Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:11].[Cl:12]C[C:14]([NH:16]CO)=O.O>C(O)(=O)C.S(=O)(=O)(O)O>[ClH:12].[NH2:16][CH2:14][C:4]1[CH:5]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:7]=[C:2]([I:1])[C:3]=1[OH:11]
Reactant: CC(C)c1ccc(O)c(I)c1
Reactant: O=C(CCl)NCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1cc(I)c(O)c(CN)c1
Product: Cl
Temperature: 20 °C
Yield: 42.7 %

Procedure:
2-Iodo-4-(1-methylethyl)phenol (13.1 g., 0.05 mole) is dissolved in a mixture of acetic acid (50 ml.) and 96% sulfuric acid (5 ml.) and powdered 2-chloro-N-(hydroxymethyl)acetamide (6.15 g., 0.05 mole) is added during 10 minutes with stirring at 20° C. The solution is stirred for 2.5 hours and then added to 300 ml. of water. The crude solid (18 g.) is collected and refluxed in ethanol (25 ml.)-hydrochloric acid (10 ml.) for 2 hours. The solid (7.5 g.) that separates on cooling, namely 2-aminomethyl-4-(1-methylethyl)-6-iodophenol hydrochloride, is purified by crystallization from ethanol 12N-hydrochloric acid (7:3) to obtain 2-aminomethyl-4-(1-methylethyl)-6-iodophenol hydrochloride (7 g.), m.p. 211°-212° C. (dec.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:12]1([S:18]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]#[N:1])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#CCCCCCCCCN
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: N#CCCCCCCCCNS(=O)(=O)c1ccccc1
Reaction time: 18 h
Yield: 19.4 %

Procedure:
A solution of 9-aminononanenitrile (2.0 g) in pyridine (60 ml) was treated with benzenesulphonyl chloride (2.29 g) in pyridine (10 ml). The solution was stirred for 18 hours when the solvent was removed in vacuo. The residue was dissolved in dilute hydrochloric acid and extracted with chloroform. The chloroform extract was dried over magnesium sulphate, the solvent was removed and the residue was chromatographed on silica gel eluted with chloroform to give the title compound (0.74 g) as a low melting solid.
Reaction SMILES: [CH3:1][I:2].[CH3:3][N:4]([CH2:6][C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[C:10]2=[N:9][C:8]=1[CH3:26])[CH3:5]>CC(C)=O.C(Cl)(Cl)Cl>[I-:2].[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][O:16][C:15]1[C:10]2[N:11]([C:7]([CH2:6][N+:4]([CH3:1])([CH3:3])[CH3:5])=[C:8]([CH3:26])[N:9]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CI
Reactant: COc1ccccc1COc1cccn2c(CN(C)C)c(C)nc12
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccccc1COc1cccn2c(C[N+](C)(C)C)c(C)nc12
Product: [I-]
Reaction time: 24 h
Yield: 102.1 %

Procedure:
Methyl iodide (1.08 g) was added dropwise to a solution of 3-dimethylaminomethyl-8-(2-methoxybenzyloxy)2-methylimidazo[1,2-a]pyridine (3.42 g) in acetone (34 ml) and chloroform (10 ml) at room temperature and the mixture was stirred for 24 hours. The resulting precipitate was collected by filtration, washed with acetone, and dried in a desiccator to give 8-(2-methoxybenzyloxy)-2-methyl-3-trimethylammoniomethylimidazo[1,2-a]pyridine iodide (3.63 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][NH2:25]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=2)[N:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[Cl:17])[N:25]=1)=[O:15]
Reactant: COC(=O)C(=O)C=Cc1cccc(Br)c1
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)C1=NN(c2ccccc2Cl)C(c2cccc(Br)c2)C1
Temperature: 125 °C
Reaction time: 4 h
Yield: 75.1 %

