Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:24]([O:28][C:29](=[O:41])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][C:33]=1[CH2:39][NH2:40])([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl.O>[C:24]([O:28][C:29](=[O:41])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][C:33]=1[CH2:39][NH:40][C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1CN
Reactant: O=C(O)c1cnccn1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)CCc1ccc(O)cc1CNC(=O)c1cnccn1
Reaction time: 0.17 h
Yield: 70.3 %

Procedure:
To a solution of pyrazine-2-carboxylic acid (0.570 g, 4.60 mmol) in CH2Cl2 (50 mL) was added EDC (0.960 g, 5.01 mmol) and HOBt (0.620 g, 4.60 mmol) at room temperature. The mixture was stirred for 10 min, and 3-(2-aminomethyl-4-hydroxy-phenyl)-propionic acid tert-butyl ester (1.05 g, 4.18 mmol) was added. The reaction mixture was stirred for 18 h at room temperature, treated with water (50 mL), and extracted with CH2Cl2 (2×50 mL). The combined organic layers were dried (Na2SO4), concentrated, and purified by silica gel chromatography (EtOAc/hexanes, 1:1 to 1:0) to obtain the title compound (1.05 g, 70%). 1H NMR (400 MHz, CDCl3): δ 1.40 (s, 9H), 2.52 (t, 2H, J=7.6 Hz), 2.91 (t, 2H, J=7.6 Hz), 4.66 (d, 2H, J=6.4 Hz), 6.73 (dd, 1H, J=2.9, 7.8 Hz), 6.83 (d, 1H, J=2.4 Hz), 7.07 (d, 1H, J=8.3 Hz), 8.17 (br s, 1H), 8.49 (dd, 1H, J=1.5, 2.4 Hz), 8.73 (d, 1H, J=2.4 Hz), 9.41 (d, 1H, J=1.5 Hz). MS (ES) m/z 356.1 ([M−H]−).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:14][CH:13]2[CH2:15][CH:9]([CH2:10][N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]2)[CH:8]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+].[C:31]1([C:37]2[CH:38]=[C:39](B(O)O)[CH:40]=[N:41][CH:42]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:31]1([C:37]2[CH:38]=[C:39]([C:7]3[CH2:14][CH:13]4[CH2:15][CH:9]([CH2:10][N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]4)[CH:8]=3)[CH:40]=[N:41][CH:42]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)N1CC2C=C(OS(=O)(=O)C(F)(F)F)CC(C2)C1
Reactant: OB(O)c1cncc(-c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)N1CC2C=C(c3cncc(-c4ccccc4)c3)CC(C2)C1
Temperature: 95 °C
Yield: 98.4 %

Procedure:
To a solution of ethyl 7-(trifluoromethylsulfonyloxy)-3-azabicyclo[3.3.1]non-6-ene-3-carboxylate (0.12 g, 0.35 mmol) in dimethoxyethane (3 mL) was added saturated sodium carbonate solution (1 mL), lithium chloride (0.04 g, 0.9 mmol) and 5-phenyl-3-pyridinylboronic acid (0.12 g, 0.7 mmol). The flask was alternately evacuated and filled with argon three times. Then tetrakis(triphenylphosphine)palladium(0) (0.01 g, 0.01 mmol) was added, and the evacuation and argon fill was performed once again. The flask was then sealed under argon, and the stirred reaction mixture was heated at 95° C. for 2 h. The mixture was cooled to ambient temperature, diluted with water (10 mL) and extracted with chloroform (3×5 mL). The combined extracts were dried over sodium sulfate and filtered. Concentration of the filtrate by rotary evaporation, followed by purification of the residue by silica gel column chromatography, using a gradient of chloroform/methanol (0-2% methanol) as eluent, gave ethyl 7-(5-phenyl-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene-3-carboxylate as a light yellow oil (0.12 g, 90%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[C:27](Br)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2.[CH3:29][N:30]([CH3:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.[OH-].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[C:27]([C:34]4[CH:35]=[CH:36][C:31]([N:30]([CH3:40])[CH3:29])=[CH:32][CH:33]=4)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)cc1
Temperature: 80 °C

