Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[C:3]([C:6]#[C:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)([OH:5])=[O:4].[CH3:24]O>>[CH3:24][O:4][C:3]([C:6]#[C:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:5]
Reactant: O=C(O)C#CCc1c(-c2cccnc2)[nH]c2ccccc12
Reactant: CO
Agent: [Li+]
Agent: [OH-]
Product: COC(=O)C#CCc1c(-c2cccnc2)[nH]c2ccccc12

Procedure:
Treatment of 330 mg of 3-(3-methoxycarbonylprop-2-ynyl)-2-(3-pyridyl)indole in 10 ml of methanol with 3.0 ml of aqueous 1N lithium hydroxide at room temperature yields 3-(3-carboxyprop-2-ynyl)-2-(3-pyridyl) indole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[C:8]#[N:9])=[CH:3][CH:2]=1.N.O>CO.[Ni]>[N:1]1[CH:2]=[CH:3][C:4]([CH:7]([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=2)[CH2:8][NH2:9])=[CH:5][CH:6]=1
Reactant: N#CC(c1ccncc1)c1ccc(C(F)(F)F)nc1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: O
Product: NCC(c1ccncc1)c1ccc(C(F)(F)F)nc1
Yield: 82.5 %

Procedure:
A mixture of 2-(pyridin-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (360 mg, 1.36 mmol) and NH3.H2O (2 mL) in MeOH (30 mL) was hydrogenated with Raney Ni (700 mg) under H2 (50 Psi) for 5 h. The reaction mixture was filtered and concentrated to give 2-(pyridin-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine (300 mg), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:17][C:18]1[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[C:20]([N:28]2[CH2:35][CH:34]3[CH:30]([CH2:31][NH:32][CH2:33]3)[CH2:29]2)[CH:19]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:6]([C:7]([N:32]2[CH2:33][CH:34]3[CH:30]([CH2:29][N:28]([C:20]4[CH:19]=[C:18]([CH3:17])[N:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[N:21]=4)[CH2:35]3)[CH2:31]2)=[O:9])[CH:10]=1
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Reactant: Cc1cc(N2CC3CNCC3C2)nc(C(F)(F)F)n1
Product: Cc1cc(N2CC3CN(C(=O)c4cc(F)ccc4-c4ncccn4)CC3C2)nc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 13 and Intermediate 31. MS (ESI): mass calculated for C23H20F4N6O, 472.45; m/z found 473.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12](=[O:14])(=[O:13])[NH:11][C:10]([CH3:16])([CH3:15])[C:9]=2[CH3:17])=[CH:4][CH:3]=1.Br[N:19]1C(=O)C[CH2:21][C:20]1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(N)C>C(Cl)(Cl)(Cl)Cl.C(O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12](=[O:14])(=[O:13])[NH:11][C:10]([CH3:16])([CH3:15])[C:9]=2[CH2:17][NH:19][CH2:20][CH3:21])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=C(c2ccc(Cl)cc2)S(=O)(=O)NC1(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCN
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CCNCC1=C(c2ccc(Cl)cc2)S(=O)(=O)NC1(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 12 %