Procedure:
4-(3-Bromo-phenyl)-2-oxo-3-butenoic acid methyl ester (10.0 g, 37.2 mmol) prepared in Step 2 and 2-chlorophenylhydrazine hydrochloride (7.3 g, 40.9 mmol) were added to acetic acid (150.0 mL). The reaction mixture was stirred at 125° C. for 4 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 11.0 g of the titled compound as a yellow liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([O:37][CH3:38])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH2:39]([NH2:43])[CH:40]([CH3:42])[CH3:41]>>[F:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][CH2:39][CH:40]([CH3:42])[CH3:41])[N:7]=2)[C:20]=1[O:37][CH3:38])(=[O:28])=[O:27]
Reactant: COc1c(NS(=O)(=O)c2c(F)cccc2F)cccc1-c1nc(N2CCOCC2)sc1-c1ccnc(Cl)n1
Reactant: CC(C)CN
Product: COc1c(NS(=O)(=O)c2c(F)cccc2F)cccc1-c1nc(N2CCOCC2)sc1-c1ccnc(NCC(C)C)n1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-[3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-(methyloxy)phenyl]-2,6-difluorobenzenesulfonamide (150 mg, 0.259 mmol) and isobutylamine (0.259 mL, 2.59 mmol) the title compound was obtained as a yellow solid (17.8 mg, 11% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.31 (s, 1H), 7.78 (d, J=5.3 Hz, 1H), 7.59-7.70 (m, 1H), 7.33 (dd, J=7.9, 1.5 Hz, 1H), 7.20 (t, J=9.1 Hz, 2H), 6.97-7.15 (m, 3H), 5.53 (d, J=5.3 Hz, 1H), 3.66 (t, J=4.7 Hz, 4H), 3.40 (t, J=4.6 Hz, 4H), 3.20 (s, 3H), 2.99 (t, J=6.3 Hz, 2H), 1.64-1.85 (m, 1H), 0.83 (d, J=6.6 Hz, 6H). MS (ESI): 617.2 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[CH3:12]O>>[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:8][CH3:12])=[O:7]
Reactant: O=C(O)c1cccc(F)c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of anhydrous hydrochloric acid (10.5 g) in anhydrous methanol (100 ml) is added m-fluorobenzoic acid (13.3 g.; 0.095 mole). The reaction mixture is stirred at room temperature overnight. The solvent and anhydrous hydrochloric acid are then removed under vacuum and the residue slurried with hexane (100 ml). The hexane insoluble layer is decanted and the hexane solution water washed (2×100 ml) before drying with anhydrous magnesium sulfate. The hexane filtrate is then concentrated under vacuum to afford 11.0 g (75% yield) of methyl 3-fluorobenzoate as a yellow liquid. Elemental anal. calcd. for C8H7FO2 : C, 62.35; H, 4.57; F, 12.33. Found: C, 62.52; H, 4.70; F, 11.89.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[Cl:7][BH2:8].CSC>[Hg].C(OCC)C>[CH:1]1([B:8]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[Cl:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1=CCCCC1
Reactant: BCl
Agent: [Hg]
Solvent: CCOCC
Solvent: CSC
Product: ClB(C1CCCCC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A 250-mL round bottom flask fitted with a rubber septum, a magnetic stirring bar, and a connecting tube attached to a mercury bubbler was cooled in an ice bath and charged with diethyl ether (90 mL) under inert atmosphere. Cyclohexene (21.2 mL, 210 mmol) was added, followed by the slow addition of monochloroborane-methyl sulfide (11.6 mL, 100 mmol). The mixture was stirred at 0° C. for 2 h. The solvent was removed under reduced pressure (25° C., 12 Torr). Distillation provided pure dicyclohexylchloroborane (δ76 ppm in hexane), 16.85 g, 80% yield, bp 104°-105° C. (0.5 mm). Synthesis of this product by this process can readily be carried out on a molar scale.