Procedure:
0.33 ml of 2 M sodium carbonate solution and 9.1 mg (0.01 mmol) of PdCl2(dppf) are added to a mixture of 100 mg (0.22 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 36.8 mg (0.22 mmol) of 4-(dimethylamino)phenylboronic acid in 1 ml of DMF. The reaction mixture is heated at 80° C. for 16 h. A further 36.8 mg (0.22 mmol) of 4-(dimethylamino)phenylboronic acid, 36.5 mg (0.04 mmol) of PdCl2(dppf) and 0.67 ml of 1N sodium hydroxide solution are added, and the mixture is heated at 80° C. for a further 3 h. Cooling is followed by filtration through kieselguhr and purification by preparative HPLC. The product fractions are concentrated, taken up in a 5:1 mixture of methanol and 1N hydrochloric acid and again concentrated. Drying under high vacuum results in 50.6 mg (47% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([O:12]C)=[O:11])=[C:7]([N:14]([CH:24]([CH3:26])[CH3:25])[C:15]([C@H:17]2[CH2:22][CH2:21][C:20]([CH3:23])=[CH:19][CH2:18]2)=[O:16])[CH:6]=1.O.[OH-].[Li+].Cl>C1COCC1.CO>[CH3:1][C:2]([CH3:27])([CH3:28])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:14]([CH:24]([CH3:25])[CH3:26])[C:15]([C@H:17]2[CH2:22][CH2:21][C:20]([CH3:23])=[CH:19][CH2:18]2)=[O:16])[CH:6]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@@H]1CC=C(C)CC1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1=CC[C@@H](C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C(C)C)CC1
Reaction time: 0.5 h
Yield: 35 %

Procedure:
(S)-Methyl 5-(3,3-dimethylbut-1-ynyl)-3-(N-isopropyl-4-methylcyclohex-3-enecarboxamido)thiophene-2-carboxylate (123 mg, 0.31 mmol) was dissolved in THF (2 mL). Water (0.5 mL), methanol (0.5 mL) and lithium hydroxide (129 mg, 3.1 mmol) were added. The mixture was sealed and heated to 45 deg C. for 30 min. After an additional 1 h at ambient temperature, the mixture was treated with 10% HCl (until the pH was less than 3) and partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulfate (anhyd) and the residue was purified by reverse phase HPLC to give the title compound, 41 mg (35% yield): MS (m/z): 388.0 [M+H]+; HPLC retention time 4.59 min (2-98% acetonitrile: water with 0.05% trifluoroacetic acid).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:14][C:13]([C:16]([F:19])([F:18])[F:17])([OH:15])[CH2:12]1)(=[O:10])=[O:9].[F:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[C:36]1[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=1>>[NH2:42][C:39]1[N:40]=[CH:41][C:36]([C:22]2[CH:23]=[CH:24][C:25]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]([N:11]3[CH2:14][C:13]([C:16]([F:19])([F:18])[F:17])([OH:15])[CH2:12]3)(=[O:10])=[O:9])=[CH:26][C:21]=2[F:20])=[CH:37][N:38]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)N1CC(O)(C(F)(F)F)C1
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)N3CC(O)(C(F)(F)F)C3)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 1-((2-bromophenyl)sulfonyl)-3-(trifluoromethyl)azetidin-3-ol and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C20H16F4N4O3S, 468.09; m/z found, 469.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 8.53-8.47 (d, J=1.4, 2H), 8.06-8.01 (dd, J=8.0, 1.3, 1H), 7.81-7.76 (m, 1H), 7.70-7.65 (m, 1H), 7.64-7.58 (m, 1H), 7.51-7.45 (m, 2H), 7.35-7.29 (dd, J=11.7, 1.8, 1H), 7.28-7.24 (dd, J=7.8, 1.7, 1H), 6.94 (s, 2H), 3.81-3.76 (d, J=9.3, 2H), 3.71-3.66 (m, 2H)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][CH2:18][C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])=CC2C=CC=CC=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:35]=[O+][O-]>ClCCl.CO>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH:19]([OH:35])[CH2:18][O:17][C@H:14]1[CH2:15][CH2:16][C@H:11]([NH:10][C:9](=[O:34])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:13]1
Reactant: O=C(N[C@H]1CC[C@H](OCC(=Cc2ccccc2)c2ccccc2F)CC1)OCc1ccccc1
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: O=C(N[C@H]1CC[C@H](OCC(O)c2ccccc2F)CC1)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of 41 g of trans-[4-(2-(2-fluorophenyl)-3-phenyl-allyloxy)-cyclohexyl]-carbamic acid benzyl ester in 750 mL of dichloromethane and 250 mL of methanol cooled to −78° C. was dispersed a stream of ozone from an ozone generator until a blue color persisted. The excess ozone was purged with nitrogen until the blue color dissipated, and 7.8 g of sodium borohydride was added. After warming to room temperature over 30 min, the solution was diluted with 50 mL of water and concentrated under reduced pressure. The residue was treated with 500 mL of 3N hydrochloric acid and extracted into 3×500 mL of ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Chromatography over silica gel eluting with a gradient of 2%-30% ethyl acetate in hexane gave 30 g of product as a white crystalline solid: MS (m+1)=388.4; 1H NMR (400 MHz, CDCl3) 7.53 (m, 1H), 7.33 (m, 5H), 7.25 (m, 1H), 7.14 (m, 1H), 7.0 (m, 1H), 5.15 (d, 1H), 5.07 (s, 2H), 4.6 (m, 1H), 3.7 (d, 1H), 3.5 (br m, 1H), 3.4 (t, 1H), 3.3 (m, 1H), 2.9 (s, 1H), 2.0 (m, 4H), 1.2 (q, 2H), 1.15 (q, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].CCOCC>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1Cl
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(F)ccc1-c1ccccc1
Temperature: 165 °C
Yield: 82.4 %

