Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][NH:4]1)[CH3:2].CCN(C(C)C)C(C)C.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[C:21]([NH:26][CH3:27])[N:20]=1>CC#N>[Cl:18][C:19]1[CH:24]=[C:23]([N:4]2[CH2:5][CH2:6][O:7][CH2:8][C@H:3]2[CH2:1][CH3:2])[N:22]=[C:21]([NH:26][CH3:27])[N:20]=1
Reactant: CC[C@@H]1COCCN1
Reactant: CNc1nc(Cl)cc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC[C@@H]1COCCN1c1cc(Cl)nc(NC)n1
Temperature: 130 °C
Yield: 15.9 %

Procedure:
(3R)-3-Ethylmorpholine (5 g, 43.4 mmol) was taken up in CH3CN (100 mL) and Hunig's base (15.2 mL, 87 mmol), followed by the addition of 4,6-dichloro-N-methyl-2-pyrimidinamine (6.96 g, 39.1 mmol), and the reaction was heated to 130° C. overnight in a sealed tube. The reaction mixture was concentrated and then purified via flash chromatography (0-15% EtOAc/CHCl3, 400 g). Fractions were combined and concentrated to afford the title compound (1.6 g) as a colorless oil. LC-MS (ES) m/z=257 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.CC[N:17](C(C)C)[CH:18]([CH3:20])[CH3:19].C(N)(C)C>>[CH:18]([NH:17][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Product: CCOC(=O)c1cnc(SC)nc1NC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.4 %

Procedure:
Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (900 g, 3.87 mol) ethanol (12 L), DIEA (876 mL, 5.05 mol), and isopropylamine (379 mL, 4.45 mol) were combined and mixed at ambient temperature for 4 h. An additional amount of isopropylamine (50 mL, 0.59 mol) was added and the mixture was stirred overnight at ambient temperature. The reaction was concentrated under reduced pressure and the crude product was diluted with water (2 L). The aqueous layer was extracted with chloroform (2×3 L). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford ethyl 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylate (1042 g, 4.08 mol, >100% yield, contaminated with trace DIEA) as a pale brown oil that was used without further purification. MS (ESI) m/z 256.4 [M+1]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][C:28]([C:30]([O:32][CH2:33][CH2:34][CH3:35])=[O:31])=[N:27][C:26]=2[C:36]=1[OH:37].[I-].[K+]>CC(C)=O.CN(C)C=O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][C:28]([C:30]([O:32][CH2:33][CH2:34][CH3:35])=[O:31])=[N:27][C:26]=2[C:36]=1[O:37][CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: CCCOC(=O)c1nc2c(O)c(Cl)ccc2o1
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1nc2c(OCc3ccc(OCc4ccc5ccccc5n4)cc3)c(Cl)ccc2o1

