Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([NH:30][CH3:31])[CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14](=[O:24])[NH:15][S:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:18])=[O:17])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:25].CO.[CH:34](=O)[CH3:35].C([BH3-])#N.[Na+]>O1CCCC1.C(Cl)(Cl)Cl.CO.C(O)(=O)C>[Cl:1][C:2]1[CH:29]=[C:28]([N:30]([CH2:34][CH3:35])[CH3:31])[CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14](=[O:24])[NH:15][S:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:18])=[O:17])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:25]
Reactant: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(NC)cc3Cl)c2n1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(N(C)CC)cc3Cl)c2n1
Reaction time: 2 h
Yield: 80.1 %

Procedure:
To a suspension of 3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (232 mg) in tetrahydrofuran (1.2 ml)—methanol (1.2 ml) were added acetaldehyde (106 mg), sodium cyanoborohydride (65 mg) and acetic acid (60 mg) at room temperature, and the mixture was stirred. After 2 hr, acetaldehyde (80 mg) was added and the mixture was stirred for 2 hr. The reaction mixture was diluted A with chloroform/methanol (10/1) (10 ml), washed successively with water, 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was recrystallized from acetone-water to give 3-(2-chloro-4-(ethylmethylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (197 mg) as a white powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:43])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[N:30]([CH3:42])[N:31]=[C:32]([CH2:34][O:35]C3CCCCO3)[CH:33]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[N:30]([CH3:42])[N:31]=[C:32]([CH2:34][OH:35])[CH:33]=4)[CH:24]=3)[CH2:20][C:19](=[O:43])[NH:18][C:9]=2[CH:10]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(COC4CCCCO4)nn3C)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3cc(CO)nn3C)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-dimethylamino-2-(3-{3-[2-methyl-5-(tetrahydro-pyran-2-yloxymethyl)-2H-pyrazol-3-yl]-phenyl}-3-oxo-propionylamino)-phenyl]-carbamic acid tert.-butyl ester (Example M35) (278 mg, 0.44 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (129 mg).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C([O-])([O-])=O.[K+].[K+].[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[OH:27]>C1COCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[O:27][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Oc1cc(F)ccc1F
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(Oc2cc(F)ccc2F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-chloro-3-nitrobenzonitrile (5 g) in THF (200 mL) at room temperature was treated with K2CO3 (19 g), followed by 2,5-difluorophenol (3.7 g). After stirring at room temperature for 18 hrs, the solid was filtered off and rinsed with copious amounts of EtOAc. The filtrate was washed sequentially with saturated aqueous NaHCO3 solution, water, and saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated in mow. The residual was triturated with hexanes and collected by suction to furnish the desired product 21, which was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.[F:25][C:26]1[CH:27]=[C:28](Br)[CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:36])([F:35])[F:34].O>C1COCC1.CCCCCC.[Cl-].[Zn+2].[Cl-]>[F:25][C:26]1[CH:27]=[C:28]([C:7]2[C:2]([F:1])=[CH:3][C:4]([C:9]3[N:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:13][N:14]=3)=[CH:5][C:6]=2[F:8])[CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:34])([F:35])[F:36]
Reactant: CCCCCc1cnc(-c2cc(F)cc(F)c2)nc1
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCCCCc1cnc(-c2cc(F)c(-c3ccc(OC(F)(F)F)c(F)c3)c(F)c2)nc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 0.7 %

