Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[ClH:6].Cl.[NH:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[NH2:9]>Cl>[ClH:6].[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([NH:8]/[N:9]=[CH:2]/[C:1]([OH:5])=[O:4])[CH:11]=1
Reactant: O=CC(=O)O
Reactant: NNc1cccnc1
Agent: Cl
Product: O=C(O)/C=N/Nc1cccnc1
Temperature: 22 °C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
Glyoxylic acid (50% in water) (54.5 mL, 494 mmol) and 1 N hydrochloric acid (˜100 mL) were added to 3-hydrazinopyridine dihydrochloride (60.0 g, 330 mmol) and the reaction mixture was stirred at room temperature (about 22° C.) for 2 hours, at which point solid had started to precipitate. The reaction was stirred for 24 hours, at which point LC/MS indicated that it was complete. The mixture was transferred to a flask using acetonitrile (1 L). The mixture was azeotroped three times from acetonitrile (1 L). The resulting suspension was filtered to afford a green solid which was washed with acetonitrile and vacuum dried at 40° C. to afford the desired product (68.3 g, 98%): mp 173-174° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.55 (d, J=1.2 Hz, 1H), 8.61 (d, J=2.5 Hz, 1H), 8.40 (dt, J=5.4, 0.9 Hz, 1H), 8.14 (ddd. J=8.7, 2.6, 1.2 Hz, 1H), 7.91 (dd, J=8.7, 5.4 Hz, 1H), 7.43 (d, J=1.0 Hz, 1H); 13C NMR (101 MHz, DMSO) δ 164.29, 143.15, 133.15, 131.85, 127.97, 127.61, 126.30; ESIMS m/z 166 ([M+H]+).
Reaction SMILES: C(OC([N:8]([CH2:20][CH:21]1[O:25][N:24]=[C:23]([Br:26])[CH2:22]1)[C:9](=[O:19])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH2:11])=O)(C)(C)C.[C:27]([C:31]([OH:33])=[O:32])([F:30])([F:29])[F:28].C(Cl)Cl>>[F:28][C:27]([F:30])([F:29])[C:31]([OH:33])=[O:32].[NH2:11][C@H:10]([C:9]([NH:8][CH2:20][CH:21]1[O:25][N:24]=[C:23]([Br:26])[CH2:22]1)=[O:19])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N(CC1CC(Br)=NO1)C(=O)[C@@H](N)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C(=O)NCC1CC(Br)=NO1

Procedure:
5-(N-tert-butoxycarbonyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole, 7 gm, was taken in 100 ml of 20% CF3CO2H/CH2Cl2 at 0° C. for 24 hrs. Concentration gave an oily foamy substance. 1H NMR [80 MHz, CDCl3 (H2O)]; delta 2.8-3.5 (m, 4H, CH2), 4.2-4.9 (m, 2H, CH), 4.7 (s, HOD), 7.3 ppm (s, 5H, pH).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].N1C=CN=C1.[Si:13](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[Si:13]([O:1][C@@H:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1OCC[C@H]1O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](O[C@@H]1CCOC1=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 93 %

Procedure:
To a stirred solution of (R)-3-hydroxydihydrofuran-2(3H)-one (41.0 g, 401 mmol), imidazole (61.4 g, 920 mmol), and CH2Cl2 (175 mL) at 0° C., under N2, was added t-butyldiphenylsilyl chloride (129 mL, 138 g, 497 mmol) dropwise over 30 minutes. The mixture was stirred at room temperature for 19 hours. The mixture was partitioned between CH2Cl2 (700 mL) and H2O (100 mL). The organic portion was concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (50% EtOAc in hexane) to afford (R)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (127 g, 373 mmol, 93% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 7.84-7.82 (m, 2H), 7.73-7.71 (m, 2H), 7.50-7.40 (m, 6H), 4.41-4.31 (m, 2H), 4.06-4.00 (m, 1H), 2.29-2.19 (m, 2H), 1.10 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=3[F:26])[C:13]([NH2:17])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28]1>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=3[F:26])[C:13]([NH:17][S:30]([CH:27]3[CH2:29][CH2:28]3)(=[O:32])=[O:31])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ncc2c(Nc3ccc(I)cc3F)c(N)ccc21
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)n1ncc2c(Nc3ccc(I)cc3F)c(NS(=O)(=O)C3CC3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a solution of 5-amino-4-(2-fluoro-4-iodo-phenylamino)-indazole-1-carboxylic acid tert-butyl ester (200 mg, 0.43 mmol) in pyridine (2 mL) was added cyclopropyl sulfonyl chloride (0.218 mL, 2.14 mmol) and the mixture stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, washed with brine, then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 10-35% ethyl acetate in cyclohexane) to yield the title compound (206 mg, 84%). LCMS (Method B): RT=4.17 min, [MH]+=573.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[O:12].[C-:16]#[N:17].[Na+]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:12])[C:16]#[N:17]
Reactant: O=CCCCCCOc1cccc(F)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC(O)CCCCCOc1cccc(F)c1
Reaction time: 8 h