Procedure:
0.78 g of 2-(4-chloromethylphenoxy)methylquinoline, 6.84 g of n-propyl 5-chloro-4-hydroxybenzoxazole-2carboxylate and a catalytic amount of potassium iodide are combined in 50 ml of acetone and 2 ml of dimethylformamide, and refluxed for 19 hours. The crude solid obtained on cooling is purified by flash chromatography to give n-propyl 5-chloro-4-(4-(quinolin-2-ylmethyloxy)benzyloxy)benzoxazole-2-carboxylate.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:51]([NH2:62])[C:52]1[CH:61]=[CH:60][C:57]([O:58][CH3:59])=[C:54]([O:55][CH3:56])[CH:53]=1>CN(C=O)C>[CH3:56][O:55][C:54]1[CH:53]=[C:52]([CH:61]=[CH:60][C:57]=1[O:58][CH3:59])[CH2:51][NH:62][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[NH:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C(O)c1cc(I)ccc1NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2cc(I)ccc2NC2CCOCC2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A mixture of 14.22 g of 5-iodo-2-(tetrahydro-2H-pyran-4-ylamino)benzoic acid, 18.4 g of HBTU, 21.28 g of DIEA and 9.18 g of veratrylamine in 200 ml of DMF is stirred overnight at room temperature. The reaction medium is evaporated under reduced pressure. The residue is taken up in 3000 mL of EtOAc. The solution is washed with aqueous 0.5N HCl solution, with saturated aqueous NaHCO3 solution, and then with saturated aqueous NaCl solution. The organic phase is dried over MgSO4, filtered and evaporated under reduced pressure to give 18 g of the expected product.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([O:15]C(=O)C)=[CH:7][C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:3])[CH3:2].[OH-].[K+].O.Cl>CO>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:9][C:8]([OH:15])=[CH:7][C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)Oc1c(C(C)(C)C)cc(O)cc1C(C)(C)C
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
The 1,4-diacetoxy-2,6-di-tert-butylbenzene obtained in Example 11 was dissolved in 60 mL of methanol and the solution was cooled to 20° C.; after adding 3.30 g (50.1 mmol) of potassium hydroxide, the mixture was stirred for 1.5 hours. The mixture was cooled to 10˜15° C. and then 30 mL of water and 12.5 mL of 6 N hydrochloric acid were gradually added. The solution was cooled to 5° C. and stirred for 0.5 hours. The crystal was centrifuged, washed with 10 mL of a methanol/water mixed solvent (methanol/water=1/1) and dried with a through-flow dryer (parallel flow) overnight at 50° C. to give 10.97 g of 4-acetoxy-3,5-di-tert-butylphenol (91.4% in yield from the 2,6-di-tert-butyl-1,4-benzoquinone of Example 10).
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[O:10]1[CH2:13][C:12](=[O:14])[CH2:11]1>>[Cl:9][C:3]1[C:2]([C:12]2([OH:14])[CH2:13][O:10][CH2:11]2)=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: O=C1COC1
Reactant: Cc1ccc(Br)c(Cl)n1
Product: Cc1ccc(C2(O)COC2)c(Cl)n1
Yield: 70.8 %

Procedure:
In analogy to the procedure described in Example 130 a), 3-bromo-2-chloro-6-methylpyridine (CAN 185017-72-5, 5 g, 24.2 mmol) was reacted with oxetan-3-one (CAN 6704-31-0, 1.75 g, 1.42 mL, 24.2 mmol) to give the title compound (3.42 g, 71%) as off-white solid, MS (ESI): m/e=200.5 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[CH:9]=[C:8](/[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)\[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCC/C(=C\C=C\C(=O)O)c1cccc(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC/C(=C\C=C\C(=O)Oc1ccc([N+](=O)[O-])cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.6 %

Procedure:
As in Example 115, (E,E)-5-(3-fluorophenyl)-2,4-decadienoic acid (3.55 g) and 4-nitrophenol (2.33 g) in 20 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (2.81 g) and the mixture was stirred at room temperature for 3 days. After the usual work up, crystallization of the crude ester from hexane gave 3.51 g of (E,E)-5-(3-fluorophenyl)-2,4-decadienoic acid 4-nitrophenyl ester, mp 46°-47° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]#[C:13][CH:14]([CH:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24]C)=[O:23])[CH2:18][CH2:17]1)[OH:15].CO.[OH-].[Na+].Cl>O1CCCC1>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]#[C:13][CH:14]([CH:16]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1)[OH:15]
Reactant: COC(=O)C1CCC(C(O)C#Cc2c(C)nc3ncnn3c2N)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2ncnn2c(N)c1C#CC(O)C1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
To a solution of Example 65C (26.5 mg, 0.077 mmol) in tetrahydrofuran (0.5 mL)/methanol (0.5 mL) was added 2N NaOH (77 μL, 0.154 mmol). The reaction mixture was stirred at room temperature overnight, and neutralized with 2N HCl (0.154 mmol). It was purified by reverse phase HPLC C-18 column, eluting with a 5-100% CH3CN gradient in 10 mM ammonium acetate(aq.)) to provide the title compound as a white solid (10 mg, 40% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.31 (s, 2H), 5.31 (s, 1H), 4.37 (d, J=5.43 Hz, 1H), 2.49 (s, 3H), 2.48-2.50 (m, 1H), 1.26-2.13 (m, 9H). MS (ESI) m/z 330 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[N+:11]([O-:12])=[N:10][C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:8][C:7]=2[CH:23]=1)[CH3:2].CO.CC[O:28]C(C)=O>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[N+:11]([O-:12])=[N:10][C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[N+:8]([O-:28])[C:7]=2[CH:23]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)nc(NCCCN1CCOCC1)n[n+]2[O-]
Reactant: CCOC(C)=O
Solvent: CO
Product: CCc1ccc2c(c1)[n+]([O-])c(NCCCN1CCOCC1)n[n+]2[O-]

