Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14][C:15]1[S:19][C:18]([NH2:20])=[N:17][CH:16]=1>>[Br:14][C:15]1[S:19][C:18]([NH:20][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[N:17][CH:16]=1
Reactant: Nc1ncc(Br)s1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(Nc1ncc(Br)s1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with 5-Bromo-thiazol-2-ylamine to produce N-(5-Bromo-thiazol-2-yl)-4-chloro-3-nitro-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 10B and 10C to provide the title product.
Reaction SMILES: C1([Mg]Br)C=CC=CC=1.[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH2:13][CH2:14][NH2:15].C[O:20][C:21](=O)[CH:22]([CH:36]([CH3:38])[CH3:37])[C:23]([NH:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])=[CH2:24].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:9][C:10]1[CH:11]=[C:12]([CH2:13][CH2:14][N:15]2[C:21](=[O:20])[C:22]([CH:36]([CH3:37])[CH3:38])=[C:23]([CH3:24])[N:25]=[C:26]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH:16]=[CH:17][CH:18]=1
Reactant: C=C(NC(=O)c1ccccc1OC)C(C(=O)OC)C(C)C
Reactant: NCCc1cccc(F)c1
Agent: Br[Mg]c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1nc(C)c(C(C)C)c(=O)n1CCc1cccc(F)c1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
Phenyl magnesium bromide (1M solution in THF, 0.0021 mol) was added to a solution of 3-fluoro-phenethyl amine (0.27 mL, 0.0021 mol) in anhydrous toluene (20 mL). After stirring the mixture at 20° C. for 10 min, 2-isopropyl-3-(2-methoxy-benzoylamino)-but-3-enoic acid methyl ester of step (b) above in this method (Method B of Example 13) (0.05 g, 0.0017 mol) was added. The mixture was refluxed for 10 hours, cooled and ethyl acetate (50 mL) was added followed by 1N HCl (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with 1N HCl (3×100 mL), water (100 mL), and brine (100 mL). After drying over sodium sulfate and concentration on a rotatory evaporator, the product was purified by column chromatography over silica gel (200-400 mesh) eluting with 12% EtOAc/hexanes to give 3-[2-(3-fluoro-phenyl)-ethyl]-5-isopropyl-2-(2-methoxy-phenyl)-6-methyl-3H-pyrimidin-4-one (0.3 g, 46%) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([OH:14])[CH:10]=[C:11]([CH3:13])[CH3:12].C[S-].[Na+].Cl>CN(C)C=O>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([OH:14])[CH:10]=[C:11]([CH3:12])[CH3:13]
Reactant: COc1ccccc1C(O)(C=C(C)C)c1ccccn1
Agent: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)=CC(O)(c1ccccn1)c1ccccc1O
Temperature: 25 °C
Reaction time: 10 h
Yield: 82.1 %

Procedure:
36.6 g of 1-(2-methoxyphenyl)-3-methyl-1-(2-pyridyl)- 2-buten-1-ol were heated at 70° C. in 200 ml of dimethylformamide with 28.6 g of sodium methanethiolate. After 10 hours the mixture was allowed to cool to room temperature, poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic extract was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate for the elution to give 28.5 g of 1-(2-hydroxyphenyl)-3-methyl-1(2-pyridyl)-2-buten-1-ol in the form of an oil.
Reaction SMILES: [I-:1].[K+].Br[C:4]1[CH:20]=[CH:19][C:7]2[C:8](=[O:18])[C:9]3[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:10]=3[O:11][CH2:12][C:6]=2[CH:5]=1.O.C(OCC)(=O)C>CN(C)P(=O)(N(C)C)N(C)C.[Cu]I>[OH:17][C:15]1[CH:14]=[CH:13][C:10]2[O:11][CH2:12][C:6]3[CH:5]=[C:4]([I:1])[CH:20]=[CH:19][C:7]=3[C:8](=[O:18])[C:9]=2[CH:16]=1
Reactant: O=C1c2ccc(Br)cc2COc2ccc(O)cc21
Reactant: [I-]
Agent: [Cu]I
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C1c2ccc(I)cc2COc2ccc(O)cc21
Temperature: 160 °C
Reaction time: 4 h
Yield: 37.3 %

