Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([NH2:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1>C(OCC)(=O)C.O.C(Cl)CCl>[F:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([NH:35][C:22](=[O:24])/[CH:21]=[CH:20]/[C:10]2[CH:11]=[CH:12][C:13]([N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]3)=[C:8]([O:7][CH3:6])[CH:9]=2)([CH3:33])[CH3:34])=[CH:30][CH:31]=1
Reactant: CC(C)(N)c1ccc(F)cc1
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COc1cc(/C=C/C(=O)NC(C)(C)c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.6 %

Procedure:
To a DMF (5 mL) solution of (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid (60 mg) obtained in Example 121, 1-(4-fluorophenyl)-1-methylethylamine (CAS#17797-10-3) (43 mg), EDC (53 mg) and HOBT (38 mg) were added at room temperature under nitrogen atmosphere, and the reaction solution was agitated at room temperature for 12 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer was washed with a saturated sodium chloride solution, and the organic layer was concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel chromatography (elution solvent: methanol-ethyl acetate system), and the title compound (60 mg) was obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[CH:16][N:17]=[C:11]2[CH:10]=1)C1C=CC=CC=1>[Pd].C1COCC1>[N:17]1[CH:16]=[N:15][N:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=12
Reactant: c1ccc(COc2ccn3ncnc3c2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Oc1ccn2ncnc2c1
Reaction time: 16 h

Procedure:
A 250 mL, single-neck, round-bottomed flask was charged with 7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine (3.20 g, 14.2 mmol), Pd/C (0.756 g, 0.710 mmol), and THF (125 mL). The reaction was stirred under an atmosphere of hydrogen for 16 hours, then filtered (GF paper) and concentrated to a white solid. The solids were titrated with EtOAc and collected by filtration to provide the desired product.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:58]2[N:59]=[C:60]([NH:63]C(OC(C)(C)C)=O)[S:61][CH:62]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([O-:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][N:42](C(OC(C)(C)C)=O)[CH2:43][C:44]3[CH:45]=[N+:46]([CH3:50])[CH:47]=[CH:48][CH:49]=3)[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:63][C:60]1[S:61][CH:62]=[C:58](/[C:22](=[N:21]/[O:20][C:17]2([C:15]([OH:16])=[O:14])[CH2:18][CH2:19]2)/[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([O-:34])(=[O:32])=[O:33])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][NH:42][CH2:43][C:44]3[CH:45]=[N+:46]([CH3:50])[CH:47]=[CH:48][CH:49]=3)[CH:38]=[N:37]2)=[O:24])[N:59]=1
Reactant: C[n+]1cccc(CN(Cc2cnn(C[C@@H]3[C@H](NC(=O)/C(=N\OC4(C(=O)OC(c5ccccc5)c5ccccc5)CC4)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N3S(=O)(=O)[O-])n2)C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[n+]1cccc(CNCc2cnn(C[C@@H]3[C@H](NC(=O)/C(=N\OC4(C(=O)O)CC4)c4csc(N)n4)C(=O)N3S(=O)(=O)[O-])n2)c1
Yield: 38.6 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(((tert-butoxycarbonyl)((1-methylpyridin-1-ium-3-yl)methyl)amino)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonate (53 mg, 0.053 mmol), TFA (81 μl, 1.1 mmol) and DCM (72 mL). The crude residue purified by reverse phase prep HPLC (Xselect CSH, 30×100 mm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (13 mg, 35%) as a white powder. LCMS: Rt=0.30 min, m/z=635.3 (M+1) Method 2m_acidic; 1H NMR (400 MHz, D2O) δ 9.00 (s, 1H), 8.78-8.67 (m, 2H), 7.97 (t, J=7.1 Hz, 1H), 7.86 (s, 1H), 6.93 (s, 1H), 5.75 (d, J=5.3 Hz, 1H), 5.11 (dd, J=14.4, 3.7 Hz, 1H), 5.06-4.99 (m, 1H), 4.70-4.46 (m, 4H), 4.38 (s, 3H), 3.77-3.62 (m, 1H), 1.35-1.26 (m, 1H), 1.20-1.10 (m, 2H), 0.93-0.82 (m, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH:8]([OH:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:13]([O:12][CH:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]([OH:11])=[O:10])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)C(O)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OC(Cc1ccccc1)C(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 24.2 %

