Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:7][C:8]([NH2:12])=[N:9][C:10]=1[CH3:11].[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=1)=O.C(O)(=O)C.[BH4-].[Na+]>C1COCC1.CO>[NH2:12][C:8]1[N:9]=[C:10]([CH3:11])[C:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:19][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:26]=2)=[C:6]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:7]=1
Reactant: CCCCCNc1nc(N)nc(C)c1CCCN
Reactant: COC(=O)Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCNc1nc(N)nc(C)c1CCCNCc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.8 %

Procedure:
The product from Example 1 step (v) (0.3 g) and methyl 2-(4-formylphenyl)acetate (0.213 g) were combined in THF (20 mL), acetic acid (0.072 g) was added and the reaction mixture stirred at rt for 16 h. Sodium borohydride (0.0677 g) and MeOH (3 drops) were added and the reaction mixture stirred for 72 h. The solvents were evaporated and the product dissolved in MeOH and purified by RPHPLC to give the title compound 0.3 g.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:26][CH:27]([CH3:29])[CH3:28])[C:7]([F:25])=[C:8]([N:10]([CH2:19][C:20]2[CH:24]=[CH:23][NH:22][N:21]=2)[C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH:9]=1)[CH3:2].N1C=CC=CC=1.[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.B(O)O>C(Cl)Cl.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:26][CH:27]([CH3:28])[CH3:29])[C:7]([F:25])=[C:8]([N:10]([CH2:19][C:20]2[CH:24]=[CH:23][N:22]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:21]=2)[C:11]2[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=2)[CH:9]=1)[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOc1cc(OC(C)C)c(F)c(N(Cc2cc[nH]n2)c2ccc(C#N)cc2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOc1cc(OC(C)C)c(F)c(N(Cc2ccn(-c3ccccc3)n2)c2ccc(C#N)cc2)c1
Reaction time: 5.5 h
Yield: 71 %

Procedure:
To a mixture of Intermediate 183.1 (39.5 mg, 0.100 mmol) and 3A molecular sieves (30 mg) in 1 mL CH2Cl2 at rt, was added TEA (0.028 mL, 0.20 mmol), pyridine (16 mg, 0.20 mmol) and phenylboronic acid (24.4 mg, 0.20 mmol). The mixture was stirred until the boronic acid dissolved, then Cu(OAc)2 (27.3 mg, 0.150 mmol) was added. The mixture was stirred for 5.5 h, then was diluted with EtOAc. The organic phase was washed with 0.5N HCl, H2O, sat. NaHCO3 and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 50% EtOAc/hexanes gradient) to afford 33.4 mg of Intermediate 183.2 as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][C@@H:26]([CH3:30])[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CCN(C(C)C)C(C)C>CS(C)=O.O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[C:3](=[O:16])[NH:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[C@@H:26]([CH3:30])[CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)nc2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 18.4 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (1.0 g, crude) in DMSO (10 mL) was added tert-butyl-(3S)-3-methylpiperazine-1-carboxylate (1.0 g, 4.99 mmol) and DIEA (1.0 g, 7.74 mmol). The resulting solution was stirred overnight at 80° C. in an oil bath and then diluted with water (100 mL), extracted with ethyl acetate (4×40 mL) and the organic layers combined and dried over anhydrous magnesium sulfate. The solids were filtered out and filtrate was concentrated in vacuo to give a residue, which was purified by a silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 3-[(2S)-4-[(tert-butoxy)carbonyl]-2-methylpiperazin-1-yl]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a light yellow solid (310 mg).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:15]([OH:21])[C:16]([O:18]CC)=[O:17])[C:10]([O:12]CC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1>[CH2:1]([O:8][C@H:9]([C@@H:15]([OH:21])[C:16]([OH:18])=[O:17])[C:10]([OH:12])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](O)[C@@H](OCc1ccccc1)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](O)[C@@H](OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
(2R,3R)-Diethyl 2-(benzyloxy)-3-hydroxysuccinate (15 g, 50.6 mmol) was dissolved in 30% aqueous THF (250 mL) and lithium hydroxide hydrate (4.25 g, 101 mmol) was added and the reaction stirred at ambient temperature overnight. The reaction was then partitioned between aqueous citric acid and EtOAc, dried over Na2SO4, filtered and concentrated to afford (2R,3R)-2-(benzyloxy)-3-hydroxysuccinic acid (11.5 g, 47.9 mmol, 94.6% yield) as a clear colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][S:11](Cl)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:15][NH:16][CH3:17]>ClCCl>[CH3:15][N:16]([CH3:17])[S:11]([CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)Cl)c1
Reactant: CNC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
To a solution of (3-Nitrophenyl)methanesulfonyl chloride (1.0 g, 0.0042 mol) in dry dichloromethane (25 mls) at room temperature dimethylamine (2M in THF, 5.3 ml, 0.105 mol) was added dropwise. The mixture was stirred for 3 hours then filtered through silica, then evaporated to give N,N-Dimethyl-C-(3-nitro-phenyl)-methanesulfonamide, 1.0 g, 1H NMR CDCl3 2.84 (6H, s, 2×CH3), 4.29 (2H, s, CH2), 7.60 (1H, m, ArH), 7.79 (1H, d, ArH), 8.25 (2H, m, ArH)
Reaction SMILES: O=[C:2]([C:15]1[CH:16]=[C:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:18][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(OC(=O)C)(=O)C>C1C=CC=CC=1.[Zn]>[CH2:3]([C:2]([C:15]1[CH:16]=[C:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:18][CH:19]=1)=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCC(=O)c1coc([Si](C)(C)C)c1
Reactant: CCOC(=O)CBr
Agent: [Zn]
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCCCCCC(=CC(=O)OCC)c1coc([Si](C)(C)C)c1
Reaction time: 14 h