Procedure:
10.35 g of copper (I) iodide and 26.9 g of potassium iodide were added to 3.3 g of 8-bromo-2-hydroxy-11-oxo-6,11-dihydrodibenz[b,e]oxepine obtained in Reference example 27 dissolved in 33 ml of hexamethylphosphoric acid triamide and the mixture was stirred under nitrogen stream at 160° C. for 4 hours. After 300 ml of water and 400 ml of ethyl acetate were added to the reaction mixture, the organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The residue obtained by removing the solvent was washed with chloroform to obtain 1.42 g of the title compound.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([CH2:4][C:5]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:11]#N)[CH2:6][CH2:7]2)[O:2]1.CC(C[AlH]CC(C)C)C.Cl.C(=O)(O)[O-:30].[Na+]>C1(C)C=CC=CC=1>[CH2:1]1[CH2:10][O:9][C:3]2([CH2:8][CH2:7][CH2:6][C:5]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([CH:11]=[O:30])[CH2:4]2)[O:2]1
Reactant: N#CC1(c2ccccc2)CCC2OCCOC2C1
Reactant: O=C([O-])O
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=CC1(c2ccccc2)CCCC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
At −78° C., 3-ethylenedioxy-1-phenylcyclohexanecarbonitrile (1.66 g, 6.83 mmol) in toluene (20 mL) was added DIBAL-H (1.0 M solution in toluene, 8.88 mL) slowly and was stirred for 1 hr. The reaction mixture was warmed up to room temperature and was added 1N HCl solution (2.60 mL) and was stirred for 1 hr. Saturated sodium bicarbonate was added to quench the reaction and the organic layer was separated. The aqueous layer was extracted with dichloromethane 3 times and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum. The crude material was purified by filtering through a short silica gel pad with dichloromethane to give the title compound as a white sticky oil (1.43 g, 85% yield). 1H NMR (400 MHz, CDCl3) δ 1.32–1.40 (1H, m), 1.46–1.54 (1H, m), 1.72–1.86 (3H, m), 2.08 (1H, d, J=16 Hz), 2.59–2.67 (2H, m), 3.94–4.07 (4H, m), 7.15–7.36 (5H, m), 9.36 (1H, d, J=4 Hz).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:14](C(O)=O)=[CH:13][CH:12]=[CH:11][C:10]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:19][C:20]1[S:21][CH2:22][CH2:23][N:24]=1.C1(N=C=NC2CCCCC2)CCCCC1.C1C[O:43][CH2:42]C1>>[CH2:1]([O:8][N:9]1[C:14]([SH:21]2[CH2:22][CH2:23][NH:24][C:20]2=[S:19])=[CH:13][CH2:12][C:11](=[C:42]=[O:43])[C:10]1=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: SC1=NCCS1
Reactant: O=C(O)c1cccc(=O)n1OCc1ccccc1
Reactant: C1CCOC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: O=C=C1CC=C([SH]2CCNC2=S)N(OCc2ccccc2)C1=O
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of 1-benzyloxy-6-carboxy-2 (1H)-pyridinone (4.90 g, 20 mmol), 2-mercaptothiazoline (2.62 g, 22 mmol), and a catalytic amount of 4-dimethyl-aminopyridine (DMAP) in dry THF (50 mL), was added N,N′-dicyclohexylcarbodiimide (DCC) (4.6 g, 22 mmol). After stirring overnight, the dicyclohexylurea (DCU) solids are removed by filtration the yellow filtrate is removed by rotary evaporation to give a yellow solid. Crystallization from isopropanol-methylene chloride gives the title compound (5.80 g, 83.7%) as a pale yellow powder, m.p.: 135-7° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:12][C:11]([CH:13]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)=[N:5][CH:4]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[CH3:60][O:61][NH:62][CH3:63]>CN(C)C=O.C(OCC)(=O)C>[OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:12][C:11]([CH:13]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([N:62]([O:61][CH3:60])[CH3:63])=[O:27])=[CH:28][CH:29]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)=[N:5][CH:4]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)cc1
Yield: 41.7 %

