Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)C=2C=CC=1.CN(C(ON1N=N[C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][C:64]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:88][C@@H:89]([CH3:108])[CH2:90][O:91][CH2:92][CH2:93][O:94][CH2:95][CH2:96][O:97][CH2:98][CH2:99][P:100](=[O:107])([O:104][CH2:105][CH3:106])[O:101][CH2:102][CH3:103]>C(Cl)Cl>[CH2:105]([O:104][P:100]([CH2:99][CH2:98][O:97][CH2:96][CH2:95][O:94][CH2:93][CH2:92][O:91][CH2:90][C@H:89]([CH3:108])[NH:88][C:20](=[O:21])[C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]1[C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][C:64]=2[C:10]2[C:11]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:23][S:24][CH2:25][C@H:26]([NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])([O:101][CH2:102][CH3:103])=[O:107])[CH3:106]
Reactant: CCOP(=O)(CCOCCOCCOC[C@H](C)N)OCC
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(=O)CCCCCCCCCCC
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)COCCOCCOCCP(=O)(OCC)OCC)NC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(((R)-2-dodecanamido-3-(dodecyloxy)propyl)thio)propanoic acid (1 eq, from example 26, step 8) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (3.5 eq), followed by (S)-diethyl (2-(2-(2-(2-aminopropoxy)ethoxy)ethoxy)ethyl)phosphonate (1.2 eq). The reaction was stirred at room temperature for 2 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give the title product as a white solid.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:20]4([CH3:25])[O:24][CH2:23][CH2:22][O:21]4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6]1)=[N+]=[N-]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO.ClCCl>[NH2:1][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:20]4([CH3:25])[O:21][CH2:22][CH2:23][O:24]4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6]1
Reactant: CC1(C2(c3ccc(N4C[C@H](CN=[N+]=[N-])OC4=O)cc3)CC2)OCCO1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Solvent: ClCCl
Product: CC1(C2(c3ccc(N4C[C@H](CN)OC4=O)cc3)CC2)OCCO1
Reaction time: 2.5 h

Procedure:
A suspension of 5(R)-azidomethyl-3-[4-(1-(2-methyl-1,3-dioxolan-2-yl)cyclopropan-1-yl)phenyl]oxazolidin-2-one (1.46 g) and Lindlar catalyst (500 mg) in methanol (20 mL) and dichloromethane (4 mL) was hydrogenated at 1 atm for 2.5 hours at room temperature. After filtration of the catalyst, the filtrate was concentrated in vacuo to give 5(S)-aminomethyl-3-[4-(1-(2-methyl-1,3-dioxolan-2-yl)cyclopropan-1-yl)phenyl]oxazolidin-2-one. To a solution of crude 5(S)-aminomethyl-3-[4-(1-(2-methyl-1,3-dioxolan-2-yl)cyclopropan-1-yl)phenyl]oxazolidin-2-one thus obtained in dichloromethane (20 mL) was added triethylamine (1.2 mL) and acetic anhydride (0.8 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour, and then concentrated in vacuo. The residue was added acetic acid (30 mL) and water (3 mL), the resulting mixture was stirred at room temperature for 8 hours, and allowed to stand for overnight. After dilution with ethyl acetate, the mixture was washed with saturated sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=20:1) of the residue gave N-[5(S)-3-[4-(1-acetylcyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (800 mg).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:6][CH2:5][CH2:4][NH:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C=O)C>[O:1]=[C:2]1[CH:7]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: O=C1NCCCC1CCc1ccc2cccnc2n1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCCC(CCc2ccc3cccnc3n2)C1=O
Reaction time: 0.5 h

Procedure:
A solution of 1-5 (0.28 g, 1.1 mmol) and DMF (10 mL) at −15° C. was treated with NaN(TMS)2 (1.2 mL, 1.2 mmol, 1M in hexanes) to give a red solution. After 30 min, the red solution was treated with ethyl bromoacetate (128 μL, 1.2 mmol), followed by continued stirring for 1 h. The reaction mixture was then quenched with sat. NH4Cl and then extracted with EtOAc (3×). The combined extracts were washed with brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 10% CH3OH/EtOAc) gave 1-6 as a yellow gum.
Reaction SMILES: [Na].Cl.[NH2:3][OH:4].[CH3:5][CH2:6][O:7][C:8]([C:10]([NH2:12])=S)=[O:9]>C(O)C>[CH3:5][CH2:6][O:7][C:8](/[C:10](/[NH2:12])=[N:3]/[OH:4])=[O:9]
Reactant: CCOC(=O)C(N)=S
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)/C(N)=N/O
Reaction time: 8 h

