Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([CH:7]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:8]([O:10]CC=C)=[O:9])=[CH:3][CH:2]=1.[H-].[Na+].Cl.[C:25]1(C)[CH:30]=CC=C[CH:26]=1>>[C:17]1([CH3:20])[CH:18]=[CH:19][C:14]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:21])=[CH:6][CH:5]=2)([CH2:30][CH:25]=[CH2:26])[C:8]([OH:10])=[O:9])=[CH:15][CH:16]=1
Reactant: C=CCOC(=O)C(c1ccc(C)cc1)c1ccc(C)cc1
Reactant: Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: C=CCC(C(=O)O)(c1ccc(C)cc1)c1ccc(C)cc1

Procedure:
A solution of allyl 2,2-bis(p-tolyl)acetate (8.00 g) in toluene (40 ml) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil) (1.6 g) in toluene (30 ml) at 130° C. under nitrogen atmosphere, and the mixture was refluxed for 6 hours. After being cooled, the mixture was poured into cooled 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give 2,2-bis(p-tolyl)-4-pentenoic acid (4.41 g). It was used for the next reaction without further purification.
Reaction SMILES: C(OC(N[C@@H](CC1N=CNC=1)C(N(CC(NCC(C)(C1C=CC=CC=1)C)=O)CCC(OC)=O)=O)=O)C1C=CC=CC=1.Cl.[CH3:43][O:44][C:45](=[O:49])[CH2:46][CH2:47][NH2:48].Br[CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53].C(N(CC)CC)C>C(Cl)Cl>[CH3:43][O:44][C:45](=[O:49])[CH2:46][CH2:47][NH:48][CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53]
Reactant: COC(=O)CCN
Reactant: CC(C)(C)OC(=O)CBr
Agent: COC(=O)CCN(CC(=O)NCC(C)(C)c1ccccc1)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCNCC(=O)OC(C)(C)C

Procedure:
Scheme 2 shows a method by which the compounds of the present invention can be prepared, by illustrating the synthesis of Example 4, methyl 3-([(2S)-2-[(benzyloxy)carbonyl]amino-3-(1H-4-imidazolyl)propanoyl]-2-[(2-methyl-2-phenylpropyl)amino]-2-oxoethylamino)propanoate. Reaction of β-alanine methyl ester hydrochloride with t-butyl bromoacetate was carried out in methylene chloride in the presence of triethylamine as the base to give 3-(tert-butoxycarbonylmethyl-amino)-propionic acid methyl ester which was then coupled to Cbz-His(trityl) in methylene chloride/acetonitrile with HBTU as coupling agent, and triethylamine as the base. The resulting product was treated with 95% aqueous TFA, to remove the trityl and the t-butyl groups, followed by coupling with β,β-dimethylphenethylamine in methylene chloride/dimethylformamide, with HBTU as coupling agent, and diisopropylethylamine as the base to give the desired product.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:30]=[CH:29][C:18]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1>>[CH:33]1([CH2:36][N:21]([CH2:20][CH2:19][C:18]2[CH:29]=[CH:30][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:31])[F:32])=[CH:9][CH:8]=4)[N:11]=3)=[CH:16][CH:17]=2)[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: BrCC1CC1
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)CC1CC1

Procedure:
The title compound was prepared as described in Example 102 using tert-butyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethylcarbamate (C50) and cyclopropylmethyl bromide and isolated as a clear oil (0.155 g, 96%): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.16-8.07 (m, 2H), 7.84-7.77 (m, 2H), 7.39 (dq, J=8.0, 0.9 Hz, 2H), 7.31 (s, 2H), 3.50 (t, J=7.6 Hz, 2H), 3.17-2.86 (m, 4H), 1.48 (s, 9H), 0.87 (ddd, J=11.2, 9.0, 6.7 Hz, 1H), 0.49 (d, J=8.0 Hz, 2H), 0.21 (s, 2H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 503 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28](O)=[O:29].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:28]([C:27]2[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:25]([O:24][CH3:23])[CH:26]=2)=[O:29])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 8 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (56 mg) and commercially available 3,4-dimethoxybenzoic acid (60 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (81 mg) was added, and the admixture was stirred at room temperature for 22 hours. The reaction mixture was partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting chloroform/acetone (10/1) to obtain 7 mg of the title compound (yield: 8%).
Reaction SMILES: OS(O)(=O)=O.[CH2:6]([O:9][C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])[CH:7]=[CH2:8].[CH3:21]O>>[CH2:6]([O:9][C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([O:20][CH3:21])=[O:19])=[O:11])[CH:7]=[CH2:8]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Yield: 43 %

