Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[F:2][C:3]([F:8])([F:7])[C:4](O)=[O:5].C[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].[CH3:19]O>>[F:2][C:3]([F:8])([F:7])[C:4](=[O:5])[CH2:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[O:12]
Reactant: CCC(=O)c1ccccc1
Reactant: CO
Reactant: O=C(O)C(F)(F)F
Agent: [Na]
Product: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 95 %

Procedure:
Sodium metal (5.76 g, 0.25 mol) was dissolved in methanol (80 ml), then trifluoroacetic acid (22 ml, 0.168 mol) was added at room temperature, followed by dropwise addition of methyl-acetophenone (21.04 g, 0.165 mol). The obtained mixture was stirred at 80° C. for 10 h, the reaction mixture was concentrated in vacuo and the residue was dissolved in water (50 ml). The solution was acidified by addition of 1N hydrochloric acid (120 ml), extracted with ethyl acetate (2×80 ml), dried over MgSO4, filtered and concentrated in vacuo to yield 34.60 g (95%) of the title compound. The obtained crystalline product was used in the next step without further purification.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:19])[N:12]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH:13]=2)[CH2:4][CH2:3]1.[NH:20]1[CH2:23][CH:22]([NH:24][C:25]([CH2:27][NH:28][C:29](=[O:40])[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[O:26])[CH2:21]1>>[O:19]=[C:11]1[N:12]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH:13]=[C:8]([CH:5]2[CH2:6][CH2:7][CH:2]([N:20]3[CH2:23][CH:22]([NH:24][C:25]([CH2:27][NH:28][C:29](=[O:40])[C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=4)=[O:26])[CH2:21]3)[CH2:3][CH2:4]2)[CH:9]=[CH:10]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(c2ccc(=O)n(CC(F)(F)F)c2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc(=O)n(CC(F)(F)F)c3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 5-(4-oxo-cyclohexyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1([S:36]([N:39]2[CH2:43][CH2:42][CH2:41][CH:40]2[CH:44]=[CH2:45])(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(CC)CC.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:30]1([S:36]([N:39]2[CH2:43][CH2:42][CH2:41][CH:40]2/[CH:44]=[CH:45]/[C:13]2[CH:12]=[CH:11][C:10]([N:16]3[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]3)=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:14]=2)(=[O:38])=[O:37])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: C=CC1CCCN1S(=O)(=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C3CCCN3S(=O)(=O)c3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (100 mg, 0.183 mmol) in acetonitrile (2 mL) is added 1-benzenesulfonyl-2-vinylpyrrolidine (43 mg, 0.183 mmol), NEt3 (0.038 mL, 0.274 mmol), Pd(OAc)2 (2 mg, 0.034 mmol), and 2-(di-t-butylphosphino)biphenyl (4 mg) and the mixture stirred at 80° C. for 48 h. The reaction is cooled to RT and partitioned between 1N HCl and EtOAc. The organic phase is washed with brine and dried over magnesium sulfate. The solvent is removed under reduced pressure and the crude material purified by column chromatography using a gradient of 10-25% EtOAc/hexane to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]([CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:14]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCC>[Br:14][CH2:13][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([Cl:1])[C:11]=1[Cl:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(Cl)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(Cl)c1Cl
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of 40 g (0.183 mol) of methyl 2,3-dichloro-4-methylbenzoate, 34.17 g (0.192 mol) of N-bromosuccinimide, 0.4 g (0.0017 mol) of benzoylperoxide, and 640 mL of carbon tetrachloride was stirred at room temperature while being irradiated with a 150 watt flood lamp for 2.5 hours. Concentration of the filtered reaction mixture under vacuum gave 54 g of material which on trituration with pentane followed by storage of the slurry at 5° C. for 18 hours gave 34.6 g (63.5%) of product; mp 57°-61° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH:13]1([N:16]2[C:24]3[C:19](=[CH:20][C:21]([CH2:25][NH:26][S:27]([C:30]4[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=4)(=[O:29])=[O:28])=[CH:22][CH:23]=3)[CH:18]=[N:17]2)[CH2:15][CH2:14]1>>[Cl:8][C:7]1[C:2]([N:26]([CH2:25][C:21]2[CH:20]=[C:19]3[C:24](=[CH:23][CH:22]=2)[N:16]([CH:13]2[CH2:15][CH2:14]2)[N:17]=[CH:18]3)[S:27]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)(=[O:29])=[O:28])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3C3CC3)c2)cc1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3C3CC3)c2)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((1-cyclopropyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-5 of Example 28).