Procedure:
A solution of 8.98 gm. (0.39 mole) of sodium in 180 ml. of anhydrous ethanol is added to a solution of 26.8 gm. (0.386 mole) of hydroxylamine hydrochloride in 270 ml. of hot ethanol. The precipitate is removed by filtration. To the stirred filtrate is added 34.2 gm. (0.26 mole) of ethyl 2-thiooxamate. The yellow solution is allowed to stand overnight. The solution is evaporated to dryness in vacuo and the residue recrystallized from diethyl ether. There is obtained 21.2 g. (68%) of a yellow solid melting at 99°-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:15])[N:11](OC)[CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8].F[C:17](F)(F)C1C=CC=C(NC(=O)N(C)C)C=1.CC1C=CC(CCOC2C=CC(NC(=O)N(OC)C)=CC=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:15])[N:11]([CH3:17])[CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CON(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: CN(C)C(=O)Nc1cccc(C(F)(F)F)c1
Agent: CON(C)C(=O)Nc1ccc(OCCc2ccc(C)cc2)cc1
Product: CN(C)C(=O)Nc1ccc(Cl)c(Cl)c1

Procedure:
3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea; 3-(α,α,α-trifluoro-m-tolyl)-1,1-dimethylurea; 3-[4-(4-methylphenethyloxy)phenyl]-1-methoxy-1-methylurea; 3-(5-t-butyl-3,4-thiadiazol-2-yl)-4-hydroxy-1-methyl-2-imidazolidone; etc.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Br:11])[CH:5]=1.Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[H-].[Na+].O>CN(C=O)C>[C:18]([O:17][C:15](=[O:16])[CH2:14][O:10][C:8]1[CH:7]=[C:6]([Br:11])[CH:5]=[C:4]([C:3]([O:2][CH3:1])=[O:12])[CH:9]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1cc(O)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)cc(OCC(=O)OC(C)(C)C)c1

Procedure:
To a stirred solution of 3-bromo-5-hydroxybenzoic acid methyl ester (10.2 g) and tert-butyl bromoacetate (9.7 ml) in anhydrous DMF was added sodium hydride (60% dispersion in mineral oil, 2.69). After 30 min water (10 ml) aws added. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was removed and the organic phase washed with further water, 1M sodium hydroxide solution and dried with brine and over sodium sulphate. Concentration under reduced pressure gave the title compound as dark yellow gum (12.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@H:8]([NH2:11])[C@@H:7]1[C:12]([O:14][CH3:15])=[O:13].C(N(CC)CC)C.[O:29]([CH2:36][C:37](Cl)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.CCOCC>[CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@H:8]([NH:11][C:37](=[O:38])[CH2:36][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:7]1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C(Cl)COc1ccccc1
Reactant: COC(=O)[C@H]1[C@@H](N)C(=O)N1Cc1ccc(OC)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@H]1[C@@H](NC(=O)COc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Reaction time: 1 h
Yield: 84 %

Procedure:
The crude amine prepared in Example 2 from 10 g of the azido precursor is taken up in 100 ml of anhydrous methylene dichloride and is cooled to 0° in an ice bath. To this solution is added 4.32 ml (0.0312 mol) of triethylamine followed by the slow addition of a solution of 5.32 g (0.0312 mol) of phenoxyacetyl chloride in 40 ml of methylene dichloride. The mixture is stirred at 0° for 1 hr. then poured into a separatory funnel and extracted successively with water, aqueous HCl, aqueous NaHCO3, brine and is dried over anhydrous magnesium sulfate. After filtration the solvent is removed in vacuo to give a yellow solid. This material is partially dissolved in ether, cooled to -25° , and filtered to afford 11.2 g (84%) of the title product as a white solid which is one spot on tlc: benzene-ethyl acetate (1:1), silica gel, Rf 0.38. An analytical sample, mp 115.5°-116.0°, is obtained by recrystallization from ethyl acetate-hexane.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12]([NH:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:14])=[O:13])[CH:8]=2)[O:3]1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[Br:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[C:46]([CH2:51]Br)[CH:45]=1>CC#N>[Br:43][C:44]1[CH:45]=[C:46]([CH:47]=[C:48]([F:50])[CH:49]=1)[CH2:51][N:15]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:24])([CH3:1])[CH2:11][CH2:10]2)(=[O:14])=[O:13]
Reactant: Fc1cc(Br)cc(CBr)c1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN(Cc1cc(F)cc(Br)c1)S(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 90 °C
Yield: 90.1 %