Procedure:
In 80 ml of THF was dissolved 8.0 g (30 mmol) of the 2-(3,5-difluorophenyl)-5-pentylpyrimidine described above, and cooled down to −60° C. under nitrogen gas atmosphere. To this solution was added dropwise 20 ml of 1.60 M solution of n-butyl lithium (32 mmol) in hexane while maintaining the condition that the temperature of the solution did not exceed −50° C., and then stirred at the same temperature for 1 hour. Subsequently, 64 ml of 0.5 M solution of zinc chloride (32 mmol) in THF was added dropwise to the reaction solution while maintaining the condition that the temperature of the solution did not exceed −50° C., warmed up to room temperature, and then stirred for 30 min. To this solution were added 0.5 g of tetrakistriphenylphosphine palladium and 8.3 g of 3-fluoro-4-trifluoromethoxybromobenzene, and heated to reflux for 3 hours. To the reaction solution was added 100 ml of water, and the product was extracted with toluene. The extract was washed with 3N-hydrochloric acid, saturated aqueous solution of sodium bicarbonate, and saturated aqueous solution of sodium chloride in turn, and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: heptane/toluene=1/1), and then recrystallized twice from heptane/ethyl acetate=1/1 to obtain 0.09 g (0.2 mmol) of 2-(4-(3-fluoro-4-trifluoromethoxyphenyl)-3,5-difluorophenyl)-5-pentylpyrimidine. Yield of this product from 2-(3,5-difluorophenyl)-5-pentylpyrimidine was 0.7%.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9](C)([CH3:11])[CH2:8][C:7]2NC=[C:4]([C:13]([OH:15])=O)[C:3]1=2.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].FC1C=CC=CC=1N.Cl>CN(C)C=O>[O:1]=[C:2]1[C:3]2[C:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:13][O:15][C:7]=2[CH2:8][CH:9]([CH3:11])[CH2:10]1
Reactant: CCOC(=O)Cl
Reactant: CC1(C)CC(=O)c2c(C(=O)O)c[nH]c2C1
Agent: Cl
Agent: Nc1ccccc1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1coc2c1C(=O)CC(C)C2
Reaction time: 0.75 h
Yield: 33 %

Procedure:
To a stirred solution of 4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (155 mg, 0.75 mmol) and triethylamine (209 μL, 1.5 mmol) in dimethylformamide (4 mL) at 0° C. was added ethyl chloroformate (143 μL, 1.5 mmol). After stirring an additional 45 minutes, 2-fluoroaniline (145 μL, 1.5 mmol) was added. The reaction mixture was stirred for 30 minutes, then poured into aqueous 3.6N hydrochloric acid and extracted 2× with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo . To the residue was added aqueous 5N sodium hydroxide (5 mL) and ethyl alcohol (1 mL), and the mixture was heated at reflux for 30 minutes. After cooling in an ice water bath, the reaction mixture was acidified with hydrochloric acid, the precipitate was collected, rinsed with water, and dried to give 55 mg of N-(2-fluorophenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3 oxamide (Compound 2).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Ga+3:4].[CH2:5]([Mg]Cl)[C:6]([CH3:9])([CH3:8])[CH3:7]>C(OCC)C>[CH2:5]([Ga:4]([CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)C[Mg]Cl
Reactant: [Ga+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CC(C)(C)C[Ga](CC(C)(C)C)CC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A flask charged with 9.578 g. (54.41 mmol) of freshly sublimed gallium trichloride dissolved in 250 ml. of dry diethyl ether (from sodium/benzophenone), was fitted with a condenser, mechanical stirrer and a pressure equalizing addition funnel. Under a cover of argon, 100 ml., 2.27M neopentyl magnesium chloride in diethyl ether solution (previously prepared from purified neopentyl chloride and magnesium turnings) was transferred to the addition funnel. The Grignard reagent was then added to the gallium trichloride solution over a period of 20 min. After the addition was complete, the reaction mixture was stirred at room temperature for 18 hours. The stirrer, condenser and addition funnel were replaced by stoppers and S Teflon valve adapter. The diethyl ether was then removed by vacuum distillation at room temperature. The crude product, a trisneopentylgallium etherate mixture, was isolated by vacuum distillation at 125° C. into a sidearm flask (cooled to -196° C.) attached to the reaction flask by means of an 85° elbow. This distillation must be continued for approximately 5 hours. The diethyl ether was then removed from stirred, crude trisneopentyl gallium by simple vacuum distillation at room temperature for 1 hour. The product was finally purified by vacuum distillation in a short path still at 59.5° C. (0.01 mm, static vacuum). The yield of purified trisneopentyl gallium was 14.04 g (49.58 mmol, 91.1% based on gallium trichloride).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].N1C=CN=C1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14]
Reactant: Oc1ccc2ccccc2c1Br
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)[Si](Oc1ccc2ccccc2c1Br)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 99.1 %