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@H:3]1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9].C(N(CC)CC)C.Cl[C:23]1[N:28]=[C:27]([NH2:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=1>C(#N)C>[NH2:29][C:27]1[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=[C:23]([N:5]2[CH2:6][CH2:7][C@H:2]([CH3:1])[C@H:3]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[O:9])[CH2:4]2)[N:28]=1
Reactant: Nc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: C[C@H]1CCNC[C@H]1C(=O)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H]1CCN(c2ncc([N+](=O)[O-])c(N)n2)C[C@H]1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
To a solution of cis-(4-methylpiperidin-3-yl)(pyrrolidin-1-yl)methanone (1.7 g, 8.60 mmol) in acetonitrile (20 mL) was added triethylamine (3.65 mL, 26.02 mmol). The mixture was stirred for 10 min at room temperature. Then 2-chloro-5-nitropyrimidin-4-amine (1.19 g, 6.9 mmol) was added and the reaction mixture was stirred at 80° C. for 3 h. The mixture was cooled to room temperature and stirred for 1 h. Ice cold water was added and the mixture was extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via column chromatography (40-100% ethyl acetate in petroleum ether) to afford cis-(1-(4-amino-5-nitropyrimidin-2-yl)-4-methylpiperidin-3-yl)(pyrrolidin-1-yl)methanone (1.6 g). MS (ES+) (M+H) 335.3.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:19])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[Si](C(C)(C)C)(C)C)(=O)=O.C1C(=O)N([Br:42])C(=O)C1>C(Cl)Cl>[Br:42][CH2:17][C:16]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[N:15]=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([CH3:19])=[N:8]2)=[O:18]
Reactant: CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2cccc(C(=O)CBr)c2nc1NC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
To a stirred solution of 1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606a) (14.96 g, 58.1 mmol) and TEA (12.15 mL, 87 mmol) in DCM (100 mL) at 0° C. was added tert-butyldimethylsilyl trifluoromethanesulfonate (13.18 mL, 57.4 mmol) dropwise. After the addition, the reaction mixture was stirred at RT for 3 h. It was cooled with an ice bath and quenched with 50 mL of saturated NaHCO3. The layers were separated. The aq. layer was extracted with DCM (2×50 mL). The combined DCM extracts were dried over Na2SO4 and concentrated. The remaining light brown oil was dissolved in THF (100 mL) and H2O (10 mL), cooled with an ice bath, and treated with NBS (10.35 g, 58.1 mmol) in a single portion. The resulting mixture was stirred at 0° C. for 2 h, quenched with 50 mL of saturated NaHCO3, and extracted with EtOAc (3×100 mL). The organic extracts were combined, washed with 20 mL of brine, dried over MgSO4 and concentrated. The resulting yellow solid was treated with 100 mL of MeOH and stirred for 10 min. The yellow solid was filtered, rinsed with MeOH (2×5 mL), collected and dried in a vacuum oven at RT for 18 h to give 2-bromo-1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606) (15.5 g, 79% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.91 (1H, dd, J=8.0, 1.6 Hz), 7.75 (1H, dd, J=7.3, 1.5 Hz), 7.41 (1H, t, J=7.6 Hz), 6.18 (1H, s), 5.15 (2H, s), 2.58 (3H, s), 1.52 (9H, s). m/z (ESI, +ve) 336/338 (M+H)+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16]C=2N=N1.N1CCCCC1.C[N:35]([CH:37]=[O:38])C>O.ClCCl>[N:8]1([C:37]([NH2:35])=[O:38])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CN(C)C=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: O
