Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH2:20]([NH:23][CH2:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)[CH2:21][CH3:22].N12CCCN=C1CCCCC2>C(#N)C>[CH2:20]([NH:23][CH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:19])[CH2:26]1)[CH2:21][CH3:22]
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CCCNCC1CCNC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCNCC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 74 %

Procedure:
A suspension of 1.13 g (4.0 mmole) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 0.63 g (4.4 mmole) of 3-[(propylamino]methyl]pyrrolidine, 1.22 g (8.0 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 30 ml of acetonitrile was stirred at room temperature for 2.5 hours. The precipitate was removed by filtration, washed with acetonitrile and dried in vacuo to give 1.15 g (74%) of the title compound, mp 230°-233° C.
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH:2]1[CH2:11][O:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:14].Br[CH2:25][CH:26]([CH3:28])[CH3:27]>>[CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH:2]1[CH2:11][O:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH:16]=1)=[O:14]
Reactant: O=C(OCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12
Reactant: CC(C)CBr
Product: CC(C)Cn1cc(C(=O)OCC2CCN3CCCCC3C2)c2ccccc21

Procedure:
eq-Quinolizidin-2-ylmethylindole-3-carboxylate (E9b) was alkylated with 1-bromo-2-methylpropane using the method in Example 18. The product was chromatographed on silica gel eluting initially with ether, then with ethyl acetate, to afford the title compound (E20) as a colourless oil. This was converted to its hydrochloride salt mp 174°-175° C. (acetone/ether).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[NH:7])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:18]N)=O)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[N:8]=[C:16]([C:15]3[CH:20]=[CH:21][C:12]([F:11])=[CH:13][CH:14]=3)[NH:18][N:7]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(F)cc1
Reactant: N=C(N)c1ccc(F)cc1
Product: Fc1ccc(-c2n[nH]c(-c3ccc(F)cc3)n2)cc1
Yield: 71.2 %

Procedure:
4 g 4-fluoro-benzamidine was added to 4.5 g 4-fluoro-benzoic acid hydrazide and this mixture was melted. This mixture was crystallized with ethyl acetate to give 5.3 g of the desired compound. Rt: 1.55 min (method A), (M+H)+: 258
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[CH2:28]([N:35]=[C:36]=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CN1CCOCC1>C(Cl)Cl>[CH2:28]([NH:35][C:36]([N:7]1[CH2:6][CH2:5][C:4]([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])([C:2]#[N:3])[CH2:9][CH2:8]1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCNCC1
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCN(C(=O)NCc2ccccc2)CC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid[1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide hydrochloride and benzyl isocyanate in the presence of a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C@H:9]([C:16]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])[CH2:10][O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[CH:26]([C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([NH:38][O:39]C(OCC(C)C)C)=[O:37])=[CH:30][CH:29]=1)=O>ClCCCl>[C:12]([O:11][CH2:10][C@@H:9]([C:16]([O:18][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23]1)=[O:17])[NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][CH2:26][C:28]2[CH:29]=[CH:30][C:31](/[CH:34]=[CH:35]/[C:36]([NH:38][OH:39])=[O:37])=[CH:32][CH:33]=2)=[CH:25][CH:24]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC[C@H](NCc1ccc(CN)cc1)C(=O)OC1CCCC1
Reactant: CC(C)COC(C)ONC(=O)/C=C/c1ccc(C=O)cc1
Solvent: ClCCCl
Product: CC(C)(C)OC[C@H](NCc1ccc(CNCc2ccc(/C=C/C(=O)NO)cc2)cc1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 1.4 %