Procedure:
1-Bromo-2-naphthol (5.00 g, 22.4 mmol) was mixed with triisopropylsilyl chloride (7.2 mL, 33.6 mmol), DMAP (402 mg, 3.30 mmol), imidazole (3.81 g, 56.0 mmol), and pyridine (6 mL) in CH2Cl2 (50 mL). The reaction was refluxed for two hours. TLC analysis (silica, 15% EtOAc-hexanes) indicated the reaction was complete. The reaction was allowed to cool to room temperature and then was diluted with H2O. The dilution was extracted three times with CH2Cl2. The organic extracts were combined, washed with brine solution, dried over Na2SO4, filtered through celite, and concentrated. The crude product was purified by flash chromatography (SiO2, 100% hexanes) to give (1-bromo-naphthalen-2-yloxy)-triisopropyl-silane (8.4 g, 22.2 mmol) as a colorless oil in 99% yield. 1H NMR (300 MHz) CDCl3 8.21 (d, J=7.5 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.54 (m, 1H), 7.38 (m, 1H), 7.15 (d, J=8.8 Hz, 1H), 1.38 (m, 3H), 1.16 (d, J=7.1 Hz, 18H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18].[BH4-].[Na+].C(=O)([O-])O.[Na+]>C1COCC1.CCO.CCO.CCO.CCO.[Ti]>[CH3:16][C:17]([S@:20]([NH:22][CH:11]([C:8]1[CH:9]=[N:10][C:5]([O:4][CH2:3][C:2]([F:15])([F:14])[F:1])=[CH:6][CH:7]=1)[CH3:12])=[O:21])([CH3:19])[CH3:18]
Reactant: CC(=O)c1ccc(OCC(F)(F)F)nc1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti]
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)(F)F)nc1
Temperature: 70 °C
Reaction time: 17 h
Yield: 93.6 %

Procedure:
A mixture of 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (4.51 g, 20.58 mmol, Step-3), (R)-2-methylpropane-2-sulfinamide (3.74 g, 30.9 mmol) and tetraethyl orthotitanate (6.47 mL, 30.9 mmol) in THF (23 mL) is stirred at 70° C. for 17 hours. The reaction mixture is cooled to 0° C., sodium borohydride (2.72 g, 72.0 mmol) is added there, and the mixture is stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate (50 mL) is added to the reaction mixture, and the mixture is stirred for 10 minutes. After filtration through a pad of Celite™, the filtrate is extracted with EtOAc (300 mL). The organic layer is washed with water (100 mL×2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (4:1 to 1:1) to give 6.25 g (94% yield) of the title compound as colorless oil.
Reaction SMILES: O=[C:2]([CH2:7][CH2:8][CH:9]=[CH2:10])[C:3]([O:5][CH3:6])=[O:4].[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:6][O:5][C:3]([C:2]1[NH:17][C:11]2[C:16]([C:7]=1[CH2:8][CH:9]=[CH2:10])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:4]
Reactant: NNc1ccccc1
Reactant: C=CCCC(=O)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C=CCc1c(C(=O)OC)[nH]c2ccccc12
Reaction time: 1 h
Yield: 46.2 %