Product: NC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80 %

Procedure:
The synthesis of compound 61 was carried out according to scheme 13 beginning with commercially available pyrazolo[1,5-a]pyridine-3-carboxylic acid and by following the procedure outlined in example 1, part C, step 2 and subsequent steps though step E, part 1. The thiazole 5-position was left unfunctionalized by omitting part D, step 3 to obtain with the carboxylic acid 57. To carboxylic acid 57 (725 mg, 2.96 mmol) in DMF (30 mL) was added BOP (392 mg, 8.87 mmol) and piperidine (2.93 mL, 29.6 mmol). The reaction was stirred at ambient temperature for 48 hrs after which time the reaction was diluted with water and dichloromethane. The organic was washed with water before concentration. The resultant residue was purified by column chromatography (silica gel, 0-60% ethyl acetate in hexanes, linear gradient) to yield the piperidine amide (739 mg, 2.366 mmol, 80% yield). The amide (420 mg, 1.34 mmol) was dissolved in dichloromethane (1.3 mL) was treated with potassium nitrate (136 mg, 1.344 mmol) and sulfuric acid (215 μL, 4.03 mmol). The reaction mixture was stirred at RT until complete, as judged by LCMS analysis. The reaction was quenched with 1N potassium hydroxide in methanol, then diluted with water, before extracting with dichloromethane. The organic layer was evaporated to dryness and taken up in methanol. The product was collected by filtration and was dried under reduced pressure to yield compound 58 (225 mg, 0.630 mmol, 46.8% yield).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].N[C@H:8]([C:19]([OH:21])=[O:20])CC1C2C(=CC=CC=2)NC=1.NCC(O)=O.N[C@H:28](C(O)=O)[CH:29]([CH3:31])[CH3:30].N[C@H](C(O)=O)[C@H](CC)C>>[NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH2:3][CH2:8][C:19](=[O:20])[O:21][C:29]([CH3:31])([CH3:30])[CH3:28]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: C[C@H](N)C(=O)O
Agent: CC[C@H](C)[C@H](N)C(=O)O
Agent: NCC(=O)O
Product: CC(C)(C)OC(=O)CC[C@H](N)C(=O)O

Procedure:
The inability to crystallize some of the above-mentioned derivatives led to the preparation of corresponding 3,4-dihydro-4-oxo-1,2,3-benzotriazine-3-yl (ODhbt) esters. The Ddz-Xxx-ODhbt esters of Ala, Pro, and Trp were easily prepared as crystalline solids, followed by Gly, Val, and Ile. In addition, the ODhbt esters of Ser and Thr were crystallized upon preparation, whereas Leu, Met, Phe, Cys(Stbu), Asp(tBu), and Glu(tBu) were obtained as foams. Ddz-Arg-(Pmc)Dhbt was isolated in about 92% purity including 5-6% of the γ-lactam impurity. Ddz-Arg(Pmc)Pfp was also isolated, but with somewhat less γ-lactam impurity. Examples of derivatives prepared are summarized in Table 1 and the examples.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:19]C(OCC)=O.[CH2:25]([NH2:28])[CH2:26][NH2:27]>C(Cl)(Cl)Cl>[ClH:19].[NH2:27][CH2:26][CH2:25][NH:28][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=1
Reactant: NCCN
Reactant: COc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)NCCN)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
To a suspension of 6.4 g (0.04 mol) of 4-methoxybenzoic acid in 60 ml of chloroform are added dropwise at 10°, 5.5 ml (0.04 mol) of triethylamine and then 3.8 ml (0.04 mol) of ethyl chloroformate. The solution obtained is then added dropwise at 5° to a solution of 10.7 ml (0.16 mol) of ethylenediamine in 100 ml of chloroform. After stirring at room temperature for 2 hours, the mixture is filtered. The filtrate is concentrated under reduced pressure and then excess ethylenediamine is removed in a high vacuum. The residue is acidified with dilute hydrochloric acid and extracted several times with ethyl acetate. The aqueous phase is made alkaline with 28% sodium hydroxide solution and extracted three times with chloroform. After drying and concentrating the chloroform extracts, the residue is converted into the hydrochloride. By recrystallization from ethanol/ether there are obtained 3.4 g of N-(2-aminoethyl)-4-anisamide hydrochloride (see Example 7 of German Offenlegungsschrift 2.616.486), m.p. 186°-189°. The free base melts at 37°-38°.