Procedure:
To the solution of tert-butyl 2-(2,2-dimethylchroman-6-sulfonamido)acetate (500 mg, 1.407 mmol) in MeCN (15 mL) was added resin-supported BEMP (786 mg, 1.547 mmol) and 1-bromo-3-(bromomethyl)-5-fluorobenzene (501 mg, 1.871 mmol). The mixture was heated in a microwave synthesizer at 90° C. for 3 hours. The reaction mixture was filtered, rinsed alternatively by dichloromethane and methanol. The filtrate was concentrated to give a reddish orange residue, which was purified by silica chromatography to obtain a white powder (688 mg, 86% yield). 1H NMR (500 MHz, CDCl3) δ 7.56 (d, J=6.2 Hz, 2H), 7.18-7.12 (m, 2H), 6.95 (d, J=9.0 Hz, 1H), 6.87-6.80 (m, 1H), 4.46 (s, 2H), 3.82 (s, 2H), 2.80 (t, J=6.7 Hz, 2H), 1.83 (t, J=6.7 Hz, 2H), 1.36 (s, 9H), 1.35 (s, 6H). 19F NMR (471 MHz, CDCl3) δ LRMS [ESI, MH+] m/z calcd for C24H30BrFNO5S 542.10, found 542.1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH:13]S(C(C)(C)C)=O)[CH3:12])[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].[ClH:20].O1CCOCC1>CO>[ClH:20].[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3]
Reactant: C[C@H](NS(=O)C(C)(C)C)c1ccnc(S(C)(=O)=O)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H](N)c1ccnc(S(C)(=O)=O)c1
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid [(S)-1-(2-methanesulfonyl-pyridin-4-yl)-ethyl]amide (29.9 g, 98.2 mmol) in methanol (160 mL) was added a solution of 4 N HCl in dioxane (25.8 mL, 103 mmol). After 1 hour, the solution was concentrated to half the original volume and diluted with toluene (100 mL), and concentrated. The crude material was diluted with toluene (3×100 mL) and concentrated in vacuo and dried in vacuo for 18 hours to afford the title compound as an off-white solid which was used without further purification.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][N:15]=1>>[CH3:12][O:13][C:14]1[N:15]=[CH:16][C:17]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH2:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Nc1nc2c(Br)cccn2n1
Product: COc1ccc(-c2cccn3nc(N)nc23)cn1

Procedure:
8-(6-Methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.0 g, 4.7 mmol) and 2-methoxypyridine-5-boronic acid (1.0 g, 6.6 mmol) in a manner analogous to Step 2c. The product of the reaction was isolated as a tan solid (0.58 g, 51%). MP=157-158° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.91 (d, J=2.5 Hz, 1H), 8.54 (dd, J=6.6, 0.9 Hz, 1H), 8.44 (dd, J=8.7, 2.5 Hz, 1H), 7.73 (dd, J=7.6, 1.0 Hz, 1H), 6.97 (t, J=6.9 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 6.12 (s, 2H), 3.92 (s, 3H). MS=242 (MH)+. 8b) [8-(6-Methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine and phenyl-(8-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine were prepared from 8-(6-methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.4145 mmol) and 4-(4-bromo-phenyl)-morpholine (120.0 mg, 0.4956 mmol) in analogous manner to Example 2d. [8-(6-Methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was isolated as a yellow solid (0.037 g, 22%). MP=200-202° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.75 (d, J=2.3 Hz, 1H), 8.39 (d, J=6.3 Hz, 1H), 8.29 (dd, J=8.8, 2.6 Hz, 1H), 7.54-7.48 (m, 3H), 7.00-6.87 (m, 4H), 6.67 (s, 1H), 4.01 (s, 3H), 3.90-3.85 (m, 4H), 3.13-3.09 (m, 4H). MS=403 (MH)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](OS(C(F)(F)F)(=O)=O)=[C:6]([CH3:18])[CH:5]=1)(=[O:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)CCC.[Cl-].[Li+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][C:6]=1[CH3:18]
Reactant: CC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccc(-c2ccco2)c(C)c1
Temperature: 25 °C
Yield: 100.5 %

Procedure:
To a stirred solution of trifluoromethanesulfonic acid 4-acetyl-2methylphenyl ester (1.19 g, 4.2 mmol) in 1,4-dioxane (40 mL) was added 2-(tributylstannyl)furan (1.81 g, 5.05 mmol), lithium chloride (0.45 g, 10.5 mmol) and tetrakis(triphenylphosphine)palladium (0.49 g, 0.42 mmol) under nitrogen. The mixture was heated at reflex temperature for 2 hours, and cooled down to room temperature. The reaction mixture was diluted with water and the whole was extracted with diethylether. The organic layer was washed with saturated NaHCO3 aqueous solution, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/hexane (1/10) to give title compound (0.845 g, quant).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19]([OH:22])[CH2:20][CH3:21]>>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:22][CH2:19][CH2:20][CH3:21])[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: CCCO
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCOc1cc[n+]([O-])c(C)c1C
Temperature: 80 °C
Reaction time: 22 h