Procedure:
The solution of methyl 2-oxo-5-hexenoate (19.5 g), phenylhydrazine (14.8 g) and anhydrous p-toluenesulfonic acid (0.5 g) in dry benzene was refluxed for 0.5 hour. The solution of anhydrous p-toluenesulfonic acid (35.3 g) in dry-benzene (150 ml) was added to the solution at 50° C. over five minutes. After being stirred at 50°-60° C. for 1 hour, the mixture was refluxed for 2 hours. After cooling, the reaction mixture was diluted with chilled water and extracted twice with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (10% ethyl acetate-toluene) to give 3-allyl-2-indolecarboxylic acid methyl ester (13.6 g) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[C:6]=1[Br:17].[F:19][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C.O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([F:19])=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[C:6]=1[Br:17]
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1Br
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Product: COC(=O)Cc1c(F)c(O)c2cc(F)ccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a solution of (1-bromo-6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (135 mg, 0.433 mmol) in acetonitrile (4 mL) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (230 mg, 0.650 mmol) at 0° C. The resulting mixture was stirred at room temperature overnight, then diluted with water (10 mL), and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (30% ethyl acetate in petroleum ether) to give (1-bromo-3,6-difluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (60 mg, 42%) as a yellow solid. MS cald. for C13H9BrF2O3 330, obsd. (ESI+) [(M+H)+] 331.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].C(OC([N:38]1[CH2:43][CH2:42][CH:41]([C:44]2[CH:49]=[CH:48][C:47]([C:50](O)=O)=[CH:46][CH:45]=2)[CH2:40][CH2:39]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:50][C:47]1[CH:46]=[CH:45][C:44]([CH:41]2[CH2:40][CH2:39][NH:38][CH2:43][CH2:42]2)=[CH:49][CH:48]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCNc1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Product: CCN(Cc1ccc(C2CCNCC2)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 36.2 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (50 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (100 mg) according to an analogous synthetic method to Example 209, the title compound (22 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18](C)=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2[CH3:20])[CH2:4][O:3]1.[OH:22][C:23]1C(C)=CC(C#N)=CC=1OC>>[CH3:21][C:2]1([CH3:1])[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:17][C:18]=2[O:22][CH3:23])[CH2:4][O:3]1
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Reactant: COc1cc(C#N)cc(C)c1O
Product: COc1cc(C(=N)NO)cc(C)c1OC[C@@H]1COC(C)(C)O1

Procedure:
The title compound is obtained as a beige oil (1.16 g) in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine starting from 4-hydroxy-3-methoxy-5-methyl-benzonitrile and L-α,β-isopropyliden glycerol; LC-MS: tR=0.65 min, [M+H]+=311.0.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[NH:9][C:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:12]=1)=[O:7])C>CO>[C:16]1([CH2:15][CH2:14][CH2:13][C:10]2[NH:9][C:8]([C:6]([OH:7])=[O:5])=[CH:12][CH:11]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1ccc(CCCc2ccccc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CCCc2ccccc2)[nH]1

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 1.22 mmol) was added to a stirring, room temperature solution of 5-(3-phenylpropyl)-1H-pyrrole-2-carboxylic acid ethyl ester (85) (0.0629 g, 0.244 mmol) in MeOH (0.61 mL, 0.4 M) under N2. The reaction was heated to reflux until the reaction was judged complete by HPLC. The product was concentrated and then 2 mL of diethyl ether and 2 mL of H2O were added. The organic layer was removed and discarded, then 2 mL of diethyl ether was added, and 10% aq. HCl was added dropwise until the pH=2. The diethyl ether later was removed, and the aqueous was extracted with another portion of diethyl ether. The combined organics were dried, and concentrated to provide the desired product. (Note: An undesired impurity has a retention time of 10.85 min by HPLC. HPLC: 9.91 min.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][N:3]=1.Cl.[NH2:18][CH2:19][C:20]1(O)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(N(CC)CC)C>[CH:14]([S:11]([C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:3][CH:4]=1)(=[O:13])=[O:12])([CH3:16])[CH3:15]
Reactant: NCC1(O)CCOCC1
Reactant: CC(C)S(=O)(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)c1cnc(NCC2CCOCC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 2-chloro-5-(isopropylsulfonyl)-3-nitropyridine (Step D), 4-(aminomethyl)tetrahydro-2H-pyran-4-ol hydrochloride (Step A of Example 19) and triethylamine.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[C:7]([NH:9][CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[C:6]([F:20])=[CH:5][N:4]=1.[CH:21]1([C:24]2[C:29]([N:30]3[C:34]([CH:35]4[CH2:37][CH2:36]4)=[N:33][N:32]=[N:31]3)=[CH:28][C:27]([NH2:38])=[C:26]([F:39])[CH:25]=2)[CH2:23][CH2:22]1>CC(O)C>[CH:21]1([C:24]2[C:29]([N:30]3[C:34]([CH:35]4[CH2:37][CH2:36]4)=[N:33][N:32]=[N:31]3)=[CH:28][C:27]([NH:38][C:3]3[N:8]=[C:7]([NH:9][CH:10]4[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]4)[C:6]([F:20])=[CH:5][N:4]=3)=[C:26]([F:39])[CH:25]=2)[CH2:23][CH2:22]1
Reactant: Nc1cc(-n2nnnc2C2CC2)c(C2CC2)cc1F
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2F)CC(C)(C)N1
Agent: Cl
Solvent: CC(C)O
Product: CC1(C)CC(Nc2nc(Nc3cc(-n4nnnc4C4CC4)c(C4CC4)cc3F)ncc2F)CC(C)(C)N1
Temperature: 70 °C
Yield: 68.5 %