Procedure:
A solution of 1 M NaOH (17.8 mL) was added to a refluxing mixture of 3-fluorophenol (2 g, 17.8 mmol) and 5-bromo-1-hexanol (3.23 g, 17.8 mmol) in water (20 mL). After 3 h, the resulting mixture was cooled to room temperature and diluted with diethyl ether. The layers were separated, the organic layer was washed sequentially with 1N NaOH and water, then dried (Na2SO4) and concentrated to yield 6-(3-fluorophenoxy)hexan-1-ol as an oil. A solution of 6-(3-fluorophenoxy)hexan-1-ol (2.9 g, 13.67 mmol) was added dropwise to a mixture of 1,1,1-tris(acetyloxy)1,1-dihydro-1,2-benziodoxol-3-(1H)-one (7.0 g, 16.4 mmol) with ice-bath cooling. The resulting solution was stirred for 2.5 h at room temperature, then poured into a solution of sodium thiosulfate in saturated aqueous sodium bicarbonate. After 0.5 h, the layers were separated and the aqueous layer was extracted with CH2Cl2. The organic phase was dried (Na2SO4) filtered and concentrated to yield 6-(3-fluorophenoxy)hexanal. A solution of 6-(3-fluorophenoxy)hexanal (2.9 g, 13.8 mmol) in ethyl acetate (20 mL) and water (20 mL) containing NaCN (2 g, 41.4 mmol) was stirred vigorously overnight. After 20 h, the phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with water, dried (Na2SO4) and concentrated to yield 7-(3-fluorophenoxy)-2-hydroxyheptanenitrile, which was dissolved in methanol (40 mL) and cooled to −78° C. The solution was saturated with HCl (g) and stored at −10° C. for 18 h. The resulting mixture was concentrated, diluted with ethyl acetate (40 mL) and water (40 mL), then stirred overnight. The layers were separated and the organic phase was dried (Na2SO4) and concentrated to yield the corresponding methyl ester which was dissolved in 9:1 dioxane:water (20 mL) and treated with a solution of LiOH (1.4 g, 58 mmol). The resulting solution was stirred for 4 h then acidified to pH˜3 with 1N HCl. The mixture was then extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with water, dried (Na2SO4) and concentrated to yield 7-(3-fluorophenoxy)-2-hydroxyheptanoic acid as a white solid. (MS m/z=257 MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([O:22][CH3:23])[C:16]([O:24][CH3:25])=[CH:15]2.[N:26]([O-])=O.[Na+].O.C(Cl)(Cl)Cl>C(O)(=O)C.Cl.C(OCC)(=O)C>[CH3:23][O:22][C:17]1[C:16]([O:24][CH3:25])=[CH:15][C:14]2[C:19]([CH:18]=1)=[CH:20][CH:21]=[C:12]1[C:13]=2[N:26]=[N:1][C:2]2[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]1=2
Reactant: O=N[O-]
Reactant: COc1cc(N)c(-c2ccc3cc(OC)c(OC)cc3c2)cc1OC
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2ccc3c4cc(OC)c(OC)cc4nnc3c2cc1OC
Reaction time: 8 h
Yield: 43.2 %