Procedure:
To a solution of 4-[1-{5-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-1H-pyrrol-2-yl}-2-(tetrahydro-2H-pyran-4-yl)ethyl]benzoic acid (200 mg) in N,N-dimethylformamide (5 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg), 1-hydroxybenzotriazole (100 mg) and N-methylmorpholine (160 μL), and the mixture was stirred for 1% hr. To the reaction mixture was added N-methoxymethanamine hydrochloride (60.0 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (92.0 mg, yield 42%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-methanol (19:1, volume ratio). MS: 456 (MH+).
Reaction SMILES: C(OC(C1CC2C(=CC=CC=2)C1[NH:15][C:16](=[O:31])[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O)C.[OH-:32].[K+].[CH3:34][CH2:35][OH:36]>O>[CH2:24]([C:18]1[CH:19]=[C:20]([Br:23])[CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:34]1([C:35]([OH:32])=[O:36])[CH2:24][C:18]2[C:17](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16]1)=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: [OH-]
Reactant: CCOC(=O)C1Cc2ccccc2C1NC(=O)c1ccc(Br)cc1Cc1ccccc1
Reactant: CCO
Agent: [K+]
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1ccc(Br)cc1Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
The mixture of 2-(2-benzyl-4-bromo-benzoylamino)-indan-2-carboxylic acid ethyl ester (240) (339 mg, 0.71 mmol), KOH (50% aqueous solution, 1.58 g, 14.14 mmol), EtOH (10 mL) and water (1 mL) are stirred in a 20 mL vial at 50° C. for 30 min. After concentration in vacuo, the residue is dissolved in water (5 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The filtration affords 2-(2-benzyl-4-bromo-benzoylamino)-indan-2-carboxylic acid (241) as white solid (310 mg, 97%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)O.CC(C)([O-])C.[K+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH3:36])[C:21](=[O:35])[C:22]3[CH:32]=[C:31]([CH2:33]Cl)[CH:30]=[N:29][C:23]=3[N:24]([CH2:27][CH3:28])[C:25]=2[N:26]=1>CS(C)=O.C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH3:36])[C:21](=[O:35])[C:22]3[CH:32]=[C:31]([CH2:33][C:1]4[CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=4)[CH:30]=[N:29][C:23]=3[N:24]([CH2:27][CH3:28])[C:25]=2[N:26]=1
Reactant: Oc1cccc(O)c1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCN1c2ncc(Cc3cccc(O)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 56.1 %

Procedure:
Resorcinol (0.082 g, 0.74 mmol) in dimethyl sulfoxide (1 mL) was treated with potassium tert-butoxide (1.0M in tetrahydrofuran, 0.15 mL, 0.15 mmol). The resulting stirred solution was treated with 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.050 g, 0.14 mmol) in dimethyl sulfoxide (1 mL) and the mixture was stirred an additional 16 hours. The mixture was diluted with ethyl acetate (50 mL) washed with brine, water, and brine (15 mL each). The organics were dried over sodium sulfate, concentrated and the residue was purified by flash chromatography (hexanes to 1:1 hexanes/ethyl acetate gradient) followed by crystallization from hexanes to give the title compound (0.031 g, 51%), m.p. 219°-220° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[Cl:30])[CH:16]=2)[CH2:10][C@H:9]1[CH3:32])=O)(C)(C)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.CO>[ClH:30].[Cl:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:22]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([NH:14][C@@H:11]2[CH2:12][CH2:13][NH:8][C@H:9]([CH3:32])[CH2:10]2)[CH:16]=1)=[O:31]
Reactant: C[C@@H]1C[C@H](Nc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CO
Product: C[C@@H]1C[C@H](Nc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1
Product: Cl
Temperature: 25 °C
Yield: 77.8 %

