Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].O>CN(C=O)C.CCOC(C)=O>[CH3:26][O:25][C:23](=[O:24])[CH2:22][CH2:21][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: COC(=O)CCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
To a solution of tert-butyl piperazine-1-carboxylate (1 g, 5.37 mmol) in DMF (20 mL) was added Cs2CO3 (589 mg, 1.81 mmol) and methyl 3-bromopropanoate (744 mg, 4.46 mmol). The resulting mixture was stirred at room temperature overnight. Water (50 m) and EtOAc (50 mL) was added. Phases were separated. The aqueous phase was extracted with EtOAc (50 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 3.5% MeOH in DCM. Collection of appropriate fractions and evaporation of solvent afforded tert-butyl 4-(3-methoxy-3-oxopropyl)piperazine-1-carboxylate (895 mg, 74%) as yellow oil. TLC: Rf=0.3; ethyl acetate/petroleum ether=1/2.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:42]=[C:43]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[CH2:44][NH:45][C:46]([C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:50][CH:49]=1)=[O:47]>CN(C=O)C.O>[OH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([N:63]1[CH2:62][CH2:61][N:60]([C:43](=[O:42])[CH2:44][NH:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:50][CH:49]=2)=[O:47])[CH2:65][CH2:64]1)=[O:15]
Reactant: O=C(O)c1ccccc1O
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2O)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 2-hydroxy-benzoic acid (35.5 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 60% EtOAc in hexane as eluent). Further purification by preparative HPLC afforded 58 mg (50.9% yield) of biphenyl-4-carboxylicacid {2-[4-(2-hydroxy-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 93.06%, 1H NMR: (DMSO) δ 8.6 (t, 1H), 8.0-7.92 (d, 2H), 7.84-7.7 (q, 4H), 7.56-7.46 (t, 2H), 7.44-7.38 (t, 1H), 7.3-7.2 (t, 1H), 7.2-7.12 (d, 1H), 6.94-6.8 (m, 2H), 4.2 (s, 2H), 3.7-3.5 (s, 5H), 3.3-3.1 (s, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH3:32])[C:15]=2[C@H:16]2[O:22][CH2:21][C@@H:20]([F:23])[C@H:19]([NH:24]C(=O)OC(C)(C)C)[CH2:18][CH2:17]2)=[O:9])[CH:5]=[CH:4][C:3]=1[F:33].[Cl:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O>>[NH2:24][C@H:19]1[C@H:20]([F:23])[CH2:21][O:22][C@H:16]([C:15]2[N:14]([CH3:32])[N:13]=[CH:12][C:11]=2[NH:10][C:8](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([F:33])=[C:2]([C:36]3[CH:37]=[CH:38][CH:39]=[C:40]([F:41])[C:35]=3[Cl:34])[N:7]=2)[CH2:17][CH2:18]1
Reactant: Cn1ncc(NC(=O)c2ccc(F)c(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: OB(O)c1cccc(F)c1Cl
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3cccc(F)c3Cl)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(6-bromo-5-fluoropicolinamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 103), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-3-fluorophenyl)boronic acid gave 227. 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.28 (dd, J=8.6, 3.9 Hz, 1H), 8.12 (t, J=8.9 Hz, 1H), 7.89 (s, 1H), 7.64-7.45 (m, 3H), 4.81 (dd, J=10.3, 3.8 Hz, 1H), 4.20 (ddt, J=49.1, 5.7, 2.7 Hz, 1H), 4.05-3.80 (m, 2H), 3.75 (s, 3H), 3.09-2.95 (m, 1H), 2.10-1.99 (m, 1H), 1.82-1.64 (m, 1H), 1.66-1.56 (m, 2H), 1.53 (br, 2H). LCMS (ES+) m/z 480 (M+1).