Procedure:
Oxidation of 1-oxide 24 (829 mg, 2.6 mmol) with CF3CO3H (ca. 26.1 mmol) gave (i) starting material 24 (270 mg, 32%) and (ii) 1,4-dioxide 25 (206 mg, 24%) as a red solid, mp (MeOH/EtOAc) 142-144° C.; 1H NMR δ 8.55 (br s, 1 H, NH), 8.22 (d, J=9.0 Hz, 1 H, H-8), 8.10 (d, J=1.7 Hz, 1 H, H-5), 7.31 (dd, J=9.0, 1.7 Hz, 1 H, H-7), 3.82-3.87 (m, 4 H, 2×CH2O), 3.66-3.72 (m, 2 H, CH2N), 2.86 (q, J=7.6 Hz, 2 H, CH2), 2.58 (br dd, J=6.2, 6.0 Hz, 2 H, CH2N), 2.49-2.55 (m, 4 H, 2×CH2N), 1.85-1.92 (m, 2 H, CH2), 1.35 (t, J=7.6 Hz, 3 H, CH3); 13C NMR δ 153.9, 150.0, 138.5, 128.8, 128.2, 121.5, 114.9, 66.9 (2), 57.8, 53.9 (2), 41.7, 29.5, 24.4, 14.5. Anal. Calcd for C15H23N5O3: C, 57.6; H, 7.0; N, 21.0. Found: C, 57.6; H, 6.9; N, 20.9%
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[CH2:8]P(=O)(OC)OC)([O-:5])=[O:4].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.O>O1CCCC1>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[CH:8][C:7]1[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=1[N+:3]([O-:5])=[O:4]
Reactant: COP(=O)(Cc1ccccc1[N+](=O)[O-])OC
Reactant: O=Cc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccccc1C=Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 68.4 %

Procedure:
1.63 g of 60 wt % sodium hydride were added to 20 ml of tetrahydrofuran under stirring at room temperature, followed by cooling thereof to 0° C. and drop-wise addition thereto of a solution of 8 g of dimethyl 2-nitrobenzylphosphonate in 20 ml of tetrahydrofuran. After completion of the drop-wise addition, the reaction mixture was stirred at 0° C. for 30 minutes, followed by drop-wise addition thereto of 6.2 g of 2-chlorobenzaldehyde. After completion of the drop-wise addition, the resulting mixture was gradually heated up to room temperature, at which stirring was then continued for 17 hours. The reaction mixture was poured into water, subjected to extraction with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified twice by silica gel column chromatography (first developing solvent:methylene chloride:hexane=7:3, and second developing solvent:methylene chloride:hexane=3:1) to obtain 5.8 g of 2-chloro-2'-nitrostilbene.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH:17][NH2:18])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](OC(OCC)OCC)C>>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:17][N:18]=[CH:19][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNc1nnc(-c2ccccc2)c2ccccc12
Reactant: CCOC(OCC)OCC
Product: c1ccc(-c2nn3cnnc3c3ccccc23)cc1