Procedure:
To a solution of 5-(4-chlorophenyl)-3,3,4-trimethyl-1,1-dioxo-2,3-dihydro-isothiazole, 1.5 g (5.5 mmol) in 150 mL of carbon tetrachloride was added 1.5 g (8.25 mmol) of N-bromosuccinimide and 0.13 g of 2,2′-azobis(2-methylpropionitrile). The mixture was heated to reflux for 4 h and then cooled to ambient temperature. Chloroform was added and the solution was washed with water, washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. To a solution of the residue in 75 mL of absolute ethanol was added 3.6 mL (55.0 mmol) of ethylamine (70% solution in water). The reaction mixture was stirred 24 h at ambient temperature then concentrated to dryness. The residue was purified by chromatography on silica gel with methanol/chloroform as eluant to yield 0.21 g (12%) of the desired title amine as a tan oil. 1H-NMR is consistent with structure; MS (ion spray) 313.0 (M−1); Anal. Calc'd for C14H19ClN2O2S.0.1CHCl3: C, 51.83; H, 5.89; N, 8.57. Found: C, 51.58; H, 6.38; N, 8.04.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH:10]([CH2:18][F:19])[CH2:9]2)=[CH:6][C:5]([C:20]#[N:21])=[CH:4][C:3]=1[NH:22]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH:10]([CH2:18][F:19])[CH2:9]2)[C:2]=1[Cl:1])[C:20]#[N:21]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN(C3COC3)C(CF)C2)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(N)c(Cl)c(N2CCN(C3COC3)C(CF)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
(+/−) Tert-butyl (2-chloro-5-cyano-3-(3-(fluoromethyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate (Peak 2)(315 mg, 0.741 mmol) was taken up in DCM (4 mL) and TFA (1.142 mL, 14.83 mmol) was added. The reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo and the material was taken up in MeOH and loaded onto an SCX column (5 g, benzenesulfonic acid sorbent). The column was rinsed with MeOH, then 7N NH3/MeOH to release the product. The solvent was removed in vacuo to give (+/−) 3-amino-4-chloro-5-(3-(fluoromethyl)-4-(oxetan-3-yl)piperazin-1-yl)benzonitrile (234 mg) as a yellow foam.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[N:19]=[CH:18][C:17]([CH:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH3:21])=[CH:16][CH:15]=1.[B:28]([O:37][CH:38]([CH3:40])[CH3:39])([O:33][CH:34]([CH3:36])[CH3:35])OC(C)C.OC(C(O)(C)C)(C)C.C(O)(=O)C>C1COCC1>[F:13][C:14]1[N:19]=[CH:18][C:17]([CH:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH3:21])=[CH:16][C:15]=1[B:28]1[O:33][C:34]([CH3:35])([CH3:36])[C:38]([CH3:39])([CH3:40])[O:37]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(c1ccc(F)nc1)N1CCOCC1
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(c1cnc(F)c(B2OC(C)(C)C(C)(C)O2)c1)N1CCOCC1
Temperature: 0 °C
Yield: 75 %

Procedure:
To a stirred solution of diisopropylamine (Aldrich, redistilled, 99.95%, 0.813 mL, 5.80 mmol) in THF (10 mL) in 150 mL round-bottomed flask, nBuLi (Aldrich, 2.5 M in hexanes, 2.32 mL, 5.80 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for min. The mixture was cooled to −78° C. and 4-(1-(6-fluoropyridin-3-yl)ethyl)morpholine (1.02 g, 4.84 mmol) in a total of 3 mL of THF was added dropwise. The mixture was stirred at −78° C. for 45 min. Triisopropyl borate (Aldrich, 1.39 mL, 6.04 mmol) in a total of 3 mL THF was added dropwise at that temperature, then the cold bath was removed. The mixture was stirred at room temperature for 1 h 20 min. Pinacol (0.773 g, 6.54 mmol) in a total of 5 mL THF was added at once and the mixture was stirred at room temperature for 10 min. Acetic acid (0.291 mL, 5.08 mmol) in a total of 3 mL THF was added at once and the mixture was stirred at room temperature for 2 h. The mixture was filtered through a pad of Celite® (diatomaceous earth), and extracted with 1 N NaOH (2×50 mL). The aqueous phase was treated with 4N HCl until a pH of about 6 to 7 while an ice-water bath was applied, then extracted with EtOAc (3×50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude 4-(1-(6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)ethyl)morpholine (1.22 g, 75% yield) as a light brown viscous oil. This material was used in the next reaction without further purification.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[C:20]([CH:25]([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=[O:24])=[CH:15][CH:14]=1>O1CCCC1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)=[C:20]([CH:25]([CH:29]([CH3:30])[CH3:31])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]([OH:24])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[CH:17][CH:18]=1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: CC(C)C(C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1)C(C)C
Solvent: C1CCOC1
Product: CC(C)C(C(C=CC(O)CC(=O)CC(=O)OC(C)(C)C)=C(c1ccc(F)cc1)c1ccc(F)cc1)C(C)C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
A solution of the dianion of 1,1-dimethylethyl acetoacetate (15 mL of 1M solution, 15 mmol) was added to a solution of 5,5-bis(4-fluorophenyl)-4-[2-methyl-1-(1-methylethyl)propyl]-2,4-pentadienal (4.1 g, 11.1 mmol) in tetrahydrofuran at -60° C. After stirring for 3 hours the reaction was quenched with 2N hydrochloric acid and the mixture extracted with diethyl ether. The extracts were dried with magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 5% ethyl acetate in hexane to give 3.2 g of the title compound as an oil. MS(CI): m/e =526 for M+ of C32H40F2O4.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl>[CH:1]([O:4][CH2:5][CH2:6][O:7][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)OCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOC(C)C)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
In a round bottom flask was placed 2-isopropoxy-ethanol (700 mg, 6.72 mmol) dissolved in methylene chloride (15 mL) and cooled to 0° C. in an ice bath. To this solution was added triethylamine (1.2 mL, 8.7 mmol) and para-toluenesulfonyl chloride (1.54 g, 8.06 mmol). The resulting solution was then slowly allowed to warm to 25° C. and was stirred for 16 h. After this time, the reaction was transferred to a separatory funnel and washed with water (15 mL). The aqueous layer was then extracted with methylene chloride (2×20 mL). The organic layers were combined and then dried over sodium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (40 g column, 25% ethyl acetate/hexanes) afforded toluene-4-sulfonic acid 2-isopropoxy-ethyl ester (1.41 g, 81%).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([CH2:24][CH2:25][N:26]([CH:34]([CH3:36])[CH3:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:14]#[N:15].C1(C)C=CC=CC=1>O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([CH2:24][CH2:25][N:26]([CH:34]([CH3:36])[CH3:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:14]([NH2:15])=[O:2]
Reactant: CC(C)N(CCC(C#N)(CCN1CCCCC1)c1ccccc1Cl)Cc1ccccc1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)N(CCC(CCN1CCCCC1)(C(N)=O)c1ccccc1Cl)Cc1ccccc1
Temperature: 70 °C
Yield: 70 %