Reaction SMILES: [CH:1]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:19][NH2:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([N:27]([CH2:34][C:35](O)=[O:36])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][C:35](=[O:36])[CH2:34][N:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CN(c1ccccc1)c1ccccc1
Reactant: NCC1CCN(C(c2ccccc2)c2ccccc2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CN(c1ccccc1)c1ccccc1)NCC1CCN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of C-(1-benzhydryl-pyrrolidin-3-yl)-methylamine (0.26 g, 0.97 mmol) in dry CH2Cl2 (20 ml) was added diphenylaminoacetic acid (0.22 g, 0.97 mmol) under nitrogen. To the reaction was added EDC (0.37 g, 1.95 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate: water (10:1) (100 ml). The organic was washed with water (25 ml, 2×) and 10% NaOH (25 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using hexane:ethyl acetate (3:1) to give the desired product in 75% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[CH3:17][CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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.CN(C=O)C>[CH3:17][CH:18]([C:20]1[CH:25]=[C:24]([C:2]2[CH:3]=[C:4]([NH:8][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16])[CH:5]=[N:6][CH:7]=2)[CH:23]=[CH:22][CH:21]=1)[CH3:19]
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: O=C(Nc1cncc(Br)c1)c1ccccc1
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: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cccc(-c2cncc(NC(=O)c3ccccc3)c2)c1
Temperature: 85 °C
Reaction time: 12 h

Procedure:
At 50° C., 1.4 g (4.9 mmol) of N-(5-bromopyridin-3-yl)benzamide, 1.0 g (5.9 mmol) of [3-(1-methylethyl)phenyl]boronic acid and 1.4 g (9.9 mmol) of potassium carbonate were dissolved in 15 ml of 1,2-dimethoxyethane, 5 ml of water and 30 ml of DMF. The mixture was flushed with argon, 29 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium(0) were added and the mixture was stirred at 85° C. for 12 h. The reaction mixture was concentrated slightly on a rotary evaporator, diluted with water and extracted with dichloromethane. The organic phase was concentrated and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 1.4 g (92% of theory)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:41]([O:43]C)=[O:42])=[N:11][C:12]([C:15]2[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[C:20]([C:30](=[O:33])[NH:31][CH3:32])[C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[C:10]([C:41]([OH:43])=[O:42])=[N:11][C:12]([C:15]2[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:37])=[O:38])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[C:20]([C:30](=[O:33])[NH:31][CH3:32])[C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)OC)n3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)O)n3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
To a suspension of methyl 3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinate (430 mg, 0.70 mmol) in MeOH (4 mL) was added 1N NaOH (2.10 ml, 2.09 mmol). The resulting mixture was stirred at RT overnight, then added 1N HCl (2.10 ml, 2.09 mmol) was added. The reaction was concentrated in vacuo. The resulting residue was treated with EtOH/DCM (1:1) and filtered to remove the solid. The filtrate was concentrated in vacuo to provide 3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinic acid (430 mg, yield: 102%). MS (M+H)+: 604.
Reaction SMILES: [CH:1]([N:4]([C:18]([C:20]1[C:21]([C:40]([F:43])([F:42])[F:41])=[CH:22][C:23]2[O:28][C:27]([CH3:30])([CH3:29])[C:26](=[O:31])[N:25]([CH2:32][CH2:33][NH:34][C:35]([O:37][CH3:38])=[O:36])[C:24]=2[CH:39]=1)=[O:19])[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:46]N(C)C=O.CI>O>[CH:1]([N:4]([C:18]([C:20]1[C:21]([C:40]([F:41])([F:42])[F:43])=[CH:22][C:23]2[O:28][C:27]([CH3:30])([CH3:29])[C:26](=[O:31])[N:25]([CH2:32][CH2:33][N:34]([C:35]([O:37][CH3:38])=[O:36])[CH3:46])[C:24]=2[CH:39]=1)=[O:19])[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: COC(=O)NCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC(=O)N(C)CCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl (3R)-3-(isopropyl{[4-{2-[(methoxycarbonyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate (110 mg) were added sodium hydride (9.3 mg) and N,N-dimethylformamide (9 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Then, to the mixture was added methyl iodide (0.02 ml), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound (110 mg) as a colorless liquid.