Procedure:
A mixture of 4-phenyl-1-hydrazinophthalazine (30 g) and triethylorthoformate (200 ml) is refluxed for 3 hours, then the excess of the orthoformate is evaporated off and the residue is crystallized from ethanol yielding 26 g of the compound of the title. M.p. 198°-99° C.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.Cl[CH:15]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH:15]([S:3][C:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:23]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: ClC(Cn1ccnc1)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
192 mg of a 55% w/w suspension of sodium hydride in mineral oil were added to 4 ml of dry dimethylformamide containing 740 mg of methyl 4-mercaptobenzoate, whilst ice-cooling, and the resulting mixture was stirred at room temperature for 30 minutes. 830 mg of 1-[2-chloro-2-(3-pyridyl)ethyl]imidazole in 4 ml of dry dimethylformamide were added to the reaction mixture, and the resulting mixture was heated at 60°-70° C. for 5 hours. At the end of this time the reaction mixture was treated and purified by the same method as described in Example 1, to give 615 mg of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.O.ClCCl.Br[CH2:14][C:15](OCC)=[O:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:14][C:15](=[O:16])[N:8]=2)[CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(Br)cn1
Solvent: ClCCl
Solvent: O
Product: O=C1CN2C=C(Br)C=CC2=N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3.0 g of 5-bromopyridin-2-ylamine in 5.8 ml of ethyl 2-bromoacetate are placed in a round-bottomed flask and stirred at ambient temperature for 48 h. A precipitate forms, and is recovered by filtration, washed with diethyl ether and oven-dried under reduced pressure. The solid is then taken up in 50 ml of ethanol, and 2.18 g of sodium hydrogencarbonate are added thereto. The reaction mixture is heated at the reflux of the solvent for 5 h, cooled to ambient temperature, and then concentrated under reduced pressure. The residue obtained is taken up between water and dichloromethane and the organic phase is separated, dried and concentrated under reduced pressure. 1.46 g of compound, used as it is in the subsequent stages, are obtained.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C@@H:42]([OH:44])[CH3:43])[C@@H:10]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=1[F:41])[CH2:11][CH2:12][CH2:13][C@H:14]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:15]([O:17]CC1C=CC=CC=1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.O>Cl>[CH2:1]([O:8][C@@H:9]([C@@H:42]([OH:44])[CH3:43])[C@@H:10]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=1[F:41])[CH2:11][CH2:12][CH2:13][C@H:14]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[C:15]([OH:17])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](O)[C@H](OCc1ccccc1)[C@H](CCC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1)Cc1ccc(F)cc1F
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](O)[C@H](OCc1ccccc1)[C@H](CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)Cc1ccc(F)cc1F
Temperature: 25 °C