Procedure:
A catalytic amount of concentrated H2SO4 (4.5 mL) was added to a solution of Alloc-hydroxyproline (2) (43 g, 200 mmol) in MeOH (300 mL) at 10° C. (ice) and the reaction mixture was then heated at reflux for 2 h. After cooling to room temperature the reaction mixture was treated with TEA (43 mL) and the MeOH evaporated in vacuo. The residue was dissolved in EtOAc (300 mL), washed with brine (200 mL), dried (MgSO4), filtered and concentrated in vacuo to give a viscous oil. Purification by flash chromatography (40% EtOAc/Petroleum Ether) removed the high Rf impurity to provide the pure ester 3 as a transparent yellow oil (19.6 g, 43%): [α]23D=−79.0° (c=0.35, CHCl3); 1H NMR (270 MHz, CDCl3) (Rotamers) δ 5.98-5.78 (m, 1H, NCO2CH2CH═CH2), 5.35-5.16 (m, 2H, NCO2CH2CH═CH2), 4.65-4.45 (m, 4H, NCO2CH2CH═CH2, NCH2CHOHCH2 and NCHCO2CH3), 3.75 and 3.72 (s×2, 3H, OCH3), 3.70-3.54 (m, 2H, NCH2CHOHCH2), 3.13 and 3.01 (br s×2, 1H, OH), 2.39-2.03 (m, 2H, NCH2CHOHCH2); 13C NMR (67.8 MHz, CDCl3) (Rotamers) δ 173.4 and 173.2 (CO2CH3), 155.0 and 154.6 (NC═O), 132.6 and 132.4 (NCO2CH2CH═CH2), 117.6 and 117.3 (NCO2CH2CH═CH2), 70.0 and 69.2 (NCH2CHOH), 66.2 (NCO2CH2CH═CH2), 57.9 and 57.7 (NCHCO2CH3), 55.2 and 54.6 (NCH2CHOH), 52.4 (OCH3), 39.1 and 38.4 (NCH2CHOHCH2); MS (EI), m/z (relative intensity) 229 (M+, 7), 170 (M-CO2Me, 100), 144 (M-CO2C3H5, 12), 126 (26), 108 (20), 68 (7), 56 (8); IR (Neat) 3438 (br, OH), 2954, 1750 and 1694 (br, C═O), 1435, 1413, 1345, 1278, 1206, 1130, 1086, 994, 771 cm−1; exact mass calcd for C10H15NO5 m/e 229.0950, obsd m/e 229.0940.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]C)=O.[NH2:12][NH2:13]>C(O)C>[NH2:12][NH:13][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: COC(=O)CN1CCCC1=O
Reactant: NN
Solvent: CCO
Product: NNC(=O)CN1CCCC1=O

Procedure:
To a solution of methyl 2-(2-oxopyrrolidinyl)acetate (0.884 mL, 6.36 mmol) in 1 mL of anhydrous ethanol was added anhydrous hydrazine (0.308 mL, 6.36 mmol). The solution was heated to reflux temperature overnight. The solvent was then removed under reduced pressure and the product was isolated as a solid in a quantitative yield and was used without further purification: 1H NMR (CDCl3) δ 8.17 (br s, 1H), 3.94 (s, 2H), 3.55 (t, 2H), 2.43 (t, 2H), 2.10 (quintet, 2H); ES-MS (m/z) 158 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH3:19])[C:7]=2[CH:20]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH3:19])[C:7]=2[CH:20]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCCCCCC(=O)c1oc2ccc(OC)cc2c1C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCCCC(Nc1ccc(C(=O)OC)cc1)c1oc2ccc(OC)cc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a mixture of 1-(5-methoxy-3-methyl-1-benzofuran-2-yl)heptan-1-one (1.18 g) synthesized above, methyl 4-aminobenzoate (715 mg), triethylamine (4.79 mL) and methylene chloride (20 mL) was added titanium (IV) chloride (566 μL), and the mixture was stirred under argon atmosphere overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, methylene chloride was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (20 mL) of the obtained oil in tetrahydrofuran were added acetic acid (1.23 mL) and sodium cyanoborohydride (540 mg), and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% ethyl acetate/hexane) to give the title object compound (1.17 g, 66%) as a pale-brown oil
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[CH:7]([C:9]1[O:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[N:13]=1)=[CH2:8].O1C=CNC1=O.C(C1C=C(O)C=CC=1O)(C)(C)C>C1C=CC=CC=1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:11](=[O:16])[C:12]([CH3:15])([NH:13][C:9](=[O:10])[CH:7]=[CH2:8])[CH3:14]
Reactant: C=CC1=NC(C)(C)C(=O)O1
Reactant: CN(C)CCN
Agent: CC(C)(C)c1cc(O)ccc1O
Agent: O=c1[nH]cco1
Solvent: c1ccccc1
Product: C=CC(=O)NC(C)(C)C(=O)NCCN(C)C
Reaction time: 2 h