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].C1(O)C=CC=CC=1.[C:16](=[O:18])=[O:17]>O>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:16]([OH:18])=[O:17])=[CH:3][CH:2]=1
Reactant: [O-]c1ccccc1
Reactant: O=C=O
Agent: [K+]
Solvent: O
Solvent: Oc1ccccc1
Product: O=C(O)c1ccc(O)cc1

Procedure:
In a pressure reaction vessel were charged 100 g of potassium phenolate, 35 g of phenol and 500 g of a mixture of hydrogenated triphenyls, and a reaction was allowed to proceed at 250° C. and at a carbon dioxide pressure of 7 kg/cm2 (G) for 20 minutes, with stirring. The reaction mixture was cooled and charged into 200 ml of water, followed by separation into the reaction medium layer and the water layer at 60° C. The water layer was made acid with dilute sulfuric acid to give 81.6 g of p-hydroxybenzoic acid (having a purity of 99%). The yield based on potassium phenolate was 77.3%, and the recovered potassium phenolate was 21.0 g, with the selectivity being 99.7%.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[OH:23][CH2:24][C:25]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:27][CH2:26]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(=O)(O)[O-].[Na+]>[CH:24]([C:25]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:27][CH2:26]1)=[O:23]
Reactant: CCOC(=O)C1(CO)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCOC(=O)C1(C=O)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
At 0° C., 5.05 g (11.9 mmol) of Dess-Martin periodane reagent were added to a solution of 1.225 g (8.5 mmol) of ethyl 1-hydroxymethylcyclopropanecarboxylate [for the preparation see, for example, T. A. Ayers, Tetrahedron Lett. 40 (30), 5467-5470 (1999)] in 43 ml of dichloromethane, and the mixture was then stirred at RT for 6 h. A solution of 6.7 g (42.5 mmol) of sodium thiosulfate in 60 ml of saturated aqueous sodium bicarbonate solution was then added to the reaction mixture. The mixture was stirred at RT for 20 min, and the phases were then separated. The organic phase was washed twice with water, dried over magnesium sulfate and concentrated at 20° C. under reduced pressure. This gave 1.139 g (80.0% of theory) of the target compound.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][C@@H:5]([CH2:7][O:8]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:4][C@H:3]1[N:28]1[CH:36]=[N:35][C:34]2[C:29]1=[N:30][CH:31]=[N:32][C:33]=2[NH2:37]>C(O)(=O)C>[F:1][C@H:2]1[CH2:6][C@@H:5]([CH2:7][OH:8])[O:4][C@H:3]1[N:28]1[CH:36]=[N:35][C:34]2[C:29]1=[N:30][CH:31]=[N:32][C:33]=2[NH2:37]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@@H]1F
Solvent: CC(=O)O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)C[C@@H]1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.7 %

Procedure:
35.3 mg (0.0710 mmols) of 9-[2,3-dideoxy-2-fluoro-5-O-(triphenylmethyl)-β-D-threo-pentofuranosyl]-9H-purine-6-amine was dissolved in 1.0 ml of acetic acid, and stirred at room temperature for about 4 hours and then at 80° C. for about 3 hours. To this was added 1.0 ml of acetic acid, and cooled to room temperature. This was concentrated, and the residue formed was taken out and purified through a silica gel plate (using 91% methylene chloride/ethanol). The fraction of the intended product was extracted with methanol, and the solvent was evaporated out to obtain 11.1 mg (yield 61.5%) of the product which was white solid. The physical data of the product obtained herein were the same as those disclosed in the literature.
Reaction SMILES: O[CH2:2][CH2:3][C@H:4]1[CH2:6][C@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:39]I.N1C=CN=C1>ClCCl.C(OCC)C>[I:39][CH2:2][CH2:3][C@H:4]1[CH2:6][C@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCC([C@@H]2C[C@@H]2CCO)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC([C@@H]2C[C@@H]2CCI)CC1
Reaction time: 0.33 h

Procedure:
rac-cis-tert-butyl 4-[2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate (100 mg, 0.37 mmol) from step 2 of this example was dissolved in dichloromethane (3.7 mL), triphenylphosphine (195 mg, 0.74 mmol), iodine (94 mg, 0.37 mmol) and imidazole (51 mg, 0.74 mmol) were added. After 20 minutes, diethyl ether (10 mL) was added, filtered through a silica gel pad (0.5 inch), concentrated and purified by column chromatography through a 24 gram AnaLogix™ silica gel cartridge eluting with 10% ethyl acetate/hexanes to give the title compound as a white solid.