Procedure:
To a suspension of cyclopentyl N-[4-(aminomethyl)benzyl]-O-tert-butyl-L-serinate (prepared as described in Example 73-0.282 g, 0.67 mmol) and (2E)-3-(4-formylphenyl)-N-(1-isobutoxyethoxy)acrylamide (prepared as described in Example 12-0.230 g, 0.79 mmol) in DCE (25 mL) was added STAB (0.700 g, 3.3 mmol). The mixture was stirred at RT for 3 h, and then quenched with sat. NaHCO3 solution (75 mL). The product was then extracted with DCM (3×100 mL) and the combined organic extracts were dried (MgSO4), concentrated and purified by preparative HPLC to yield the desired product (5 mg, 2%). LCMS purity 98%, m/z=524.25 [M+H]+, 1H NMR (300 MHz, CD3OD) δ: 7.41 (2H, d, J=7.9 Hz), 7.24 (2H, d, J=7.7 Hz), 7.20 (3H, br s), 6.37 (1H, d, J=15.6 Hz), 5.09 (1H, t, J=5.7 Hz), 3.44-3.75 (8H, m), 3.25 (1H, t, J=3 Hz), 1.45-1.90 (8H, m), 1.04 (9H, s).
Reaction SMILES: [CH3:1][N:2]([CH2:19][CH2:20][CH3:21])[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:13]=1)[C:8]([OH:10])=O)=[O:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:57][C@@H:58]([CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1>CN(C=O)C>[CH2:72]([C@H:58]([NH:57][C:8](=[O:10])[C:7]1[CH:11]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:13]=[C:5]([C:3]([N:2]([CH3:1])[CH2:19][CH2:20][CH3:21])=[O:4])[CH:6]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1)[C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2ccccc2)c1
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(C)C(=O)c1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 3-{[methyl(propyl)amino]carbonyl}-5-(1,3-oxazol-2-yl)benzoic acid (206 mg, 0.71 mmol) in DMF (5 mL) is added diisopropylethylamine (174 μL, 1.1 mmol), HATU (323 mg, 0.85 mmol), then (2R,3S)-3-amino-1-[(3-ethylbenzyl)amino]-4-phenylbutan-2-ol dihydrochloride prepared by the method of Example SP-272 (292 mg, 0.79 mmol). The reaction is stirred 4 h at room temperature. The reaction is partitioned between chloroform and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/chloroform) gives the title compound. ESI MS m/z 569.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH:5]=[C:6]([CH3:11])[C:7]=1[C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH3:27]O>>[CH3:27][O:9][C:8]([C:7]1[C:6]([CH3:11])=[CH:5][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)=[CH:3][C:2]=1[OH:1])=[O:10]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)cc(O)c1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)cc1O
Temperature: 25 °C
Yield: 45 %

Procedure:
A solution of 2.20 g (7.40 mmol) of 3-hydroxy-5-methyl-3′-trifluoromethyl-biphenyl-4-carboxylic acid in 70 ml of MeOH was treated at RT with 0.84 ml=1.53 g (14.9 mmol) of sulfuric acid (95%) and 0.5 g of molecular sieves (0.4 nm) and the reaction mixture was heated at reflux for 72 hours. It was then cooled down to RT, filtered and the residue was washed with MeOH. The filtrate was evaporated and this residue was dissolved in CH2Cl2 and poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (heptane/EtOAc 4:1) to give 1.04 g (45%) of the title compound as colorless solid. MS: 310.0 (M+).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]([CH:14]([CH3:16])[CH3:15])[C:12](=[O:17])[O:11][C:10]2=O)=[CH:5][CH:4]=1.[O:21]=[C:22]1[N:26](CO)[C:25](=[O:29])[CH2:24][N:23]1[CH2:30][C:31]#[CH:32]>>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:13]([CH:14]([CH3:15])[CH3:16])[C:12]([O:11][CH2:10][N:26]2[C:25](=[O:29])[CH2:24][N:23]([CH2:30][C:31]#[CH:32])[C:22]2=[O:21])=[O:17])=[CH:7][CH:8]=1
Reactant: CC(C)C1C(=O)OC(=O)N1c1ccc(C(F)(F)F)cc1
Reactant: C#CCN1CC(=O)N(CO)C1=O
Product: C#CCN1CC(=O)N(COC(=O)C(Nc2ccc(C(F)(F)F)cc2)C(C)C)C1=O

