Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[H-].[Na+].I[CH3:17]>C1COCC1>[CH3:17][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:11][C:2]([CH3:13])([CH3:1])[C:3]1=[O:12]
Reactant: CC1(C)Nc2ccccc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)C(C)(C)Nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
In a 200-mL r.b. flask, a solution of 3,4-dihydro-3,3-dimethylquinoxalin-2(1H)-one (1.00 g, 5.66 mmol) in dry THF was treated with NaH (0.28 g, 7.09 mmol, 1.25 equiv). The reaction mixture was stirred at room temperature for 30 minutes before iodomethane (0.39 mL, 6.24 mmol, 1.1 equiv) was added to the reaction flask. The reaction was then stirred at room temperature overnight then partitioned between EtOAc (100 mL) and H2O (20 mL). The aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were then washed with brine (20 mL), dried (MgSO4), filtered, and concentrated to a thick oil. Purification by flash chromatography (25% EtOAc/hexane) afforded 830 mg (78%) of 3,4-dihydro-1,3,3-trimethylquinoxalin-2(1H)-one as a white solid. Data for 3,4-dihydro-1,3,3-trimethylquinoxalin-2(1H)-one: 1H NMR (400 MHz, CDCl3) δ 6.90 (m, 3H), 6.67 (d, J=7.7, 1H), 3.69 (bs, 1H), 3.36 (s, 3H), 1.37 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:9][C:8]2([CH2:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:20]=[CH:21]/[C:22](O)=[O:23])[CH:15]=3)[O:10]2)[CH2:7]1)=[O:5])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:39][O:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:9][C:8]2([CH2:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:20]=[CH:21]/[C:22]([NH:39][O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)=[O:23])[CH:15]=3)[O:10]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: NOC1CCCCO1
Reactant: CCOC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Yield: 60.2 %

Procedure:
(E)-3-[1′-Ethyloxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (200 mg, 0.54 mmol) in DCM (5 ml) was treated with TEA (0.12 ml, 0.90 mmol) and then with EDC (172 mg, 0.900 mmol), HOBt (121 mg, 0.896 mmol) and NH2OTHP (84 mg, 0.72 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′-ethyloxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (140 mg) as a light yellow solid.
Reaction SMILES: C(C1C(O[SiH](C)C)=CC(CBr)=CC=1[N:17]1[N:21]=[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]2=[N:18]1)(C)(C)C.CN1C(C)(C)CC(O)CC1(C)C.[H-].[Na+]>CN(C)C=O>[NH:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[N:17]1
Reactant: C[SiH](C)Oc1cc(CBr)cc(-n2nc3ccccc3n2)c1C(C)(C)C
Agent: CN1C(C)(C)CC(O)CC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2[nH]nnc2c1
Temperature: 6 °C

Procedure:
This compound was synthesized strictly under dry and inert reaction conditions. The compound 2-(2′-tert-butyl-di-metylsilyloxy-5′-bromomethylphenyl)benzotriazole (2.1 gms, 0.00501 M) was taken in one 25 mL capacity RB and dissolved in 8 mL dry dimethylformamide (DMF) under Argon atmosphere with stirring. In another two-necked RB, 1,2,2,6,6-pentarnethyl-4-piperidinol (1.0356 gm, 0.00601 M) and sodium hydride (0.3 gms, 0.01252 M) were taken and dissolved in 6 mL dry DMF with stirring under Argon atmosphere. This reaction mixture was agitated for almost 60 min and then cooled to 4-8° C. To this reaction mixture the contents of the first RB was added gradually over a period of 30-60 min. This reaction mixture was further agitated for 2-4 hrs followed by refluxing the same for a period of 2-4 hrs. The contents of the RB were cooled to room temperature and further agitated for 4-6 hrs at room temperature. The solvent in the RB was evaporated under reduced pressure and the solid mass in the RB was dissolved in 15 mL water and repeatedly extracted with dichloromethane (4×10 mL). Dichloromethane was then evaporated under vacuum at 38° C. over a rotavapor to give pale yellow colored crystalline product 2-[2′-tert-butyldimetylsilyloxy-5′-methyleneoxy((1″, 2″, 2″, 6″, 6″-pentamethyl-4″-piperidinyl) phenyl)benzotriazole. The TLC showed very little amount of unreacted starting material. The crude yield was 2.22 gms (87%). The product was purified by recrystalization technique using an appropriate organic solvent to get (83%) yield of pure product.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]#[C:4][C:5]([F:8])([F:7])[F:6].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[N:20][OH:21])[CH3:19])=[CH:14][CH:13]=1.CO.CC(C)([O-])C.[K+]>O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[N:20][OH:21])[CH3:19])=[C:16]([C:4]([C:5]([F:8])([F:7])[F:6])=[CH:3][C:2]([F:10])([F:9])[F:1])[CH:17]=1
Reactant: CC(=NO)c1ccc(Cl)cc1
Reactant: FC(F)(F)C#CC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=NO)c1ccc(Cl)cc1C(=CC(F)(F)F)C(F)(F)F