Procedure:
Dissolve (2R,4R)-4-(3-(2-chloro-4-fluoro-benzoylamino)-phenylamino)-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (Preparation 59, 119 mg, 0.258 mmol) in toluene (5 mL). Add p-toluenesulfonyl chloride (152 mg, 0.798 mmol) and heat to 100° C. for 3 hr. Cool to room temperature and load onto an SCX column with methanol. Wash the column with methanol, flush with 2M ammonia in methanol, and concentrate in vacuo. Purify by column chromatography (0%–10% 2M NH3 in methanol/CH2Cl2) to yield an oil. Make the hydrochloride salt by sonication with one equivalent of ammonium chloride dissolved in methanol to yield 40 mg (39%) of the title compound: mass spectrum (ion spray): m/z=362.1 (M+1); 1H NMR δ (D2O/DCl, ppm) 7.78 (s, 1H), 7.49 (m, 3H), 7.21 (t, J=9.0 Hz, 18.0 Hz, 2H), 7.07 (t, J=9.0 Hz, 18.0 Hz, 1H), 3.83 (m, 1H), 3.45 (m, 1H), 3.20 (m, 1H), 2.95 (m, 1H), 2.18 (m, 2H), 1.80 (m, 1H), 1.65 (m, 1H), 1.20 (d, J=6.6 Hz, 3H); mp 182–5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)Cl.[C:15](Cl)(=O)[C:16](Cl)=O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH2:8][C:9](=[O:11])[CH2:16][CH2:15]2
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCc2cc(Br)ccc2C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
A single neck 3 liter round bottom flask under an Ar atmosphere was charged with 4-bromo-phenyl acetic acid (250.0 g, 1.15 m), methylene chloride (1.5 L), and dimethylformamide (0.5 mL). This magnetically stirred solution was cooled to 0° C. and treated dropwise with oxalyl chloride (156 mL, 1.74 m). The reaction was allowed to reach room temperature and stirred 16 hrs. The reaction was concentrated on a rotary evaporator to approximately 1 L of volume. A separate dry 5 liter 3 neck round bottom flask under Ar, fitted with gas inlet tube, overhead stirrer, and digital thermometer was charged with methylene chloride (1.5 L) and AlCl3 (312.0 g, 2.34 m). This suspension was cooled to 0° C. and stirred while the above solution of acid chloride was added to it slowly via cannula. When the addition was complete, ethylene gas was introduced for 1-2 hrs to the vigorously stirred suspension while maintaining the internal temperature at 15° C. Upon completion by HPLC, the reaction was warmed to room temperature and stirred for 0.5 hrs. The mixture was recooled to 0° C. and cautiously quenched slowly with water (1.5L). The layers were separated, and the aqueous one washed with 500 mL of methylene chloride. The organic portion was washed with 2N aqueous HCl (2×800 mL), brine (400 mL), and saturated aqueous NaHCO3 (2×800 mL). Each aqueous extract was washed with the same 500 mL methylene chloride extract from above. The methylene chloride extracts were combined, dried (Na2SO4), filtered, and concentrated to approximately 500 mL of volume. This was then added to 5.0L of hexane warmed to 50° C. The methylene chloride was distilled off and the hot solution decanted from an insoluble brown tar. The solution was allowed to cool to 25° C. and placed in the freezer overnight. The precipitate was collected and washed with hexane (200 mL), and dried in vacuo to give 229.0 g of the compound as a pale yellow solid (88%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].Br[C:8]([F:28])([F:27])[C:9]([NH:11][CH2:12][C:13]1(O)[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:10]>O1CCCC1.[Cl-].[Na+].O.C(OCC)(=O)C>[F:27][C:8]1([F:28])[CH2:1][C:13]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH2:12][NH:11][C:9]1=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CNC(=O)C(F)(F)Br)CC1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)C(F)(F)C2
Yield: 30.7 %

Procedure:
To a stirring solution of potassium tert-butoxide (7.23 mL of 1 M, 7.23 mmol) in tetrahydrofuran (20 mL) at 70° C. was added a solution of tert-butyl 4-[[(2-bromo-2,2-difluoro-acetyl)amino]methyl]-4-hydroxy-piperidine-1-carboxylate (1.4 g, 3.62 mmol) in tetrahydrofuran (20 mL) over 15 min. After 20 min the reaction mixture was diluted with 1:1 brine/saturated NH4Cl and ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography (40 g silica, 30-100% ethyl acetate/hexane, product visualized by TLC with ninhydrin staining+heat) provided tert-butyl 4,4-difluoro-3-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (340 mg, 1.11 mmol, 31%) as a white solid. ESI-MS m/z calc. 306.1. found 307.5 (M+1)+; Retention time: 1.32 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 3.75 (d, J=13.3 Hz, 2H), 3.45 (d, J=3.2 Hz, 2H), 3.07 (br s, 2H), 1.79 (d, J=13.6 Hz, 2H), 1.72-1.60 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][O:16][S:27]([CH3:26])(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CCO)CCOCOCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CCOCOCc1ccccc1)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.99 g (3.92 mmol) of 1-benzyloxymethoxy-3,3-dimethyl-5-pentanol and 0.60 ml (4.3 mmol) of triethylamine in 15 ml of dichloromethane, 0.33 ml (4.3 mmol) of methanesulfonyl chloride was added at 0° C., followed by stirring at room temperature for 30 minutes, after which saturated aqueous sodium hydrogen carbonate was added. The mixture was extracted with dichloromethane and dried, after which the solvent was distilled off to yield 1-benzyloxymethoxy-3,3-dimethyl-5-methanesulfonyloxypentane.
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(Cl)(Cl)Cl>[N:1]1([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: C1=CCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1CC=CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.1 %