Procedure:
A 50 mL three-necked flask was charged with 3-phenyllactic acid (1.0 g, 6.0 mmol) and dry CH2Cl2 (12 mL). To this white slurry was added benzoyl chloride (1.04 mL, 9.0 mmol) and the mixture was cooled to 0° C. Triethylamine (0.8 mL, 6.0 mmol) was added and a light yellow solution resulted. 4-Dimethylaminopyridine (367 mg, 3.0 mmol) was added and the reaction mixture was warmed to 25° C. and stirred for 3 hours. The reaction mixture was concentrated on a rotary evaporator and ether, ethyl acetate, and water were added. The mixture was extracted with ether (3×) and ethyl acetate, dried over MgSO4, filtered and evaporated. Purification by silica gel chromatography (4:1 hexanes/ethyl acetate increased to 1:1 hexanes/ethyl acetate) yielded 392 mg (24%) of 11 as a white solid. Rf 0.15 (1:1 hexanes/ethyl acetate); mp 113° C.; IR (CDCl3) 3564-2560 (broad acid), 3028, 2924, 1720 (broad), 1452, 1268, 716 cm−1; 1H NMR (300 MHz, CDCl3) 11.25 (s, 1H), 8.08 (d, J=7.2 Hz, 2H) 7.45 (m, 8H), 5.56 (m, 1H), 3.38 (m, 2H); 13C NMR (75 MHz, CDCl3) 175.5, 165.9, 149.9, 135.6, 133.4, 130.1, 129.7, 129.3, 128.9, 128.5, 128.4, 127.1, 72.9, 37.2; HRMS (FAB): Calcd for (M+Li) C16H14O4Li, 277.1052; Found, 277.1065; EA Calcd for C16H14O4: C, 71.10; H, 5.22; Found: C, 71.04; H, 5.24.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:17][C:18]1([CH3:24])[CH2:22][CH2:21][CH2:20][C:19]1=O.C(OCC)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:17][C:18]1([CH3:24])[CH2:22][CH2:21][CH2:20]/[C:19]/1=[N:9]\[C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC1(C)CCCC1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H](/N=C1\CCCC1(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice cold solution of (R)-1-phenylethanamine (3.11 g, 25.7 mmol) and triethylamine (17.9 mL, 128 mmol) in dichloromethane (60 mL) was added dropwise neat titanium tetrachloride (10.7 mL, 10.7 mmol) to afford a light brown mixture. The cold bath was removed and 2,2-dimethylcyclopentanone (2.68 mL, 21.4 mmol) was added and the resulting mixture was allowed to stir at rt for ˜16 h. To this mixture was added 75 mL of diethyl ether and the resulting mixture was stirred at rt for 15 min then filtered thru a pad of Celite to remove the solids. The solids were rinsed with additional ether (30 mL×2) and the resulting clear yellow filtrate was concentrated on a rotovap to afford 4.86 g (quantitative) of the title compound as a yellow liquid. HPLC (condition B): retention time=1.58 min. LCMS (condition E): m/z 216+ve.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1.C(O)C>C(O)(=O)C>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1ccc(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)cc1
Yield: 87.5 %

Procedure:
The starting material used in the above example can be prepared as follows: 57.9 g (0.3 mol) of 3-nitrophthalic anhydride and 41.1 g (0.3 mol) of 4-aminobenzoic acid in 600 ml of acetic acid are refluxed for 6 hours and the mixture is then stirred into 1,000 ml of 50% aqueous ethanol. The yellow product which has precipitated is filtered off with suction, washed with water and dried at 80° C./30 mm Hg for 24 hours. 82 g (88% of theory) of 4-(3-nitrophthalimidyl)-benzoic acid are obtained; melting point >300° C. IR spectrum (KBr): 1790 and 1740 cm-1 (CO--N--CO); 1550 and 1370 cm-1 (NO2).
Reaction SMILES: [CH2:1]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20](=[O:32])[CH:21]=[CH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:17][CH:18]=2)[C:13]([CH3:34])([CH3:33])[CH2:12][C:11]1=[O:35])CCCCCCCC.BrC1C=CC(C=CC(C2C=C3C(=CC=2)N(C)C(=O)CC3(C)C)=O)=CC=1>>[CH3:1][N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20](=[O:32])[CH:21]=[CH:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:30][CH:31]=3)=[CH:17][CH:18]=2)[C:13]([CH3:33])([CH3:34])[CH2:12][C:11]1=[O:35]
Reactant: CCCCCCCCCN1C(=O)CC(C)(C)c2cc(C(=O)C=Cc3ccc(C(=O)O)cc3)ccc21
Agent: CN1C(=O)CC(C)(C)c2cc(C(=O)C=Cc3ccc(Br)cc3)ccc21
Product: CN1C(=O)CC(C)(C)c2cc(C(=O)C=Cc3ccc(C(=O)O)cc3)ccc21
Yield: 20 %

