Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:39]=[CH:38][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([NH:21][C:22]([C:24]3[N:28](CC4C=CC(OC)=CC=4)[N:27]=[N:26][N:25]=3)=[O:23])[C:16]([CH3:20])=[CH:17][C:18]=2[Cl:19])=[C:6]([CH2:40][CH2:41][C:42]([F:45])([F:44])[F:43])[C:5]=1[OH:46])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:1]([C:4]1[CH:39]=[CH:38][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([NH:21][C:22]([C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[O:23])[C:16]([CH3:20])=[CH:17][C:18]=2[Cl:19])=[C:6]([CH2:40][CH2:41][C:42]([F:44])([F:45])[F:43])[C:5]=1[OH:46])(=[O:3])[CH3:2]
Reactant: COc1ccc(Cn2nnnc2C(=O)Nc2cc(OCCCOc3ccc(C(C)=O)c(O)c3CCC(F)(F)F)c(Cl)cc2C)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1ccc(OCCCOc2cc(NC(=O)c3nnn[nH]3)c(C)cc2Cl)c(CCC(F)(F)F)c1O

Procedure:
A solution of 3 g (4.5 mmol) of N{{3-{3[- 4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy}-propoxy}-4-chloro-6-methyl-phenyl}}-1-(4-methoxybenzyl)-tetrazole-5-carboxamide in 90 ml of trifluoroacetic acid and 9 ml of anisole is refluxed for 60 minutes. The reaction mixture is concentrated under reduced pressure, about 150 ml of ether and 300 ml of petroleum ether are added and the crystals are filtered off. The N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-chloro-6-methyl-phenyl}}-1H-tetrazole-5-carboxamide thus obtained, of melting point 236°-238° (decomposition) is dissolved in 50 ml of tetrahydrofuran, and one equivalent of sodium, dissolved in 5 ml of methanol, is added. After addition of ether, crystallisation starts. The sodium salt of N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-chloro-6-methylphenyl}}-1 H-tetrazole-5-carboxamide of melting point 9020 (decomposition) is thus obtained.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[Cl:19][C:20]1[CH:25]=[C:24]([N:26]=C=O)[CH:23]=[C:22]([Cl:29])[CH:21]=1.[CH2:30]([N:32]1[C:44]2[CH:43]=[CH:42][C:41]([NH2:45])=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:31]>>[Cl:19][C:20]1[CH:25]=[C:24]([NH:26][C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:45][C:41]2[CH:42]=[CH:43][C:44]3[N:32]([CH2:30][CH3:31])[C:33]4[C:38]([C:39]=3[CH:40]=2)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:18])=[O:7])[CH:23]=[C:22]([Cl:29])[CH:21]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=NOC)CN3C(=O)Nc3cc(Cl)cc(Cl)c3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 1,3-dichloro-5-isocyanatobenzene, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 42% purity by LC/MS. MS(ESI+): m/z=538.2.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[C:22]([F:28])[CH:23]=[C:24]([F:27])[CH:25]=3)[CH:20]=[CH:19][C:18]2=[O:29])[CH:11]([CH3:30])[CH2:10]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[C:22]([F:28])[CH:23]=[C:24]([F:27])[CH:25]=3)[CH:20]=[CH:19][C:18]2=[O:29])[CH:11]([CH3:30])[CH2:10]1
Reactant: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CCN1CCn1c(=O)ccc2c(F)cc(F)cc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1CC(N)CCN1CCn1c(=O)ccc2c(F)cc(F)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.6 %

Procedure:
A solution of 1-{2-[4-(dibenzylamino)-2-methylpiperidin-1-yl]ethyl}-5,7-difluoroquinolin-2(1H)-one (Intermediate 214 358 mg, 0.71 mmol) in methanol (6 mL) was treated with palladium hydroxide on carbon (100 mg). The reaction was stirred at room temperature under hydrogen gas for 18 hours, filtered through celite, rinsed with methanol (100 mL), and concentrated under reduced pressure to afford 225 mg (96%) of a yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:64])([CH3:63])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[N:56]([CH3:57])[C:55]3[CH:58]=[CH:59][CH:60]=[CH:61][C:54]=3[N:53]=2)[C:47]1=[O:62])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:64])([CH3:63])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[N:56]([CH3:57])[C:55]3[CH:58]=[CH:59][CH:60]=[CH:61][C:54]=3[N:53]=2)[C:47]1=[O:62])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: Cn1c(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)nc2ccccc21
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2nc3ccccc3n2C)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.4 %