Procedure:
A solution of 100 g. of N,N-dimethylethylenediamine in 40 cc. of benzene was added dropwise to a stirring solution of 16.4 g. of 2-vinyl-4,4-dimethyl-5-oxazolone in 50 cc. of benzene. The oxazolone solution contained a few milligrams of t-butylhydroquinone as a polymerization inhibitor. An external water bath was used to maintain the resultant solution at about 25° C. The solution was stirred about 2 hours, filtered through Celite, and evaporated. The residue after evaporation was triturated with hexane and the mixture filtered to provide N-(N',N'-dimethyl-β-aminoethyl)-2-methyl-2-acrylamidopropanoic acid amide as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+:6].[CH2:7]([O:9][CH2:10][CH2:11][SH:12])[CH3:8].[C:13](=[S:15])=[S:14]>O1CCCC1>[C:13](=[S:14])([S-:15])[S:12][CH2:11][CH2:10][O:9][CH2:7][CH3:8].[K+:6]
Reactant: S=C=S
Reactant: CCOCCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOCCSC(=S)[S-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6.79 g potassium t-butoxide in 300 ml of anhydrous tetrahydrofuran cooled to 0° C. under a nitrogen atmosphere was added 6.42 g of 2-mercaptoethyl ethyl ether. The resulting slurry was stirred at 25° C. for 1 hour, then 4.4 ml. of carbon disulfide was added dropwise at 0° C. The resulting solution was stirred at 25° C. for 30 min., then concentrated in vacuo. Diethyl ether (300 ml) was added and the mixture was filtered, washed with ether and dried under nitrogen to yield 12.6 g of the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:37])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([C:34](O)=[O:35])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[NH4+].O[N:40]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN(C)C=O>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:37])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([C:34]([NH2:40])=[O:35])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(=O)O)CC2)c2ncnn12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(N)=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanecarboxylic acid (0.5 g), 1-hydroxybenzotriazole ammonium salt (0.21 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.36 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[NH:26][C:25]2[CH:27]=[CH:28][C:29]([N+:31]([O-])=O)=[CH:30][C:24]=2[N:23]=1>C(O)C.Cl.[Pd]>[NH2:31][C:29]1[CH:28]=[CH:27][C:25]2[NH:26][C:22]([C:3]3[CH:4]=[C:5]([NH:8][C:9](=[O:21])[C:10]4[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[N:12][C:11]=4[CH3:20])[CH:6]=[CH:7][C:2]=3[Cl:1])=[N:23][C:24]=2[CH:30]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2nc3cc([N+](=O)[O-])ccc3[nH]2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2nc3cc(N)ccc3[nH]2)c1
Reaction time: 3 h
Yield: 98.7 %

Procedure:
N-[4-chloro-3-(5-nitro-1H-benzoimidazol-2-yl)-phenyl]-2-methyl-6-trifluoromethyl-nicotinamide (212 mg; 0.45 mmol) was dissolved in ethanol (4 ml) with 2 drops of concentrated hydrochloric acid. This was added to 5% palladium on charcoal (42 mg; 20 wt %) and the reaction stirred under an atmosphere of hydrogen for 3 hours. The catalyst was removed by filtering through celite and then the solvent by evaporation to leave N-[3-(5-amino-1H-benzoimidazol-2-yl)-4-chloro-phenyl]-2-methyl-6-trifluoromethyl-nicotinamide (198 mg, 100%).
Reaction SMILES: [CH:1]1([C:4]([NH2:6])=[O:5])[CH2:3][CH2:2]1.[Cl:7][CH2:8][C:9](=O)[CH2:10]Cl>O>[Cl:7][CH2:8][C:9]1[N:6]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[O:5][CH:10]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)C1CC1
Solvent: O
Product: ClCc1coc(C2CC2)n1
Temperature: 110 °C
Yield: 43.2 %