Procedure:
A nitrogen atmosphere was applied to a reaction vessel containing 109.3 L of sulfuric acid (96% w/w) which was warmed to 70° C. with stirring. Heating was discontinued, and 89.2 kg of α-(2-chlorophenyl)-α-[2-[(1-methylethyl)(phenylmethyl)amino]ethyl]-1-piperidinebutanenitrile (product of Example 4) was added at a rate such that the temperature was maintained at 80°-85° C. The reaction mixture was stirred at 80°-85° C. for 2.5 h and cooled to 75° C. The reaction mixture was added to a cooled and stirred mixture of 322 L of water and 219 L of toluene at 5° C. at a rate such that the temperature did not exceed 30° C. An additional 127 L of water was added to rinse the reactor. The mixture was cooled to 5° C. and basified to pH>12 with 219 L of sodium hydroxide solution (50% w/w) while maintaining the temperature below 35° C. Near the end of the base addition, the mixture was allowed to warm to 45° C. and stirred for 15 min. After separation of the layers, the aqueous phase was maintained at 45° C. and extracted with two 126-L portions of toluene. The organic phases were combined using 126 L of toluene. The combined organic phase was washed with 126 L of water at 45° C. The solution was cooled to 25° C. and stirred with 64.3 kg of neutral alumina for 1 h. The slurry was filtered through a layer of diatomaceous earth, and the filter cake was washed with 126 L of toluene. Alternatively, the solution may be passed through a bed of neutral alumina followed by a toluene wash of the bed. The solvent was removed by distillation under reduced pressure, and the residue was dissolved in 322 L of heptane by heating to reflux. The solution was allowed to cool to 25° C. with stirring, and the resulting slurry was cooled to less than 10° C. The solid was collected by filtration and washed twice with 200 L of heptane. The solid was dried under vacuum at 35 to 40° C. to give 65.0 kg (70.0%) of the title product α-(2-chlorophenyl)-α-[ 2-[(1-methylethyl)(phenylmethyl) amino]ethyl]-1-piperidinebutanamide. Analysis calcd for C27H38ClN3O: C,71.11; H,8.40; Cl,7.77; N,9.21. Found C,71.09; H,8.50; Cl,7.94; N,9.17. mp 104°-111° C. The purity of the title compound was estimated to be >95% based on TLC Method A.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10])=[CH2:2].[CH2:11]([O:13][SiH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])[CH3:12].C([Si]([CH:30]=[CH2:31])(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[CH2:11]([O:13][Si:14]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])[CH2:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][Si:14]([O:18][CH2:30][CH3:31])([O:15][CH2:16][CH3:17])[O:13][CH2:11][CH3:12])[CH3:12]
Reactant: C=Cc1ccccc1C=C
Reactant: C=C[Si](C)(C=C)O[Si](C)(C)C
Reactant: CCO[SiH](OCC)OCC
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccccc1CC[Si](OCC)(OCC)OCC)(OCC)OCC
Temperature: 50 °C
Yield: 2.8 %