Reaction SMILES: I[C:2]1[C:3](=[O:7])[CH2:4][CH2:5][CH:6]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.O1CCCC1.O>[Cl-].[NH4+].[Ag-]=O.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[C:3](=[O:7])[CH2:4][CH2:5][CH:6]=2)=[CH:11][CH:10]=1
Reactant: O=C1CCC=C1I
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=[Ag-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCC=C1c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 77.4 %

Procedure:
4.8 g 2-Iodo-cyclopent-2-enone (prepared as described in Org. Lett. 6, 2004, page 3289), 5.4 g 4-chlorophenylboronic acid, 8.5 g silver(I)oxide, 0.425 g triphenylarsine and 0.265 g Pd(C6H5CN)2Cl2 were added to 90 ml tetrahydrofurane and 20 ml water. The reaction mixture was stirred under nitrogen atmosphere for 16 hours. The reaction mixture was diluted with ammonium chloride, filtered and extracted twice with ethyl acetate. The residue was purified by chromatography and the solvent was evaporated. 3.44 g 2-(4′chlorophenyl)cyclopent-2-enone were obtained (m.p. 71-72° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26]>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[F:17])=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccccc1F
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Product: COc1ccc(NC(=O)Nc2ccccc2F)cc1-c1c(Cl)cnn1C
Yield: 26.7 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (20 mg, 0.08 mmol) was treated with 2-Fluorophenyl isocyanate (10 μL, 0.09 mmol) in a similar manner to Example 1.53, providing 8.0 mg (26%) of Compound 97: LCMS m/z (%)=375 (M+H35Cl, 100), 377 (M+H37Cl, 43). 1H NMR (400 MHz, CDCl3) δ: 8.26 (t, 1H), 7.73 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.69 (s, 1H), 7.36 (t, 1H), 7.35 (d, J=4 Hz, 1H), 7.29 (t, 1H), 7.24 (d, J=8 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 3.97 (s, 3H), 3.86 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]([NH:19][C@H:20]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=2)[CH3:21])=[O:18])[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[CH3:16])=[N:6][CH:7]=1.[OH-].[Na+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]([NH:19][C@H:20]([C:22]2[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=2)[CH3:21])=[O:18])[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[CH3:16])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(Cl)c2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1Oc1ncc(Cl)cc1C(=O)N[C@@H](C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
A mixture of methyl 4-[(1S)-1-({[5-chloro-2-(3-chloro-2-methylphenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoate (step 2, 230 mg, 0.56 mmol), N,N-dimethylformamide (5 mL), and 2 M sodium hydroxide aqueous solution (2.5 mL) was stirred at room temperature for 16 h. The mixture was poured into 2 M hydrochloric acid (30 mL), and extracted with ethyl acetate (100 mL×2). The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flush column chromatography on silica gel eluting with dichloromethane/methanol (20/1) to give 191 mg (86%) of the title compound as white solids: 1H-NMR (DMSO-d6) δ 9.06 (1H, d, J=7.9 Hz), 8.25 (1H, d, J=2.6 Hz), 8.15 (1H, d, J=2.6 Hz), 7.88 (2H, d, J=8.1 Hz), 7.53 (2H, d, J=8.2 Hz), 7.46–7.15 (1H, m), 5.24–5.14 (1H, m), 2.10 (3H, s), 1.47 (3H, d, J=6.9 Hz); MS (ESI) m/z 445 (M+H)+, 443 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:3]=1.[NH2:15][NH2:16]>O1CCOCC1.O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[NH:3]/[C:2](=[N:15]\[NH2:16])/[CH:7]=[N:6][CH:5]=2)=[CH:9][CH:10]=1
Reactant: NN
Reactant: Fc1ccc(-c2cncc(Cl)n2)cc1
Solvent: C1COCCO1
Solvent: O
Product: N/N=c1/cncc(-c2ccc(F)cc2)[nH]1
Yield: 88.6 %

Procedure:
A mixture of 2-chloro-6-(4-fluoro-phenyl)-pyrazine (1.0 g, 4.7 mmol) and anhydrous hydrazine (1.5 mL, 47 mmol) in dioxane (20 mL) was heated to reflux for two hours, then cooled and diluted with cold water. The resulting precipitate was collected by filtration, washed with cold water, and dried to give 0.85 g of [6-(4-fluoro-phenyl)-1H-pyrazin-(2Z)-ylidene]-hydrazine.