Reaction SMILES: [CH3:1][C:2]1[S:19][C:5]2[O:6][C:7]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=3[NH:9][C:10](=O)[C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:1][C:2]1[S:19][C:5]2[O:6][C:7]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=3[N:9]=[C:10]([N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(s1)Oc1ccc([N+](=O)[O-])cc1NC2=O
Reactant: CN1CCNCC1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2c(s1)Oc1ccc([N+](=O)[O-])cc1N=C2N1CCN(C)CC1

Procedure:
In the same manner as in Example 125 and using 2-methyl-7-nitrothieno[2,3-b][1,5]benzoxazepin-4(5H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 2-methyl-4-(4-methylpiperazin-1-yl)-7-nitrothieno[2,3-b][1,5]benzoxazepine is obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[NH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1>CCOCC>[Cl:5][CH2:4][CH2:3][CH2:2][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C1CCNC1
Reactant: ClCCCBr
Solvent: CCOCC
Product: ClCCCN1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To the solution of about 186 g (1.18 mol) of 1-bromo-3-chloropropane in about 200 ml of ether was added about 2 equivalent of pyrrolidine at about 0° C. After addition, the mixture was allowed to warm to room temperature and stirred overnight. The resulting white solid residue was removed and to the clear solution was added ice-cold 10% hydrochloric acid. The ether layer was discarded and the acid layer was basified with ice-cold 20% NaOH, extracted with ether and dried over Na2SO4. Ether was removed and the residue was distilled under vacuum (95° C./30 mmHg). About 91 g of product having formula (VIII) was obtained in a form of a pale yellow liquid. The yield was about 53%.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]\[CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1.[C:13]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[H-].[Na+]>O1CCCC1.CN(C)C=O>[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[O:6][CH2:5]/[CH:4]=[CH:3]\[CH2:2][CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClC/C=C\COC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C/C=C\COC1CCCCO1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
2-[4-Chloro-(Z)-2-butenyloxy]tetrahydro-2H-pyran (100 g) was dissolved in 2000 ml of dry tetrahydrofuran/600 ml of dry N,N-dimethylformamide. To the solution was added 100 g of diethyl malonate, and then 25 g of 60% sodium hydride with stirring under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=9:1) to provide 65.5 g of the objective compound as oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]2)=[CH:4][CH:3]=1.Cl[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1.N1C(C)=CC(C)=CC=1C>CN(C)C=O>[N+:26]([C:25]1[C:20]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]3)=[CH:4][CH:3]=2)=[N:21][CH:22]=[CH:23][CH:24]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CN1CCCC(c2cccc3ccc(N)cc23)C1
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CN1CCCC(c2cccc3ccc(Nc4ncccc4[N+](=O)[O-])cc23)C1

Procedure:
A mixture of 7-amino-1-(1-methyl-3-piperidinyl)-naphthalene (0.252 g, 1.05 mmol from Example 61 ), 2-chloro-3-nitropyridine (0.333 g, 2.1 mmol) and collidine (0.139 mL, 1.05 mmol) in dimethylformamide (10 mL) was refluxed overnight. The reaction was concentrated at reduced pressure and the residue was taken up in methylene chloride. The organic phase was washed with 0.5N sodium hydroxide and brine, dried, concentrated onto silica gel and flash chromatographed (1×3 inches). Elution proceeded as follows: 50% ethyl acetate/hexane (500 mL) unweighed forrun; 75% ethyl acetate/hexane (400 mL) and ethyl acetate (100 mL) 0.151 g (51%) of red oil product. A sample crystallized from ether gave the title compound as red crystals. mp 107°-108° C. Analysis calculated for C21H22N4O2 ; C, 69.59; H, 6.12; N, 15.46. Found: C, 69.30; H, 5.91; N, 14.92.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([CH3:12])[CH:4]=1.[Br-].[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1)=O>O1CCCC1.BrCCBr>[Br:23][C:19]1[CH:18]=[C:17]([C:15]([C:3]2[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([CH3:12])[CH:4]=2)=[CH2:14])[CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: CCOc1ccc(Br)cc1C
Agent: [Br-]