Procedure:
A microwave reaction vessel was charged with 2-chloro-5-fluoronitrobenzene (0.175 g, 1 mmol), phenylboronic acid (0.134 g, 1.1 mmol), sodium carbonate (0.317 g, 3 mmol), palladium diacetate (0.009 g, 0.04 mmol), tetrabutylammonium bromide (0.322 g, 1 mmol) in water (2 mL). The mixture was heated to 165° C. in a microwave reactor for 7.5 minutes. The reaction was cooled and poured into ether and 0.1N aqueous sodium hydroxide. The ether layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated. The crude product was purified by silica gel column chromatography (5-30% methylene chloride in hexanes) to give the desired product as a pale yellow oil (0.179 g, 82%). 1H NMR (CDCl3, 300 MHz) δ 7.62-7.58 (dd, 1H, J=2.7, 8.1 Hz), 7.46-7.40 (m, 4H), 7.38-7.34 (m, 1H), 7.31-7.26 (m, 2H). HPLC analysis (C18, 5-95% acetonitrile in H2O+0.1% trifluoroacetic acid over 20 min: retention time, % area at 254 nm): 9.95 min, 96.3%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[CH:3]=1.[Cl-].[C:13]([O:17][C:18](=[O:21])[CH2:19][Zn+])([CH3:16])([CH3:15])[CH3:14]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2]>[Cl:11][C:4]1[CH:3]=[C:2]([CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:21])[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: O=[N+]([O-])c1cc(Cl)cc(Br)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1cc(Cl)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
To a solution of 1-bromo-3-chloro-5-nitrobenzene 52.A (10.23 g, 43 mmol, available from Synchem Inc), Pd2(dba)3 (0.79 g, 0.87 mmol) and CTC-QPhos (1.20 g, 1.40 mmol) in THF (100 mL) was added 2-tert-Butoxy-2-oxoethylzinc chloride (95 mL, 0.5M solution in diethyl ether, 48 mmol, available from Rieke Metals). The mixture was stirred for 3 hours at room temperature. The reaction was then quenched by adding water (100 mL), washed with 1N HCl solution (2×100 mL), concentrated and purified by using flash chromatography on silica gel (0-10% AcOEt/Hexanes) to afford tert-butyl 2-(3-chloro-5-nitrophenyl)acetate 52.B (9.60 g, 82% yield) as a light pink oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1.[CH2:24](N)[CH2:25][NH2:26].C(=S)=S>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:26][CH2:25][CH2:24][N:22]=2)=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Reactant: NCCN
Solvent: CN(C)C=O
Solvent: S=C=S
Product: Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(C2=NCCN2)cc1
Yield: 45 %

Procedure:
N-(2-Amino-5-(thiophen-2-yl)phenyl)-4-cyanobenzamide 173 (30 mg, 0.1 mmol), ethylenediamine (0.126 mL, 1.9 mmol.) and carbon disulfide (catalyst) were stirred at 50° C. in DMF overnight. The reaction mixture was then evaporated to dryness, taken up in methanol and filtered to give the title compound 174 as a yellow solid (16.3 mg, 48%). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 9.78 (s, 1H), 8.02 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H), 7.45 (s, 1H), 7.33 (d, J=5.1 Hz, 1H), 7.28 (d, J=8.2 Hz, 1H), 7.22 (d, J=3.3 Hz, 1H), 7.03 (t, J=3.9 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 5.18 (s, 2H), 3.63 (s, 4H). MS: 362.12 (calc), 363.1 (obs).
Reaction SMILES: C(O[C:4](=[O:36])[C@:5]([O:11][CH2:12][C@@:13]([C:28]1[CH:33]=[C:32]([Br:34])[CH:31]=[CH:30][C:29]=1[F:35])([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[CH3:14])([CH3:10])[C:6]([F:9])([F:8])[F:7])C.[NH3:37]>CO>[Br:34][C:32]1[CH:31]=[CH:30][C:29]([F:35])=[C:28]([C@:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])(=[O:17])=[O:18])([CH3:14])[CH2:12][O:11][C@@:5]([CH3:10])([C:6]([F:8])([F:7])[F:9])[C:4]([NH2:37])=[O:36])[CH:33]=1
Reactant: CCOC(=O)[C@@](C)(OC[C@](C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F)C(F)(F)F
Reactant: N
Solvent: CO
Product: C[C@@](CO[C@](C)(C(N)=O)C(F)(F)F)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F