Procedure:
A mixture of cyclopropanecarboxylic acid amide (5.0 g, 58.74 mmol) and 1,3-dichloro-propan-2-one (14.92 g, 117.49 mmol) was heated at 110° C. for 4 h. The mixture was cooled to room temperature and water (75 mL) was added and the mixture was extracted with dichloromethane (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and evaporated in vacuo to get crude residue. After purification via column chromatography (100-200 silica gel, elution with 2% EtOAc in hexane), 4 g of 4-chloromethyl-2-cyclopropyl-oxazole was obtained as a dark brown liquid, 158.0 (M+H)+. But it contained impurities. This compound was used for the next step as such.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Br[C:34]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]2[CH2:54][CH2:53][C:52]3[C:47](=[CH:48][CH:49]=[C:50]([NH:55][CH3:56])[CH:51]=3)[C:46]2=[O:57])[C:35]=1[CH2:36][O:37]C(=O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Li+]>>[OH:37][CH2:36][C:35]1[C:34]([C:6]2[CH:5]=[C:4]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][N:19]=3)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=2)=[CH:44][CH:43]=[CH:42][C:41]=1[N:45]1[CH2:54][CH2:53][C:52]2[C:47](=[CH:48][CH:49]=[C:50]([NH:55][CH3:56])[CH:51]=2)[C:46]1=[O:57]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: CNc1ccc2c(c1)CCN(c1cccc(Br)c1COC(C)=O)C2=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Li+]
Product: CNc1ccc2c(c1)CCN(c1cccc(-c3cc(Nc4ccc(C(=O)N5CCOCC5)cn4)c(=O)n(C)c3)c1CO)C2=O
Temperature: 100 °C
Reaction time: 18 h
Yield: 32.7 %

Procedure:
To 1-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (96 mg, 0.22 mmol), acetic acid 2-bromo-6-(6-methylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-benzyl ester (88 mg, 0.22 mmol), potassium phosphate (46 mg, 0.22 mmol), 2-(dicyclohexylphoshphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (6.2 mg, 0.013 mmol), and bis(dibenzylidineacetone)palladium(0) (3.7 mg, 0064 mmol) was added 4 mL of degassed 1:3 water/n-butanol. The headspace of the vessel was evacuated and backfilled with argon 4 times. This was heated at 100° C. for 2 hours. This was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. This was dissolved in 2 mL tetrahydrofuran, 1 mL methanol, and 1 mL water. 1M aq. lithium hydroxide solution (0.65 mL, 0.65 mmol) was added. After stirring for 18 hours, the resulting mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by preparative TLC (5% methanol/dichloromethane) to yield 2-(2-Hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-6-methylamino-3,4-dihydro-2H-isoquinolin-1-one (43 mg, 0.072 mmol). MS (ESI) 595 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Cl[C:10]1[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([CH3:25])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1>[CH3:25][C:17]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=1
Reactant: CCOC(=O)c1c(C)cc(C(F)(F)F)nc1Cl
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)cc(C(F)(F)F)nc1OCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 55.6 %