Procedure:
In n-propanol (42 ml) was dissolved 2,3-dimethyl-4-nitropyridine-1-oxide (841 mg). To the solution was added anhydrous potassium carbonate (2.1 g), and the mixture was stirred at 80° C. for 22 hours, followed by filtration with celite. The filtrate was concentrated, and the residue was chromatographed on a column of silica-gel (50 g), which was eluted with 5% methanol.chloroform to yield 2,3-dimethyl-4-propoxypyridine-1-oxide (360 mg) as an oily substance.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.C[O:10][C:11]([C:13]1[CH:18]=[N:17][C:16]([NH:19][CH2:20][C:21]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:23][O:24][C:25]=2[CH3:26])=[CH:15][N:14]=1)=O.O>O1CCOCC1>[CH:1]([NH:4][C:11]([C:13]1[CH:18]=[N:17][C:16]([NH:19][CH2:20][C:21]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:23][O:24][C:25]=2[CH3:26])=[CH:15][N:14]=1)=[O:10])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cnc(NCc2c(-c3ccccc3)noc2C)cn1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1onc(-c2ccccc2)c1CNc1cnc(C(=O)NC(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of isopropylamine (0.69 mL, 8 mmol) in dioxane (5 mL) was added dropwise trimethylaluminum solution (2M solution in hexane, 4 mL, 8 mmol). After stirring for 1 h at room temperature a suspension of 5-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-pyrazine-2-carboxylic acid methyl ester (650 mg, 2 mmol) in dioxane (5 mL) was added. The reaction mixture was stirred at 90° C. for 90 min, cooled to room temperature and poured into water. Extraction (ethyl acetate/saturated aqueous Seignette salt solution) followed by drying of the organic phase over sodium sulfate and evaporation afforded an oil. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 20:80) afforded the title compound (600 mg, 85%) as a white solid MS: m/e=352.3 [M+H]+.
Reaction SMILES: [H-].[Na+].[N:3]1[NH:4][N:5]=[CH:6][CH:7]=1.Br[CH:9]([C:11]1[CH:12]=[C:13]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[C:18]2=[O:28])[CH:14]=[N:15][CH:16]=1)[CH3:10]>CN(C=O)C>[Cl:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:28])[N:17]([C:13]1[CH:14]=[N:15][CH:16]=[C:11]([CH:9]([N:4]3[N:5]=[CH:6][CH:7]=[N:3]3)[CH3:10])[CH:12]=1)[CH2:26][CH2:25]2
Reactant: CC(Br)c1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Reactant: c1cn[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1cncc(N2CCc3cc(Cl)ccc3C2=O)c1)n1nccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
NaH (30 mg, 0.12 mmol) was added to a solution of 2H-[1,2,3]triazole (8.3 mg, 0.12 mmol) in DMF (5 mL) at 0° C. and the resulting reaction mixture was stirred for 10 min before 2-[5-(1-bromo-ethyl)-pyridin-3-yl]-6-chloro-3,4-dihydro-2H-isoquinolin-1-one (36.5 mg, 0.1 mmol) was added. After additional stirring at RT for 1 hour, it was poured into ice-water (5 mL) and extracted with EtOAc (2×10 mL). The organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give title compound (7.5 mg, 21%) as a white solid. MS: 354.2 (M+H+).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C@@H:9]([CH3:11])[CH2:8][C@H:7]([CH3:12])[CH2:6]1.[Cl-:13]>ClCCl>[ClH:13].[Cl:13][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C@@H:9]([CH3:11])[CH2:8][C@H:7]([CH3:12])[CH2:6]1
Reactant: C[C@H]1C[C@H](C)CN(CCCO)C1
Reactant: [Cl-]
Solvent: ClCCl
Product: C[C@H]1C[C@H](C)CN(CCCCl)C1
Product: Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of (3S,5S)-1-(3-hydroxypropyl)-3,5-dimethylpiperidine (1.91 g), thionyle chloride (0.96 mL) and dichloromethane (10 mL) is stirred at room temperature for 5 h, concentrated under reduced pressure and triturated in diethyl oxide to give 2.0 g of (3S,5S)-1-(3-chloropropyl)-3,5-dimethylpiperidine, hydrochloride as a beige powder used without further purification.
Reaction SMILES: N.[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16]2)=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5].[Li].C(O)C>C(OCC)C>[CH2:2]([O:6][C:7]1[CH2:12][CH:11]=[C:10]([CH2:13][CH2:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16]2)[CH2:9][CH:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(OCCCC)cc2)CC1
Agent: N
Agent: [Li]
Solvent: CCO
Solvent: CCOCC
Product: CCCCC[C@H]1CC[C@H](CCC2=CCC(OCCCC)=CC2)CC1
Temperature: 10 °C
Reaction time: 2 h
Yield: 100.9 %