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: C=C(c1cccc(Br)c1)c1ccc(OCC)c(C)c1
Temperature: 0 °C

Procedure:
To a suspension of magnesium turnings (963 mg, 39.6 mmol, 1.2 eq) in 5 mL of dry tetrahydrofuran, 0.1 mL of 1,2-dibromoethane were added followed by 5 mL of a tetrahydrofuran solution of 4-bromo-1-ethoxy-2-methyl-benzene (7.8 g, 36.3 mmol, 1.1 eq in 25 mL tetrahydrofuran). The resulting mixture was gently heated to initiate the reaction. The remaining solution of bromide was added dropwise at such a rate that the reaction could reflux without external heating. After the addition the reaction mixture was heated at reflux for further 2 hours. The mixture was cooled to 0° C. and a solution of 3-bromoacetophenone (6.56 g, 33.0 mmol, 1.0 eq) in tetrahydrofuran (30 mL) was added dropwise. After 2 hours LCMS showed complete conversion to the desired product. 50 mL of water were added followed by 35 mL of 1M aqueous HCl. The organic fraction was washed with brine, dried over sodium sulfate and concentrated to give a yellow oil. The oil was dissolved in 10 mL of acetic acid. 0.3 mL of 98% sulfuric acid were added and the dark solution was stirred at room temperature. After 30 min LCMS showed complete conversion to the desired product. Crushed ice was added to the reaction mixture which was then extracted with dichloromethane. The organic fraction was collected, washed with water, saturated sodium bicarbonate solution and dried with over sodium sulfate. The crude product was purified by flash chromatography eluting with cyclohexane. 7.5 g of clean product was obtained as colorless liquid (yield: 63%)
Reaction SMILES: CO.[NH2:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([CH3:11])=[CH:6][C:5]=1[OH:12].[C:13](OC(=O)C)(=[O:15])[CH3:14]>O>[Cl:10][C:8]1[C:7]([CH3:11])=[CH:6][C:5]([OH:12])=[C:4]([NH:3][C:13](=[O:15])[CH3:14])[CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(O)c(N)cc1Cl
Solvent: CO
Solvent: O
Product: CC(=O)Nc1cc(Cl)c(C)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
To 30 ml of methanol, there were added 1.0 g (6.4 mmol) of 2-amino-4-chloro-5-methylphenol and 0.71 g (7.0 mmol) of acetic anhydride and stirred at room temperature for 30 minutes. To this solution, there was added 60 ml of water. The crystals thus precipitated were filtered and recrystallized from methanol. Thus 0.89 g (4.5 mmol) of N-(5-chloro-2-hydroxy-4-methylphenyl)acetamide was obtained as pale brown crystals. The yield was 70%.
Reaction SMILES: CCCC[CH2:5][CH3:6].C([Li])CCC.C[Si](C)(C)[N:14]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1)[Si](C)(C)C.[C:28](=[O:30])=[O:29]>O1CCCC1>[NH2:14][C:19]1[N:20]=[C:21]([CH2:25][C:28]([O:30][CH2:5][CH3:6])=[O:29])[CH:22]=[CH:23][CH:24]=1
Reactant: CCCCCC
Reactant: Cc1cccc(N([Si](C)(C)C)[Si](C)(C)C)n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cccc(N)n1
Reaction time: 1 h
Yield: 42.3 %

Procedure:
A 15% n-hexane solution (338.6 g.) of n-butyllithium was dropwise added to a solution of 2-[N,N-bis(trimethylsilyl)amino]-6-methylpyridine (100 g.) in anhydrous tetrahydrofuran (300 ml.) at -20° to -30° C. over one hour and the solution was stirred at 20° to 23° C. for one hour. The resultant solution was added in small portions to crushed dry ice (1 kg.) under stirring, and stirred till a room temperature. After removing tetrahydrofuran from the solution under reduce pressure, absolute ethanol (1 l.) was added to the residue. 30% Ethanol solution (660 ml.) of hydrochloric acid was dropwise added to the solution at -5° to -10° C., and further hydrogen chloride gas was bubbled at 0° to 5° C. for 30 minutes and then the solution was stirred at 10° C. overnight. After removing ethanol from the resultant solution, the residue was dissolved in water, and washed with ethyl acetate 3 times. The solution was adjusted to pH 7 to 8 with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extract was washed with a saturated aqueous solution of sodium chloride, dried and concentrated under reduced pressure to give the crude product (54 g.). The product was purified by column chromatography on silica gel (1 kg.) with an eluent (ethyl acetate+benzene) to give ethyl 2-(6-aminopyridin-2-yl)acetate (30.2 g.), mp. 66° to 68° C.