Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[N:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:39][CH:38]=4)=[CH:33][N:32]=3)=[CH:27][CH:26]=2)[C:14]([N:16]2[CH2:19][CH:18]([C:20]([O:22]C)=[O:21])[CH2:17]2)=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O>C1COCC1.O>[C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[N:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:39][CH:38]=4)=[CH:33][N:32]=3)=[CH:27][CH:26]=2)[C:14]([N:16]2[CH2:19][CH:18]([C:20]([OH:22])=[O:21])[CH2:17]2)=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N4CC(C(=O)OC)C4)cc3)nc2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N4CC(C(=O)O)C4)cc3)nc2)cc1
Reaction time: 24 h
Yield: 69.8 %

Procedure:
To a stirred solution of (S)-methyl 1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate (341 mg, 0.489 mmol) in THF (10 mL) was added sulfuric acid (3 mL of a 5 M aqueous solution, 15 mmol). After 24 h, the mixture was diluted with water (100 mL) and extracted with EA (2×100 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and solvents evaporated. Column chromatography (AcOH/EA/DCM/iso-hexanes) gave 233 mg (70%) of (S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylic acid Compound 635 as a white solid. LCMS-ESI (m/z) calculated for C39H46N4O5S: 682.3; no m/z observed, tR=10.17 min (Method 10). The chiral purity was >98% e.e. (Chiral Method). 1H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 9.17 (d, J=1.8 Hz, 2H), 8.77 (app dd, J=8.3, 2.7 Hz, 1H), 8.32 (dd, J=8.2, 4.7 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H), 7.70 (d, J=3.9 Hz, 1H), 7.47-7.52 (m, 2H), 7.11-7.07 (m, 2H), 6.93 (app dd, J=3.9, 1.4 Hz, 1H), 4.70-4.63 (m, 1H), 4.43 (t, J=9.0 Hz, 0.5H), 4.30 (dd, J=8.7, 6.0 Hz, 0.5H), 4.21 (t, J=8.9 Hz, 0.5H), 4.15 (dd, J=8.5, 6.3 Hz, 0.5H), 4.08-3.99 (m, 3H), 3.47-3.40 (m, 1H), 3.93-3.87 (m, 1H), 3.15-3.01 (m, 2H), 1.77-1.70 (m, 2H), 1.49-1.16 (m, 17H), 0.88 (t, J=6.8 Hz, 3H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:38]2[CH2:51][CH2:50][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[C:48]([F:49])=[C:40]3[C:39]2=[O:52])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][C@@H:26]3[CH3:35])=[CH:21][N:20]=2)[C:15](=[O:36])[N:14]([CH3:37])[N:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[F:49][C:48]1[C:47]2[CH2:46][CH2:45][CH2:44][CH2:43][C:42]=2[N:41]2[CH2:50][CH2:51][N:38]([C:7]3[C:6]([CH2:5][OH:4])=[C:11]([C:12]4[CH:17]=[C:16]([NH:18][C:19]5[CH:24]=[CH:23][C:22]([N:25]6[CH2:30][CH2:29][N:28]([CH:31]7[CH2:34][O:33][CH2:32]7)[CH2:27][C@@H:26]6[CH3:35])=[CH:21][N:20]=5)[C:15](=[O:36])[N:14]([CH3:37])[N:13]=4)[CH:10]=[CH:9][N:8]=3)[C:39](=[O:52])[C:40]=12
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)n2)ccnc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c6c(c(F)c5C4=O)CCCC6)c3CO)nn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A mixture of 231d (150 mg, 0.21 mmol) and lithium hydroxide (51 mg, 2.1 mmol) in i-propanol/THF (1:1, 10 mL) and water (3 mL) was stirred at room temperature for 1 h. The mixture was evaporated under reduced pressure and the residue was extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 231 (83 mg, 59%) as a yellow solid. MS-ESI: [M+H]+ 670.3. 