:17]=1
Reactant: NC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(N)=O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: NC(=O)C(Cc1ccc(N)cc1)C(N)=O
Reaction time: 56 h
Yield: 48.8 %

Procedure:
A 100-mL round bottom flask was charged with 2-(4-nitrobenzyl)malonamide (0.40 g, 1.68 mmol) and 10% palladium on carbon (0.10 g) in 1:2 ethyl acetate/ethanol (15 mL). This mixture was vigorously stirred under H2 (1 atm) for 56 h. After this time, the mixture was filtered through celite to afford the title compound (0.17 g, 49%) as a white solid. MW=207.23. 1H NMR (DMSO-d6, 500 MHz) δ 7.16 (s, 2H), 6.95 (s, 2H), 6.82 (d, J=8.5 Hz, 2H), 6.43 (d, J=8.5 Hz, 2H), 4.81 (s, 2H), 3.17 (t, J=8.0 Hz, 1H), 2.78 (d, J=7.5 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:17]([CH3:19])[CH3:18]>CC(C)=O>[CH:17]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2])([CH3:19])[CH3:18]
Reactant: N#Cc1ccccc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)Oc1ccccc1C#N
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 98.5 %

Procedure:
A reaction mixture of 2-cyanophenol (5 g, 41.55 mmol), cesium carbonate (27.1 g, 83.10 mmol) and 2-iodopropane (7.634 mL, 74.79 mmol) in acetone (80 mL) was heated at 60° C. with vigorous stirring. After 45 min, the gray brown mixture was decanted and the acetone layer was concentrated in vacuo. Water was added to dissolve cesium carbonate, and the product was extracted with diethyl ether (3×200 mL). The organic layers were washed with water, 1 N ammonium hydroxide, brine and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 5% ethyl acetate in hexanes yielded 2-isopropoxy-benzonitrile as a colorless liquid (6.6 g, 99%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=2)=[CH:6][C:7]=1[CH3:8].[C:19]([NH:22][NH2:23])(=O)[CH3:20]>C(O)CCC>[CH3:20][C:19]1[N:3]2[N:4]=[C:5]([C:9]3[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=3)[CH:6]=[C:7]([CH3:8])[C:2]2=[N:23][N:22]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)nnc1Cl
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)nn2c(C)nnc12

Procedure:
As in Example 36, a mixture of 8.0 g. of 3-chloro-4-methyl-6-(α,α,α-trifluoro-m-tolyl)pyridazine, 4.34 g. of acetylhydrazine in 125 ml. of n-butanol is refluxed for 48 hrs. to give 3.9 g. of product as crystals, m.p. 196°-198° C.
Reaction SMILES: BrC1C=CC(S(O[C@H:12]2[C@@H:19]3[C@@H:15]([CH2:16][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=4)[CH2:18]3)[CH2:14][CH2:13]2)(=O)=O)=CC=1.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>C1(C)C=CC=CC=1>[N:30]1([C@@H:12]2[C@@H:19]3[C@@H:15]([CH2:16][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=4)[CH2:18]3)[CH2:14][CH2:13]2)[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: c1c[nH]cn1
Reactant: O=S(=O)(O[C@@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21)c1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc(N2C[C@H]3CC[C@H](n4ccnc4)[C@H]3C2)n1
Temperature: 90 °C

