Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]1([C@@:14]2([C:26]#N)[CH2:16][C@H:15]2[CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].C([Al+]CC(C)C)C(C)C.[OH2:38]>O1CCCC1>[C:8]1([C@@:14]2([CH:26]=[O:38])[CH2:16][C@H:15]2[CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#C[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
To a solution of 300 mL toluene and (1R,2R)-1-phenyl-2-{[(phenylmethyl)oxy]methyl}cyclopropanecarbonitrile (12.0 g, 45.57 mmol, 1 eq), accessed via the method of Preparation 3B, at 0° C. was added 59.3 mL 1M diisobutylaluminum hydride (59.3 mmol, 1.3 eq) in tetrahydrofuran. The mixture was stirred at 0° C. for 4 h and then at ambient temperature for 18 h before dilution with 500 mL toluene and 500 mL water. The mixture was stirred for 30 min and then filtered through a pad of celite. The organics were isolated, dried over Na2SO4, filtered and concentrated to give the title compound (7.8 g, 29.3 mmol, 64%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 7.39-7.19 (m, 10H), 4.33-4.23 (m, 2H), 3.36-3.33 (m, 1H), 3.03-2.98 (m, 1H), 2.16-2.11(m, 1H), 1.77-1.73 (m, 1H), 1.46-1.43 (m, 1H).
Reaction SMILES: [CH:1](O)=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[O:16]=[C:17]1[N:22]2[C:23]3[C:28]([NH:29][CH2:30][C:21]2=[N:20][CH:19]=[C:18]1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][CH:26]=[CH:25][CH:24]=3.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]([N:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]2[C:17](=[O:16])[C:18]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:19][N:20]=[C:21]2[CH2:30]1)=[O:2]
Reactant: O=CO
Reactant: CCOC(=O)c1cnc2n(c1=O)-c1ccccc1NC2
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cnc2n(c1=O)-c1ccccc1N(C=O)C2
Reaction time: 6 h
Yield: 66.5 %

Procedure:
A solution of 700 mg of formic acid (98%) in 70 ml of CH2Cl2 was stirred at room temperature under nitrogen while 100 mg of carbonyldiimidazole were added thereto. After 30, minutes 1.5 g of ethyl 5,6-dihydro-1-oxo-1H-pyrimido [1,2-a] quinoxaline-2-carboxylate were added thereto and the mixture was stirred for another 6 hours. Then, the solution was poured into an aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over MgSO4, decolorized with charcoal and evaporated to dryness. The residue was crystallized from ethyl acetate to obtain 1.1 g (67% yield) of ethyl 5,6-dihydro-6-formyl-1-oxo-1H-pyrimido [1,2-a] quinoxaline-2-carboxylate melting at 172°-4° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6].C(N(CC)CC)C.[CH2:20]([N:22]([CH:26]([CH3:28])[CH3:27])[C:23](Cl)=[O:24])[CH3:21]>O1CCCC1>[CH2:20]([N:22]([CH:26]([CH3:28])[CH3:27])[C:23]([N:10]1[CH:11]=[N:12][C:8]([S:5]([CH2:4][CH2:3][O:2][CH3:1])(=[O:6])=[O:7])=[N:9]1)=[O:24])[CH3:21]
Reactant: CCN(C(=O)Cl)C(C)C
Reactant: COCCS(=O)(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(C(=O)n1cnc(S(=O)(=O)CCOC)n1)C(C)C

Procedure:
A solution of 0.03 mole of 3-(2-methoxyethylsulphonyl)-1,2,4-triazole, 6 ml. of triethylamine and 0.033 mole of N-ethyl-N-isopropylcarbamoyl chloride in 40 ml. of dry tetrahydrofuran was heated under reflux for 15 hours. The cooled reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate was evaporated to remove solvent. The product crystallized on cooling and treatment with 100 ml. of petroleum ether (b.p. 62°-68° C.). Thin solid was collected and recrystallized from 100 ml. benzene petroleum ether (b.p. 40°-60° C.) to give 1-(N-ethyl-N-isopropylcarbamoyl)-3-(2-methoxyethylsulphonyl)-1,2,4-triazole, m.p. 64°-65° C. Elemental analysis satisfactory.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:20]=[C:19]([NH2:29])[N:18]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[CH2:30]([N:32]([CH2:36][CH3:37])[C:33](Cl)=[O:34])[CH3:31]>C1COCC1>[NH2:29][C:19]1[N:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([O:9][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][NH:1][C:33](=[O:34])[N:32]([CH2:36][CH3:37])[CH2:30][CH3:31])[CH:8]=3)=[CH:15][CH:14]=2)[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]=1
Reactant: NCc1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Reactant: CCN(CC)C(=O)Cl
Solvent: C1CCOC1
Product: CCN(CC)C(=O)NCc1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.6 %