Procedure:
A mixture of 4-(1-ketotridecyl)-2-trimethylsilylfuran (Compound 26, 84.5 mg, 0.25 mmol), zinc (100 mg, 1.53 mmol) and ethyl bromoacetate (105 mg, 0.63 mmol) in benzene (6 ml) was refluxed for 2 hours. After cooling to 0°, acetic anhydride (83 ul, 0.88 mmol) was added. Stirring was continued for 14 hours while the cooling bath attained room temperature. The mixture was washed with 5% sodium bicarbonate and water. Evaporation of the dried (magnesium sulfate) organic phase gave a residue which was purified by a silica column using 2% ethyl ether/hexane to give the title ester.
Reaction SMILES: C([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1([CH3:14])[CH3:13])C.I[CH2:16][CH2:17][CH3:18]>>[CH3:14][C:4]1([CH3:13])[CH2:3][CH:12]([CH2:16][CH2:17][CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1
Reactant: CCCI
Reactant: CCC1Cc2ccccc2NC1(C)C
Product: CCCC1CC(C)(C)Nc2ccccc21

Procedure:
This compound was prepared in a manner similar to that described for (R/S)-3-ethyl-1,2,3,4-tetrahydro-2,2-dimethylquinoline (EXAMPLE 348) but using iodopropane in place of iodoethane. (R/S)-1,2,3,4-Tetrahydro-2,2-dimethyl-4-propylquinoline was obtained in 16% overall yield as a colorless oil. Data for (R/S)-1,2,3,4-tetrahydro-2,2-dimethyl-4-propylquinoline: 1H NMR (400 MHz, CDCl3) 6.98 (d, J=7.4, 1H), 6.96 (t, J=7.4, 1H), 6.61 (t, J=7.4, 1H), 6.45 (d, J=7.4, 1H), 3.60 (brs, 1H), 2.87 (dd, J=16.6, 5.2, 1H), 2.42 (dd, J=16.6, 10.7, 1H), 1.66-1.49 (m, 3H), 1.40-1.25 (m, 2H), 1.21 (s, 3H), 1.05 (s, 3H), 0.92 (t, J=7.1, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([CH2:11][CH2:12][CH:13]1[CH2:15][O:14]1)[C:7]([CH3:16])=[CH:6][CH:5]=2.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[N:27]1[CH2:34][C@H:33]2[NH:35][CH2:36][C@@H:28]1[CH2:29][CH:30]=[CH:31][CH2:32]2.CCN(C(C)C)C(C)C>C(O)C>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([CH2:11][CH2:12][CH:13]([OH:14])[CH2:15][N:35]1[CH2:36][CH:28]3[N:27]([C:18]4[CH:19]=[CH:20][C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH:17]=4)[CH2:34][CH:33]1[CH2:32][CH:31]=[CH:30][CH2:29]3)[C:7]([CH3:16])=[CH:6][CH:5]=2
Reactant: Cc1cc2c(CCC3CO3)c(C)ccc2[nH]1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(CCC(O)CN3CC4CC=CCC3CN4c3ccc4ccccc4c3)c(C)ccc2[nH]1