Procedure:
A mixture of 2-chloro-5-fluoro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine hydrochloride (256 mg, 0.791 mmol, 1 equiv), 4-cyclopropyl-5-(5-cyclopropyl-1H-tetrazol-1-yl)-2-fluorobenzenamine (205 mg, 0.791 mmol, 1 equiv), and PTSA monohydrate (120 mg, 0.633 mmol, 0.8 equiv) in IPA (8 mL) were heated to 70° C. for 8 days. After cooling to ambient temperature, the crude mixture was concentrated to dryness and taken in water, EtOAc, and 1N NaOH. The layers were separated. The organic layer was washed with 1N NaOH 2×, dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by trituration from EtOAc:hexane to give compound N2-(4-cyclopropyl-5-(5-cyclopropyl-1H-tetrazol-1-yl)-2-fluorophenyl)-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine (276 mg, 68%) as a solid.
Reaction SMILES: Cl.Cl.Cl.[N:4]1([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][N:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH2:22]([C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[N:30]1[C:35](=[O:45])[C@H:36]([CH2:40][S:41](Cl)(=[O:43])=[O:42])[CH:37]([CH3:39])[CH3:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[N:30]1[C:35](=[O:45])[C@H:36]([CH2:40][S:41]([N:7]1[CH2:6][CH2:5][N:4]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][N:11]=2)[CH2:9][CH2:8]1)(=[O:43])=[O:42])[CH:37]([CH3:39])[CH3:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1cncc(-c2cnc(N3CCNCC3)nc2)c1
Reactant: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3cccnc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 81.6 %

Procedure:
Prepared according to the method for the preparation of4-(R)-benzyl-3-(2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methyl-butyryl)oxazolidin-2-one, from 2-piperazin-1-yl-5-pyridin-3-ylpyrimidine, trihydrochloride (0.292 g) and 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)oxazolidin-2-one (0.343 g), to yield the title compound as a yellow solid (0.393 g, 82%).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:10]=[C:11]([CH:20]3[NH:24][C:23](=[O:25])[CH2:22][CH2:21]3)[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[I-].[Na+].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Cl>C1COCC1>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][N:24]1[CH:20]([C:11]2[O:12][C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:10]=2)[CH2:21][CH2:22][C:23]1=[O:25]
Reactant: O=C1CCC(c2nc(-c3ccccc3)c(-c3ccccc3)o2)N1
Reactant: COc1cccc(CCl)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(CN2C(=O)CCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 66.9 %

Procedure:
To a solution of NaH (60% oil, 28 mg), 5-(4,5-diphenyloxazol-2-yl)pyrrolidin-2-one (0.15 g) and sodium iodide (catalytic amount) in THF (1 ml) was added a solution of 3-methoxybenzyl chloride (0.11 g) in THF (2 ml). After being stirred for 4 days at room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-(3-methoxybenzyl)-5-(4,5-diphenyloxazol-2-yl)pyrrolidin-2-one (0.14 g).