Procedure:
6-(2-Amino-4,5-dimethoxyphenyl)-2,3-dimethoxynaphthalene (18) (11 mg, 0.033 mmol) in acetic acid (0.6 mL) and concentrated hydrochloric acid (0.06 mL) was cooled to 0° C. and diazotised with a solution of sodium nitrite (0.026 g in 0.5 mL water). The diazonium solution was allowed to rise slowly to room temperature and left overnight. Water (30 mL) was added to the red solution with some precipitate. The resulting mixture was extracted with ethyl acetate, washed with diluted sodium hydroxide solution, then with water, dried (anhydrous Na2SO4) and rotaevaporated to give the crude product. Chromatography on silica gel using 40:60 chloroform:ethyl acetate afforded the title compound (5 mg) in 44% yield; 1H NMR (CDCl3) d 4.09(3H, s), 4.18(6H, s), 4.23(3H, s), 7.31(1H, s), 7.74(1H, s), 8.00(1H, s), 8.01(1H, d, J=8.5), 8.20(1H, d, J=8.9), 9.15(1H, s); 13C NMR d 56.5, 56.9, 99.9, 104.5, 107.9, 109.5, 116.9, 118.5, 118.9, 127.0, 128.4, 131.6, 141.8, 144.6, 151.1, 151.2, 152.0, 153.9.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[N:14]=[N:15]NN=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](Cl)(=[O:28])[C:19]1[CH:27]=[CH:26][CH:25]=[C:21]([C:22](Cl)=[O:23])[CH:20]=1.O.[OH-].[Na+]>N1C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[O:28][C:18]([C:19]4[CH:27]=[CH:26][CH:25]=[C:21]([C:22]5[O:23][C:13]([C:9]6[N:8]=[C:7]([C:1]7[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=7)[CH:12]=[CH:11][CH:10]=6)=[N:14][N:15]=5)[CH:20]=4)=[N:15][N:14]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cccc(-c3nn[nH]n3)n2)cc1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: c1ccc(-c2cccc(-c3nnc(-c4cccc(-c5nnc(-c6cccc(-c7ccccc7)n6)o5)c4)o3)n2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
5.0 g of 2-phenyl-6-(2H-tetrazol-5-yl)pyridine was dissolved in 125 ml of dehydrated pyridine. Temperature was elevated to 120° C., and 75 ml was dehydrated by azeotropy. After cooling to 50° C., 2.28 g of isophthaloyl dichloride was added. Temperature was elevated to 100° C., and stirring was conducted for 1 hour. After cooling to room temperature, the reaction solution was poured into 300 ml water, and after adjusting pH to 12 with 20% sodium hydroxide aqueous solution, stirring was conducted for 1 hour. A precipitated brown solid was taken out by suction filtration, and washed with water. The solid obtained was vacuum dried at 70° C. for 20 hours, and purified with column chromatography (carrier: NH silica gel, eluting solution: chloroform) to obtain 4.27 g (yield 73%) of PhpyOXDm. The product was identified with NMR analysis. The result of NMR analysis (CDCl3) was as follows. 9.07 ppm (1H), 8.46 ppm (2H), 8.28 ppm (2H), 8.17 ppm (4H), 7.92-8.15 ppm (4H), 7.78 ppm (1H), 7.46-7.55 ppm (6H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:26])[CH2:21][S:22][CH2:23][CH2:24][OH:25])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:26])[CH2:21][S:22][CH2:23][CH2:24][O:25][C:29](=[O:30])[C:28]([CH3:33])([CH3:32])[CH3:27])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(CSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: CC(C)(C)C(=O)OCCSCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 63 %

Procedure:
Following a procedure similar to that described in Example 7, but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) and 2,2-dimethylpropionyl chloride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a 63% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C@H:9]([C:21](O)=[O:22])[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[CH2:14]([O:13][C:11]([NH:10][C@@H:9]([CH2:21][OH:22])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 0.1 %

Procedure:
To a solution of N-(benzyloxy)carbonyl-D-glutamic acid 5-tert-butyl ester (35 g, 102 mol) in THF (500 ml) was added at −30° C. triethylamine (17 ml, 122 mmol), followed by addition of ethyl chloroformate (12 ml, 122 mmol) and the mixture was stirred at the same temperature. Then to the mixture was added at −30° C. a solution of sodium borohydride (11.6 g, 306 mmol) in water (51 ml) and the mixture was stirred for 30 minutes. Then the solution was raised to 0° C. and stirred for 30 minutes. To the reaction mixture was added water and the solution was extracted three times with ethyl acetate and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the organic solvent was removed under reduced pressure. The residue was purified by silica gel (210 g) chromatography (Hexane/ethyl acetate: 3/2→1/1) to give tert-butyl (4R)-4-{[(benzyloxy)carbonyl]amino}-5-hydroxypentanoate (16.5 g, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].Br[C:15]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([C:15]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])=[O:7]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: COc1ccc(Br)c(C(=O)O)c1
Product: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)c(C(=O)O)c1