Procedure:
2,5-Dimethyl-4-(2-oxiranyl-ethyl)-1H-indole (50 mg, 0.23 mmol), Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (45 mg, 0.17 mmol), DIPEA (0.1 mL, 0.55 mmol), ethanol (3 mL) were heated for 900 sec. at 120° C. in a μW reaction tube. The solvent was evaporated under reduced pressure to yield a crude solid that was purified with flash chromatography gradient [20% Ethyl acetate/heptane to 100% Ethyl acetate] to yield the title compound as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[CH:6][C:7]=1[CH:8](Cl)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16].[Cu](C#N)[C:27]#[N:28]>ClC(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[CH:6][C:7]=1[CH:8]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])[C:27]#[N:28]
Reactant: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3Cl)c(Cl)c2)c(=O)[nH]1
Reactant: N#C[Cu]C#N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N#CC(c1ccc(Cl)cc1Cl)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 180 °C

Procedure:
A mixture of 12 parts of 2-[3-chloro-4-[chloro(2,4-dichlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione and 5.4 parts of copper cyanide is stirred and heated first for 3 hours at 130° C. and for 3 hours at 180° C. After cooling, the precipitated product is dissolved in a mixture of trichloromethane and methanol (90:10 by volume). The inorganic precipitate is filtered off and the filtrate is evaporated in vacuo. The residue is purified by column chromatography over silica gel using first a mixture of trichloromethane and acetonitrile (93:7 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is dissolved in 20 parts of N,N-dimethylformamide and 25 parts of 1,1'-oxybisethane. The product is allowed to crystallize, filtered off and dried, yielding 2-chloro-α-(2,4-dichloro- phenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitrile (intermediate 1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13](=[S:15])[NH2:14])=[CH:9]2)[CH3:2].[C:27]([O:32][CH2:33][CH3:34])(=[O:31])[C:28]#[C:29][CH3:30].O1CCCC1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:15][CH:29]([CH2:28][C:27]([O:32][CH2:33][CH3:34])=[O:31])[CH2:30][N:14]=1)=[CH:9]2)[CH3:2]
Reactant: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OCC)c3[nH]2)S1
Temperature: 40 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a stirred solution of 7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carbothioamide (0.41 g), ethyl 2-butynoate (0.25 mL), tetrahydrofuran (10 mL) and toluene (15 mL) was added tributylphosphine (0.31 mL) at room temperature under argon atmosphere. After stirring at 40° C. for 3 h, the reaction mixture was concentrated to give a light brown oil, which was purified by silica gel chromatography (ethyl acetate:hexane=30:70 to 50:50, volume ratio) to give the title compound (350 mg, 66%) as a light yellow oil. MS 504 (MH+).
Reaction SMILES: [CH3:1][C:2]([N:5]1[CH:9]=[C:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([NH:20][CH2:21][C@:22]3([F:35])[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)[N:11]=2)[CH:7]=[N:6]1)([CH3:4])[CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:4][C:2]([N:5]1[CH:9]=[C:8]([C:10]2[N:11]=[C:12]([NH:20][CH2:21][C@:22]3([F:35])[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[C:13]3[CH:14]=[CH:15][CH:16]=[N:17][C:18]=3[CH:19]=2)[CH:7]=[N:6]1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(CNc2nc(-c3cnn(C(C)(C)C)c3)cc3ncccc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)n1cc(-c2cc3ncccc3c(NC[C@]3(F)CCCNC3)n2)cn1
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 93.1 %

Procedure:
1,1-Dimethylethyl (3R)-3-[({7-[1-(1,1-dimethylethyl)-1H-pyrazol-4-yl]-1,6-naphthyridin-5-yl}amino)methyl]-3-fluoro-1-piperidinecarboxylate (1.586 g, 3.29 mmol) was dissolved in DCM (5 ml) and trifluoroacetic acid (5.06 ml, 65.7 mmol) was added. The reaction was stirred for 20 min at 20° C. LCMS showed main peak of product. The reaction mixture was loaded onto a 20 g SCX cartridge and washed with methanol. The compound was eluted with 2M methanolic ammonia. The solvent from the ammonia fractions was evaporated and was kept under high vacuum for 2 h to give a yellow crystalline solid (1.171 g). The free base (1.12 g) was purified by High pH preparative MDAP (Method B). The appropriate fractions were combined, concentrated in vacuo and kept on high vacuum overnight to give the title compound as a yellow crystalline solid (688.1 mg).
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:6](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:5][N:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:3]1.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C>[N:28]([C@H:6]1[C@@H:2]([CH3:1])[CH2:3][N:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:5]1)=[N+:29]=[N-:30]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Temperature: 85 °C
Yield: 97.2 %