Procedure:
A 4 mL vial was charged with (3aR,4R,6aS)-2-[6-(trifluoromethyl)pyridin-2-yl]octahydrocyclopenta[c]pyrrol-4-yl 4-bromobenzenesulfonate (100 mg, 0.204 mmol) from Example 39 and 1H-imidazole (55.4 mg, 0.814 mmol) in toluene (0.5 mL). The reaction was heated at 90° C. for 24 hours, and then the reaction mixture was concentrated. The residue was purified by silica gel chromatography using 0-4% methanol (2 N ammonia)/dichloromethane as eluent to give the title compound: 1H NMR (400 MHz, pyridine-d5) δ ppm 7.98 (s, 1H), 7.55 (d, J=8.1, 1H), 7.43 (s, 1H), 7.28 (t, J=1.2, 1H), 7.03 (d, J=7.3, 1H), 6.53 (d, J=8.6, 1H), 4.29 (dt, J=8.5, 6.6, 1H), 3.57-3.44 (m, 2H), 3.39 (dd, J=11.2, 7.2, 1H), 3.27 (dd, J=10.9, 4.2, 1H), 2.89-2.72 (m, 2H), 2.12 (dtd, J=11.3, 7.1, 3.8, 1H), 2.03-1.94 (m, 1H), 1.87 (ddd, J=17.3, 12.6, 8.6, 1H), 1.49-1.32 (m, 1H); MS (ESI+) m/z 323 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C@@:4]1([C:15]([O:17][CH3:18])=[O:16])[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[C:5]1([CH3:14])[CH3:13]>O1CCCC1>[CH3:3][C@@:4]1([C:15]([O:17][CH3:18])=[O:16])[CH2:8][CH2:7][C@@H:6]([C:9]([O:11][CH3:12])=[O:10])[C:5]1([CH3:13])[CH3:14]
Reactant: COC(=O)[C@H]1CC[C@@](C)(C(=O)OC)C1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CC[C@@](C)(C(=O)OC)C1(C)C
Temperature: 25 °C
Yield: 96.7 %

Procedure:
Sodium hydride (0.788 g, 19.71 mmol, 60% suspension in mineral oil) was added to a solution of (1R,3S)-dimethyl 1,2,2-trimethylcyclopentane-1,3-dicarboxylate (1.50 g, 6.57 mmol, from Step 1) in tetrahydrofuran (20 mL) at room temperature. The resulting mixture was heated to reflux for 1 h, cooled to room temperature, and carefully quenched with saturated ammonium chloride (10 mL). After dilution with ethyl acetate (100 mL), the mixture was washed with water, brine, dried (MgSO4), filtered and concentrated to give crude product (1.45 g), which was found to be roughly a 1:1 mixture of the desired (1R,3R)-product and the (1R,3S)-starting material based on 1H NMR analysis. The mixture was taken to the next reaction without purification.
Reaction SMILES: [Li].C[O:3][C:4](=O)[CH2:5][N:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:27])[CH2:7]1.O>C1COCC1>[F:26][C:22]1[CH:21]=[C:20]([S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH:8]3[CH2:9][CH2:10][N:6]([CH2:5][CH2:4][OH:3])[CH2:7]3)=[C:12]([CH3:27])[CH:13]=2)(=[O:19])=[O:18])[CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)CN1CCC(c2ccc(S(=O)(=O)c3cccc(F)c3)cc2C)C1
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(CCO)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.5 %

Procedure:
Lithium alluminiumhydride (1.0 M in THF, 0.51 mL) was added to a solution of {3-[4-(3-fluoro-benzenesulfonyl)-2-methyl-phenyl]-pyrrolidin-1-yl}-acetic acid methyl ester (100 mg, 0.2554 mmol) in THF (1 mL) and the resulting mixture was stirred at room temperature for 1 hour. Water was slowly added and the mixture was extracted with DCM. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting crude material was purified via flash chromatography (DCM/MeOH/NH4OH) to give 7 mg of 2-{3-[4-(3-fluoro-benzenesulfonyl)-2-methyl-phenyl]-pyrrolidin-1-yl}-ethanol, MS (M+H)=364.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[O:27]1[CH2:32][CH2:31][CH:30]([CH2:33]O)[CH2:29][CH2:28]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][C:4]2[CH:5]=[C:6]3[C:10](=[C:2]([O:1][CH2:33][CH:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)[CH:3]=2)[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]3)=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O)c2[nH]1
Reactant: OCC1CCOCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OCC3CCOCC3)c2[nH]1
Temperature: 50 °C
Reaction time: 13 h
Yield: 128.8 %