Procedure:
A mixture of 3-pyrroline (9.1 g), N,N-diisopropylethylamine (28 mL), and chloroform (46 mL) was ice-cooled, benzyl chloroformate (26 g) was added dropwise, and then the mixture was stirred at room temperature for 15 h. The reaction solution was diluted with chloroform, washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine, and then dried with anhydrous sodium sulfate. The desiccant was removed by filtration, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7:3) to obtain benzyl 2,5-dihydropyrrole-1-carboxylate (26 g).
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13](O)=O)[C@@H:11]([CH3:16])[O:10]C1(C)C)=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.[NH2:47][C:48]1[CH:49]=[C:50]([C:55]2[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[CH:57][C:56]=2[F:63])[CH:51]=[CH:52][C:53]=1[NH2:54]>CN(C=O)C.CCOC(C)=O>[NH2:8][C@H:12]([C:13]1[NH:54][C:53]2[CH:52]=[CH:51][C:50]([C:55]3[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[CH:57][C:56]=3[F:63])=[CH:49][C:48]=2[N:47]=1)[C@H:11]([OH:10])[CH3:16]
Reactant: N#Cc1ccc(-c2ccc(N)c(N)c2)c(F)c1
Reactant: C[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H](N)c1nc2cc(-c3ccc(C#N)cc3F)ccc2[nH]1
Temperature: -5 °C
Reaction time: 1.5 h
Yield: 13.4 %

Procedure:
To a solution of (4S,5R)-3-(tert-butoxycarbonyl)-2,2,5-trimethyl-1,3-oxazolidine-4-carboxylic acid (Preparation 57, 778 mg, 3 mmol) and HOBt (551 mg, 3.60 mmol) in DMF (23 mL) was added NMM (0.33 mL, 3 mmol) and the mixture cooled to −5° C. EDCI (690 mg, 3.60 mmol) was added and the reaction stirred at −5° C. for 90 minutes. A solution of 3′,4′-diamino-2-fluorobiphenyl-4-carbonitrile (Preparation 79, 750 mg, 3.30 mmol) in DMF (7 mL) was added and the reaction was allowed to warm to room temperature for 3 days. The reaction was poured in EtOAc (120 mL), washed with 3% aqueous NaHCO3 solution (4×120 mL), brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EtOAc:Heptane 1:1. The residue was dissolved in AcOH (7 mL) and stirred at 40° C. for 18 hours. The reaction was concentrated in vacuo and treated with saturated aqueous NaHCO3 solution (15 mL), extracted into EtOAc (2×15 mL), the organic layers combined, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with acetone:heptanes 1:3. The residue was dissolved in 4M HCl in dioxane with 1 drop of water and stirred at room temperature for 2 hours. The reaction was eluted through an SCX column washing through with MeOH followed by 3N NH3 in MeOH and the filtrate concentrated in vacuo. The residue was treated with water (1 mL) and MeOH (0.5 mL) and freeze dried to afford the title compound (125 mg, 75%).
Reaction SMILES: [N+:1]1([O-])[C:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1.C[Si]([C:18]#[N:19])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:18]([C:6]1[N:1]=[C:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:3]=[CH:4][CH:5]=1)#[N:19]
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1ccccc1-c1ccccn1
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: N#Cc1cccc(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 36 h
Yield: 41.4 %

Procedure:
2,2′-Bipyridyl N-oxide (2.8 g, 16 mmol) was dissolved in nitroethane (50 ml), and trimethylsilyl cyanide (6.4 g, 65 mmol) and N,N-dimethylcarbamoyl chloride (3.7 g, 35 mmol) were added thereto. The mixture was stirred at room temperature for 36 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (1.2 g, 43%) as white crystals.