Procedure:
(3S,4R)-Benzyl 3-methyl-4-(tosyloxy)pyrrolidine-1-carboxylate (20 g, 51.4 mmol) was dissolved in DMF (42.8 ml). Sodium azide (5.68 g, 87 mmol) was added at rt and heated up to 85° C. overnight. LCMS shows a complete conversion. The reaction mixture was cooled to rt, quenched with ice water, extracted with ethyl acetate. Organic phases were combined, washed with water, brine, then dried with Na2SO4. After concentration, (3S,4S)-benzyl 3-azido-4-methylpyrrolidine-1-carboxylate (13 g, 97% yield) was obtained as a yellowish oil and used directly for the next reduction. 1H NMR (400 MHz, chloroform-d) δ ppm 7.29-7.44 (5H, m), 5.08-5.22 (2H, m), 3.94-4.04 (1H, m), 3.52-3.76 (3H, m), 3.00-3.15 (1H, m), 2.29-2.48 (1H, m), 1.13 (3H, t, J=7.04 Hz); LCMS (CHROMOLITH® RP-18e 2.0×50 mm, 0.8 mL/min, Solvent A: 10% MeOH/water with 0.1% TFA, Solvent B: 90% MeOH/water with 0.1% TFA, gradient with 0-100% B over 4 minutes) retention time: 3.41 min; MS(ES+) m/z: 261.0 (M+H+).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[N:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH:54]1[CH2:59][CH2:58][CH:57]([NH:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=2[Cl:67])[CH2:56][CH2:55]1>CN(C=O)C.O>[Cl:67][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=1[NH:60][CH:57]1[CH2:58][CH2:59][N:54]([C:18](=[O:20])[CH2:17][NH:16][C:14]([C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:13][N:12]=2)=[O:15])[CH2:55][CH2:56]1
Reactant: O=C(O)CNC(=O)c1ccc(Nc2ccccc2)cn1
Reactant: Clc1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1ccc(Nc2ccccc2)cn1
Reaction time: 8 h
Yield: 63 %

Procedure:
To a stirred solution of [(5-phenylamino-pyridine-2-carbonyl)-amino]-acetic acid (0.035 g, 0.00013 mol) in DMF (1 mL) was added DIPEA (0.05 g, 0.00039 mol), HOBt (0.0209 g, 0.00015 mol) and EDCI.HCl (0.0296 g, 0.00015 mol) at ambient temperature. After 2 minutes piperidin-4-yl-(2-chloro-phenyl)-amine dihydrochloride (0.0382 g, 0.00015 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration and dried to afford 0.038 g (64%) of 5-phenylamino-pyridine-2-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 464.18 (M+1)+, 92.88%, 1H NMR (DMSO-d6): δ 8.9 (s, 1H), 8.5 (t, 1H), 8.3 (d, 1H), 7.9 (d, 1H), 7.55 (dd, 1H), 7.35 (t, 2H), 7.2 (m, 4H), 7.0 (t, 1H), 6.9 (d, 1H), 6.6 (t, 1H), 4.9 (d, 1H), 4.35 (d, 1H), 4.2 (d, 2H), 3.85 (d, 1H), 3.55 (s, 1H), 3.2 (m, 2H), 2.85 (m, 1H), 1.95 (t, 2H), 1.5 (m, 1H), 1.35 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][N:11]([C:16](=[O:30])[C@@H:17]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:10]([C:31]([NH:33][C@:34]1([C:39]([O:41]CC)=[O:40])[CH2:36][C@H:35]1[CH:37]=[CH2:38])=[O:32])[CH2:9]2.O.[OH-].[Li+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][N:11]([C:16](=[O:30])[C@@H:17]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:10]([C:31]([NH:33][C@:34]1([C:39]([OH:41])=[O:40])[CH2:36][C@H:35]1[CH:37]=[CH2:38])=[O:32])[CH2:9]2
Reactant: C=C[C@@H]1C[C@]1(NC(=O)C1Cc2cc(Oc3cccc(Cl)c3)ccc2CN1C(=O)[C@@H](Nc1ccc(F)cc1)C(C)(C)C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)C1Cc2cc(Oc3cccc(Cl)c3)ccc2CN1C(=O)[C@@H](Nc1ccc(F)cc1)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
The crude (1R,2S)-ethyl 1-(6-(3-chlorophenoxy)-2-((S)-2-(4-fluorophenylamino)-3,3-dimethylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)-2-vinylcyclopropanecarboxylate (130 mg, 0.20 mmol) was dissolved in 1.0 mL of a mixture of THF:MeOH:H2O (2:1:1). Lithium hydroxide monohydrate (0.050 g, 1.2 mmol) was added and reaction stirred at rt overnight. The reaction was then concentrated under vacuum and quenched with 5 mL of 1 N HCl. The product precipitated and could be filtered off giving an off-white powder (110 mg). It was directly used in the next step without further purification. MS m/e 619 (M−−H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH2:15]([Cl:18])[CH:16]=[CH2:17]>CN(C)C=O>[ClH:18].[CH2:17]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH:16]=[CH2:15]
Reactant: C=CCCl
Reactant: Oc1ccccc1-n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccccc1-n1ccnc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.6 g. of 2-(1-imidazolyl)-phenol [Khim. Geterotsikl. Soedin Akad. Nauk Latv. SSR 1966, 143; Chem. Abstr. 65 (1966) 13686] is dissolved in 20 ml. of dimethylformamide and combined with 300 mg. of a sodium hydride - oil suspension (80%). The mixture is agitated for one hour at room temperature, and then 760 mg. of allyl chloride is added thereto. After three hours of agitation at room temperature, the solution is added to 100 ml. of 1N sulfuric acid and extracted with ether. The aqueous phase is rendered alkaline with 40% sodium hydroxide solution and extracted with methylene chloride. After drying and evaporation of the solvent, the crude product is dissolved in a small amount of methanol and combined with methanolic hydrochloric acid until a weakly acidic reaction is observed. After the solvent has been evaporated under vacuum, the residue is dissolved in methylene chloride and mixed with ether until the onset of crystallization.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11][C:10]=1[C:20]([OH:22])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.CN>C1COCC1>[CH3:23][NH:24][C:20]([C:10]1[N:11]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[S:13][C:9]=1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:22]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2)nc1C(=O)O
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CNC(=O)c1nc(-c2ccccc2)sc1NC(=O)OC(C)(C)C
Temperature: 75 °C
Reaction time: 6 h