Procedure:
A solution containing the product from Example 23S (0.011 g, 0.021 mmol) in THF (0.3 mL) was treated with the product from Example 59F (0.007 g, 0.020 mmol), DEPBT (0.009 g, 0.030 mmol), and N,N-diisopropylethylamine (0.018 mL, 0.103 mmol), stirred at 25° C. for 3 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (0.009 g, 51% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.82 (s, 9 H), 0.86 (s, 9 H), 1.27 (m, 1 H), 1.53 (m, 2 H), 2.36 (m, 2 H), 2.72 (m, 3 H), 2.98 (m, 1 H), 3.10 (m, 1 H), 3.48 (d, J=13.97 Hz, 3 H), 3.61 (m, 1 H), 3.80 (s, 3 H), 3.93 (m, 2 H), 4.16 (m, 2 H), 4.60 (m, 2 H), 4.83 (d, J=5.52 Hz, 1 H), 6.91 (m, 4 H), 7.02 (m, 2 H), 7.20 (m, 2 H), 7.29 (m, 3 H), 7.58 (m, 3 H), 7.87 (m, 5 H), 8.63 (d, J=4.78 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:10]=1[C:11]#[N:12]>CS(C)=O>[F:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:9]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[C:11]#[N:12]
Reactant: Nc1ccccc1
Reactant: N#Cc1c(F)cccc1F
Solvent: CS(C)=O
Product: N#Cc1c(F)cccc1Nc1ccccc1
Temperature: 25 °C

Procedure:
Aniline (4.66 g, 50 mmol) was dissolved in dimethyl sulfoxide (20 mL) and stirred under argon at room temperature. Sodium hydride, dry, 95% (1.51 g, 60 mmol) was added in portions and a deep purple color developed while the mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0° C. in an ice bath and 2,6-difluorobenzonitrile (7.15 g, 50 mmol) dissolved in dimethyl sulfoxide (5 mL) was added and the mixture stirred at room temperature for 1.5 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic phase was washed with water (5×), brine (1×) dried over anhydrous Na2SO4 filtered, and evaporated to give the crude product which was then chromatographed on silica gel eluted with 0–25% CH2Cl2 in hexane to give the title compound as a white amorphous solid. ES (+) MS m/e=213 (MH+).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:17])[N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([CH3:16])[CH:8]=2)[CH:6]=1.[OH-].[Na+]>C(O)C>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([N:5]2[CH:6]=[C:2]([I:1])[N:3]=[C:4]2[CH3:17])=[CH:8][C:9]=1[CH3:16]
Reactant: Cc1cc(-n2cc(I)nc2C)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(-n2cc(I)nc2C)ccc1N

Procedure:
Stannous chloride dihydrate (9.04 g) was added portionwise to a stirred suspension of 4-Iodo-1-(3-methyl-4-nitrophenyl)-2-methylimidazole (2.75 g) in absolute ethanol (50 cm3) under nitrogen. After heating under reflux for 1 hour, the cooled mixture was basified to pH8 with aqueous 2.5M sodium hydroxide, and extracted with chloroform (3×100 cm3). The combined and dried (MgSO4) organic extracts were evaporated in vacuo to give a residue which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with methanol:dichloromethane, 1:25 by volume. Combination and evaporation of appropriate fractions afforded the title compound as a crude oil (2.41 g), which was used directly without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:9]=[C:10]2[C:22](=[O:23])[NH:21][N:20]=[CH:19][C:12]3=[C:13]([CH:17]=[CH2:18])[NH:14][C:15]([CH:16]=1)=[C:11]23)([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.CO>[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:9]=[C:10]2[C:22](=[O:23])[NH:21][N:20]=[CH:19][C:12]3=[C:13]([CH2:17][CH3:18])[NH:14][C:15]([CH:16]=1)=[C:11]23)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.8 %