Procedure:
In the same way, 3-(4-trifluoromethylphenyl)-4-isopropyloxazolidine-2,5-dione is reacted with (2,4-dioxo-1-propargyl-3-imidazolidinyl)methanol to give (2,4-dioxo-1-propargyl-3-imidazolidinyl)methyl 2-(4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.O[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: Oc1ccccn1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
Diethyl azodicarboxylate (630 μL, 4.00 mmol) was added to a mixture of 2-hydroxypyridine (0.380 g, 4.0 mmol), tert-butyl (2-hydroxyethyl)carbamate (0.322 g, 2.0 mmol) and triphenylphosphine (1.05 g, 4.0 mmol) in THF (6.0 mL). The mixture was stirred overnight at RT, and concentrated. The residue was chromatographed on silica gel with EtOAc in hexanes to give the product (0.353 g, 74.1%). LCMS: (M+H)=239.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.C([CH2:20][NH2:21])C1C=CC=CC=1>C(Cl)Cl>[CH3:20][NH:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: NCCc1ccccc1
Reactant: Cc1cc(Cl)c2ccccc2n1
Solvent: ClCCl
Product: CNc1cc(C)nc2ccccc12
Temperature: 120 °C
Reaction time: 15 h

Procedure:
A mixture of 4-chloro-2-methyl-quinoline (4.36 g, 24.5 mmol) and benzylmethylamine (3.13 g, 25.8 mmol) is heated under N2 at 120° C. for 12 h. The residue is dissolved in CH2Cl2 (50 ml) and washed successively with aqueous saturated Na2CO3 (50 mL) and 1M aqueous NaOH (50 ml). The CH2Cl2 layer is evaporated, and the residue is dissolved in MeOH (400 mL) and 4M HCl in dioxane (12 mL). 10% Pd—C (410 mg) are added and the suspension is hydrogenated for 15 h under ambient pressure. The reaction mixture is filtered through a pad of Celite. 1M aqueous NaOH (100 mL) is added and the filtrate is evaporated. The residue is dissolved in water and extracted with CH2Cl2 (3×50 mL). The combined organic extracts are dried and evaporated to provide the title compound.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[N:20][N:21]=[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=3)[NH:24][C:23]2=[O:32])=[CH:15][CH:14]=1.CO.[Li+].[OH-].Cl>O>[F:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:32])[C:22]2=[N:21][N:20]=[CH:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:34])=[O:2])=[O:33])=[CH:18][CH:17]=1
Reactant: COC(=O)CCCCCCCNC(=O)c1ccc(C=NN=C2C(=O)Nc3ccc(F)cc32)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCCNC(=O)c1ccc(C=NN=C2C(=O)Nc3ccc(F)cc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.9 %

Procedure:
8-(4-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)benzamido)octanoic acid methyl ester (466 mg, 1 mmol) and 300ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (149 mg, 33% yield) as a brown solid. LC-MS (m/z) 453 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:14])[CH:4]=1)=O.[CH:15](C1C=CC(C(O)=O)=C(C)C=1)=O.OS(O)(=O)=O>CCO>[CH3:14][C:5]1[CH:4]=[C:3]([CH:1]=[CH2:15])[CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: Cc1cc(C=O)ccc1C(=O)O
Reactant: CCOC(=O)c1ccc(C=O)cc1C
Agent: O=S(=O)(O)O
Solvent: CCO
Product: C=Cc1ccc(C(=O)OCC)c(C)c1
Temperature: 80 °C
Yield: 80 %

Procedure:
Ethyl 4-formyl-2-methylbenzoate (AI16). To a stirred solution of 4-formyl-2-methylbenzoic acid (3 g, 18.2 mmol) in EtOH (30 mL) was added conc. H2SO4 (2 mL) and the reaction mixture was heated at 80° C. for 18 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water. The combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a solid (2.8 g, 80%): 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.04 (m, 1H), 7.75 (m, 2H), 4.43 (m, 2H), 2.65 (s, 3H), 1.42 (m, 3H).
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH:1]1([N:6]([CH2:7][C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[C:14]([Cl:13])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1csc(CNC2CCCC2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)N(Cc1cccs1)C1CCCC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 147.5 %

