Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:21]([CH3:23])[CH3:22])[CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1.O.C(N(CC)CC)C.[CH3:54][C:55]1[O:56][C:57]([C:60]2[C:61]([N:69]3[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]3)=[C:62]3[CH:68]=[CH:67][NH:66][C:63]3=[N:64][CH:65]=2)=[N:58][N:59]=1>C(Cl)Cl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:10]([C:11]([N:72]2[CH2:71][CH2:70][N:69]([C:61]3[C:60]([C:57]4[O:56][C:55]([CH3:54])=[N:59][N:58]=4)=[CH:65][N:64]=[C:63]4[NH:66][CH:67]=[CH:68][C:62]=34)[CH2:74][CH2:73]2)=[O:12])[CH2:9][N:8]([CH:21]([CH3:22])[CH3:23])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:15][CH:16]=1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: Cc1nnc(-c2cnc3[nH]ccc3c2N2CCNCC2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nnc(-c2cnc3[nH]ccc3c2N2CCN(C(=O)[C@H](CN(C(=O)OC(C)(C)C)C(C)C)c3ccc(Cl)cc3)CC2)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.4 %

Procedure:
(S)-3-(tert-Butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (180 mg, 0.52 mmol, see Example H), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (134 mg, 0.70 mmol), HOBt-H2O (108 mg, 0.70 mmol) and triethylamine (106 mg, 1 mmol) were added to 2-methyl-5-(4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3,4-oxadiazole (100 mg, 0.36 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 18 hours. After dilution with DCM, the mixture was washed with 1N HCl, 10% K2CO3 and brine. The organic phase was dried over MgSO4 and purified by chromatography (SP4, 12+M, water/ACN 90/10→10/90, 20CV) to yield (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (60 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.C1(N)CCCCC1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Cc1ccc(Cl)cc1-c1ccc(C(=O)CCC(=O)O)cc1
Solvent: NC1CCCCC1
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)cc1-c1ccc(C(O)CCC(=O)O)cc1
Yield: 90 %

Procedure:
Prepared analogous to Example 25 from 4-(5'-chloro-2'-methyl-4-biphenylyl)-4-oxo-butyric acid. Yield: 90% of theory. Melting point of the cyclohexylamine salt: 114°-115° C. (from ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.[C:16]1([CH:22]([NH2:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C@H:9]([C:10](=[O:12])[NH:33][CH:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)[CH3:13])=[O:7])=[CH:14][CH:15]=1
Reactant: C[C@H](NC(=O)c1ccc(F)cc1)C(=O)O
Reactant: NC(c1ccccc1)c1cccc(C(F)(F)F)c1
Product: C[C@H](NC(=O)c1ccc(F)cc1)C(=O)NC(c1ccccc1)c1cccc(C(F)(F)F)c1

Procedure:
Prepared in analogy to example 1.1 from (S)-2-(4-fluoro-benzoylamino)-propionic acid (CA [214629-12-6]) and rac-C-phenyl-C-(3-trifluoromethyl-phenyl)-methylamine (CA [70428-92-1]).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([C:21]1[CH:22]=[N:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:25][CH:26]=1)=[O:20].O>O1CCCC1>[C:1]1([CH2:7][C:8]([O:10][CH2:18][C:19](=[O:20])[C:21]2[CH:26]=[N:25][C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:23][CH:22]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CBr)c1cnc(-c2ccccc2)nc1
Reactant: O=C(O)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)OCC(=O)c1cnc(-c2ccccc2)nc1
Temperature: 40 °C
Yield: 57.7 %