Procedure:
Palladium (10% on activated carbon) (0.23 g, 0.198 mmol) was added to a solution of the title compound of Example 164 (0.65 g, 1.99 mmol) in 1:10 N,N-dimethylformamide:methanol (11 mL). The reaction mixture was purged with H2 and stirred at room temperature under H2 (1 atm.) for 5 hours. The palladium was filtered and the volatile components were removed in vacuo. The resulting residue was dissolved in methanol and loaded onto a silica gel plug. The plug was then loaded onto a silica gel column and eluted with 1.2:1 dichloromethane:ethyl acetate to afford the title compound (0.45 g, 1.37 mmol) as a yellow solid in 69% yield.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].I[C:27]1[N:31]([CH3:32])[C:30]([CH3:33])=[N:29][CH:28]=1.C([Mg]Cl)(C)C>C(Cl)Cl>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:27]3[N:31]([CH3:32])[C:30]([CH3:33])=[N:29][CH:28]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: Cc1ncc(I)n1C
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Product: Cc1ncc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)n1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 120 mg (0.30 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 3 mL DCM and 146 mg (0.66 mmol) of 5-iodo-1,2-dimethyl-1H-imidazole in 1 mL DCM with 0.34 mL 2M isopropylmagnesium chloride. Yield: 36 mg of a white powder. LC-MSD, m/z for C21H17BrN4O2 [M+H]+=437.0, 439.0; HPLC retention time: 0.4 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([CH:22]=2)[C:18]([O:20][CH3:21])=[O:19])[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]([F:12])([F:11])[F:10].Cl>CO.[Pt](=O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:14][NH:15][CH2:16][CH:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:22]2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]([F:12])([F:10])[F:11]
Reactant: COC(=O)c1cncc(-c2ccc(CC(F)(F)F)c(F)c2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CNCC(c2ccc(CC(F)(F)F)c(F)c2)C1

Procedure:
A solution of 7.75 g (17.1 mmol, purity 69%) of the compound from Example 75A in methanol (107 ml) was admixed with 1.50 g of platinum(IV) oxide and concentrated hydrochloric acid solution (13.4 ml). This was followed by hydrogenation under a hydrogen atmosphere at 3.5 bar overnight, then addition of another 800 mg of platinum(IV) oxide and again by hydrogenation under a hydrogen atmosphere at 3.5 bar overnight. Addition of another 1.00 g of platinum(IV) oxide was followed by hydrogenation under a hydrogen atmosphere at 3.5 bar overnight. The reaction solution was filtered through Celite, the filter residue was washed with methanol and the combined filtrates were concentrated under reduced pressure. The residue was taken up in water, then adjusted to pH=9 with a 1 N aqueous sodium hydroxide solution and subsequently extracted with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 6.01 g (86% of theory, purity 78%)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16](=[O:21])[C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)C(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)OCC1CCNCC1
Yield: 33 %

Procedure:
To 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butylester (480 mg, 2.1 mmol) dissolved in dry DMF (10 ml) was added NaH (120 mg, 3.0 mmol, 55-65% in mineral oil) and the mixture was warmed to 60° C. for 2 h. The mixture was allowed to cool to rt and then pivaloyl chloride (0.1.6 ml, 1.3 mmol) was added. The reaction was allowed to stir over night and then poured into water and the mixture was extracted with ether. The combined organic phases were washed with brine, dried (Na2SO4), filtered, concentrated under reduced pressure and the oily residue was purified by Flash column chromatography (SiO2; heptane/EtOAc 70:30) to yield 4-(2,2-dimethylpropionyloxymethyl)piperidine-1-carboxylic acid t-butyl ester as an oil. Deprotection of 4-(2,2-dimethylpropionyloxymethyl)piperidine-1-carboxylic acid t-butyl ester was conducted using the method (CH2Cl2:TFA; 1:1) to yield the title compound as an oil (85 mg, 0.43 mmol, 33 %). This crude was used without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4]/[N:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[SH:25][C@@H:26]([CH2:30][C:31]([OH:33])=[O:32])[C:27](O)=[O:28]>C1(C)C=CC=CC=1>[O:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][NH:14][C:8]2[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]2[N:5]([CH2:4][CH2:3][C:2]([CH3:24])([CH3:23])[CH3:1])[C:27](=[O:28])[CH:26]([CH2:30][C:31]([OH:33])=[O:32])[S:25]2)[CH2:18][CH2:19]1
Reactant: O=C(O)C[C@H](S)C(=O)O
Reactant: CC(C)(C)CC/N=C/c1cccc(F)c1NCCN1CCOCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)CCN1C(=O)C(CC(=O)O)SC1c1cccc(F)c1NCCN1CCOCC1