Procedure:
Hexafluoro-2-butyne is slowly bubbled through a 55°-60° C. solution of p-chloroacetophenone oxime (17.0 g, 0.10 mol), methanol (80 mL) and potassium tert-butoxide (1.12 g, 0.01 mol) over a 5 hour period. The solvent is removed in vacuo to obtain a liquid which is poured into water and extracted with ether. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give an oil. The oil is chromatographed using silica gel and eluted with 1% ethylacetate in methylene chloride to 5% ethyl acetate in methylene chloride to give p-chloro-0-[1,2-bis(trifluoromethyl)vinyl]acetophenone oxime, vinyl-(Z) as a yellow liquid (21.5 g, 65%) and 2-(p-chlorophenyl)-4,5-trans-bis(trifluoromethyl)-1-pyrrolin-5-ol as a white solid (2.35 g, mp 152.5°-153° C., 7%).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]([NH2:14])=O)[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+].P(Cl)(Cl)([Cl:25])=O>>[Cl:25][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]#[N:14])[CH:7]=1
Reactant: Cn1nc(C(N)=O)cc1CCCCO
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: Cn1nc(C#N)cc1CCCCCl
Temperature: 90 °C

Procedure:
A modification of the method described in Part E of Examples 1-4 was used to treat 5-(4-hydroxybutyl)-1-methyl-1H-pyrazole-3-carboxamide (42.9 g, 218 mmol) with phosphorous oxychloride (130 mL). The reaction was heated for two hours at 90° C. before cooling to 0° C. and pouring into ice water. The mixture was adjusted to pH 12 with the addition of 2 N aqueous sodium carbonate and 50% aqueous sodium hydroxide. The mixture was extracted with chloroform. The combined extracts were passed through a layer of silica gel (eluting first with chloroform and then with ethyl acetate to provide 23.0 g of 5-(4-chlorobutyl)-1-methyl-1H-pyrazole-3-carbonitrile as a dark oil that was used in the next step without further purification.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=CC=CC=1.[Mg].[CH:17]([N:30]1[CH2:33][CH2:32][CH:31]1[C:34]#[N:35])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[CH:17]([N:30]1[CH2:33][CH2:32][CH:31]1[C:34](=[NH:35])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#CC1CCN1C(c1ccccc1)c1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Solvent: Brc1ccccc1
Product: N=C(c1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Suspend phenylmagnesium bromide in ether by adding under gentle reflux a solution of 189.2 g of bromobenzene in 500 ml of ether to a stirred suspension of 24.4 g of magnesium turnings in 1000 ml. of dry ether. Upon completion of the addition, reflux for another 30 minutes, then allow the mixture to cool for 15 minutes at room temperature. Add portionwise, over 3 to 4 minutes, 119.6 g of 1-benzhydryl-2-cyanoazetidine. Stir the mixture for 18 hours at room temperature, cool to 0° C and quench by the sequential addition of 750 ml. of water, 250 ml. of ether and 400 ml. of methylene chloride. Filter the mixture. Remove the aqueous layer of the filtrate. Wash the organic phase with water and dry over anhydrous sodium sulfate. Remove the solvent in vacuo. Triturate the solid residue with 500 ml of isopropyl ether and filter to obtain the analytically pure title product, m.p. 123.5°-126.5° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:21][C:22]1[C:26]([C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[CH:25][NH:24][C:23]=1[CH:36]=O>C(O)C.N1CCCCC1>[CH3:21][C:22]1[C:26]([C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)=[O:28])=[CH:25][NH:24][C:23]=1[CH:36]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=2)[NH:13][C:12]1=[O:18]
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3cccc(C(F)(F)F)c3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.9 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (46.9 mg, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8](N)=[CH:7]2.N([O-])=O.[Na+].C(=O)(O)[O-].[Na+].[ClH:22]>>[Cl:22][C:8]1[N:9]=[CH:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1]
Reactant: Cl
Reactant: Nc1cc2cccc(Cl)c2cn1
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Product: Clc1cc2cccc(Cl)c2cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
8-Chloroisoquinolin-3-amine (724 mg, 4.05 mmol) was suspended in 10 M HCl and cooled to 0° C. Sodium nitrite (336 mg, 4.86 mmol) was added in portions over 10 minutes. The reaction mixture was stirred for 2 hours, slowly warming to room temperature over an additional 1 hour. After 3 hours, the mixture was poured cautiously into saturated sodium bicarbonate solution, and extracted into ethyl acetate. The organic extract was washed with brine, dried (Na2SO4) and concentrated. Flash chromatography on silica, eluting with dichloromethane, gave the title compound as a white solid (362 mg, 1.83 mmol, 45%). 1H NMR (d6-DMSO, 400 MHz) δ 9.40 (br t, 1H, J=0.8 Hz), 8.20 (br s, 1H), 8.00-7.98 (m, 1H), 7.88-7.81 (m, 2H). LCMS (3) Rt=2.49 min; m/z (ESI+) 198 (MH+).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH:10]([CH3:12])[CH3:11])[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[N:3]1.N[C@@H]1C(=O)N(C)C2C=CC=CC=2C(C2C=CC=CC=2)=N1.[Cl:44][C:45]1[CH:46]=[C:47]([CH:56]=[CH:57][C:58]=1[Cl:59])[CH2:48][C@H:49]([CH2:53][CH:54]=[CH2:55])[C:50](O)=[O:51]>>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:4]1[C:5]2[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=2[N:7]([CH:10]([CH3:12])[CH3:11])[C:8](=[O:9])[CH:2]([NH:1][C:50](=[O:51])[C@H:49]([CH2:48][C:47]2[CH:56]=[CH:57][C:58]([Cl:59])=[C:45]([Cl:44])[CH:46]=2)[CH2:53][CH:54]=[CH2:55])[N:3]=1
Reactant: C=CC[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: CC(C)N1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Agent: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Product: C=CC[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)NC1N=C(c2ccccc2F)c2ccccc2N(C(C)C)C1=O