Reaction SMILES: [Li]C[CH2:3][CH2:4][CH3:5].Br[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:11][CH:12]=1.[CH:22]([O:25][B:26](OC(C)C)[O:27][CH:28](C)C)(C)C.OCC(C)(CO)C>C1COCC1>[C:17]([O:16][C:15](=[O:21])[NH:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([B:26]2[O:27][CH2:28][C:4]([CH3:3])([CH3:5])[CH2:22][O:25]2)=[CH:12][N:11]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: [Li]CCCC
Agent: CC(C)(CO)CO
Solvent: C1CCOC1
Product: CC1(C)COB(c2ccc(CNC(=O)OC(C)(C)C)nc2)OC1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
n-BuLi (27 mL, 2.5 M) was slowly added to a stirred solution of tert-butyl (5-bromopyridin-2-yl)methylcarbamate (17.7 g, 61.6 mmol) in THF (280 mL) at −78° C. under an argon atmosphere. After 5 min at −78° C., triisopropylborate (28.5 mL, 123 mmol) was added and the mixture was stirred at −78° C. for 1 h. Neopentyl glycol (6.4 g, 61.4 mmol) was added and the reaction mixture was allowed to reach rt and was stirred for 2.5 d. The reaction was quenched with water (300 mL). The phases were separated and the aqueous phase was extracted with DCM. The organic layer was concentrated and the residue was purified by two successive flash chromatographies (Heptane/EtOAc 9:1→1:4 and DCM/MeOH 24:1 respectively) to give the product (2.23 g) as a white solid. 1H NMR δ 8.57 (dd, 1H) 7.94 (dd, 1H) 7.65 (dd, 1H) 3.76 (s, 4H) 3.30 (s, 3H) 1.47 (s, 9H) 0.96 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[OH-].[Na+].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[C:14]([O:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(C=O)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C=O)cc1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred suspension of 3-hydroxy-4-methoxybenzaldehyde (50 g) in water (200 mL) at between 0 and 5° C. is treated dropwise with an aqueous solution of sodium hydroxide (200 mL; 20% w/v), followed at between 0 and 5° C. by benzoyl chloride (38 mL). The reaction mixture is stirred at between 0 and 5° C. for 1 hour and then it is allowed to warm to room temperature and is stirred for a further period of 2 hours. The resulting solution is extracted with dichloromethane (2×200 mL) and the combined extract is washed with water (200 mL), dried over magnesium sulfate and concentrated, to give 2-methoxy-5-formylphenyl benzoate (35.2 g), m.p. 70-72° C.
Reaction SMILES: C[O:2][C:3](=[O:31])[C@@H:4]([O:28][CH2:29][CH3:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[CH3:27].[Li+].[OH-].Cl>C1COCC1.CO>[CH2:29]([O:28][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[CH3:27])[C:3]([OH:31])=[O:2])[CH3:30]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3C)oc2C)cc1C)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3C)oc2C)cc1C)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.5 %

Procedure:
To a solution of (S)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid methyl ester (100 mg, 0.24 mmol) in THF/methanol 2/1 (1.5 ml) was added a 1 N aqueous LiOH solution (1.4 ml, 1.4 mmol). The reaction mixture was stirred for 1.5 h at ambient temperature, neutralized with 1 N aqueous HCl solution under ice cooling and concentrated under reduced pressure. The residue was dissolved in 1 N HCl/ice water 1/1 and ethyl acetate, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with ice water/brine 1/1, dried over sodium sulfate and the solvent was evaporated in vacuo to give the title compound (88 mg, 0.21 mmol, 91%) as off-white solid, which was crystalized from dichloromethane/hexane to afford colorless crystals. According to chiral HPLC of the corresponding methyl ester (Chiralcel-ODH), the enantiomeric excess amounts to 98.6%.