Procedure:
Heated 2-((E)-(3,3-dimethylbutylimino)methyl)-6-fluoro-N-(2-morpholinoethyl)benzenamine (606 mg, 1.806 mmol) and (S)-2-mercaptosuccinic acid (282 mg, 1.878 mmol) in toluene (10 mL) at 80° C. for 1 day. Volatiles were removed on a rotary evaporator under high vacuum to give 2-(2-(2-(2-morpholinoethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid as a yellow gum which was carried on to the next step as is. LC/MS: 468.39 (M+1) Rt=diastereomers at 1.91 and 1.93 min (10-90% 3/5 min (grad/run) w/formic acid).
Reaction SMILES: C([O:5][C:6](=[O:46])[C:7]([O:10]/[N:11]=[C:12](/[C:33]1[N:34]=[C:35]([NH:38]C(OC(C)(C)C)=O)[S:36][CH:37]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[CH:30]=[C:29]([CH2:31][OH:32])[N:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:38][C:35]1[S:36][CH:37]=[C:33](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:46])=[O:5])/[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:22])=[O:23])[C@@H:17]2[CH2:25][N:26]2[CH:30]=[C:29]([CH2:31][OH:32])[N:28]=[N:27]2)=[O:14])[N:34]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cc(CO)nn2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cc(CO)nn1)c1csc(N)n1)C(=O)O
Yield: 28.5 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (100 mg, 0.145 mmol), DCM (4 mL) and TFA (1 mL, 13 mmol). The crude residue was purified by reverse phase prep HPLC (T3, 30×100 mm, 5 μm, C18 column; acetonitrile-water with 0.1% formic acid modifier, 1 mL/min), affording the title compound (22 mg, 29%) as a white solid. LCMS: m/z=530.9 (M−1); 1H NMR (400 MHz, DMSO-d6): δ 12.50 (br s, 1H), 9.36 (d, J=9.2 Hz, 1H), 7.97 (s, 1H), 7.50 (br s, 2H), 6.70 (s, 1H), 5.28 (dd, J=8.8, 5.2, Hz, 1H), 4.86 (dd, J=14.4, 4.0 Hz, 1H), 4.69 (dd, J=14.8, 7.2 Hz, 1H), 4.48 (s, 2H), 4.27-4.21 (m, 1H), 1.35 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=2)[O:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[N:4][N:3]=[N:2]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[NH2:46][C:47]1[CH:48]=[CH:49][C:50]([Cl:57])=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:52]=1>C(OCC)(=O)C.CN(C=O)C>[Cl:57][C:50]1[CH:49]=[CH:48][C:47]([NH:46][C:11](=[O:13])[CH2:10][O:9][C:8]2[CH:14]=[CH:15][CH:16]=[C:6]([N:1]3[CH:5]=[N:4][N:3]=[N:2]3)[CH:7]=2)=[CH:52][C:51]=1[C:53]([F:54])([F:55])[F:56]
Reactant: O=C(O)COc1cccc(-n2cnnn2)c1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(COc1cccc(-n2cnnn2)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 25 mL recovery flask was added 3-tetrazol-1-ylphenoxyacetic acid 3 (200 mg, 0.908 mmol, 1.0 eq.) and a stirbar. 1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (261 mg, 1.36 mmol, 1.5 eq.) and 1-hydroxybenzotriazole (184 mg, 1.36 mmol, 1.5 eq.) were added to the flask. DMF (10 mL) and N-methylmorpholine (300 μL, 2.72 mmol, 3.0 eq.) were added to the reaction flask. The mixture was allowed to stir for 30 min at room temperature. 5-amino-2-chlorobenzotrifluoride (355 mg, 1.82 mmol, 2.0 eq.) was added to the flask and the resulting mixture was allowed to stir overnight at room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with a succession of H2O (1×50 mL), 10% aq. LiCl (3×50 mL), and sat'd aq. NaCl (1×50 mL). The aqueous phases were combined and extracted with ethyl acetate (2×30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to yield an off-white solid, which did not require further purification (165 mg, 46%). LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 398.0 (M+H)+1 1H-NMR, Varian 400 MHz (DMSO-d6) δ 10.55 (bs, 1H), 10.09 (s, 1H), 8.22 (d, 1H), 7.93-7.91 (m, 1H), 7.68 (d, 1H), 7.61-7.51 (m, 3H), 7.21-7.18 (m, 1H), 4.88 (s, 2H) ppm.
Reaction SMILES: I[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccccc1B(O)O
Reactant: O=C(O)c1ccncc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccccc1-c1cnccc1C(=O)O
Temperature: 80 °C
Yield: 75.7 %