Procedure:
This compound is obtained according to the procedure described in 1.1. by reacting 3,4-dimethoxybenzoyl chloride and 2-bromo-5-methoxybenzoic acid after halogen-lithium exchange. It is used in crude form in the following reaction.
Reaction SMILES: [CH2:1]([C:3]1[S:17][C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14]CC)=[O:13])[C:10]([OH:11])=[C:5]2[CH:4]=1)[CH3:2].[CH2:18](I)[CH3:19]>>[CH2:1]([C:3]1[S:17][C:6]2[N:7]([CH2:18][CH3:19])[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2sc(CC)cc2c1O
Product: CCc1cc2c(=O)c(C(=O)O)cn(CC)c2s1

Procedure:
In a manner similar to that described in Example 13, ethyl 2-ethyl-4-hydroxythieno[2,3-b]pyridine-5-carboxylate is reacted with ethyl iodide to obtain 2,7-diethyl-4,7-dihydro-4-oxothieno-[2,3-b]pyridine-5-carboxylic acid. Recrystallization from methanol gives colorless prisms melting at 197°-198°C.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[OH-:13].[Na+]>O1CCOCC1>[I:11][C:10]1[C:3]2[C:2](=[O:13])[NH:7][CH:6]=[N:5][C:4]=2[N:8]([CH3:12])[CH:9]=1
Reactant: Cn1cc(I)c2c(Cl)ncnc21
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cc(I)c2c(=O)[nH]cnc21
Temperature: 100 °C

Procedure:
To a stirred solution of 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (19.0 g, 64.9 mmol) in 1,4-dioxane (481 ml) was added 2M sodium hydroxide (aq) solution (479 ml, 959 mmol). The solution was heated to 100° C. and heated for 4 h. The solution was cooled. The organic solvent was removed in vacuo. The aqueous was acidified to ca pH 4 using concentrated hydrochloric acid. The resulting suspension was filtered and dried under vacuum and flowing nitrogen to afford the title compound which was used without further purification (15.7 g, 88%). LCMS RT=0.65 min, M+H+=276.0. 1H NMR (500 MHz, d6-DMSO) 11.93 (br s, 1H), 7.90 (s, 1H), 3.68 (s, 3H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C@@H:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH2:29][C:30]([O:32]C(C)(C)C)=[O:31].O.[OH-].[Li+]>C1COCC1.CO.O>[CH3:1][C@@H:2]1[CH2:7][N:6]([C@@H:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[CH:10]=[CH:11][C:12]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[CH2:5][CH2:4][N:3]1[CH2:29][C:30]([OH:32])=[O:31]
Reactant: C[C@@H]1CN([C@@H](c2ccccc2)c2ccc(C#Cc3ccccc3)cc2)CCN1CC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@@H]1CN([C@@H](c2ccccc2)c2ccc(C#Cc3ccccc3)cc2)CCN1CC(=O)O
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a solution of tert-butyl 2-((R)-2-methyl-4-((S)-phenyl(4-(2-phenylethynyl)phenyl)-methyl)piperazin-1-yl)acetate (320 mg, 0.666 mmol) in THF/MeOH/H2O=5:5:1 (5.5 mL) was added lithium hydroxide monohydrate (279 mg, 6.658 mmol) and the resulting solution was stirred overnight. The solvent was evaporated to dryness under high vacuum and the residue was diluted with water, adjusted pH=5, extracted with DCM, dried over Na2SO4, filtered and evaporated to dryness. The residue was loaded onto flash column (SiO2, DCM to DCM/MeOH=100:5 to 100:10 to 100:15 to 100:20) to give 2-((R)-2-methyl-4-((S)-phenyl(4-(2-phenylethynyl)phenyl)methyl)piperazin-1-yl)acetic acid (240 mg) as a white solid.
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][N:18]=2)[C:12]([O:14]C)=[O:13])[O:6][N:5]=1>C(O)C>[CH3:3][C:4]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][N:18]=2)[C:12]([OH:14])=[O:13])[O:6][N:5]=1
Reactant: COC(=O)c1ccnc(-c2nc(C)no2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: Cc1noc(-c2cc(C(=O)O)ccn2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
A mixture of lithium hydroxide (15 g, 0.35 mol), ethanol (500 mL) and methyl 2-(3-methyl-1,2,4-oxadiazol-5-yl)isonicotinate (52 g, 0.23 mol) were stirred at room temperature for 5 hours, then mixture was concentrated in vacuo. Water was added then extracted with ethyl acetate. The water layer was brought to pH 1.5 with aqueous 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was concentrated in vacuo to afford the title compound as a white solid (42 g). 1H NMR (300 MHz, DMSO-d6) δ ppm 14.08 (br s, 1H) 9.00-8.98 (m, 1H) 8.50 (s, 1H) 8.09-8.07 (m, 1H), 2.46 (s, 3H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)O1.Br[C:21]1[S:22][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:24][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:26]1([C:23]2[S:22][C:21]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][C:13](=[O:18])[CH2:12]4)=[N:25][N:24]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CC(=O)N3)OC1(C)C
Reactant: Brc1nnc(-c2ccccc2)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1Cc2cc(-c3nnc(-c4ccccc4)s3)ccc2N1
Temperature: 90 °C
Reaction time: 4 h
Yield: 25.1 %