Reaction SMILES: OC[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1/[N+:9](/[O-:12])=[N:10]/[O-:11].[Na+].Br[CH2:15][CH2:16][CH2:17][CH3:18].CN([CH:22]=[O:23])C>>[CH2:15]([O:11]/[N:10]=[N+:9](\[N:4]1[CH2:3][CH2:8][CH:7]([CH2:22][OH:23])[CH2:6][CH2:5]1)/[O-:12])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCBr
Reactant: CN(C)C=O
Reactant: [O-]/N=[N+](\[O-])N1CCCC[C@H]1CO
Agent: [Na+]
Product: CCCCO/N=[N+](/[O-])N1CCC(CO)CC1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium (2S)-2-(hydroxymethyl)-1-[(Z)-oxido-NNO-azoxy]piperidine (1.04 g, 5.27 mmol) and 1-bromobutane (681 μL, 6.33 mmol) in DMF (5 mL) was stirred at 100° C. for 30 min in a microwave reactor. After cooling to rt, the mixture was partitioned between Et2O (50 mL) and brine (50 mL). The organic layer was separated and washed with brine (2×50 mL), dried over MgSO4 and concentrated. The residue was purified by flash chromatography (Biotage 40+M) using 40-50% EtOAc in hexanes gradient, affording the title product: 1H NMR (500 MHz, CDCl3) δ 4.23 (t, 6.9 Hz, 2H), 3.82-3.78 (m, 2H), 3.53 (d, J=6.4, Hz, 2H), 2.95 (dt, J=2.5, 11.9 Hz, 2H), 1.90 (d, J=7.1 Hz, 2H), 1.77-1.71 (m, 2H), 1.65 (m, 2H), 1.50-1.40 (m, 4H), 0.94 (t, J=7.5 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.C([C:11]1([Br:21])[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:19])[CH3:18])[CH:12]1N)(C)C.[CH2:22](ON=O)[CH2:23][CH:24](C)C.O[PH2]=O>CCO>[CH:23]([C:16]1[CH:15]=[CH:14][C:13]([CH:17]([CH3:18])[CH3:19])=[CH:12][C:11]=1[Br:21])([CH3:24])[CH3:22]
Reactant: CC(C)C1=CC=CC(Br)(C(C)C)C1N
Reactant: CC(C)CCON=O
Agent: O=[PH2]O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)c1ccc(C(C)C)c(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trifluoroacetic acid (75 mL was added to a solution of Intermediate 34 in EtOH (100 mL) at 0° C. After stirring for 10 min, iso-amylnitrite (100 mL) was then added and the mixture was stirred for another 70 min. H3PO2 (70 mL) was added slowly and the mixture was warmed to ambient temperature over 5 hours. After dilution with ethyl acetate and sodium bicarbonate solution, the organic layer was separated, dried and concentrated to give the title compound in a crude form (17 g). Purification of the crude product by Kugelrohr distillation gave the title compound in pure form (13 g, 44% yield over 4 steps from 1,3-di-iso-propyl-benzene) as a colorless oil:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1.[NH2:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([O:41][CH2:42][CH:43]([C:45]2[CH:50]=[CH:49][N:48]=[C:47]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH:46]=2)[CH3:44])=[CH:33][CH:32]=1>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:23](=[O:24])[NH:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]([O:41][CH2:42][CH:43]([C:45]3[CH:50]=[CH:49][N:48]=[C:47]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH:46]=3)[CH3:44])=[CH:33][CH:32]=2)[N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(COc1ccc(N)c2ccccc12)c1ccnc(NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCC(C)c3ccnc(NC(=O)OC(C)(C)C)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
A solution of 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (5) 612 mg, 2.67 mmol) in DCM (2.0 mL) was added dropwise over 1.5 hr to a suspension of CDI (433 mg, 2.67 mmol) in DCM (2.0 mL) under nitrogen and the solution was stirred at RT for 1 hr. A solution of the naphthyl amine (55) (700 mg, 1.78 mmol) in DCM (4.0 mL) was added in a single portion and the solution was stirred for 16 hr, during which time a precipitate formed. The reaction mixture was taken up in DCM (10 mL) and purified by flash column chromatography (SiO2, 80 g, 0-20% EtOAc in isohexane, gradient elution) to afford the title compound (56) (0.59 g, 50%): m/z 649 (M+H)+ (ES+)