Procedure:
To a suspension of 1.05 g (4.21 mmol) 3-iodo-isonicotinic acid in 15 ml dimethoxyethane were added successively 0.243 g tetrakis(triphenylphosphine)palladium(0), 4.2 ml 2 M sodium carbonate solution in water and 0.69 g (5.05 mmol) o-tolylboronic acid. The mixture was heated under argon at 80° C. for 18 h. After cooling to room temperature the phases were separated and the organic phase was washed twice with water (pH=9). The combined aqueous layers were than adjusted to pH=3 and extracted with five portions ethyl acetate. The combined organic layers were washed with brine, dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 0.68 g (75%) of the title compound as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N:8]1[CH:13]=[C:12]([CH:14]=O)[CH:11]=[N:10][CH:9]=1>C(Cl)(Cl)Cl>[N:8]1[CH:13]=[C:12]([CH:14]=[N:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:11]=[N:10][CH:9]=1
Reactant: O=Cc1cncnc1
Reactant: Nc1ccccn1
Solvent: ClC(Cl)Cl
Product: C(=Nc1ccccn1)c1cncnc1
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
A solution of 2-aminopyridine (11.314 g, 120.3 mmole) and pyrimidine-5-carboxaldehyde (14.0 g, 129.6 mmole) in chloroform (300 mL) was stirred at room temperature for 15 minutes. The volatiles were then removed under reduced pressure (1 hour at 75° C.) to yield a yellow solid. The crude solid was dissolved in chloroform (300 mL), and the solution was stirred for 15 minutes. The volatiles were then removed under reduced pressure (1 hour at 75° C.) to yield a yellow solid. The crude solid was again dissolved in chloroform (300 mL), the solution was stirred for 15 minutes, and the volatiles were removed under reduced pressure (1 hour at 85° C.) to yield a yellow solid. This solid was dried in a vacuum oven overnight at 80° C. to yield 22.090 g (99.8%) of the title compound. 1H NMR (CDCl3) δ 9.26-9.32 (m, 4H), 8.52 (d, 1H), 7.82 (t, 1H), 7.42 (d, 1H), 7.26 (t, 1H).
Reaction SMILES: [O-]CC.[Na+].Cl[CH2:6][CH2:7][C:8]([N:10]([CH3:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].[CH3:18][N:19]1[C:28]2[C:23](=[CH:24][C:25]([O:29][CH2:30][CH2:31][CH2:32][NH:33][CH2:34][C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]1=[O:41]>C(O)C>[CH3:17][N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8](=[O:9])[CH2:7][CH2:6][N:33]([CH2:32][CH2:31][CH2:30][O:29][C:25]1[CH:24]=[C:23]2[C:28](=[CH:27][CH:26]=1)[N:19]([CH3:18])[C:20](=[O:41])[CH:21]=[CH:22]2)[CH2:34][C:35]1[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=1
Reactant: Cn1c(=O)ccc2cc(OCCCNCc3ccncc3)ccc21
Reactant: CN(C(=O)CCCl)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C(=O)CCN(CCCOc1ccc2c(ccc(=O)n2C)c1)Cc1ccncc1)c1ccccc1
Temperature: 60 °C
Reaction time: 8.5 h
Yield: 2.3 %

Procedure:
Sodium ethoxide (34 mg) and 3-chloro-N-methyl-N-phenylpropionamide (148 mg) were added to a ethanol solution (5 ml) of 1-methyl-6-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one (161 mg), and stirred at 60° C. for 8.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:0→4:1). The purified product was condensed under reduced pressure to give the title compound (5.6 mg) as a colorless oil.