Procedure:
To a solution consisting of phenylacetic acid (27 mg, 0.20 mmol) and cesium carbonate (117 mg, 0.360 mmol) in tetrahydrofuran (1.5 mL) at room temperature was added 2-bromo-1-(2-phenylpyrimidin-5-yl)ethanone (Step B, 50 mg, 0.18 mmol). The reaction mixture was heated at 40° C. for one hour and cooled to room temperature. To the mixture was added water (10 mL) with vigorous stirring and the precipitate was filtered, washed with water, and dried on the suction filter to provide 2-oxo-2-(2-phenylpyrimidin-5-yl)ethyl 2-phenylacetate as a tan solid (34.5 mg, 57% yield) as an isolated intermediate. The tan solid was dissolved in toluene (4 mL) and freshly prepared ammonium acetate under toluene (300 mg wet with toluene) was added and the mixture was stirred vigorously and heated in a capped vial at 112° C. overnight. The brown reaction mixture was poured into aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to dryness. The brown solid was dissolved in dichloromethane and chromatographed on a 4 g silica column eluted with 1:4:5 to 1:6:3 dichloromethane-ethyl acetate-hexane to afford the title compound as a tan solid; Rf 0.08 with 6:4 v/v hexanes-ethyl acetate and Rf 0.61 with 3:7 v/v hexanes-ethyl acetate; melting point 235° C.; 1H-NMR (400 MHz; DMSO-d6) δ 9.21 (s, 2H), 8.3-8.5 (m, 2H), 7.82 (d, 1H), 7.5-7.6 (m, 3H), 7.2-7.4 (m, 5H), 4.08 (s, 2H); MS (ESI+) m/z 313 (M+1); H-PGDS FPBA IC50: 0.625 μM; H-PGDS inhibitor EIA IC50: 0.059 μM.
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10](Cl)[C:9]=1[CH:15]=O)(C)(C)C.[CH3:18][O-].[Na+]>>[N:7]1[C:8]2[C:9](=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:15]=[CH:18][CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1C=O
Reactant: C[O-]
Agent: [Na+]
Product: c1cnc2ccncc2c1

Procedure:
Reaction Scheme X illustrates an alternative preparation of the 1,6-naphthyridin-5(6H)-one compounds. In this Scheme, Weinreb amide VIII-2 is reacted with an aryl lithium reagent, generated from aryl bromide X-1, in which R is a protected or masked amino methyl derivative such as 1-(1-azido-1-methylethyl), to give ketone X-2. Condensation of this ketone with tert-butyl(2-chloro-3-formylpyridin-4-yl)carbamate in the presence of sodium methoxide, gives the 1,6-naphthyridine X-3. Deprotection or unmasking of the amine, in this case by palladium catalyzed reduction with hydrogen provides amine X-4. Treatment of X-4 with hydrochloric acid gives 1,6-naphthyridin-5(6H)-one X-5.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1F>C1COCC1.C(OCC)(=O)C>[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1[N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-n2ccc3ccccc32)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.5 %

Procedure:
A slurry of 334 mg(374 mg of 60% in oil, 9.35 mmol) of sodium hydride in 5 mL THF was treated with a solution of 1.0 g(8.5 mmol) of indole in 5 mL THF, followed by stirring at ambient temperature for 15 min. The solution was then treated with 1.35 g(8.5 mmol) of 3,4-difluoronitrobenzene. The solution was stirred at ambient temperature for 48 h, followed by concentration in vacuo to afford brown oil which was dissolved in ethyl acetate and washed with water. Drying (Na2SO4) and concentration in vacuo afforded an oil which was chromatographed over 100 g of 230-400 mesh silica gel, eluting with 20%(v/v) ethyl acetate in hexane. These procedures afforded 1.1 g(51%) of the title compound as a yellow solid. 1H NMR (CDCl3): δ8.23, 7.74, 7.40, 7.35, 7.30, 6.80.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([CH3:10])[C:3]=1[OH:11].C(O)(=[O:14])C>>[CH3:10][C:4]1[C:3](=[O:11])[C:2]([CH3:1])=[C:7]([CH3:8])[C:6](=[O:14])[C:5]=1[CH3:9]
Reactant: Cc1cc(C)c(C)c(O)c1C
Reactant: CC(=O)O
Product: CC1=C(C)C(=O)C(C)=C(C)C1=O
Yield: 53 %