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.Cl.Cl.[C:15]([C:17]1([NH:26][C:27](=[O:35])[CH:28]([NH2:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:18]1)#[N:16]>>[C:15]([C:17]1([NH:26][C:27](=[O:35])[CH:28]([NH:34][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH3:25])[CH2:21][CH2:22]1)#[N:16]
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CC(C)(C)C)CC1
Agent: Cl
Product: CCCN1CCC(C#N)(NC(=O)C(CC(C)(C)C)NC2=NS(=O)(=O)c3ccccc32)CC1

Procedure:
The title compound was prepared starting from 3-chloro-benzo[d]isothiazole 1,1-dioxide and 2-amino-4,4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl)amide bis hydrochloride salt according to the procedure from Example 81, except that the compound was further purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 20% acetonitrile in water to acetonitrile. MS, m/z 460=M+1.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N+:7]([O-])=[CH:6][C:5]=2[N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:12]2=[O:26])[CH2:3][CH2:2]1.C(OC(=O)C)(=[O:29])C>>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([OH:29])[C:5]=2[N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:12]2=[O:26])[CH2:3][CH2:2]1
Reactant: O=C1N(c2ccnc(C(F)(F)F)c2)CCN1c1c[n+]([O-])ccc1C1CC1
Reactant: CC(=O)OC(C)=O
Product: O=C1N(c2ccnc(C(F)(F)F)c2)CCN1c1c(C2CC2)ccnc1O
Yield: 8 %

Procedure:
4-Cyclopropyl-3-(2-oxo-3-(2-(trifluoromethyl)pyridin-4-yl)imidazolidin-1-yl)pyridine 1-oxide (I-50b: 100 mg, 0.273 mmol) was heated with acetic anhydride (5 mL) at 120° C. for 3 hours. The resulting mixture was concentrated, basified with dilute sodium bicarbonate solution, and diluted with DCM. The organic layer was dried over sodium sulphate and concentrated to afford the crude product. Purification by column chromatography on silica gel (3% methanol in chloroform), followed by preparative HPLC afforded 8 mg of the product (8% yield).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].O=[C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8][NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8][NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])=[S:4]
Reactant: O=C(CNC(=O)C1CCCCC1)c1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=S)NN=C(CNC(=O)C1CCCCC1)c1ccccc1
Yield: 105.1 %

Procedure:
Thiosemicarbazide (2.23 g, 24.5 mmol) was added to a solution of cyclohexane carboxylic acid (2-oxo-2-phenyl-ethyl)-amide (6.0 g, 24.5 mmol), prepared in the previous step, in 87 ml of methanol plus 6.75 ml of 1N HCl plus 6.25 ml of water and the reaction stirred at room temperature for 4 days. The solvent was removed under reduced pressure to give 8.2 g of a green oil which was chromatographed on 400 g of silica gel (230-400 mesh) using ethyl acetate-methylene chloride as the eluent. The material isolated was recrystallized from isopropyl alcohol to give the title compound (3.55 g, 46%) as a white solid, mp 104-110° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:23])=[CH:5][C:6]([Cl:22])=[C:7]([N:9]2[C:13](=[O:14])[NH:12][C:11]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)=[N:10]2)[CH:8]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>C1COCC1>[Cl:22][C:6]1[C:7]([N:9]2[C:13](=[O:14])[NH:12][C:11]([C:15]3[CH:16]=[CH:17][C:18]([I:21])=[CH:19][CH:20]=3)=[N:10]2)=[CH:8][C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:4]([F:23])[CH:5]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1cc(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c(Cl)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1cc(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c(Cl)cc1F