Procedure:
Following a procedure similar to that used for the preparation of Compound 8d but using 6-[3-(4-bromophenyl)-acryloyl]-4,4-dimethyl-1-methyl-3,4-dihydro-1H-quinolin-2-one (Intermediate 7f) as the starting material afforded the title compound as a light yellow solid (20% yield).
Reaction SMILES: [C:1]([C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=1)#[CH:2].I[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:9][C:8]1[C:3]([C:1]#[C:2][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])=[N:4][C:5]([CH3:10])=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(I)c1
Reactant: C#Cc1nc(C)ccc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(N)c(C#Cc2cccc(C#N)c2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.6 %

Procedure:
To a solution of Cul (2.4 mg, 12 μmol) in triethylamine (4 ml) were added (2-ethynyl-6-methyl-pyridin-3-yl)amine (33 mg, 0.33 mmol described in Example 7), (PPh3)2PdCl2 (8.8 mg, 12 μmol), and 3-iodobenzonitrile (57 mg, 0.25 mmol). The reaction mixture was stirred at room temperature for 48 h. The solvent was evaporated and the crude residue was purified by flash chromatography (cyclohexane/ethyl acetate 1:1) to yield 16 mg (69 μmol, 21%) of 3-(3-amino-6-methyl-pyridin-2-ylethynyl)-benzonitrile as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].IC1C=C(C2O[CH2:21][C@@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=2)C=CC=1>>[F:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[O:5][CH2:21][C@@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:23]=1
Reactant: O=C(Cl)c1cccc(I)c1F
Reactant: Ic1cccc(C2=N[C@H](c3ccccc3)CO2)c1
Product: Fc1c(I)cccc1C1=N[C@H](c2ccccc2)CO1

Procedure:
4,5-Dihydro-2-(2-fluoro-3-iodophenyl)-4(R)-phenyloxazole was prepared from 2-fluoro-3-iodobenzoyl chloride in a similar manner to that of (+)-4,5-dihydro-2-(3-iodophenyl)-4(R)-phenyloxazole as described in Example 1.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17]C(OC(C)(C)C)=O)[CH2:9][C@:10]([CH2:15][OH:16])([CH3:14])[C:11](O)=[O:12])=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[OH:52][CH2:53][CH2:54][N:55]1[CH2:59][CH2:58][CH2:57][C:56]1=[O:60].CN1CCOCC1.CC#N.Cl>C(Cl)Cl.O1CCOCC1>[O:60]=[C:56]1[CH2:57][CH2:58][CH2:59][N:55]1[CH2:54][CH2:53][O:52][C:11](=[O:12])[C@@:10]([CH2:15][OH:16])([CH3:14])[CH2:9][C@H:8]([NH2:17])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:2][CH:3]=1
Reactant: O=C1CCCN1CCO
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCCN1CCCC1=O
Reaction time: 0.25 h

Procedure:
(2S,4R)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol), HOBt (98 mg, 726 μmol), and EDCI (128 μL, 726 μmol) were dissolved in DCM (2 mL). After stirring for 15 minutes, 1-(2-hydroxyethyl)-2-pyrrolidone (218 μL, 1.9 mmol) and 4-methylmorpholine (106 μL, 967 μmol) were added. The resulting mixture was stirred at room temperature overnight, and then the reaction was quenched with water. The DCM layer was separated, concentrated, purified ((Interchim reverse phase chromatography column), and dried under vacuum. The purified material was combined with MeCN (1 mL, 20 mmol) and 4 M HCl in dioxane (240 μL, 970 μmmol) and stirred at room temperature for 1 hour. The solvent was then removed to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-(2-oxo-pyrrolidin-1-yl)-ethyl ester.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[CH:33]2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]4[CH:36]=[CH:35][N:34]=[CH:33]4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3ccnc3)c1)=N2