Procedure:
A suspension of sodium hydride (150 mg of 60% in mineral oil, 3.7 mmol) was formed in THF (10 mL) and cooled in an ice bath. 2,2,2-Trifluoroethanol (0.34 mL, 4.7 mmol) was added dropwise, then the mixture was stirred at 0° C. for 5 mins. A solution of ethyl 2-chloro4-methyl-6-(trifluoromethyl)nicotinate (500 mg, 1.9 mmol) in THF (10 mL) was added and the mixture heated at reflux for 18 hours then cooled to room temperature. The mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was dried over magnesium sulphate, filtered and evaporated to give an oil. Purification by flash column chromatography on silica gel using 40% hexane: 60% DCM as eluent gave ethyl 4-methyl-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)nicotinate as a colourless oil (350 mg): 1H NMR (500 MHz, CDCl3): δ 7.24 (1H, s), 4.83-4.77 (2H, q, J 8.3), 4.43 (2H, q, J 7.1), 2.43 (3H, s), 1.38 (3H, t, J 7.1).
Reaction SMILES: [CH:1]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:20]([CH2:23][CH2:24][C@@H:25]([NH:33][C:34]([N:36]1[CH2:45][CH2:44][C:43]2[CH:42]=[N:41][C:40]([NH:46][CH:47]([CH3:49])[CH3:48])=[N:39][C:38]=2[CH2:37]1)=[O:35])[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)=[N+]=[N-].CI.[OH-].[K+]>C1COCC1.CO>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C@H:25]([NH:33][C:34]([N:36]2[CH2:45][CH2:44][C:43]3[CH:42]=[N:41][C:40]([NH:46][CH:47]([CH3:49])[CH3:48])=[N:39][C:38]=3[CH2:37]2)=[O:35])[CH2:24][CH2:23][NH:20][CH3:1])=[CH:27][CH:28]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)N[C@H](CCN=[N+]=[N-])c1ccc(Cl)cc1)CC2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CI
Product: CNCC[C@@H](NC(=O)N1CCc2cnc(NC(C)C)nc2C1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of PS—PPh3 (278 mg, 2.28 mmol/g, 0.634 mmol) and THF (5 mL) was was allowed to stand for 5 min then a solution 332 (136 mg, 0.317 mmol) in THF (1 mL) was added. The suspension was stirred at RT for 4 h then MeI (0.0593 mL, 0.951 mmol) was added. The mixture was stirred at RT for 17 h, filtered through a fritted funnel and the resin washed with THF (5×10 mL) and DCM (5×10 mL). The resin was transferred to a pressure tube and suspended in MeOH (8 mL) and a solution of KOH (178 mg, 3.17 mmol) in MeOH (2 mL) was added. The mixture was heated to 65° C. for 4 h, cooled to RT, filtered and the resin washed with DCM (4×3 mL) and MeOH (2×3 mL). The filtrate and washings were combined and concentrated to a white solid. The crude product was partitioned between DCM and dilute aq. NaHCO3 and the aqueous layer extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered, and concentrated. The crude product was purified on a preparative TLC plate (0.5 mm) developed with MeOH/DCM/NH4OH (9/90/1) to afford 50 mg (38%) of I-117 as a pale yellow foam: 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.72 (br s, 1H), 7.22-7.28 (m, 4H), 4.95 (m, 1H), 4.80 (d, 1H), 4.37 (m, 2H), 4.10 (m, 1H), 3.69 (m, 1H), 3.60 (m, 1H), 2.72 (m, 2H), 2.65 (t, 2H), 2.48 (s, 3H), 2.05 (m, 1H), 1.80 (m, 1H), 1.22 (d, 6H); LRMS (APCI pos) m/e=417.4 (M+H).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[Br:6][C:7]1[CH:8]=[C:9]([N+:15]([O-])=O)[C:10]([C:13]#[N:14])=[N:11][CH:12]=1.C[OH:19]>>[NH2:15][C:9]1[C:10]([C:13]([NH2:14])=[O:19])=[N:11][CH:12]=[C:7]([Br:6])[CH:8]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: CO
Agent: Cl[Sn](Cl)(Cl)Cl
Product: NC(=O)c1ncc(Br)cc1N
Temperature: 40 °C

Procedure:
Tin chloride (90 g, 400 mmol) was added to a solution of 5-bromo-3-nitropicolinonitrile (17 g, 74 mmol) in methanol (800 mL) and the reaction was heated to 40° C. for 4.75 h. The solvent was removed in vacuo and toluene added and removed in vacuo. The crude was suspended in EtOAc and the mixture basified to pH 8 with saturated NaHCO3 (aq). The organic layer was separated and the aqueous slurry extracted with CHCl3 (×3). The combined organics were filtered through Celite, dried (MgSO4) and concentrated in vacuo to give crude 3-amino-5-bromopyridine-2-carboxamide which was used directly without further purification.
Reaction SMILES: [CH:1]1([NH:4][C@@H:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=3)[CH2:7][C@@H:6]2[F:21])[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[N:35][N:34]=[N:33]1)[C:26](O)=[O:27]>>[CH:1]1([N:4]([C@@H:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][N:12]=3)[CH2:7][C@@H:6]2[F:21])[C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([N:32]3[CH:36]=[N:35][N:34]=[N:33]3)=[C:23]([F:22])[CH:24]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(-n2cnnn2)c(F)c1
Reactant: F[C@H]1CN(c2ccc(C(F)(F)F)cn2)CC[C@H]1NC1CC1
Product: O=C(c1ccc(-n2cnnn2)c(F)c1)N(C1CC1)[C@@H]1CCN(c2ccc(C(F)(F)F)cn2)C[C@@H]1F

Procedure:
The title compound is prepared from (3S,4R)-cyclopropyl-(3-fluoro-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amine and 3-fluoro-4-tetrazol-1-yl-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.39 min; Mass spectrum (ESI+): m/z=494 [M+H]+.