Procedure:
500 mg of 2,3,5,6-tetramethylphenol and 10 mg of RuCl3.3H2O were reacted in 5 ml of acetic acid in the same manner as in Example 1, followed by the same treatment as in Example 1, whereby 288 mg (53% yield) of tetramethylbenzoquinone and 228 mg of a mixture of three unidentified substances were obtained. The tetramethylbenzoquinone was recrystallized from hexane to obtain yellow needle-like crystals having a melting point of from 114° to 115° C.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:22]1([N:25]2[C:33]3[C:28](=[C:29]([O:37][CH3:38])[CH:30]=[C:31]([C:34]([OH:36])=O)[CH:32]=3)[CH:27]=[CH:26]2)[CH2:24][CH2:23]1.Cl.[C:40]([CH2:43][NH:44][C:45]([C:47]1[CH:48]=[C:49]2[C:59](=[CH:60][CH:61]=1)[O:58][C:52]1([CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)[CH2:51][C:50]2=[O:62])=[O:46])(=[O:42])[NH2:41]>CN(C=O)C.O.CCN(CC)CC>[C:40]([CH2:43][NH:44][C:45]([C:47]1[CH:48]=[C:49]2[C:59](=[CH:60][CH:61]=1)[O:58][C:52]1([CH2:57][CH2:56][N:55]([C:34]([C:31]3[CH:32]=[C:33]4[C:28]([CH:27]=[CH:26][N:25]4[CH:22]4[CH2:23][CH2:24]4)=[C:29]([O:37][CH3:38])[CH:30]=3)=[O:36])[CH2:54][CH2:53]1)[CH2:51][C:50]2=[O:62])=[O:46])(=[O:42])[NH2:41]
Reactant: COc1cc(C(=O)O)cc2c1ccn2C1CC1
Reactant: NC(=O)CNC(=O)c1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(=O)NCC(N)=O)ccc2O3)cc2c1ccn2C1CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Et3N (209 uL), HOBT (91.2 mg) and WSC (115 mg) were added to a suspension of 1-cyclopropyl-4-(methyloxy)-1H-indole-6-carboxylic acid (145 mg) and N-carbamoylmethyl-4-oxo-spiro[chroman-2,4′-piperidine]-6-carboxamide hydrochloride (354 mg) in DMF (3 mL), and the mixture was stirred overnight at 50° C. After cooled to room temperature, the mixture was diluted with water, and the formed solid was collected by filtration. The solid was dried and purified on silica gel preparative TLC (development: CHCl3/MeOH) to obtain the intended compound as colorless foam. 1H-NMR (400 MHz, DMSO-d6) δ: 8.84-8.72 (1H, m), 8.80-8.62 (1H, m), 8.33-8.29 (1H, m), 8.08 (1H, dd, J=8.7, 2.3 Hz), 7.35 (1H, s), 7.28 (1H, d, J=3.2 Hz), 7.23-7.16 (2H, m), 6.99 (1H, s), 6.58 (1H, d, J=1.0 Hz), 6.39 (1H, dd, J=3.2, 0.7 Hz), 4.40-4.02 (2H, br m), 3.87 (3H, s), 3.80-3.76 (2H, br m), 3.48-3.25 (4H, m), 2.98 (2H, s), 2.06-1.56 (2H, m), 1.09-1.01 (2H, m), 0.95-0.89 (2H, m); MS [M+H]+=531.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6]2([C:10]([OH:12])=[O:11])[C:7]([CH2:9][CH:3]1[CH2:4][CH2:5]2)=[O:8].[C:14]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[CH3:14][O:11][C:10]([C@@:6]12[C:2]([CH3:13])([CH3:1])[C@@H:3]([CH2:4][CH2:5]1)[CH2:9][C:7]2=[O:8])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)C2CCC1(C(=O)O)C(=O)C2