Procedure:
Prepared from 3-amino-5-(2-fluoro-phenyl)-1-isopropyl-2-oxo-1,3-dihydro-2H-benzo[e][1,4]diazepine [available in an analogous fashion to (S)-3amino-1-methyl-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (i.e. J. Org. Chem. 1987, 52, 3232)] and (2S)-2-(3,4dichlorobenzyl)-pent-4-enoic acid using the procedure of Step 1E shown in Scheme 1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([OH:22])([C:18]([F:21])([F:20])[F:19])[CH2:6][C:7]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])=[CH2:8])[CH3:2].II.I[CH2:27]I>CCOCC.CCOC(C)=O.[Cu].[Zn]>[CH2:1]([O:3][C:4](=[O:23])[C:5]([CH2:6][C:7]1([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[CH2:27][CH2:8]1)([OH:22])[C:18]([F:19])([F:20])[F:21])[CH3:2]
Reactant: C=C(CC(O)(C(=O)OCC)C(F)(F)F)c1cc(F)ccc1OC
Reactant: ICI
Agent: [Cu]
Agent: II
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(O)(CC1(c2cc(F)ccc2OC)CC1)C(F)(F)F
Reaction time: 18 h
Yield: 76.6 %

Procedure:
To a solution of 620 mg (1.84 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-2-trifluoromethylpent-4-enoic acid ethyl ester, 475 mg zinc copper couple, and an iodine crystal in anhydrous ether in a sealed tube warmed to 55° C. was added dropwise 500 μL (6.20 mmol) of diiodomethane. The reaction was monitored by TLC in dichloromethane-hexanes (1:1) or ether-hexanes (2:8). After 18 hours, the mixture was cooled, diluted with EtOAc and filtered through diatomaceous earth. The filtrate was washed with three 10 mL portions of 1 N aqueous HCl, 10 mL of brine, three 10 mL portions of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated. The crude material was adsorbed onto silica gel and chromatographed on silica gel using ether-hexanes (0:100, then 1:99, then 2:98) to afford 494 mg (76%) of 3,3,3-trifluoro-2-[1-(5-fluoro-2-methoxyphenyl)cyclopropylmethyl]-2-hydroxypropionic acid ethyl ester.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][C:12]=2[F:21])=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.[CH3:22][O:23][C:24]([C:26]1[S:30][C:29]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=2[CH3:38])=[N:28][C:27]=1[CH3:39])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:22][O:23][C:24]([C:26]1[S:30][C:29]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:2][C:3]3[C:4]([C:11]4[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][C:12]=4[F:21])=[N:5][O:6][C:7]=3[CH:8]3[CH2:10][CH2:9]3)=[CH:33][C:32]=2[CH3:38])=[N:28][C:27]=1[CH3:39])=[O:25]
Reactant: COC(=O)c1sc(-c2ccc(O)cc2C)nc1C
Reactant: Fc1cccc(C(F)(F)F)c1-c1noc(C2CC2)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccc(OCc3c(-c4c(F)cccc4C(F)(F)F)noc3C3CC3)cc2C)nc1C
Reaction time: 60 h
Yield: 19.3 %

Procedure:
To a solution of 4-bromomethyl-5-cyclopropyl-3-(2-fluoro-6-trifluoromethyl-phenyl)-isoxazole (0.083 g, 0.256 mmol) and 2-(4-Hydroxy-2-methyl-phenyl)-4-methyl-thiazole-5-carboxylic acid methyl ester (0.067 g, 0.256 mmol) in 1 mL of DMF is added potassium carbonate (0.035 g, 0.256). The reaction is stirred for 60 hours. The reaction is partitioned between ethyl acetate and water. The layers are separated and the organic layer is washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue is chromatographed using a gradient of 5% ethyl acetate in hexanes to 40% ethyl acetate in hexanes to yield the title compound (0.027 g, 18%). ES/MS m/e 547.0 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[CH:6]=1)(=[NH:4])=[O:3].[OH-].[Na+].C(OCC)(=O)C>C1COCC1.Cl>[NH2:11][C:7]1[CH:6]=[C:5]([S:2]([CH3:1])(=[NH:4])=[O:3])[CH:10]=[CH:9][CH:8]=1
Reactant: CS(=N)(=O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=N)(=O)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 200 mg (1.00 mmol) of (RS)—S-methyl-S-(3-nitrophenyl)sulfoximide in 20 ml of THF is mixed at room temperature with 8 ml of an approximately 10% solution of Ti(III)Cl in 20-30% hydrochloric acid. After 3 hours, another 2 ml of the approximately 10% solution of Ti(III)Cl in 20-30% hydrochloric acid is added and stirred overnight at room temperature. The batch is made basic with 1N NaOH solution and mixed with ethyl acetate. It is filtered, and the filter cakes are washed with ethyl acetate/MeOH (3:2). The organic solvent is drawn off in a rotary evaporator, and the residue is extracted from ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The residue that is obtained is purified by chromatography (DCM/EtOH 95:5). 82 mg (0.48 mmol, corresponding to 48% of theory) of the product is obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].C1OCCOCCOCCOCCOCCOC1.[CH:37]([Mg]Br)([CH2:39][CH3:40])[CH3:38].O1CCCC1.S(=O)(=O)(O)O>>[CH3:38][CH:37]([CH2:39][CH3:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCC(C)[Mg]Br
Reactant: O=C(O)CCCCCCCCCCCCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CCC(C)CCCCCCCCCCCCCCC(=O)O
Reaction time: 1 h
Yield: 95 %

Procedure:
To a four-necked 50 mL of flask equipped with a refluxing condenser tube, a 10 mL of dropping funnel, a magnetic stirrer and a temperature sensor, 15-bromopentadecanoic acid of 1.01 g (3.14 mmol) and 18-crown-6 of 823.3 mg (1.0 eq) were added and dried under reduced pressure. Under argon atmosphere, copper bromide (I) of 13.3 mg (0.03 eq) and anhydrous tetrahydrofuran of 6 mL were added to dissolve the materials. At room temperature, sec-butyl magnesium bromide of 7.85 mL (2.5 eq, 1.0M tetrahydrofuran solution) was added dropwise thereto over thirty minutes. After stirring for one hour, 5 mL of 6N aqueous sulfuric acid solution was added and the extraction was carried out by using 10 mL of hexane. After washing twice with 10 mL ion exchange water, the mixture was dried over magnesium sulfate. After the filtration, the crude product (0.84 g) was obtained by concentration under reduced pressure.
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].N1C(Cl)=NC(Cl)=NC=1Cl.O>CN(C)C=O>[C:2]([C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4])#[N:1]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](C#N)NC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 58.8 %