Procedure:
A solution of (R)-2-[(R)-2-(5-bromo-2-fluoro-phenyl)-2-(2-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionic acid ethyl ester (26.6 g, 44.2 mmol) in 7N NH3 in MeOH (75 ml) was stirred for 16 h at 50° C. The solvent was removed under reduced pressure and the residual solid re-crystallized from Et2O to give the title compound as yellow crystals: TLC (hexane-EtOAc 1:1): Rf=0.35; UPLC RtH5=1.184 min; ESIMS: 589, 591 [(M+NH4)+]; 1H NMR (360 MHz, CDCl3): δ 7.85 (d, 1H), 7.64 (m, 3H), 7.44 (d, 1H), 7.41 (dd, 1H), 7.26 (m, 1H), 6.68 (br s, 1H), 6.57 (dd, 1H), 6.19 (s, 1H), 5.54 (br s, 1H), 4.24 (d, 1H), 3.93 (d, 1H), 1.79 (s, 3H), 1.67 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([OH:31])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: Oc1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3O)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-bromophenol. MS (ESI): mass calcd. for C16H12FN3O, 281.10; m/z found, 282.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.36 (s, 1H), 8.01 (d, J=1.4, 1H), 7.87 (m, 1H), 7.49 (dd, J=4.4, 1.3, 1H), 7.45 (s, 1H), 7.34 (dd, J=7.4, 1.3, 1H), 7.19 (m, 1H), 6.95 (d, J=7.3, 1H), 6.89 (m, 1H), 6.68 (s, 2H).
Reaction SMILES: Cl.C([N:9]1[CH2:13][C@@H:12]([S:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:11]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:10]1)(OC(C)(C)C)=O.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.O.[C:53]([O:57][C:58]([NH:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][C:66](O)=[O:67])=[O:59])([CH3:56])([CH3:55])[CH3:54].C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C>[C:53]([O:57][C:58]([NH:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][C:66]([N:9]1[CH2:13][C@@H:12]([S:14][C:15]([CH3:17])([CH3:18])[CH3:16])[C@H:11]([NH:19][S:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH2:10]1)=[O:67])=[O:59])([CH3:56])([CH3:55])[CH3:54]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NS(=O)(=O)c2ccc(-c3ccccc3)cc2)[C@H](SC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCCCC(=O)N1C[C@@H](NS(=O)(=O)c2ccc(-c3ccccc3)cc2)[C@H](SC(C)(C)C)C1
Temperature: 0 °C
Yield: 93.4 %