Procedure:
A solution of 5-tert-butoxycarbonylamino-2-phenyl-thiazole-4-carboxylic acid (138 mg, 0.43 mmol) in THF (2.5 ml) was treated with HATU (187 mg, 0.49 mmol), N-methylmorpholin (0.25 ml, 2.24 mmol) and methylamine (0.29 ml, 2M THF solution) and stirred at 75° C. for 6 h. The reaction mixture was partitioned between potassium hydrogen sulfate (10% aqueous solution) and ethyl acetate and extracted. The organic layer was washed with water, sodium bicarbonate and brine. The combined organic phases were dried and the solvent was evaporated. The product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as light yellow solid (98 mg, 65%).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[C@H:15]([CH2:17][CH3:18])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CN1CCOCC1.ClC1C=C(Cl)C(Cl)=CC=1[O:38][C:39](=O)[C@H:40]([CH:52]([CH3:54])[CH3:53])[NH:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43].Cl>CS(C)=O>[NH:41]([C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C@H:40]([C:39]([NH:1][C@H:2]([C:11]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[C@H:15]([CH2:17][CH3:18])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:38])[CH:52]([CH3:54])[CH3:53]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Agent: Cl
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Tyrosylisoleucine (29.4 parts) is suspended in 300 parts by volume of dimethyl sulfoxide and 10.1 parts of N-methylmorpholine added. Carbobenzoxyvaline-2,4,5-trichlorophenyl ester is added and the mixture stirred 48 hours at room temperature. The clear solution is poured into 6000 parts by volume of 0.1 N hydrochloric acid and the mixture is stirred until the initially oily product solidifies. The crude product, after washing with water and drying, is boiled with 1 l. of ether. The desired tri-peptide, Z-Val-Tyr-Ile, is obtained as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]=[C:12]=[S:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl[CH2:23][C:24](O)=[O:25]>>[CH3:1][C:2]1[CH:3]=[C:4]([N:11]=[C:12]2[N:21]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:24](=[O:25])[CH2:23][S:13]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: NCc1ccccc1
Reactant: Cc1cc(N=C=S)ccc1[N+](=O)[O-]
Reactant: O=C(O)CCl
Product: Cc1cc(N=C2SCC(=O)N2Cc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
3-Methyl-4-nitrophenyl isothiocyanate was reacted with benzylamine followed by chloroacetic acid according to Method C8a to afford 2-(3-methyl-4-nitrophenylimino)-3-(phenylmethyl)-1,3-thiazolidin-4-one.