Procedure:
To a stirred solution of tert-butyl [(1S)-2-amino-1-methyl-2-oxoethyl]carbamate (Step 1, 0.7 g, 0.004 mol) in N,N-dimethylformamide (5 mL) was added 343 mg of cyanuric chloride (0.00186 mol) at once. The reaction mixture was stirred for 4 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with EtOAc in hexane (30-50%) to yield the desired product (400 mg, 63%). 1H-NMR (300 MHz, DMSO-d6): 7.74 (d, J=7.0 Hz, 1H), 4.48 (m, 1H), 1.40 (s, 9H), 1.35 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=O.[CH2:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH2:7][C:17]2[CH:18]=[CH:19][C:14]([CH2:12][CH3:13])=[CH:15][CH:16]=2)[CH:10]=1
Reactant: CCc1ccccc1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Product: CCc1ccc(Cc2cc(Br)ccc2Cl)cc1

Procedure:
Synthesis was performed by a similar method as in Preparation Example 14 using 5-bromo-2-chlorobenzoic acid and ethylbenzene.
Reaction SMILES: [C:1]1([CH3:35])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH:28]4[O:32]N=[C:30]([O:33][CH3:34])[CH2:29]4)[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.B(O)(O)O.[OH2:40]>CO>[C:1]1([CH3:35])[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([OH:32])[CH2:29][C:30]([O:33][CH3:34])=[O:40])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:5][CH:6]=1
Reactant: O
Reactant: COC1=NOC(CCCCN2CCCc3nc(-c4ccc(C)cc4)c(-c4ccc(C)cc4)nc32)C1
Agent: OB(O)O
Solvent: CO
Product: COC(=O)CC(O)CCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C

Procedure:
A solution of 5-(4-(2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)butyl)-3-methoxy-4,5-dihydroisoxazole (step 2) (94 mg, 0.2 mmol) in MeOH (3 ml) and water (0.2 ml) was treated with boric acid (37.1 mg, 0.600 mmol) followed by Mo(CO)6 (37.0 mg, 0.140 mmol). The resulting mixture was heated at overnight. After cooling to RT, the mixture was concentrated under reduced pressure and diluted with DCM. The organic portion was washed with water and dried by passing through a phase separating column. The solvent was removed under reduced pressure and purification of the crude product by chromatography on silica eluting with 0-60% EtOAc in iso-hexane afforded the titled compound;
Reaction SMILES: C(O[CH:5](OC(C)C)[N:6]([CH3:8])[CH3:7])(C)C.[Br:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[C:17]([CH3:23])=[CH:16][C:15]=1[F:24]>CN(C=O)C>[Br:13][C:14]1[C:15]([F:24])=[CH:16][C:17]([CH:23]=[CH:5][N:6]([CH3:7])[CH3:8])=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1
Reactant: Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Reactant: CC(C)OC(OC(C)C)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Temperature: 125 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
A mixture of N,N-dimethylformamide diisopropyl acetal (1.32 mL, 6.31 mmol) and 1-bromo-2-fluoro-4-methyl-5-nitro-benzene (1.23 g, 5.26 mmol) in dry DMF (15.0 mL) was stirred at 125° C. for 3 h. The resulting mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was washed with hexane to give [2-(4-bromo-5-fluoro-2-nitro-phenyl)-vinyl]-dimethyl-amine as dark red solid (1.89 mg, 83%). 1H NMR (CDCl3, 400 MHz): 2.92 (s, 6H), 5.88 (d, J=12.3 Hz, 1H), 6.98 (d, J=13.2 Hz, 1H), 7.11 (d, J=10.8 Hz, 1H), 8.10 (d, J=6.9 Hz, 1H).
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([NH:2][OH:1])=[O:5])=[N:21][CH:22]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(OCc2ccccc2)cn1
Reactant: NO
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CCCCCCN(c1ccccn1)c1ccc(OCc2ccccc2)cn1)NO
Reaction time: 72 h
Yield: 74 %

Procedure:
HONH2 (50% aqueous, 0.5 mL) was added to III (26 mg, 0.06 mmol) in DMF (0.2 mL) and MeOH (0.5 mL) at rt. The reaction mixture was stirred for 72 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×10 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 to 100:8) to furnish IV as a colourless oil (18.66 mg, 74%).