Procedure:
To a solution of 5.0 g (27.58 mmol) of cyclopentylthiophen-2-ylmethylamine in 40 ml of methylene chloride at 10° C. was added slowly with stirring 4.09 g (13.79 mmol) of triphosgene in 35 ml of methylene chloride. The reaction was allowed to continue stirring at room temperature for 64 hours, refluxed for 4 hours and 25 hours more at room temperature. The solvent was evaporated and the residue extracted with n-hexane. The organic solution was concentrated to yield 4.96 g (20.34 mmol) of a brown oil (74%). 1H-NMR (CDCl3): δ 1.4 (m, 8H), 4.2 (bs, 1H), 4.5 (m, 2H), 6.8-7.3 (m, 3H).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C:8]([CH2:10][C:11]1([N:30]2[CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=[N:31]2)[CH2:14][N:13]([C:15]2[N:16]=[CH:17][C:18]([C:21]([NH:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:22])=[N:19][CH:20]=2)[CH2:12]1)#[N:9].Br[C:45]1[C:46]([CH2:50][CH3:51])=[N:47][NH:48][CH:49]=1>>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[C:8]([CH2:10][C:11]1([N:30]2[CH:34]=[C:33]([C:45]3[C:46]([CH2:50][CH3:51])=[N:47][NH:48][CH:49]=3)[CH:32]=[N:31]2)[CH2:14][N:13]([C:15]2[N:16]=[CH:17][C:18]([C:21]([NH:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:26])[F:27])=[O:22])=[N:19][CH:20]=2)[CH2:12]1)#[N:9]
Reactant: CCc1n[nH]cc1Br
Reactant: C[C@H](NC(=O)c1cnc(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cn1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCc1n[nH]cc1-c1cnn(C2(CC#N)CN(c3cnc(C(=O)N[C@@H](C)C(F)(F)F)cn3)C2)c1

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 4, Step 6 starting from 5-{3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide (Example 1, Step 5) and 4-bromo-3-ethyl-1H-pyrazole. LCMS calculated for C21H23F3N9O (M+1)+: m/z=474.2. Found: 474.0.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[CH:28](I)([CH3:30])[CH3:29]>C1COCC1>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@:22]([CH:28]([CH3:30])[CH3:29])([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)I
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@@]1(C(C)C)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a 1.00 M solution of lithium hexamethyldisilazide in THF (202 mL) at −78° C. was added a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (22.10 g, 91.59 mmol) in THF (36.2 mL) over 10 min. The solution was stirred at −78° C. for 30 min before isopropyl iodide (10.0 mL, 100 mmol) was added in one portion. The mixture was then moved to a freezer reading at −24° C. and kept overnight. The reaction was quenched with aqueous ammonium chloride and the resulting solution was extracted with ether three times. The ether layers were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica eluting with 10% ethyl acetate/hexane to give the title compound (20.2 g). MS calculated for C15H25NO4: (M+H)+284; found 184.2 (M−Boc+H)+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.N(OC(C)(C)C)=O.[ClH:21]>C(#N)C.[Cu](Cl)Cl>[Cl:21][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Cl
Reactant: Nc1cc(CO)cc(C(F)(F)F)c1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: OCc1cc(Cl)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(3-Amino-5-(trifluoromethyl)phenyl)methanol (1.0 g, 5.23 mmol) in dry acetonitrile (6 mL) was added dropwise to a solution of copper (II) chloride (0.83 g, 6.2 mmol) and tert-butyl nitrite (0.9 mL, 7.5 mmol) in acetonitrile (6 mL) at 65° C. After 30 min at 65° C., the reaction mixture was cooled to room temperature, poured into a 1 N hydrochloric acid solution, and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (30% ethyl acetate/hexanes) afforded 0.8 g (73%). 1H-NMR (CDCl3, 500 MHz) δ 7.54 (s, 1H), 7.52 (s, 1H), 7.50 (s, 1H), 4.74 (s, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Si]([O:28][CH2:29][CH:30]1[CH:34]([CH2:35][O:36][Si](C(C)(C)C)(C)C)[CH2:33][C:32]([CH2:44]Br)=[CH:31]1)(C(C)(C)C)(C)C>>[OH:28][CH2:29][CH:30]1[CH:34]([CH2:35][OH:36])[CH2:33][C:32]([CH2:44][N:7]2[C:8]([C:9](=[O:18])[C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]2=[O:19])=[CH:31]1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)OCC1C=C(CBr)CC1CO[Si](C)(C)C(C)(C)C
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(CC2=CC(CO)C(CO)C2)c(=O)[nH]c1=O
Yield: 25 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and [3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-1-en-1-yl]methyl bromide were reacted by the same method with example 28 to obtain the titled compound (68 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([NH:14][NH2:15])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N+:16]([C:19]1[O:23][C:22](/[CH:24]=[CH:25]/[CH:26]=O)=[CH:21][CH:20]=1)([O-:18])=[O:17]>C(O)(=O)C>[OH:1][C:2]1[C:3]([C:12]([NH:14]/[N:15]=[CH:26]/[CH:25]=[CH:24]/[C:22]2[O:23][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: NNC(=O)c1cc2ccccc2cc1O
Reactant: O=C/C=C/c1ccc([N+](=O)[O-])o1
Solvent: CC(=O)O
Product: O=C(N/N=C/C=C/c1ccc([N+](=O)[O-])o1)c1cc2ccccc2cc1O
Reaction time: 2 h
Yield: 97.9 %