Procedure:
N4-(4-{[2-(Aminomethyl)pyridin-4-yl]oxy} phenyl)-6-phenylpyrimidine-2,4-diamine (50 mg, 0.13 mmol, Example 39) and diethylcarbamyl chloride (20.6 mg, 0.13 mmol) were suspended in THF (1 mL) and stirred at rt for 24 h. TLC and LC-MS indicated that the reaction was complete. The mixture was extracted with EtOAc and washed with 1N aqueous sodium hydroxide solution (2×) and H2O (3×). The organic layer was dried and concentrated to give 72 mg of the crude product. The residue was purified by Prep-TLC (CH3OH:EtOAc=2:8) to obtain 40 mg (63%) of the title product as a yellowish oil. 1H NMR (CD3OD) δ 8.28 (d, 1H), 7.84 (m, 3H), 7.81 (s, 1H), 7.48 (m, 3H), 7.05 (d, 2H), 6.84 (m, 1H), 6.75 (s, 1H), 6.44 (s, 1H), 4.39 (s, 2H), 3.23 (m, 4H), 1.20 (t, 6H); MS ES 484 (M+H)+, calcd 484, RT=2.37 min; TLC (MeOH/EtOAc=20/80) Rf=0.4
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>N1C=CC=CC=1>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Nc1ccc2nnc(Cl)n2n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccc2nnc(Cl)n2n1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
A mixture of 193 mg of 3-chloro[1,2,4]triazolo[4,3-b]pyridazin-6-amine and 0.14 cm3 of pivaloyl chloride in 5 cm3 of pyridine is stirred for 5 h at 20° C. 0.14 cm3 of pivaloyl chloride is again added and the mixture is left to stir overnight. The reaction medium obtained is concentrated to dryness under vacuum. The residue is washed with ethyl ether and pentane. The precipitate is taken up in a solution of ammonium chloride and then extracted with a 90/10 ethyl acetate/methanol mixture. The organic phase is evaporated to dryness. 157 mg of N-(3-chloro[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2,2-dimethylpropanamide are thus obtained in the form of a brown powder, the characteristics of which are as follows:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[N:10]1([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Oc1ccc(CN2CCCCC2)cc1
Reaction time: 16 h

Procedure:
A solution of 4-hydroxybenzaldehyde (10 g), piperidine (8.9 mL), and acetic acid (4.7 mL) in DCE (200 mL) was treated with sodium triacetoxyborohydride (24 g). After 16 h, the resulting mixture was treated with saturated aqueous sodium bicarbonate (100 mL) and extracted with DCM (5×100 mL). The combined organic phases were dried (magnesium sulfate) and evaporated. Trituration of the residue with ethyl acetate gave the title compound as a white crystalline solid (5.5 g).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([Br:29])[CH:27]=[CH:28][C:4]=2[N:3]=1>N.CO>[Br:29][C:26]1[CH:27]=[CH:28][C:4]2[N:3]=[C:2]([Cl:1])[N:6]([C@@H:7]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]3[OH:9])[C:5]=2[CH:25]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3ccc(Br)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3ccc(Br)cc32)[C@H](O)[C@@H]1O

Procedure:
A solution of 0.176 g (0.359 mmole) of 89 in 10 mL of NH3 /MeOH was stirred in a pressure bottle at room temperature for 5 hr. The reaction mixture was evaporated and coevaporated with MeOH (3×, bath temperature<40° C.). The resulting solid was recrystallized from MeOH to give 0.097 g (2 crops, 74%) of 90 as white crystals. MP 152°-153° C. MS (EI) m/6361.9685 (10%, M+ =361.9669). 1H NMR (DMSO-d6): d 8.43 (d, 1, 7-H, J7-5 =2.0 Hz), 7.59 (d, 1, 4-H, J4-5 =8.5 Hz), 7.43 (dd, 1, 5-H), 5.88 (d, 1, 1'-H, J1'-2' =8.0 Hz), 5.49 (d, 1, 2'-OH, J2'-2'OH =6.5 Hz), 5.34 (t, 1, 5'-OH, J5'-5'OH =4.5 Hz), 5.27 (d, 1, 3'-OH, J3'-3'OH =4.5 Hz), 4.45 (m, 1, 2'-H, J2'-3' =5.5 Hz), 4.14, (m, 1, 3'-H, J3'-4' =2.0 Hz), 4.00 (m, 1, 4'-H, J4'-5' =J4'-5" =3.5 Hz), 3.70 (m, 2, 5'-H and 5"-H, J5'-5" =12.0 Hz). 13C NMR (DMSO-d6): d 140.70 (C2), 140.49 (C3a), 134.02 (C7a), 125.95 (C5), 120.46 (C4), 116.01 (C7), 115.87 (C6), 88.99 (C1'), 86.32 (C4'), 71.40 (C2'), 69.79 (C3'), 61.15 (C5').
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]3[O:35][CH2:34][CH2:33][O:32][C:29]=3[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]5[O:35][CH2:34][CH2:33][O:32][C:29]=5[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Reactant: Clc1ncnc2cc3c(cc12)OCCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4cc5c(cc34)OCCO5)c2)no1
Temperature: 70 °C