Procedure:
871 mg Of divinylbenzene and 4.35 g of triethoxysilane were placed in a glass reaction tube and 0.015 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.2 Wt. %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the tube contents were analyzed by GC-MS following cooling, the conversion rate of divinylbenzene was 56%; bis (2-triethoxysilylethyl) benzene was produced at a yield of 2.8%, (1-triethoxysilylethyl) (2-triethoxysilylethyl) benzene was produced at a yield of 3.7%, and bis (1-triethoxysilylethyl) benzene was produced at a yield of 0.1%. No production of (triethoxysilyl) ethylstyrene was observed.
Reaction SMILES: [CH3:1][C:2]([O:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=1)([CH3:6])[C:3]([OH:5])=[O:4].Cl[CH:26]1[C:35]2C(=CC=CC=2)CC[CH2:27]1>>[CH3:6][C:2]([O:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:35][CH2:26][CH2:27]2)[N:10]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(OCc1nn(Cc2ccccc2)c2ccccc12)C(=O)O
Reactant: ClC1CCCc2ccccc21
Product: CC(C)(OCc1nn(C2CCCc3ccccc32)c2ccccc12)C(=O)O

Procedure:
The product was prepared according to the procedure described in Example 6b), using as starting material 2-methyl-2-[(1-benzyl-1H-indazol-3-yl)methoxy]propanoic acid as starting material and 1-chloro-1,2,3,4-tetrahydronaphthalene as reagent.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][C:16]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:15]3=[O:32])[O:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH:41]([CH3:43])[CH3:42]>CN(C)C=O>[CH2:40]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][C:16]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:15]3=[O:32])[O:10][N:9]=2)=[CH:6][CH:7]=1)[CH:41]([CH3:43])[CH3:42]
Reactant: O=C1N(Cc2nc(-c3ccc(O)cc3)no2)CCCC1(c1ccccc1)c1ccccc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(-c2noc(CN3CCCC(c4ccccc4)(c4ccccc4)C3=O)n2)cc1
Temperature: 75 °C