Yield: 63 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-83 by using 2-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-5-(4-iodophenyl)-2H-1,2,4-triazol-3(4H)-one (0.400 g, 0.900 mmol), pivaloyl chloride (0.2 mL, 1.35 mmol), DIPEA (2 mL), and THF (10 mL) to afford 0.300 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.10 (s, 9H), 4.30 (d, J=5.4 Hz, 2H), 7.42-7.44 (m, 1H), 7.62-7.66 (m, 3H), 7.88-7.91 (br d, 1H), 8.14 (m, 1H); MS (m/z): 529.42 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH3:19])[C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:55][CH:56]([CH2:69][C:70]1[CH:75]=[CH:74][C:73]([O:76][CH2:77][C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)=[CH:72][CH:71]=1)[C:57]([NH:59][CH:60]1[CH2:65][CH2:64][CH2:63][N:62]([CH2:66][CH2:67][CH3:68])[CH2:61]1)=[O:58]>CN(C=O)C.C(OCC)(=O)C>[CH2:77]([O:76][C:73]1[CH:74]=[CH:75][C:70]([CH2:69][CH:56]([NH:55][C:12](=[O:14])[CH:11]([N:10]([CH2:9][C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:21][CH:20]=2)[CH3:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:57](=[O:58])[NH:59][CH:60]2[CH2:65][CH2:64][CH2:63][N:62]([CH2:66][CH2:67][CH3:68])[CH2:61]2)=[CH:71][CH:72]=1)[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: CCCN1CCCC(NC(=O)C(N)Cc2ccc(OCc3ccccc3)cc2)C1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)Cc1ccc(C(C)(C)C)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN1CCCC(NC(=O)C(Cc2ccc(OCc3ccccc3)cc2)NC(=O)C(CC(C)C)N(C)Cc2ccc(C(C)(C)C)cc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
To a solution of (S)-2-[(4-tert-butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid (0.3 g, 1.01 mmol) in 15 mL of DMF was added HBTU (0.38 g, 1.01 mmol) and diisopropylethylamine (0.65 g, 5.05 mmol). The mixture was stirred for 30 minutes at 0° C. A solution of 2-amino-3-(4-benzyloxyphenyl)-N-(1-propyl-piperidin-3-yl)propionamide (0.4 g, 1.01 mmol) in 15 mL of DMF was added to the reaction mixture. The reaction mixture was allowed to warm to room temperature and was stirred for another 30 minutes. The mixture was diluted with 20 mL of ethyl acetate, washed with 1N HCl (2×10 mL), saturated NaHCO3 (2×10 mL) and saturated solution of brine (2×10 mL). The organic layer was separated, dried with Na2SO4 and evaporated to dryness. The crude residue was purified by chromatography (silica gel, 7:3 hexane/ethyl acetate). The purified product was dissolved in minimum volume of diethylether and an ethereal solution of HCl was added dropwise. The solid which formed was washed several times with diethylether. The solid was dissolved in methanol and treated with activated charcoal, filtered, and evaporated. The residue was crystallized from methanol-ether to give the title compound (0.16 g, 23%) as a light yellow powder; mp 160-164° C. (dec).
Reaction SMILES: [I-].[I-].[Sm+2].[CH3:4][CH:5]([C:8]1[CH:21]=[CH:20][C:19]2[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[CH:14][CH:13]=[N:12]3)[N:9]=1)[CH2:6][CH3:7].[CH3:22][C:23](=[O:26])[CH2:24][CH3:25]>>[CH3:4][CH:5]([C:8]1[CH:21]=[CH:20][C:19]2[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[CH:14][C:13]([C:23]([OH:26])([CH3:22])[CH2:24][CH3:25])=[N:12]3)[N:9]=1)[CH2:6][CH3:7]
Reactant: CCC(C)c1ccc2ccc3cccnc3c2n1
Reactant: CCC(C)=O
Agent: [I-]
Agent: [Sm+2]
Product: CCC(C)c1ccc2ccc3ccc(C(C)(O)CC)nc3c2n1

Procedure:
The title compound is prepared by following the General Procedure I with samarium diiodide and 2-(2-butyl)-1,10-phenanthroline, prepared as described by Example 16, and 2-butanone.