Procedure:
To a solution of 1.5 M HCl in ethyl acetate (1 mL) was added (±)-N-Boc-trans-3-(4-phenylbenzenesulfonamido)-4-tert-butylmercaptopyrrolidine (220 mg, 0.45 mmol) and the mixture was stirred until no starting material could be detected by TLC (50% ethyl acetate). The solvent was evaporated under reduced pressure and the residue was dissolved in CH2Cl2 (2 mL) and cooled to 0° C. To the solution was added triethylamine (69 μL, 0.50 mmol), HOBt.H2O (61 mg, 0.45 mmol), and 6-(tert-butoxy-carbonylamino)hexanoic acid (104 mg, 0.39 mmol) and DCC (92 mg, 0.45 mmol). The mixture was stirred overnight, then it was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL) and the organic layer was washed with 10% citric acid and sat. aq NaHCO3, then it was dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (50% ethyl acetate in hexane) to give (±)-N-(6-(tert-butoxycarbonylamino)hexanoyl)-trans-3-(4-phenylbenzenesulfonamido)-4-tert-butylmercaptopyrrolidine (220 mg, 81%): 1H NMR (300 MHz, CDCl3) δ 7.94 (dd, J=9, 4, 2H), 7.75 (t, J=8, 2H), 7.61 (m, 2H), 7.46 (m, 3H), 5.21 (br s, 1H, NH), 4.56 (br s, 1H, NH), 3.77-4.11 (m, 2H), 3.02-3.49 (m, 6H), 2.22 (t, J=7, 2H), 1.63 (m, 2H), 1.49 (m, 2H), 1.44 (s, 9H), 1.36 & 1.29 (s, 9H), 1.25 (m, 2H); HRMS (ESI) calculated for C31H45N3O5S2Na+ 626.2698. found 626.2699.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24](CC2C=CC=CC=2)[CH2:25][C@@H:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34]CC3C=CC=CC=3)=[C:30]([NH:42][CH:43]=[O:44])[CH:29]=2)[OH:27])=[CH:17][CH:16]=1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:24][CH2:25][C@@H:26]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([NH:42][CH:43]=[O:44])[CH:29]=2)[OH:27])=[CH:17][CH:16]=1
Reactant: O=CNc1cc([C@@H](O)CN(CCOc2ccc(CCCCNC(=O)OCc3ccccc3)cc2)Cc2ccccc2)ccc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: NCCCCc1ccc(OCCNC[C@H](O)c2ccc(O)c(NC=O)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.1 %

Procedure:
α-Aminoalcohol 17 (500 mg, 0.71 mmol) was dissolved in ethanol (20 mL). Following the standard hydrogenation procedure, palladium dihydroxide (20% on carbon, 50% wet) was added. The reaction mixture was stirred for 15 h at ambient temperature under atmospheric H2 pressure. The catalyst was removed by filtration through diatomaceous earth and the filtrate was concentrated to a yellow solid. Purification of the crude solid by column chromatography eluting with 10-30% (20% concentrated ammonium hydroxide in methanol) in dichloromethane gave 18 (146 mg, 53%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 1.29-1.72 (m, 5H), 1.93 (s, 3H), 2.58 (t, 2H), 2.71-2.90 (m, 4H), 2.99 (t, 2H), 4.05 (t, 2H), 4.66-4.72 (m, 1H), 6.78-6.85 (m, 3H), 6.97-7.16 (m, 3H), 7.82-8.04 (m, 1H), 8.29 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[C:18]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:27]2[CH2:28][CH2:29][N:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25][CH2:26]2)[N:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCO)nc(NCCO)nc1N1CCN(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 4-phenyl-piperazine in N,N-dimethylformamide in the presence of N-ethyl-diisopropylamine at 40° C. to yield 2,4-bis-(2-hydroxy-ethylamino)-6-(4-phenyl-piperazin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, colorless solid; MS: [M+H]+=384.
Reaction SMILES: [Cl:1][C:2]1([Cl:13])[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@@H:3]1[CH2:11]O.[C:14]([O:18][C:19]([NH:21][O:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[C:14]([O:18][C:19]([N:21]([CH2:11][C@H:3]1[C@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1([Cl:13])[Cl:1])[O:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Reactant: OC[C@H]1[C@H](c2ccccc2)C1(Cl)Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)ON(C[C@H]1[C@H](c2ccccc2)C1(Cl)Cl)C(=O)OC(C)(C)C
Temperature: -42 °C
Yield: 94 %

Procedure:
A solution of KOH (3.36 g, 60 mmol) and the product of Step 1, above, (10.36 g, 40 mmol) in a mixture of methanol (30 ml), tetrahydrofuran (30 ml) and water (90 ml) was stirred for 3 hours at room temperature. The reaction mixture was neutralized with 1N aqueous hydrochloric acid and extracted with diethyl ether (100 ml+2×50 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (2×50 ml) and brine (50 ml), then dried over MgSO4. Evaporation of the solvent afforded (2,2-dichloro-trans-3-phenylcyclopropyl)methanol in quantitative yield. To a stirred solution of the alcohol thus prepared (4.34 g, 20 mmol), N,O-di-tert-butoxycarbonylhydroxylamine (5.83 g, 25 mmol), and triphenylphosphine (6.56 g, 25 mmol) in toluene (40 ml), cooled to −42° C. was added dropwise a solution of diethyl azodicarboxylate (4.35 g, 25 mmol) in toluene (5 ml) over 15 minutes under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature overnight, insolubles were removed by filtration and the filtrate concentrated under reduced pressure. The resultant residue was purified by column chromatography (SiO2, 300 g; 8% ethyl acetate in n-hexane) affording the title compound (8.09 g, 94% yield).