Procedure:
A 250 mL round bottom flask was charged with (2S,6R,7R,8S)-benzyl 7-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-6-(2,4-difluorobenzyl)-8-hydroxynonanoate (2.10 g, 3.43 mmol), THF (24 mL) and H2O (6 mL). LiO.H2O (153 mg, 3.64 mmol) was added, and the resulting mixture was allowed to stir at room temperature. After stirring for 2.5 h, the reaction mixture was heated to 50° C. and was stirred for an additional 17 h at that temperature. Additional portions of water (3 mL) and LiO.H2O (152 mg, 3.62 mmol) were added and the reaction was stirred at room temperature for 4.5 h. The reaction mixture was diluted with 1.0 M aqueous HCl (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (NaCl, brine; 50 mL), dried over anhydrous MgSO4, filtered, concentrated, and dried under high vacuum to obtain the title compound as a colorless oil contaminated with 10% BnOH (1.55 g, 87%): 1H NMR (400 MHz, CDCl3) δ 7.39-7.26 (m, 5H), 7.15-7.05 (m, 1H), 6.82-6.69 (m, 2H), 5.03 (d, J=8.3 Hz, 1H), 4.64 (d, J=11.5 Hz, 1H), 4.55 (d, J=11.6 Hz, 1H), 4.20 (q, J=7.4 Hz, 1H), 4.03 (p, J=6.2 Hz, 1H), 3.37-3.24 (m, 1H), 2.99 (dd, J=14.0, 4.6 Hz, 1H), 2.51 (dd, J=14.0, 9.9 Hz, 1H), 2.01-1.90 (m, 1H), 1.75-1.60 (m, 1H), 1.56-1.15 (m, 17H); 13C NMR (101 MHz, CDCl3) δ 176.51, 161.26 (dd, J=246.7, 12.7 Hz), 161.07 (dd, J=247.1, 12.0 Hz), 155.60, 138.35, 131.98 (dd, J=9.3, 6.9 Hz), 128.37, 127.77, 126.97, 124.00 (dd, J=15.8, 3.8 Hz), 110.83 (dd, J=20.8, 3.6 Hz), 104.38 102.95 (m), 83.36, 80.11, 73.75, 68.11, 53.17, 39.82, 32.49, 29.71, 28.85, 28.25, 22.55, 19.22; 19F NMR (376 MHz, CDCl3) δ −113.45 (d, J=7.0 Hz), −113.63 (d, J=6.7 Hz); ESIMS: m/z 522 ([M+H]+).
Reaction SMILES: C(OC(N[C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][CH:13]=2)=O)(C)(C)C.N([O-])=O.[Na+].C(Cl)Cl.[BrH:28]>O>[Br:28][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][CH:13]=2
Reactant: Br
Reactant: COc1cccc2ncc(NC(=O)OC(C)(C)C)cc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cccc2ncc(Br)cc12
Reaction time: 1 h