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C@H:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:10][C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=2)C=CC=CC=1.Cl>O1CCCC1>[CH3:18][O:17][C:12]1[C:11]([CH2:10][C@@H:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH2:8])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: CCOC(=O)[C@H](Cc1cccnc1OC)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](N)Cc1cccnc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 100-mL round-bottomed flask was added ethyl N-(diphenylmethylidene)-3-(2-methoxy-3-pyridinyl)alaninate (1.52 g, 3.91 mmol) and 5N hydrochloric acid (1.72 mL, 8.61 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at 0° C. for 1 h. The solvent was removed in vacuo to give crude ethyl 3-(2-methoxy-3-pyridinyl)alaninate as a white tar, which was used without purification.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[O:10][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[C:52]([Zn]C#N)#[N:53]>CC(N(C)C)=O.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].[Zn]>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:52]#[N:53])=[N:3][C:4]=1[C:9]1[O:10][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[N:12][N:13]=1
Reactant: N#C[Zn]C#N
Reactant: CC(C)(C)c1nnc(-c2nc(Br)cnc2N)o1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1nnc(-c2nc(C#N)cnc2N)o1
Temperature: 100 °C
Reaction time: 1 h
Yield: 158.5 %

Procedure:
A stream of nitrogen gas was passed through a solution of 5-bromo-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (89.35 g, 239.75 mmol) in DMA (1.2 L) for 20 minutes. Dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (11.43 g, 23.98 mmol), tris(dibenzylideneacetone)dipalladium(0) (5.49 g, 5.99 mmol), zinc (1.568 g, 23.98 mmol) and dicyanozinc (16.89 g, 143.85 mmol) were added sequentially to the stirred mixture. The mixture was heated to 100° C. and stirred for 1 hour. The mixture was cooled and partitioned between DCM (3 L) and water (1 L). The black mixture was filtered through celite and the organic layer was separated. The solution was washed with water then brine. The solution was dried with magnesium sulfate and concentrated under reduced pressure. The residue was triturated with MTBE and isolated by filtration, washing with MTBE. The filter cake was dried in vacuo to afford 5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazine-2-carbonitrile (55.7 g, 95%) as a pale orange solid: 1H NMR Spectrum: (DMSO-d6) 1.46 (9H, s), 6.02 (1H, s), 8.38 (2H, s); Mass Spectrum [M−H]−=242.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12](OC)=[O:13].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13]
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(CCO)c(F)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 77.2 %

Procedure:
To a stirred solution of methyl 2-(2-fluoro-4-nitrophenyl)acetate (3.0 g, 14.0 mmol, 1.0 eq) in methanol (30 mL) was added NaBH4 (2.08 g, 36.3 mmol, 4.0 eg) at 0° C. and stirred at 70° C. for 16 h, then the methanol was evaporated and the residue was diluted with water (30 mL), the pH adjusted to being neutral with 2N HCl and the mixture extracted with EtOAc (50 mL×3). The organic layer was separated, washed with brine, dried over Na2SO4 and the solvent evaporated to yield 2-(2-fluoro-4-nitrophenyl)ethanol (2.0 g, 77%) as a viscous oil (TLC system: EtOAc/PE (3:7), Rf: 0.3).