Procedure:
According to the procedure described in Example 13B Step 1, a mixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (0.138 g, 0.5 mmol), 4-chloro-7,8-dihydro-[1,4]dioxino[2,3-g]quinazoline from the previous step (0.111 g, 0.5 mmol), and Cs2CO3 (0.326 g, 1 mmol) in isopropanol (7 mL) was heated at 70° C. for 13 hours, to afford 1-(5-tert-butylisoxazol-3-yl)-3-[3-(7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-yloxy]phenyl)urea as a solid. 1H NMR (300 MHz, CDCl3) δ 9.3 (br, 1H), 9.10 (s, 1H), 8.59 (s, 1H), 7.72 (s, 1H), 7.60 (m, 1H), 7.42 (s, 1H), 7.31 (m, 2H), 6.95 (d, 1H), 6.02 (s, 1H), 4.41 (m 4H), 1.30 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][CH2:26][S:27][C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][CH2:26][S:27][C:28]4[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: Cn1ccnc1SCCCl
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCSc1nccn1C
Temperature: 90 °C
Yield: 18.1 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 0.9 mmol), (prepared as described for the starting material in Example 24), 2-(2-chloroethylthio)-1-methylimidazole hydrochloride (203 mg, 0.95 mmol) and potassium carbonate (303 mg 2.2 mmol) in NMP (20 ml) was heated at 90° C. for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (100/0 increasing to 90/10) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1-methylimidazol-2-ylthio)ethoxy)quinazoline (75 mg, 17%) as a solid. 1H NMR Spectrum: (DMSOd6) 3.46(s, 3H); 3.93(s, 3H); 4.39-4.44(m, 4H); 7.13(dd, 2H); 7.23(s, 1H); 7.31(dd, 1H); 7.49-7.60(m, 2H); 7.79(s, 1H); 8.37(s, 1H); 9.51(s, 1H) MS-ESI: 460 [MH]+
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Na+].[H-].[Na+].F[C:19]1[CH:26]=[C:25]([O:27][CH2:28][C:29]2[CH:33]=[CH:32][S:31][CH:30]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]>O1CCCC1.Cl.C(OC(C)C)(C)C>[C:21]([C:20]1[CH:23]=[CH:24][C:25]([O:27][CH2:28][C:29]2[CH:33]=[CH:32][S:31][CH:30]=2)=[CH:26][C:19]=1[O:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])#[N:22]
Reactant: N#Cc1ccc(OCc2ccsc2)cc1F
Reactant: Cc1ccccc1C(O)CCC(=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: Cc1ccccc1C(CCC(=O)O)Oc1cc(OCc2ccsc2)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of sodium 4-hydroxy-4-(2-methyl-phenyl)butanoate, thought to be the (R)-enantiomer, (3 g) and sodium hydride (1.5 g; 60% w/v dispersion in mineral oil; 37.5 mmol) in tetrahydrofuran (50 mL) is stirred at ambient temperature for 1 hour under an atmosphere of argon, and is then warmed to 55° C. It is then treated with 2-fluoro-4-(3-thienylmethoxy)benzonitrile (3 g), in one portion, and stirring is continued at 55° C. for 15 hours. The mixture is then cooled, diluted with hydrochloric acid (200 mL; 1 N) and extracted with ethyl acetate (4×100 mL). The combined extracts are dried over magnesium sulphate and concentrated in vacuo, to give an oily residue. This residue is boiled in isopropyl ether, and the resulting mixture is filtered while hot, and then allowed to cool. The yellow solid which separates is collected and recrystallized from a mixture of ethyl acetate and hexane, to give 4-[2-cyano-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid, thought to be the (R)-enantiomer, (1.5 g) in the form of a white fluffy solid, m.p. 145° C. Chiral HPLC assay showed a 98% enantiomeric excess. [Elemental analysis:- C,67.82;H,5.18; N,3.24%; Calculated:- C,67.80;H,5.19;N,3.44%].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[OH:9].Cl.[C:11](OC(=O)C)(=[O:13])[CH3:12]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([C:11](=[O:13])[CH3:12])[CH:5]=[C:4]([Br:8])[C:3]=1[OH:9]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1c(Br)cccc1Br
Agent: Cl
Agent: O=S(=O)(O)O
Product: CC(=O)c1cc(Br)c(O)c(Br)c1
Temperature: 0 °C
Reaction time: 50 h