Procedure:
The title compound was prepared from {5-dimethylamino-2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M57) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (132 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.[N:10]1[C:19]2[C:14](=[CH:15][C:16]([CH:20]([NH2:22])[CH3:21])=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>CCCCO>[Br:9][C:5]1[N:6]=[C:7]([NH:22][CH:20]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[N:10]=[CH:11][CH:12]=[CH:13]3)[CH3:21])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CC(N)c1ccc2ncccc2c1
Reactant: Nc1ncc(Br)nc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1nc(Br)cnc1N)c1ccc2ncccc2c1
Yield: 30.5 %

Procedure:
To a solution of 2-amino-dibromopyrazine (5.1 g, 20 mmol) and 1-quinolin-6-yl-ethylamine (3.43 g, 20 mmol) in n-BuOH (5 mL) was added DIPEA (10.5 mL, 60 mmol). The reaction was irradiated in a microwave at 225° C. for 1 hour. The reaction mixture was concentrated and purified by column chromatography Biotage 40+M 0-50% EtOAc:Hexanes (7 column volume), 50-100% (10 column volume), and EtOAc with 10% MeOH to give 5-bromo-N*3*-(1-quinolin-6-yl-ethyl)-pyrazine-2,3-diamine (2.1 g, 66%).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14][PH:15](=[O:17])[CH3:16].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:14][P:15]([NH:6][C:5]1[CH:7]=[CH:8][CH:2]=[CH:3][C:4]=1[O:9][C:10]([F:13])([F:12])[F:11])([CH3:16])=[O:17]
Reactant: Nc1ccc(I)cc1OC(F)(F)F
Reactant: C[PH](C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: CP(C)(=O)Nc1ccccc1OC(F)(F)F
Reaction time: 0.33 h

Procedure:
To a solution of 4-iodo-2-(trifluoromethoxy)aniline (0.606 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane) and acidified with HCl in methanol to afford the desired product as its hydrochloride salt (0.573 g, 98% yield).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]([C:12](=O)[CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH4+].[OH-]>C(O)C>[NH2:1][C:2]1[S:3][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([CH2:13][CH3:14])[N:4]=1
Reactant: CCOC(=O)C(Br)C(=O)CC
Reactant: NC(N)=S
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1CC
Temperature: 25 °C
Yield: 103.8 %

Procedure:
To a refluxing solution of thiourea (2.6 g, 34.3 mmol) in absolute ethanol (30 mL) was slowly added at reflux ethyl 2-bromo-3-oxopentanoate (7.3 g, 32.7 mmol). The solution was stirred at reflux for 1.5 hours. After cooling to room temperature, the solution was poured in ice/water (150 mL). The mixture was neutralized with concentrated NH4OH. The solid material was recovered by filtration, washed with water (2×50 mL) and hexanes (3×50 mL), and dried in vacuo, affording ethyl 2-amino-4-ethyl-1,3-thiazole-5-carboxylate (6.8 g, 94% yield). The product was used without further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](OS(C)(=O)=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:10])([F:11])[F:1])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C(F)(F)F)CC1
Temperature: 60 °C
Yield: 33.8 %

Procedure:
To a stirred solution of 2-trifluoromethyl-phenol (1 g, 0.00617 mole) in DMF (10 mL) was added cesium carbonate (4.01 g, 0.0123 mole), followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (1.72 g, 0.00616 mole). The reaction mixture was heated at 60° C. overnight. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (0.1% ethyl acetate in hexane) to afford 0.72 g (34%) of 4-(2-trifluoromethyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 346.16 (M+1)+, 94.42%. A solution of 4-(2-trifluoromethyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.72 g, 0.00208 mole) in dichloromethane was stirred at 0-5° C. To the cold solution was added TFA (1 mL) dropwise and stirring was continued at 10° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was washed with ether and dried to afford 0.22 g (99%) of 4-(2-trifluoromethyl-phenoxy)-piperidine trifluoracetate. LCMS: 360.1 (M+1)+, 99.3%, 1H NMR (CDCl3): δ 8.9-8.5 (bd, 2H), 7.62-7.6 (d, 1H), 7.56-7.46 (t, 1H), 7.1-7.02 (t, 1H), 7.0-6.94 (d, 1H), 5.0-4.8 (m, 1H), 3.5-3.3 (s, 4H), 2.3-2.2 (s, 4H).
Reaction SMILES: [NH:1]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@@H:2]([C:12]([NH:14][C@H:15]([C:20]([N:22]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:23]1[C:24]([O:26]CC1C=CC=CC=1)=[O:25])=[O:21])[C@H:16]([CH2:18][CH3:19])[CH3:17])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1>CO.[Pd]>[NH:1]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[C@@H:2]([C:12]([NH:14][C@H:15]([C:20]([N:22]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:23]1[C:24]([OH:26])=[O:25])=[O:21])[C@H:16]([CH2:18][CH3:19])[CH3:17])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](Cc1ccc(OC)cc1)NC(=O)OC(C)(C)C)C(=O)N1CCCCC1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](Cc1ccc(OC)cc1)NC(=O)OC(C)(C)C)C(=O)N1CCCCC1C(=O)O
Reaction time: 8 h