Procedure:
To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (98 mg, 0.38 mmol) in dioxane (0.76 ml) was added PdCl2(dppf) CH2Cl2 (28 mg, 0.039 mmol), 2-bromo-5-phenyl-1,3,4-thiadiazole (138 mg, 0.57 mmol) and 2 M potassium carbonate (aq, 568 μL). The mixture was stirred at 90° C. for 4 hour. The residue was extracted with EtOAc, and the organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (n-hexane/EtOAc) to give 5-(5-phenyl-1,3,4-thiadiazol-2-yl)indolin-2-one (28 mg) as brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([CH2:29][CH2:30][CH2:31][OH:32])[S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[OH-:33].[K+].Cl>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:21]1([C:13]2[C:12]([N:24]([CH2:29][CH2:30][CH2:31][OH:32])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:11][C:10]3[C:15](=[C:16]([C:17]([NH:19][CH3:20])=[O:18])[N:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:33])=[CH:3][CH:4]=4)[N:9]=3)[CH:14]=2)[CH2:23][CH2:22]1
Reactant: [OH-]
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(O)cc1
Temperature: 100 °C
Yield: 109 %

Procedure:
2-(4-Bromophenyl)-5-cyclopropyl-6-[(3-hydroxypropyl)(methylsulfonyl)amino]-N-methyl-2H-indazole-3-carboxamide (i) (16 mg, 0.031 mmol) in 1,4-dioxane (0.5 mL) had a solution of potassium hydroxide (9 mg, 0.016 mmol) in water (0.5 mL) added and was degassed. tert-Butyl-XPhos (4 mg, 0.009 mmol) and Pd2(dba)3 (4 mg, 0.004 mmol) were added and the reaction was heated at 100° C. for 4 h. The mixture was cooled to RT, 1 M hydrochloric acid (0.5 mL) was added and this was then concentrated to dryness. The residue was purified by reverse phase flash column chromatography eluting with ACN/water (5-100%) to afford 5-cyclopropyl-2-(4-hydroxyphenyl)-6-[(3-hydroxypropyl)(methylsulfonyl)amino]-N-methyl-2H-indazole-3-carboxamide (ii) as a white solid (8 mg, 57%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:9]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CCCCCN1c1ccc(F)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)C1CCCCN(c2ccc(F)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.3 %

Procedure:
A solution of 1-(4-fluorophenyl)azepan-2-one (1.1 g, 5.3 mmol) was dissolved in THF (5 mL) and was added into LDA (11 mmol) at −78° C. and stirred for 5 minutes. Benzyl chloroformate (1.6 ml, 11 mmol) was added at −78° C. and the reaction warmed to ambient temperature. The solution was poured into ice and diluted with EtOAc (100 mL). The organic layer washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by column chromatography (50% EtOAc in hexane) to afford the product (1 g, 55% yield) as brown oil.
Reaction SMILES: [CH:1]1([C:7]2[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=2[CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:19].[CH3:20][C:21](=[CH2:23])[CH3:22].OS(O)(=O)=O.Cl>O1CCOCC1>[CH:1]1([C:7]2[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=2[CH2:9][C@@H:10]([C:12]([O:14][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:13])[NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:19]
Reactant: N[C@@H](Cc1ccccc1C1CCCCC1)C(=O)O
Reactant: C=C(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1C1CCCCC1
Yield: 80 %

Procedure:
According to example 54, 0.73 g of 2-cyclohexyl-L-phenylalanine·HCl was treated with 25 mL of isobutylene in 25 mL of 1,4-dioxane in the presence of 0.4 mL of conc. H2SO4. Work-up followed by acidification of the free amine with ethereal HCl afforded 0.70 g (80%) of tert-butyl 2-cyclohexyl-L-phenylalaninate·HCl as a yellow foam.