Procedure:
In 5 ml of acetic anhydride was dissolved 5.0 g of 2,6-dibromophenol and, one drop of conc. sulfuric acid was added to the solution. While sometimes manually shaking, the mixture was stirred. When generation of heat stopped, the solution was poured onto 50 ml of ice water and the precipitated crystals of acetic acid-2,6-dibromophenyl were taken by filtration. The crystals were washed with chilled water and dried under reduced pressure. Next, this acetic acid-2,6-dibromophenyl was dissolved in 20 ml of nitrobenzene and 4.0 g of powdery aluminum chloride was gradually added to the solution. The reaction was carried out at 60° to 70° C. for 50 hours to effect Fries rearrangement. After completion of the reaction, the reaction solution was poured onto 100 ml of cold dil. hydrochloric acid. After allowing to stand at 5° C. overnight, the precipitated crystals were taken out by filtration, washed with n-hexane and dried under reduced pressure to give 3.87 g of 2,6-dibromo-4-acetylphenol as crude crystals. The crystals were recrystallized from hot ethyl acetate to give 2.42 g of pure 2,6-dibromo-4-acetylphenol as light brown crystals. 2,6-Dibromo-4-acetylphenol (3,5-dibromo-4-hydroxyacetophenone): C8H6Br2O2
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([NH:14][NH2:15])=[O:13])=[CH:8][C:7]([O:16]CC1C=CC3C(=CC=CC=3)N=1)=[CH:6][CH:5]=2.[H-].[Na+].Br[CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>CS(C)=O.O>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][CH2:39][CH2:38][O:16][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:2]([CH3:1])=[C:10]2[CH2:11][C:12]([NH:14][NH2:15])=[O:13])[CH3:45]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1c(CC(=O)NN)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CCCOc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1ccccc1
Reaction time: 4 h
Yield: 68.5 %