Procedure:
Acetic acid (3 mL) is added to a mixture of 3-Hydroxy-2-naphthoic acid hydrazide (100 mg, 0.50 mmol) and (E)-3-(5-nitrofuran-2-yl)acrylaldehyde (99 mg, 0.59 mmol) and the resulting mixture is stirred for 2 h (Note: Immediate precipitation of the yellowish hydrazone product is observed after which the reaction mixture is stirred for another 2 h for completion). The reaction mixture is then diluted with 50% ether/hexanes. The yellowish solid is filtered with suction, washed with 50% ether/hexanes (100 mL) and dried to furnish 172 mg (99%) of the desired product as a yellowish solid. m. p. 259° C. 1H NMR (DMSO) δ 12.00 (br s, 1H), 11.3 (br s, 1H), 8.42 (s, 1H), 8.25 (d, 1H, J=8.1 Hz), 7.91 (d, 1H, J=8.4 Hz), 7.86-7.66 (m, 2H), 7.58-7.45 (m, 1H), 7.42-7.29 (m, 1H), 7.32 (s, 1H) and 7.25-7.06 (m, 3H); 13C NMR (DMSO) δ 163.7, 154.8, 153.8, 151.4, 148.5, 135.9, 130.5, 130.4, 128.7, 128.3, 126.8, 125.8, 124.3, 123.8, 120.5, 115.4, 113.6 and 110.5.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[N+:12]([O-])=O>C(O)C.[Ni]>[NH2:12][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[NH:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: O=[N+]([O-])c1cnccc1NCCCO
Agent: [Ni]
Solvent: CCO
Product: Nc1cnccc1NCCCO
Reaction time: 72 h

Procedure:
4-(3-Hydroxypropylamino)-3-nitropyridine (4.12 g, 20.9 mmol) was dissolved in ethanol (130 ml) and Raney nickel (411 mg, 7.0 mmol) added. The stirred mixture was hydrogenated for 3 days. The catalyst was removed by filtration under argon and the solvent removed under reduced pressure to give 3-amino-4-(3- hydroxypropylamino)pyridine as a brown oil which was used directly in the next step.
Reaction SMILES: [CH2:1]([N:8]([CH3:31])[C:9](=[O:30])[C@@H:10]([N:18]([CH2:26][CH2:27][CH:28]=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH2:42][C@H:43]([NH2:48])[CH2:44][C:45]([OH:47])=[O:46])=[CH:34]1>>[CH2:1]([N:8]([CH3:31])[C:9](=[O:30])[C@@H:10]([N:18]([CH2:26][CH2:27][CH2:28][NH:48][C@H:43]([CH2:44][C:45]([OH:47])=[O:46])[CH2:42][C:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[NH:33][CH:34]=1)[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H](CC(=O)O)Cc1c[nH]c2ccccc12
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)N(CCC=O)C(=O)OC(C)(C)C
Agent: Cl
Product: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)N(CCCN[C@H](CC(=O)O)Cc1c[nH]c2ccccc12)C(=O)OC(C)(C)C

Procedure:
Prepare by the method of Example 1 using (S)-N-benzyl-N-methyl-2-[N'-(t-butoxycarbonyl)-3-oxo-propylamino]-3-phenyl-propionamide (2 mmol) and (S)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylamine hydrochloride salt ((S)-tryptophan methyl ester hydrochloride salt) (2 mmol). Purify by chromatography to give the title compound.