Procedure:
To 1-{[3-(4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl]methyl}-3,3-diphenylpiperidin-2-one (Example 206, 0.040 g, 0.094 mmol) and potassium carbonate (0.019 g, 0.141 mmol) in N,N-dimethylformamide (0.5 mL) was added 1-bromo-2-methylpropane (0.012 mL, 0.113 mmol) and the reaction heated to 75° C. for 3 hours. The reaction was cooled, loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 40% ethyl acetate/hexanes (Flow=35 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.11-7.94 (m, 2H), 7.39-7.13 (m, 10H), 7.06-6.93 (m, 2H), 4.90 (s, 2H), 3.80 (d, J=6.5, 2H), 3.61 (t, J=6.5, 2H), 2.77-2.62 (m, 2H), 2.13 (dp, J=6.8, 13.4, 1H), 2.01-1.80 (m, 2H), 1.04 (t, J=10.1, 6H); MS (ESI+) m/z 482.3 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:27][C:28]1[C:29]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[N:30][CH:31]=[CH:32][CH:33]=1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:37]3[CH2:38][CH2:39][N:34]([C:29]4[C:28]([Cl:27])=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:35][CH2:36]3)=[O:16])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1cccnc1N1CCNCC1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1c1ccccc1Cl
Agent: Cl
Product: O=C(C1CN(S(=O)(=O)c2ccccc2)C(=O)N1c1ccccc1Cl)N1CCN(c2ncccc2Cl)CC1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid (example 49, step 2) was coupled with 1-(3-chloro-pyridin-2-yl)-piperazine hydrochloride (CAS 85386-86-3) to give the title compound as a colorless solid. MS: 560.2 ([M+H]+)
Reaction SMILES: C([NH:4][OH:5])(=O)C.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:14]=[C:15]([C:44]2[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[C:46](F)[CH:45]=2)[CH:16]=[C:17]([Cl:43])[C:18]=1[CH2:19][C@@H:20]1[CH2:24][CH2:23][N:22]([N:25]2[CH2:30][CH2:29][CH:28]([O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH2:27][CH2:26]2)[C:21]1=[O:42]>CN(C=O)C.O.C(OCC)(=O)C>[NH2:51][C:50]1[C:47]2[CH:48]=[CH:49][C:44]([C:15]3[CH:16]=[C:17]([Cl:43])[C:18]([CH2:19][C@@H:20]4[CH2:24][CH2:23][N:22]([N:25]5[CH2:30][CH2:29][CH:28]([O:31][Si:32]([CH:33]([CH3:35])[CH3:34])([CH:36]([CH3:37])[CH3:38])[CH:39]([CH3:40])[CH3:41])[CH2:27][CH2:26]5)[C:21]4=[O:42])=[C:13]([Cl:12])[CH:14]=3)=[CH:45][C:46]=2[O:5][N:4]=1
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C#N)c(F)c4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reactant: CC(=O)NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc5c(N)noc5c4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
Stir a mixture of acetohydroxamic acid (0.046 g, 0.61 mmol), potassium carbonate (0.169 g, 1.22 mmol) in DMF (5 mL) and water (2 mL) at room temperature for 10 minutes. To the mixture, add a solution of (R)-3′,5′-Dichloro-3-fluoro-4′-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carbonitrile (0.151 g, 0.244 mmol) and stir the reaction at room temperature for 5 hours and then at 60° C. for 1 hour. Cool the reaction, dilute with ethyl acetate (40 mL), and wash three times with water (15 mL each) then brine (15 mL). After drying the organic layer over sodium sulfate, filter and concentrate under vacuum. Purify the residue by silica gel chromatography with 0% to 50% ethyl acetate/hexane gradient to afford 0.095 g (62%) of the title compound. MS (m/z): 631 (M+).
Reaction SMILES: Cl.[CH2:2]([C:5]1([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:14][CH2:13][C:8]2(OCC[O:9]2)[CH2:7][CH2:6]1)[CH:3]=[CH2:4].C(=O)([O-])O.[Na+].ClCCl>CC(C)=O.O>[CH2:2]([C:5]1([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH2:14][CH2:13][C:8](=[O:9])[CH2:7][CH2:6]1)[CH:3]=[CH2:4]
Reactant: C=CCC1(NCc2ccc(OC)cc2)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: C=CCC1(NCc2ccc(OC)cc2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Concentrated hydrochloric acid (0.5 ml) was added to a solution of (8-allyl-1,4-dioxaspiro[4.5]dec-8-yl)-(4-methoxybenzyl)amine (C-9) (1.0 g, 3.15 mmol) in acetone (10 ml) and water (0.5 liter), and the mixture was stirred for 16 h at room temperature. Then saturated sodium hydrogen carbonate solution (40 ml) was added to the solution, and extraction with dichloromethane (3×40 ml) was carried out. The combined organic phases were dried with sodium sulfate and concentrated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]2[NH:7][C:8](=[O:35])[N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([O:24][C:25]5[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[C:27]([CH3:34])[CH:26]=5)[N:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.CO.[H][H]>C1COCC1.[Pd]>[NH2:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:22]2[N:21]=[CH:20][N:19]=[C:18]([N:15]3[CH2:14][CH2:13][CH:12]([N:9]4[CH2:10][CH2:11][C:5]5[CH:4]=[C:3]([O:2][CH3:1])[CH:37]=[CH:36][C:6]=5[NH:7][C:8]4=[O:35])[CH2:17][CH2:16]3)[CH:23]=2)=[CH:26][C:27]=1[CH3:34]
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4ccc([N+](=O)[O-])c(C)c4)ncn3)CC1)C(=O)N2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4ccc(N)c(C)c4)ncn3)CC1)C(=O)N2

Procedure:
930 mg (1.84 mmol) 7-methoxy-3-(1-(6-(3-methyl-4-nitrophenoxy)pyrimidin-4-yl)piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one were placed in 20 mL THF and 20 mL MeOH and hydrogenated under a hydrogen atmosphere with the addition of 150 mg Pd/C (10%) at RT and a hydrogen pressure of 3 bar until all the hydrogen had been taken up. The catalyst was filtered off. Everything was distilled off from the filtrate to leave a residual volume of 15 mL. DIPE was added. The precipitate was suction filtered, washed and dried.
Reaction SMILES: [NH:1]1[C:7](=O)[CH2:6][CH2:5][NH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14].O.C(OCC)(=O)C>N1C=CC=CC=1>[NH:1]1[C:7](=[S:14])[CH2:6][CH2:5][NH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CCNc2ccccc2N1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: S=C1CCNc2ccccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
A solution of 4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (3.2 g, 19.6 mmol) and P2S5 (5.2 g, 23.5 mmol) in pyridine (100 mL) was heated at 120° C. and stirred for 30 min. After being cooled to room temperature, water (100 mL) and ethyl acetate (200 mL) were added, the separated organic layer was dried over Na2SO4, concentrated in vacuum, and the residue was purified by CombiFlash (DCM:MeOH=20:1) to give 4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione as a yellow solid (2.1 g, 59%). LRMS (M+H)+: 177 m/z.