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@@]12CC[C@@H](CC1=O)C2(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
To a mixture of ketopinic acid 6a 0.182 g (1 mmol) and K2CO3 1.1 g (8 mmol) stirred in DMF 10 ml was added MeI 0.125 ml (0.284 g, 2 mmol). The reaction mixture was allowed to stir for 18 hrs at ambient temperature. The reaction mixture was dissolved in water 80 ml and extracted with 3×30 ml portions of diethyl ether. The organic phase was washed with NaHCO3 saturated solution, dried over MgSO4 and concentrated in vacuo to give yellow oil 0.184 g (94%). 1H NMR (300 MHz, CDCl3) δ ppm 3.75 (s, 3H), 2.53 (ddd, J=18.29, 3.7 Hz, 1H), 2.36 (ddd, J=14.99, 11.82, 3.99 Hz, 1H), 2.10 (t, J=4.4 Hz, 1H), 2.02 (m, 1H), 1.92-1.98 (d, J=18.40 Hz, 1H), 1.79 (ddd, J=14.16, 9.35, 4.95 Hz, 1H), 1.41 (ddd, J=12.65, 9.49, 4.26 Hz, 1H), 1.15 (s, 3H), 1.07 (s, 3H). Exact mass calculated for C11H16O3 m/e 196.11. found 196.22.
Reaction SMILES: C([NH:11][CH:12]([CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)[C:13]([O:15][CH3:16])=[O:14])(OCC1C=CC=CC=1)=O.[H][H]>CO.[Pd]>[NH2:11][CH:12]([CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(CN1CCN(C(=O)OC(C)(C)C)CC1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)CN1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title material from Step A was dissolved in methanol with catalytic amount of 10% Pd on C. The reaction mixture was hydrogenated for 2 hours at room temperature in methanol under 25 psi of hydrogen. After filtration of the crude reaction mixture through a pad of Celite, the solvent was evaporated under reduced pressure to afford the title compound.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1([CH3:13])[C@H:11]([OH:12])[C:9](=[O:10])[O:8][CH2:7]1.N1C2C(=CC=CC=2)C=CC=1.C(N(CC)CC)C.[NH2:31][C@@H:32]([CH2:46][CH2:47][CH2:48][CH3:49])[CH:33]([OH:45])[C:34]([NH:36][C@@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:38])=[O:35]>O1CCCC1>[OH:45][CH:33]([C@@H:32]([NH:31][C:1](=[O:2])[O:12][C@H:11]1[C:6]([CH3:13])([CH3:5])[CH2:7][O:8][C:9]1=[O:10])[CH2:46][CH2:47][CH2:48][CH3:49])[C:34](=[O:35])[NH:36][C@@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:38]
Reactant: CC1(C)COC(=O)[C@H]1O
Reactant: O=C(Cl)Cl
Reactant: CCCC[C@H](N)C(O)C(=O)N[C@H](C)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccc2ncccc2c1
Solvent: C1CCOC1
Product: CCCC[C@H](NC(=O)O[C@@H]1C(=O)OCC1(C)C)C(O)C(=O)N[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.1 %