Procedure:
A mixture of ethyl 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (400 mg), tetrahydro-2H-pyran-4-ylmethanol (250 mg), 1,1′-(azodicarbonyl)dipiperidine (540 mg), tributylphosphine (0.5 mL) and tetrahydrofuran (10 mL) was stirred at 50° C. for 13 hr. The reaction solution was allowed to cool to room temperature, and the precipitated solid was filtered off. The filtrate was concentrated under reduced pressure, and the residue was subjected to basic silica gel column chromatography (ethyl acetate:hexane=3:97-45:55, volume ratio) to give the crude title compound (650 mg) as an orange oil. MS 474 (MH+).
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:2]2[C:7]([CH:8]3[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:27][CH:26]=1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: O=C1CCC(c2cccnc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1CCC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
4-(2-Fluoropyridin-3-yl)cyclohexanone (0.05 g, 0.26 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (0.19 g, 0.78 mmol) and cesium carbonate (0.25 g, 0.78 mmol) were mixed in NMP (1 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 120° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (4×). The combined organic layers were washed with 1 M aqueous sodium hydroxide, washed with sat. sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give 4-(2-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyridin-3-yl)cyclohexanone. MS (ESI, pos. ion) m/z: 416.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O[N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34]>CN(C=O)C.C(Cl)Cl>[NH:1]([C:10]([O:12][CH2:13][CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[C:26]1=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:11])[C@H:2]([C:7]([O:9][N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Fmoc-L-Leu-OH (10 g,28.32 mmol) was dissolved in a mixture of DMF (10 ml)-CH2Cl2 (70 ml) and cooled in an ice-bath. N-Hydroxysuccinimide (3.58 g, 31.14 mmol, 1.1 equiv.) and dicyclohexylcarbodiimiide (6.06 g, 31.14 mmol, 1.1 equiv.) were added and the mixture was stirred at 0° C. for 1 hour and 25° C. for 14 hour. The reaction mixture was cooled in an ice-bath, filtered and the precipitate washed with CH2Cl2 (40 ml). The filtrate was evaporated to dryness and the residue dissolved in a mixture of dioxane (80 ml)-H2O (10 ml) to form a solution of Fmoc-Leu-OSu. A solution of anhydrous L-asparagine (5.606 g, 42.48 mmol, 1.5 equiv.) in 60 ml of Na2CO3 (2.50 g, 42.28 mmol, 1.5 equiv.) was added to the above solution of Fmoc-Leu-OSu. An additional 10 ml of dioxane was added and the reaction mixture was stirred at 25° C. for 2 hours. Ethyl acetate (200 ml) was added to the reaction mixture and the pH adjusted to about 2 by the addition of 5% aqueous HCl with stirring. The EtOAc layer was separated and the aqueous layer was extracted 4 more times with 100 ml each. The combined EtOAc extract was washed with saturated NaCl (100 ml), H2O (3×100 ml), dried over anhydrous Na2SO4, filtered and evporated to dryness. The residue was dissolved in DMF (60 ml) with warming (40-45° C.) and H2O added to the cloud point. The product crystallized after standing overnight. It was filtered, washed with ether and recrystallized from DMF-H2O. Lyophilization from dioxane gave 9.45 g (71.3%) of product. NMR and FAB mass spectroscopy confirmed the molecular formula C25H29N3O6 with an observed mass for (M+H)+, 468.3. The product Fmoc-Leu-Asn-OH was shown to be >95% pure by analytical HPLC. HPLC conditions were: column: Lichrosorb RP-8 (5μ); eluant: (A) 0.1M NaClO4 (pH 2.5)-(B) CH3CN; gradient: 40%-80% (B) in 20 minutes; flow 1 ml/l minute.; and detection: 210 nm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]([CH2:31][O:32][CH2:33][O:34][CH3:35])([CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:43](Br)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]([CH2:31][O:32][CH2:33][O:34][CH3:35])([CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[C:13]([C:18]([F:20])([F:21])[F:19])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCOCC(CCOC1CCCCO1)(CCc1ccc(O)c(C(F)(F)F)c1)NC(=O)OC(C)(C)C
Reactant: CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(CCC(CCOC2CCCCO2)(COCOC)NC(=O)OC(C)(C)C)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Compound 21-6 (1.24 g) was dissolved in N,N-dimethylformamide (20 ml), potassium carbonate (986 mg) and n-heptyl bromide (0.458 ml) were added, and the mixture was stirred at 80° C. for 2.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (1.49 g) as a pale-yellow oil.