Procedure:
To a solution of 3-(tert-butoxycarbonylamino)-5-methoxyquinoline (2.74 g, 10 mmol) in aqueous 48% HBr (40 mL), NaNO2 (2.1 g, 30 mmol) in water (20 mL) is added at 0° C. The reaction mixture is stirred 1 hour. The reaction mixture is extrated with CH2Cl2 (3×30 mL). After drying over MgSO4, dichloromethane is evaporated affording the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:27])[C:13](=[N:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH3:14])=[CH:6][CH:5]=1.CI.[C:30](OCC)(=O)C>CN(C)C=O>[Cl:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:27])[C:13](=[N:15][N:16]([CH3:30])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=2)[CH3:14])=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: CC(=NNc1ccc(C(F)(F)F)cc1)C(=O)NCc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=NN(C)c1ccc(C(F)(F)F)cc1)C(=O)NCc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
60% sodium hydride (0.12 g, 3.0 mmol) was added to a solution of N-(6-chloro-3-pyridylmethyl)-2-(4-trifluoromethylphenyl hydrazono) propionic acid amide (Compound No. 63) (1.0 g, 2.7 mmol) in N,N-dimethylformamide (5 ml) and stirred for 10 minutes. Methyl iodide (0.40 g, 2.8 mmol) was gradually added thereto, and stirred at room temperature for 2 hours. To the reaction mixture, ice water and ethyl acetate were added, and subjected to extraction. The organic phase was washed with a saturated brine, then dried on anhydrous sodium sulfate and concentrated. The resulting residue was purified with a silica gel chromatography to obtain N-(6-chloro-3-pyridylmethyl)-2-[N-methyl-N-(4-trifluoromethylphenyl) hydrazono]propionic acid amide (Compound No. 110) (0.80 g, 2.1 mmol, 77%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([N:18]2[CH2:22][CH2:21][C@@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19]2)[C:15]2[C:10](=[CH:11][C:12]([CH3:31])=[CH:13][CH:14]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C([O-])(O)=O.[Na+].C(Cl)Cl>[NH2:23][C@@H:20]1[CH2:21][CH2:22][N:18]([C:16]2[C:15]3[C:10](=[CH:11][C:12]([CH3:31])=[CH:13][CH:14]=3)[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:17]=2)[CH2:19]1
Reactant: Cc1ccc2c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To tert-butyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (907.2 mg, 2.16 mmol) was added 4 mL of 1:1 TFA:CH2Cl2. The mixture was stirred at room temperature for 5 hours. The reaction was diluted with a solution of saturated aqueous NaHCO3 and CH2Cl2. The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure to give 2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol. To this free amine (640 mg, 2 mmol) was added 8 ml of CH2Cl2 and triethylamine (335 μL, 2.4 mmol). After cooling the mixture to 0° C., (S)-tetrahydrofuran-3-yl chloroformate (271 mg, 1.8 mmol) was added, and the reaction was allowed to stir for 30 minutes. Purification on silica gel using 30-100% ethyl acetate/hexanes gave (S)-tetrahydrofuran-3-yl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate. 1H NMR (400 MHz, CDCl3) δ 14.8 (bs, 1H), 8.34 (d, J=6.4 Hz, 1H), 7.83 (d, J=4.0 Hz, 1H), 7.48 (bs, 1H), 7.27 (m, 1H), 7.08 (d, J=8.1 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.82 (t, J=7.5 Hz, 1H), 5.21 (s, 1H), 5.06 (s, 1H), 4.37 (s, 1H), 4.15 (m, 1H), 4.02 (s, 1H), 3.97 (d, J=5.6 Hz, 1H), 3.87-3.77 (m, 5H), 2.42 (s, 3H), 2.24 (t, J=6.0 Hz, 1H), 2.15-2.06 (m, 1H), 1.98 (q, J=9.3 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[CH:17]=[O:18])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O.CO>CC(C)=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]([OH:26])=[O:18])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)=O
Reactant: O=Cc1cccc(CNC(=O)OCc2ccc([N+](=O)[O-])cc2)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(NCc1cccc(C(=O)O)c1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
To 3-(p-nitrobenzyloxycarbonyl)aminomethylbenzaldehyde (1.5 g) in acetone (30 ml) was added Jones' reagent with ice-cooling, and the mixture was stirred for 2 hours. After addition of methanol (1.5 ml), the mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and evaporated to give 3-(p-nitrobenzyloxycarbonyl)aminomethylbenzoic acid
Reaction SMILES: O[CH:2]([C:15]1[CH:19]=[CH:18][O:17][C:16]=1[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1(P([N:41]=[N+:42]=[N-:43])(C2C=CC=CC=2)=O)C=CC=CC=1>>[N:41]([CH:2]([C:15]1[CH:19]=[CH:18][O:17][C:16]=1[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N+:42]=[N-:43]
Reactant: CCCCCCCCCCCCC(O)c1ccoc1[Si](CC)(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: CCCCCCCCCCCCC(N=[N+]=[N-])c1ccoc1[Si](CC)(CC)CC

Procedure:
Reacting 3-(I-hydroxytridecyl)-2-triethylsilylfuran with diphenylphosphoryl azide and diethyl azidocarboxylate gives 3-(1-azidotridecyl)-2-triethylsilylfuran. Reducing this intermediate with lithium aluminum hydride, followed by acetylation with acetic anhydide gives 3-(1-acetamido tridecyl)-2-triethylsilylfuran. Singlet oxygen oxidation of this amide, followed by reduction with sodium borohydride gives 3-(1-acetamidotridecyl)-2(5H)-furanone.
Reaction SMILES: [ClH:1].Cl.[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]C)=[O:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl>>[ClH:1].[ClH:1].[N:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)CN1CCN(c2ccncc2)CC1
Agent: Cl
Product: O=C(O)CN1CCN(c2ccncc2)CC1

Procedure:
Prepared from methyl [4-(4-pyridyl)-piperazin-1-yl]acetate dihydrochloride and semiconcentrated hydrochloric acid analogously to Example IIb.