Procedure:
Phosgene (1.04 mL, 1.93 M, 2.00 mmol) was added dropwise to a solution of (S)-(+)-pantolactone (130 mg, 1.00 mmol) and quinoline (0.241 mL, 2.00 mmol) in anhydrous tetrahydrofuran (3 mL) at 0° C. under nitrogen. The cold bath was removed, and the mixture was stirred for 18 h at room temperature. Volatiles were then removed under vacuum, and the resulting solid was slurried in anhydrous tetrahydrofuran (4 mL) under nitrogen. A solution of triethylamine (0.153 mL, 1.10 mmol) and (3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide (264 mg, 1.00 mmol) in anhydrous tetrahydrofuran was added. The resulting mixture was stirred for 18 h, and was then partitioned between ethyl acetate (70 mL) and 1 N hydrochloric acid (35 mL). The ethyl acetate layer was washed further with two 35 mL portions of 1 N hydrochloric acid, followed by saturated aqueous sodium chloride (35 mL). After drying over magnesium sulfate, volatiles were removed to afford (3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate as a tan oil (358 mg, 85%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])=[C:4]([CH3:15])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH3:24]>C(#N)C>[CH3:14][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:23][CH3:24])=[CH:3][C:4]=2[CH3:15])[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: CCBr
Reactant: Cc1cc(O)ccc1-n1c(C)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-n2c(C)ccc2C)c(C)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-hydroxy-2-methylphenyl)-2,5-dimethylpyrrole (˜50 mmol) in acetonitrile (300 mL) was added potassium carbonate (55 mmol) and an excess of bromoethane (>100 mmol). The reaction mixture was stirred at 50° C. overnight, cooled to room temperature, and partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered, concentrated in vacuo, and purified by column chromatography (15% EtOAc/hexanes) to give 2,5-dimethyl-1-(4-ethoxy-2-methylphenyl)pyrrole as a colorless oil: 1H NMR (CDCl3, 500 MHz) δ 7.07 (d, 1H), 6.84 (d, 1H), 6.79 (dd, 1H), 5.90 (s, 2H), 4.07 (q, 2H), 1.92 (s, 6H), 1.90 (s, 3H), 1.45 (t, 3H; MS (ESI) 230 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[NH:13][C:14]1[O:18][C:17]([C:19]([NH:21][C:22]2[CH:38]=[CH:37][C:25]([O:26][C@H:27]3[CH2:32][CH2:31][C@H:30]([C:33]([O:35]C)=[O:34])[CH2:29][CH2:28]3)=[CH:24][CH:23]=2)=[O:20])=[N:16][N:15]=1.O.CO>C1COCC1>[F:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[NH:13][C:14]1[O:18][C:17]([C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([O:26][C@H:27]3[CH2:28][CH2:29][C@H:30]([C:33]([OH:35])=[O:34])[CH2:31][CH2:32]3)=[CH:37][CH:38]=2)=[O:20])=[N:16][N:15]=1
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(O[C@H]2CC[C@H](C(=O)O)CC2)cc1)c1nnc(Nc2cc(F)c(F)cc2F)o1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
Lithium hydroxide monohydrate (104 mg, 2.48 mmol) was added in one portion to a solution of methyl trans-4-{4-[({5-[(2,4,5-trifluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)-amino]phenoxy}cyclohexanecarboxylate (Example 449, 125 mg, 0.25 mmol) in a mixture of THF (2 mL), H2O (2 mL) and MeOH (4 mL) and the reaction mixture was stirred at 35° C. for 1 h. The reaction mixture was concentrated in vacuo and citric acid (15 mL) was added. The resulting mixture was filtered, washed with H2O and the white solid was then triturated with hot MeOH and filtered to give the title compound (93 mg, 79%) as a solid. The compound may be recrystallised from a 4:6:1 mixture of EtOH:MeOH:H2O; melting point 263-265° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:10]([NH2:23])[CH:9]=2)=[O:5])C.O.[OH-].[K+]>C(O)C>[NH2:23][C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2)=[CH:12][C:11]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)c(N)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc2[nH]c(C(=O)O)cc2cc1OCc1ccccc1
Temperature: 75 °C
Reaction time: 2.5 h