1H NMR (500 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.42 (s, 1H), 7.91 (s, 1H), 7.43-7.40 (m, 3H), 4.76 (bs, 1H), 4.60-4.54 (m, 3H), 4.49-4.46 (m, 1H), 4.43-4.37 (m, 2H), 4.21-4.56 (m, 2H), 4.07-4.03 (m, 1H), 3.89-3.83 (m, 2H), 3.78 (s, 3H), 3.41-3.37 (m, 1H), 3.22-3.19 (m, 1H), 3.00-2.93 (m, 1H), 2.65-2.60 (m, 2H), 2.55-2.54 (m, 1H), 2.43-2.39 (m, 3H), 2.27-2.24 (m, 1H), 2.12-2.07 (m, 1H), 1.76-1.66 (m, 4H), 0.97 (d, J=9.0 Hz, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:5]([Cl:24])=[C:6]([C:20]([Cl:23])=[CH:21][CH:22]=1)[CH2:7][O:8][C:9]1[C:10]2[N:11]([C:15]([Br:19])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1.CN1C[CH2:35][CH2:34][C:33]1=[O:37].C(Cl)(=O)CC>O>[Br:19][C:15]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:6]3[C:20]([Cl:23])=[CH:21][CH:22]=[C:4]([NH:3][C:33](=[O:37])[CH2:34][CH3:35])[C:5]=3[Cl:24])[C:10]2=[N:17][C:16]=1[CH3:18]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N)c3Cl)cccn2c1Br
Reactant: CN1CCCC1=O
Agent: CCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)Nc1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a suspension of 8-(3-amino-2,6-dichlorobenzyloxy)-3-bromo-2-methylimidazo[1,2-a]pyridine dihydrochloride (200 mg), pyridine (1 ml) and N-methylpyrrolidone (3 ml) was added propionyl chloride (78 mg) and the mixture was stirred at 60° C. for 1 hour. To the cooled mixture was added water, and the precipitate was collected by filtration and dissolved in chloroform. This organic solution was washed with water and brine respectively, dried with magnesium sulfate and concentrated in vacuo. The residue was collected by filtration and washed with ethyl acetate to give 3-bromo-8-(2,6-dichloro-3-propionylaminobenzyloxy)-2-methylimidazo [1,2-a]pyridine (158 mg).
Reaction SMILES: C([O:5][C:6](=[O:48])[C:7]1[CH:12]=[C:11]([C:13]2[C:17]([CH3:18])=[CH:16][S:15][CH:14]=2)[CH:10]=[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:27]=2[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:8]=1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[CH2:46]([O:45][C:43]([CH2:42][CH2:41][C:27]1[C:28]([O:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([C:13]2[C:17]([CH3:18])=[CH:16][S:15][CH:14]=2)[CH:10]=1)[C:6]([OH:48])=[O:5])=[O:44])[CH3:47]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)OC(C)(C)C)cc(-c3cscc3C)c2)c1CCC(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3cscc3C)c2)c1CCC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
3-{6-[2-(2-Ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-5-(4-methyl-thiophen-3-yl)-benzoic acid tert-butyl ester (1.8 g) was dissolved in a mixture of TFA and dichloromethane (1:1, 20 mL) and stirred at room temperature for 1 h. The solvents were removed under reduced pressure and the crude material was purified on a silica gel column using ethyl acetate and hexanes to yield the title compound (1.2 g, 73% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]3[S:17][C:18]([C:22]([OH:24])=[O:23])=[C:19]([CH3:21])[N:20]=3)=[N:11]2)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]CN)[CH:26]=1.F[P-](F)(F)(F)(F)F.[N:41]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]3[S:17][C:18]([C:22]([OH:24])=[O:23])=[C:19]([CH3:21])[N:20]=3)=[N:11]2)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:41][C:22]([C:18]2[S:17][C:16]([C:12]3[CH:13]=[C:14]([CH3:15])[N:10]([CH2:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:11]=3)=[N:20][C:19]=2[CH3:21])=[O:24])[CH:26]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: NCCc1cccnc1
Agent: Cc1nc(-c2cc(C)n(CCc3ccc(F)cc3)n2)sc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(-c2cc(C)n(CCc3ccc(F)cc3)n2)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.5 %

Procedure:
To a solution of 2-{1-[2-(4-fluoro-phenyl)-ethyl]-5-methyl-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid (0.15 g, 0.43 mmol) in methylene chloride (10 mL) was added 2-pyridin-3-yl-ethylamine (0.05 g, 0.48 mmol), benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate (0.21 g, 0.48 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.87 mmol). The reaction mixture was stirred under nitrogen at room temperature for 16 hr. The reaction mixture was diluted with methylene chloride (50 mL), washed with water (50 mL) and brine (2×50 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel (methylene chloride:methanol, 98:2) to provide 2-{1-[2-(4-fluoro-phenyl)-ethyl]-5-methyl-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid (pyridin-3-ylmethyl-amide as a white solid (0.052 g, 29% yield). 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.57 (d, J=4 Hz, 1H), 7.73 (d, J=4 Hz, 1H), 7.27-7.32 (m, 1H), 6.90-6.99 (m, 4H), 6.49 (s, 1H), 6.05-6.11 (bm, 1H), 4.64 (d, J=4 Hz, 2H), 4.23 (t, J=7 Hz, 2H), 3.13 (t, J=7 Hz, 2H), 2.76 (s, 3H), 1.56 (s, 3H); MS (M+H)+=435.9; Rt=1.31 min; HRMS (M+H)+=436.16.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])C.[K+].[C:7]1([SH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.BrC1CC1.O>CS(C)=O>[CH:5]1([S:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:1]1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: BrC1CC1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(SC2CC2)cc1
Temperature: 22.5 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of potassium tert-butoxide (52.4 g, 467 mmol) in DMSO (200 mL) was added thiophenol (42.9 g, 389 mmol) at 0° C. and stirred for 30 minutes at 20-25° C., followed by addition of bromocyclopropane (37.3 mL, 467 mmol). The reaction mixture was heated to 60° C. and continued to stir for 24 hours at the same temperature (with cold water circulation in the condenser). Reaction monitoring was done by TLC showed completion of reaction. The reaction mixture was then cooled to 20-25° C., added water (800 mL) then extracted with diethyl ether (3×400 mL). Diethyl ether layer was washed with water (500 mL) then with brine (150 mL) and dried over anhydrous sodium sulfate (75 g). Sodium sulfate was filtered and wash with diethyl ether (50 mL), solvent was removed under reduced pressure using rotavapour (bath temperature 30-35° C.) to get the required oily product which was dried under vacuum for 30 minutes. The crude material was used for the next step with out any purification.
Reaction SMILES: CO[C:3]1[CH:11]=[CH:10][C:6]([CH2:7][NH:8][OH:9])=[CH:5][CH:4]=1.Br.C1(O)C=CC=CC=1>C(O)(=O)C>[CH2:7]([NH:8][OH:9])[C:6]1[CH:10]=[CH:11][CH:3]=[CH:4][CH:5]=1
Reactant: COc1ccc(CNO)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: CC(=O)O
Product: ONCc1ccccc1
Reaction time: 5 h
Yield: 33 %

Procedure:
1.28 g (4 mmoles) of N-benzyl-N-mesyl-O-(p-methoxybenzylhydroxylamine prepared as described in Example 1 was treated with 15 ml of a 38% hydrogen bromide solution in acetic acid at room temperature for 20 hours in the presence of 1.5 g of phenol, and the mixture was then concentrated under a reduced pressure. 30 ml of diethyl ether and 10 ml of water and were then added to the resulting residue, and the aqueous layer was separated, concentrated under a reduced pressure to a small volume, adjusted to a pH of 8 with sodium carbonate and allowed to stand for 5 hours in a refrigerator. The crystals precipitated were collected by filtration to obtain 0.15 g (33% yield) of N-benzylhydroxylamine having a melting point of 56°-57° C. (The melting point reported in the literature is 57° C).