Procedure:
A solution of 310 mg (1 mmol) of 5-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid hydrazide (Example 62) in 25 mL of DMSO was treated with 45 mg (1.1 mmol) of 60% NaH/mineral oil and after 0.25 hours, 0.16 mL (1.1 mmol) of ethyl 4-bromobutyrate was added. The mixture was stirred for 4 hours, diluted with water and extracted with EtOAc. The EtOAc solution was washed with NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica eluting with CH2Cl2 →4% MeOH/CH2C2, to give 290 mg (68% yield) of 4-[[3-(2-hydrazino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indole-5-yl]oxy]butanoic acid ethyl ester. This ester (0.685 mmol) and 2 mL of 2N NaOH in 25 mL of EtOH and 5 mL of THF was stirred for 22.5 hours. The mixture was diluted with water, made acidic to pH 6 with 1N HCl and extracted with EtOAc, the EtOAc dried (Na2SO4), and concentrated at reduced pressure. The residue was dissolved in EtOH and precipitated with ether to give 50 mg (47% yield) of 4-[[3-(2-hydrazino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indole-5-yl]oxy]butanoic acid, mp, 160° C. (decomposition).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12].[OH-].[Na+].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>O>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([NH:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:10][C:11]([OH:13])=[O:12])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: NCc1ccccc1CC(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCc2ccccc2CC(=O)O)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of o-aminomethylphenylacetic acid hydrochloride (7.50 g., 37 m.mol.) and sodium hydroxide (4.74 g., 118 m.mol.) in water (100 ml.) was added p-toluenesulfonyl chloride (7.64 g., 40 m.mol.) in portions at 60° C. The mixture was stirred for 1 hour at the same temperature and acidified with hydrochloric acid. The mixture was extracted with ethyl acetate (4×50 ml.). The combined extracts were washed with water, treated with a small amount of carbon and dried. The solvent was evaporated under reduced pressure and the residue crystallized from ethyl acetate to afford 2 as colorless prisms. Yield, 9.84 g. (84%). M.p. 155°-156° C.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:15]C)(=[O:14])[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].[CH3:17][C:18]([CH3:22])([CH3:21])[CH:19]=O>C(O)(C)(C)C>[CH3:13][O:12][C:10](=[O:11])[C:9](=[CH:17][C:18]([CH3:22])([CH3:21])[CH3:19])[CH2:8][C:7]([OH:15])=[O:14]
Reactant: CC(C)(C)C=O
Reactant: COC(=O)CCC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)C(=CC(C)(C)C)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
To a solution of 11.2 g (0.1 mol) potassium tert-butoxide in 100 ml tert-butanol was added a mixture of 14.6 g (0.1 mol) dimethyl succinate and 8.6 g (0.1 mol) trirnethylacetaldehyde over a period of 30 min. The mixture was allowed to stir at room temperature for one hour and heated to 50° C. for an additional hour. The solvent was removed under reduced pressure, the residue was dissolved in 100 ml water and transferred into a separation funnel. The solution was extracted twice with 50 ml ethyl acetate to remove neutral impurities, acidified with 6M HCl and extracted again twice with 20 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure, to give 14.9 g (75%) of a light yellow creamy solid. 1H-NMR:>95% E-isomer.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]2[CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18][N:13]2[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1.CC(C)([O-])C.[K+]>CO>[OH:9][C@H:10]1[C@@H:14]2[CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18][N:13]2[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN2CC[C@@H](OC(=O)c3ccccc3)[C@@H]2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN2CC[C@@H](O)[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 100E (8 g, 0.023 mol) in methanol (25 mL) was added potassium t-butoxide (14.5 g, 0.129 mol), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, the residue was diluted with 5% citric acid in water (100 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The combined organic layers were discarded. The aqueous layer was basified using K2CO3 to pH 8-9 and extracted with ethyl acetate (50 mL×2). The combined organic layers were dried over Na2SO4 and concentrated to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.48 (s, 9H), 1.56-1.69 (m, 1H), 1.86-1.97 (m, 1H), 2.10-2.35 (m, 3H), 2.35-2.48 (m, 1H), 2.52-2.72 (m, 1H), 2.78-2.97 (m, 2H), 3.03 (dt, 1H, J=17.1, 2.4 Hz), 3.92-4.15 (m, 2H), 4.32 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)[CH:10]=2)=[CH:6][N:5]=[C:4]([N+:21]([O-])=O)[CH:3]=1>CO.C1COCC1.[Pd]>[CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)[CH:10]=2)=[CH:6][N:5]=[C:4]([NH2:21])[CH:3]=1
Reactant: Cc1cn(-c2cc(Oc3cnc([N+](=O)[O-])cc3C)ccn2)cn1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cn(-c2cc(Oc3cnc(N)cc3C)ccn2)cn1
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
A solution of 4-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)-2-nitropyridine (2.5 g, 8.03 mmol) in MeOH (40 mL) and THF (20 mL) was treated with 10% Pd/C (50% w/w water, 0.855 g, 0.8 mmol) and hydrogenated (50 psi) for 24 h. The solids were removed via filtration through diatomaceous earth, washed with MeOH and the filtrate concentrated to dryness. The residue was stirred with 60% EtOAc/Hex for 15 min. The suspension was collected by filtration, washed with 60% EtOAc/Hex, and dried in vacuo to afford 4-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-amine (1.75 g, 77%). 1H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J=1.3 Hz, 1H), 8.27 (d, J=5.8 Hz, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 7.30 (d, J=2.2 Hz, 1H), 6.62 (dd, J=5.8, 2.2 Hz, 1H), 6.39 (s, 1H), 5.94 (s, 2H), 2.13 (s, 3H), 1.96 (s, 3H); MS (ESI) m/z: 282.2 (M+H+).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].C([O-])(=O)C.[Na+].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)([O-:16])=[O:15]>O.C(O)C>[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]2[NH:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][S:5]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)[C@@H]1CSC(c2ccc([N+](=O)[O-])cc2)N1
Temperature: 0 °C
Yield: 87 %

Procedure:
3 g (17.08 mmoles) of L-Cysteine hydrochloride and 2.18 g (22.2 mmoles) of sodium acetate are dissolved in 75 ml of water. The solution is agitated vigorously during the addition, by portions, of 3.10 g (20.5 mmoles) of 4-nitrobenzaldehyde in solution in 80 ml of 95% ethanol. A white precipitate rapidly appears in this pale yellow solution which forms abundantly. Agitation is maintained for one hour, the reaction mixture is then cooled down to 0° C. and filtered. The precipitate is successively rinsed with 200 ml of water, 100 ml of cold ethanol and 100 ml of ethyl ether. After drying, a white powder is obtained with a yield of 87%. Melting point: 120-121° C.