Procedure:
6-Amino-5-benzyloxy-1H-indole-2-carboxylic acid ethyl ester (65, step E) (500 mg) is suspended in ethanol (15 mL). Water (10 mL) is added, followed by KOH (1M, 5 mL). The suspension is stirred at 75° C. for 2.5 h. The solvent is evaporated to afford 6-amino-5-benzyloxy-1H-indole-2-carboxylic acid.
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.Cl.[N:29]1([C:35]2[N:44]=[C:43]([NH2:45])[C:42]3[C:37](=[CH:38][C:39]([O:48][CH3:49])=[C:40]([O:46][CH3:47])[CH:41]=3)[N:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CC(C)=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([N:32]2[CH2:33][CH2:34][N:29]([C:35]3[N:44]=[C:43]([NH2:45])[C:42]4[C:37](=[CH:38][C:39]([O:48][CH3:49])=[C:40]([O:46][CH3:47])[CH:41]=4)[N:36]=3)[CH2:30][CH2:31]2)=[O:12])=[CH:13][CH:14]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc(C=CC(=O)O)cc1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc2nc(N3CCN(C(=O)C=Cc4ccc(C(C)C)cc4)CC3)nc(N)c2cc1OC
Reaction time: 8 h

Procedure:
To a mixture of 342 mg. of 4-isopropylcinnamic acid and 727 mg. of triethylamine in 20 ml. of acetone were added dropwise under ice-cooling 195 mg. of ethyl chlorocarbonate and the resulting mixture was stirred for 3.5 hours. Then, 543 mg. of 2-(piperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline.hydrochloride were added thereto and stirring was continued at room temperature overnight. Then, the acetone was distilled off, the residue was dissolved in 20 ml. of 10% K2CO3 and extracted with ethyl acetate. After drying over magnesium sulfate, the extract was concentrated and recrystallization from methanol gave 361 mg. of the desired product.
Reaction SMILES: [CH2:1]([CH:9]1[O:14][CH2:13][CH2:12][NH:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([CH:9]1[O:14][CH2:13][CH2:12][N:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: OCCCCCCl
Reactant: CCCCCCCCC1CNCCO1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCC1CN(CCCCCO)CCO1

Procedure:
20.0 grams (0.1 mole) 2-octylmorpholine, 13 grams (0.1 mole) of 5-chloropentanol and 12 grams of triethylamine in 150 ml. toluene were kept at 140°-150° C. for 12 hours in an autoclave. After cooling, the organic phase was washed twice with water, dried, and the solvent was evaporated and the base distilled at 128° C./0.01 mm Hg.; yield: 22.0 grams (77%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.[CH3:13][C:14](C)([O-:16])C.[K+].[CH2:19](O)C>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([O:11][CH2:12][CH3:19])=[O:10])[CH:5]=[C:6]([O:16][CH2:14][CH3:13])[N:7]=1
Reactant: CC(C)(C)[O-]
Reactant: CCO
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: [K+]
Product: CCOC(=O)c1cc(OCC)nc(Cl)n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
A mixture of methyl 2,4-dichloropyrimidine-6-carboxylate (2.07 g, 10.0 mmol) and potassium tert.-butoxide (1.12 g, 10.0 mmol) in ethanol (50 mL) was stirred for 4 h at 60° C. The mixture was cooled to, insoluble material was removed by filtration, and the filtrate was evaporated under reduced pressure. The oily residue was partitioned between ethyl acetate and brine, and the organic layer was dried over sodium sulfate and evaporated under reduced pressure to give crude title compound (0.98 g, 43%) as colorless oil. MS ISP (m/e): 231.1 [(M+H)+].
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[C:20](=[O:37])[N:19]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:18]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:3][C:4](=[O:7])[O:5][N:36]=3)=[CH:25][CH:24]=2)[C:20](=[O:37])[N:19]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nn(-c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nn(-c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
A mixture of hydroxylammonium chloride (3.20 g), sodium hydrogen carbonate (4.55 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-[(3-butyl-5-oxo-1-phenyl-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile (1.26 g) was added, and the mixture was stirred at 90° C. 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. The residue was dissolved in tetrahydrofuran (30 mL), N,N′-carbonyldiimidazole (0.58 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.54 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution 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 colorless crystals (0.85 g, 34%).