Reaction SMILES: [Na].[CH3:2][CH2:3][C@@H:4]([C:25]([C@H:27]([C@@H:29]([OH:45])[C@H:30]([C@H:32]1[O:37][C@@H:36]([CH2:38][C:39]([O:41][OH:42])=[O:40])[C@H:35]([CH3:43])[CH2:34][C@@H:33]1[CH3:44])[CH3:31])[CH3:28])=[O:26])[C@H:5]1[O:9][C@@:8]([C@:11]2([OH:23])[O:15][C@@:14]([C@@H:18]([OH:21])[CH2:19][CH3:20])([CH2:16][CH3:17])[CH2:13][C@H:12]2[CH3:22])([CH3:10])[CH2:7][C@@H:6]1[CH3:24].O.O.C([O-])(=O)C.[Co+2:52].C([O-])(=O)C.O>C(O)C>[Co:52].[CH3:2][CH2:3][C@@H:4]([C:25]([C@H:27]([C@@H:29]([OH:45])[C@H:30]([C@H:32]1[O:37][C@@H:36]([CH2:38][C:39]([O:41][OH:42])=[O:40])[C@H:35]([CH3:43])[CH2:34][C@@H:33]1[CH3:44])[CH3:31])[CH3:28])=[O:26])[C@H:5]1[O:9][C@@:8]([C@:11]2([OH:23])[O:15][C@@:14]([C@@H:18]([OH:21])[CH2:19][CH3:20])([CH2:16][CH3:17])[CH2:13][C@H:12]2[CH3:22])([CH3:10])[CH2:7][C@@H:6]1[CH3:24]
Reactant: [Co+2]
Agent: CC(=O)[O-]
Agent: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H]1O[C@@H](CC(=O)OO)[C@H](C)C[C@@H]1C)[C@H]1O[C@](C)([C@]2(O)O[C@](CC)([C@@H](O)CC)C[C@H]2C)C[C@@H]1C
Agent: [Na]
Solvent: CCO
Solvent: O
Product: [Co]
Reaction time: 18 h

Procedure:
A mixture of 13.0 g (0.02 mole) of sodium lysocellin and 2.5 g of cobalt acetate dihydrate in 150 ml of ethanol was stirred and held at ambient temperature for approximately 18 hours. Two volumes of water were added to the reaction mixture slowly. A tacky semi-solid precipitate formed. On continued stirring and trituration with fresh water, a filtrable solid was obtained. The removed cobalt salt was isolated and dried (13.1 g). The product had a melting point at 119.2° C. Analysis: Calculated % Co (4.48), Found (4.54).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]1[C:14]([C:18]([OH:20])=O)=[CH:15][CH:16]=[CH:17][N:8]1[C:7]2=[O:21])[CH3:3].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH2:46][CH2:47][CH2:48][NH2:49])[CH:40]=1.C(N(CC)CC)C>CN(C)C=O.O>[CH3:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]1[C:14]([C:18]([NH:49][CH2:48][CH2:47][CH2:46][CH2:45][C:41]3[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=3)=[O:20])=[CH:15][CH:16]=[CH:17][N:8]1[C:7]2=[O:21])[CH3:3]
Reactant: NCCCCc1cccnc1
Reactant: CC(C)c1ccc2nc3c(C(=O)O)cccn3c(=O)c2c1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1ccc2nc3c(C(=O)NCCCCc4cccnc4)cccn3c(=O)c2c1
Temperature: 25 °C
Yield: 6 %

Procedure:
A solution of 2.82 g of 2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-6-carboxylic acid, 2.75 g of diphenylphosphoryl azide, and 1.50 g of 3-pyridinebutanamine in 30 ml of dry dimethylformamide was cooled in an ice bath as 1.0 g of triethylamine was added to the mixture. The reaction mixture was allowed to warm to room temperature over 18 hours, was diluted with water and was extracted with dichloromethane. The combined organic layer was washed with dilute sodium carbonate solution, dried over potassium carbonate and evaporated to dryness. The residue was crystallized repeatedly from ethyl acetate to give 0.25 g (6%) of 2-(1-methylethyl)-N-[4-(3-pyridinyl)butyl]-11-oxo-11H-pyrido[2,1-b]quinazoline-6-carboxamide, mp 129°-130° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[NH2:14][C:15]1[N:19]=[C:18]([NH2:20])[NH:17][N:16]=1>O1CCCC1>[NH2:20][C:18]1[N:19]=[C:15]([NH:14][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:13])[NH:16][N:17]=1
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: Nc1n[nH]c(N)n1
Solvent: C1CCOC1
Product: Nc1n[nH]c(NC(=O)c2ccc3ccccc3c2)n1
Yield: 32.3 %

Procedure:
A mixture of 2-naphthyl carboxylic acid (2.0 g, 11.6 mmol) and N,N'-carbonyldiimidazole (2.07 g, 12.8 mmol) in dry tetrahydrofuran (50 ml) was stirred at reflux temperature for 1 h. To the cooled reaction mixture was added 3,5-diamino-1,2,4-triazole (1.15 g, 11.6 mmol) and the resulting mixture was refluxed for 3 h. The cooled reaction mixture was quenched with water (75 ml) and extracted with diethyl ether (2×75 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (2×50 ml), dried (MgSO4), filtered and evaporated in vacuo. The residue was crystallised from diethyl ether (20 ml), filtered off and washed with diethyl ether (2×10 ml), dried in vacuo afforded 0.95 g (32%) of the title compound as a solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[CH:22]4)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>C1COCC1.C(O)(C)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:22]4)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CCOC(=O)CCc1cc2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4[nH]c(CCC(=O)O)cc4c3)no2)cc1Cl
Temperature: 25 °C
Yield: 37.5 %

Procedure:
Sodium hydroxide (24 mg) was added to a solution of ethyl 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]propanoate (D115) (54 mg) in THF (1 mL), isopropanol (1 mL) and water (0.5 mL). The reaction mixture was stirred at room temperature until LCMS showed no starting material. The mixture was neutralized with 2 M HCl till pH ˜6.0. The crude product was purified by Mass Directed Auto Prep to afford 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]propanoic acid (E90) (19 mg). δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 2.70 (2H, t), 2.99 (2H, t), 5.46 (1H, m), 6.34 (1H, s), 7.45 (1H, d), 7.76 (1H, dd), 8.22 (1H, s), 8.55 (1H, d), 8.93 (1H, d), 11.35 (1H, s), 12.26 (1H, s); MS (ES): C21H19ClN4O4 requires 426; found 427.1 (M+H+).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[Cl-].[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([O-])=[O:17]>>[O:17]=[C:16]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:8][CH:9]=1)[CH2:15][C:14]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CC(=O)NCCc1ccccc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Product: CCOC(=O)CC(=O)c1ccc(CCNC(C)=O)cc1

Procedure:
N-Acetyl-phenethylamine is reacted with ethyl malonate chloride to give ethyl β-oxo-β-[4-(2-acetamidoethyl)-phenyl]-propionate (m.p. 89°-92° C.), which is reduced to ethyl β-[4-(2-acetamidoethyl)-phenyl]-propionate (m.p. 96°-98° C.) and this then subjected to alkaline saponification to give β-[4-(2-aminoethyl)-phenyl]-propionic acid (m.p. 270°-272° C.) followed by esterification to give the desired ethyl ester hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1>ClCCCl>[NH2:1][C:2]1[C:7]([NH:8][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cccnc1N
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccnc2N)CC1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
To a solution of 2,3-diaminopyridine (3.0 g, 27.5 mmol) in DCE (45 ml) was added tert-butyl 4-oxopiperidine-1-carboxylate (5.75 g, 28.8 mmol) and the reaction mixture stirred for min at RT before the portion-wise addition of NaBH(Oac)3 (8.7 g, 41.7 mmol) and continued stirring at RT until the reaction judged complete by LCMS. The reaction was quenched with 5% NaOH, the layers separated and the organic layer was dried over Na2SO4. Evaporation gave the desired product as a brown solid (4.96 g). LC/MS (10% to 99%): M/Z (M+H)+ (obs)=293; tR=2.31.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[P:16](Cl)([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17].N1C=CC=CC=1.ClCCl>CCCCCC.C(OCC)(=O)C>[P:16]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3](=[O:13])[C:2]([F:14])([F:15])[F:1])=[CH:7][CH:8]=1)([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOP(=O)(Cl)OCC