Procedure:
Boc-D-Tyr(Me)-L-Ile-DL-Pip-OBzl (3.46 g, 7.37 mmol) was dissolved in methanol (30 ml) and subjected to catalytic hydrogenation in the presence of the 5% Pd-C (230 mg). After 8 hours, the catalyst Pd-C was filtered and the reaction solution was evaporated to obtain Boc-D-Tyr(Me)-L-Ile-DL-Pip-OH.
Reaction SMILES: [C:1]([CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]1[C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])#[N:2].[F:18][B-:19]([F:22])([F:21])[F:20].[H+]>C(O)(=O)C>[F:18][B-:19]([F:22])([F:21])[F:20].[NH2:2][C:1]1[O:17][C:13]([CH:14]([CH3:15])[CH3:16])=[N+:4]2[N:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]=12
Reactant: CC(C)C(=O)N1N=Cc2ccccc2C1C#N
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC(=O)O
Product: CC(C)c1oc(N)c2c3ccccc3cn[n+]12
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 1-cyano-2-isobutyryl-1,2-dihydrophthalazine (12.6 g) in glacial acetic acid (50 ml) at 60° C. was treated with an aqueous solution of fluoroboric acid (48% w/v; 50 ml). After stirring for 15 minutes the mixture was chilled to 15° C. and stirring was continued for a further period of 1 hour. The solid which separated was collected, washed thoroughly with diethyl ether, and dried, to give 1-amino-3-isopropyloxazolo[4,3-a]phthalazinium tetrafluoroborate (15.58 g) in the form of a bright yellow solid, m.p. 180°-182° C. [NMR (in DMSO-d6) : 1.42 (6H, d, J=7 Hz), 3.74 (1H, septet, J=7 Hz), 7.50-7.60 (1H, m), 7.85-8.05 (3H, m), 8.12 (2H, broad singlet), 8.99 (1H, s)].
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:20])[CH:8]=2)[N:3]=1.[CH3:21][CH:22]1[CH2:26][CH2:25][CH2:24][NH:23]1>>[Cl:20][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]1[CH2:24][CH2:25][CH2:26][CH:22]1[CH3:21])[C:11]([C:12]#[N:13])=[C:10]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#Cc1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: CC1CCCN1
Product: CC1CCCN1c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C#N

Procedure:
The title compound was prepared in analogy to example 27 step C from 2,6-dichloro-4-phenyl-quinoline-3-carbonitrile (prepared as described in example 27 step B) and 2-methylpyrrolidine. Yellow solid. MS (ESI): 348.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][NH2:5]
Reactant: Cc1ccc(Cl)cc1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1CN
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-methyl-5-chlorobenzonitrile (2 g, 13.2 mmol), in THF (30 mL) was cooled to −15° C. and treated with 1 M lithium aluminum hydride in THF (13.4 mL). The reaction mixture was allowed to warm gradually to 0° C. over 2 h and was then stirred at room temperature for 1.5 h. It was then cooled to 0° C. and quenched sequentially with EtOAc (1 mL), water (0,5 mL), 15% NaOH (0.5 mL), and water (1.5 mL). After stirring for 1 h, the solids were removed via filtration. The filtrate was concentrated and the resulting residue purified by flash chromatography (98:2 methylene chloride/methanol) to give the product as an oil: 1H NMR (CDCl3) δ7.33 (d, J=2.0 Hz, 1H), 7.08 (m, 2H),, 3.83 (s, 2H),, 2.28 (s, 3H), 1.42 (br s, 2H).