Procedure:
1306 ml of liquid ammonia were placed in a sulphonation flask and then a solution of 38.4 g of 4-butyloxy-1-[2-(trans-4-pentylcyclohexyl)ethyl]benzene in 1.1 l of diethyl ether was added dropwise within 40 minutes while cooling. 23.3 g of lithium wire were subsequently added within 35 minutes and the mixture was stirred for 2 hours. 420 ml of ethanol were then added dropwise to the mixture within 70 minutes and the ammonia was allowed to evaporate overnight under nitrogen. The mixture was cooled to 10° C. and 1.5 l of water were then added dropwise within 35 minutes in such a manner that the temperature did not rise above 10° C. The mixture was extracted three times with 0.5 l of diethyl ether each time. The organic phases were washed twice with 0.5 l of water each time, dried over potassium carbonate, filtered and concentrated, there being obtained 39.0 g of 4-butyloxy-1-[2-(trans-4-pentylcyclohexyl)ethyl]-1,4-cyclohexadiene as a colourless crystallizing oil.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.O.[F:10][C:11]1[C:12]([N+:19]([O-:21])=[O:20])=[C:13](O)[CH:14]=[C:15]([F:17])[CH:16]=1>CN(C=O)C>[F:10][C:11]1[C:12]([N+:19]([O-:21])=[O:20])=[C:13]([O:4][CH3:1])[CH:14]=[C:15]([F:17])[CH:16]=1
Reactant: O=[N+]([O-])c1c(O)cc(F)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(F)cc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In DMF (50 ml) was dissolved 3,5-difluoro-2-nitrophenol. Potassium carbonate (10.4 g, 75.5 mmol) and methyl iodide (6.3 ml, 100.6 mmol) were added and the mixture was stirred for 15 hours at room temperature. Water (300 ml) was added, followed by extraction with ether (500 ml). The extract was washed with saturated brine (2×200 ml), dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, whereby the title compound (8.29 g, 87%) was obtained as a yellow crystalline powder.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CN1CCOCC1>CN1CCCC1=O>[N:17]1[CH:18]=[CH:19][C:14]([N:1]2[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]2)=[CH:15][CH:16]=1
Reactant: Clc1ccncc1
Reactant: CCOC(=O)C1CCNCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1CCN(c2ccncc2)CC1

Procedure:
Ethyl isonipecotate (6.0 g, 38.66 mmol), 4-chloropyridine hydrochloride (5.9 g, 38.66 mmol) and N-methylmorpholine (9.3 mL, 85.0 mmol) were dissolved in N-methylpyrrolidinone (50 mL) and the resulting solution heated at 100° for 48 h. The solution was concentrated in vacuo and the residue dissolved in ethyl acetate (200 mL), washed with water and brine (2×100 mL), then dried (Na2SO4) and evaporated. The resulting residue was purified by flash chromatography (5%MeOH/CH2Cl2) to afford 21-1 as a crystalline solid.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[N-].Cl[O:16][C:17]([CH3:20])(C)C.[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][CH:3]([O:16][CH2:17][CH3:20])[C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[CH3:22]
Reactant: CC(C)(C)OCl
Reactant: CCO
Reactant: COc1ccc(CC(=O)C=[N+]=[N-])cc1
Product: CCOC(OCC)C(=O)Cc1ccc(OC)cc1
Temperature: 0 °C

Procedure:
Under an argon atmosphere, 1-diazo-3-(4-methoxyphenyl)propan-2-one (62) (477 mg, 2.51 mmol) was dissolved in anhydrous ethanol (5 mL) and cooled to 0° C. To this was added tert-butyl hypochloride (285 μL, 2.52 mmol) and stirred for an hour at the same temperature. After concentrating under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=10/1) to give 1,1-diethoxy-3-(4-methoxyphenyl)propan-2-one (63) as a colorless oily substance (357 mg, 1.41 mmol, 56.4%).