Reactant: O=C(CCc1ccc(O)cc1)C(F)(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOP(=O)(OCC)Oc1ccc(CCC(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
A 10 mL one neck round bottom flask, fitted with argon inlet and magnetic stirrer was placed in an ice bath and charged with 400 mg(1.8 mM) of 1,1,1-trifluoro-4-(4-hydroxyphenyl)-2-butanone, 400 mg(2.4 mM) of diethyl chlorophosphate, 0.15 mL of dry pyridine and 5 mL of dichloromethane at 5° C. The mixture was stirred overnight at ambient temperature, filtered to remove pyridine HCl, extracted with 0.2N HCl, extracted with water, and dried (anhydrous MgSO4). Solvent removal under reduced pressure gave a crude yield of 600 mg of a brown oil. Preparative TLC using 1:1 ethyl acetate:hexane gave 600 mg(92%) of a clear oil nmr(CDCl3) - L 1.50(m,6H), 3.0(m,4H), 4.20(m,4H), 7.15(s,4H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=[CH:16]4)[NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>CN(C=O)C.CCOC(C)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]=[C:18]([C:21]([NH:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[O:23])[CH:17]=[CH:16]4)[NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1
Reactant: O=C(O)c1ccc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1ccc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
8-(4-Oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoline-2-carboxylic acid (Example 94e; 80 mg, 0.26 mmol) was dissolved in DMF (2.5 mL), HATU (119 mg, 0.31 mmol), Et3N (0.04 mL, 0.31 mmol), and aniline (0.05 mL, 0.52 mmol) were added, and the resulting mixture was stirred at RT for 20 min. The mixture was then treated with EtOAc and washed with water. The organic layer was separated, and the aq. layer was extracted with EtOAc (2×). The combined organic layers were then dried over MgSO4, filtered, and concentrated to in vacuo. DCM was added to the crude material and a precipitate was formed, which contained both the desired product and impurities. Most of the impurities crystallized from hot DCM, and were removed by filtration. The mother liquor was concentrated and the material (desired product and ca. 10% impurity) was suspended in EtOAc. The desired product was recrystallized from hot EtOAc and was isolated by filtration affording 8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-N-phenylquinoline-2-carboxamide (12.9 mg, 0.034 mmol, 13.0% yield) as an amorphous tan solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.04 (br. s., 1H), 10.55 (s, 1H), 8.68 (d, J=8.4 Hz, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.11 (d, J=7.2 Hz, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.72-7.81 (m, 1H), 7.44 (t, J=7.7 Hz, 2H), 7.13-7.22 (m, 1H), 7.07 (d, J=10.8 Hz, 2H), 3.44-3.53 (m, 2H), 2.95 (t, J=6.7 Hz, 2H). m/z (ESI, +ve ion) 383.0 (M+H)+.
Reaction SMILES: [C:1]1([N:7]=[N+:8]=[N-:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)C.[CH2:15]([OH:18])[C:16]#[CH:17]>>[C:1]1([N:7]2[CH:17]=[C:16]([CH2:15][OH:18])[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: C#CCO
Solvent: CCOCC
Product: OCc1cn(-c2ccccc2)nn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
Phenyl azide (2.02 g, 17.0 mmol) was dissolved in neat propargyl alcohol (3 mL) and the mixture was heated to 90° C. for 2 h. The reaction mixture was cooled to room temperature and the reaction mixture was diluted into diethyl ether and left overnight during which time 7 precipitated as a crystalline solid to afford 1.03 g (35%) of the desired product 7 while the mother liquor contained primarily the regioisomer 9: 1H NMR (400 MHz, CDCl3) δ 7.97, (s, 1H), 7.70, (d, J=8.40 Hz, 2H), 7.50, (m, 2H), 7.41 (m, 1H), 4.88, (d, J=6.00 Hz, 2H), 2.70, (bs, 1H).