Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Li].[CH2:3]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][C:13]2([O:20][CH2:19][CH2:18][O:17]2)[C:12]1([CH3:26])[CH2:21][CH2:22][CH2:23][CH:24]=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCOCC>[CH2:3]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][C:13]2([O:17][CH2:18][CH2:19][O:20]2)[C:12]1([CH3:26])[CH2:21][CH2:22][CH2:23][CH:24]([OH:25])[CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [Li]C
Reactant: CC1(CCCC=O)C(OCc2ccccc2)CCCC12OCCO2
Solvent: CCOCC
Product: CC(O)CCCC1(C)C(OCc2ccccc2)CCCC12OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
Methyllithium (63.3 ml, 0.0918 mol, 1.45 M in ether) is added dropwise to a solution of the aldehyde, (2S*, 3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-oxobutyl)-cyclohexane (25.4 g, 0.0765 mol) in ether (1000 ml) at 0° C. in a nitrogen atmosphere. The cooling bath is removed and the mixture is stirred for 0.5 hours at ambient temperature. The mixture is then poured into a cold saturated sodium chloride solution (500 ml). The ether phase is separated and the aqueous phase is extracted with ether (3×100 ml). The ether phases are combined, dried (MgSO4) and the solvent is removed at reduced pressure. The crude product (27.1 g) is chromatographed on SilicAR CC-7 (300 g, Mallinckrodt) in hexane. Elution with 10% ethyl acetate/hexane gives (2S*, 3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-hydroxypentyl)-cyclohexane as a colorless oil (25.8 g, 97%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[N:5]([CH2:7][CH2:8][OH:9])[CH:6]=1.CCN(CC)CC.[S:30](Cl)([CH3:33])(=[O:32])=[O:31]>C(Cl)Cl>[Br:1][C:2]1[N:3]=[C:4]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[N:5]([CH2:7][CH2:8][O:9][S:30]([CH3:33])(=[O:32])=[O:31])[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCOS(C)(=O)=O)CC1
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4-(4-bromo-1-(2-hydroxyethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (22.0 g) and Et3N (24.5 ml) in DCM (250 ml) and cool to 0° C. Mesyl chloride (6.8 ml) was added dropwisely and the resulting mixture was stirred for 1 h. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM. The organic layer was concentrated to give tert-butyl 4-(4-bromo-1-(2-((methylsulfonyl)oxy)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (28.0 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([CH3:13])[N:3]=1.[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1.[F-].[K+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([CH3:13])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:18]2[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=2)[N:7]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)c1c(C)nc(Cl)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1c(C)nc(Cl)nc1-c1cnn(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.1 %

Procedure:
A mixture of methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate (0.79 g, 3.57 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.595 g, 2.86 mmol) and bis(triphenylphosphine)palladium chloride (0.050 g, 0.071 mmol) in dioxane (5 mL) was stirred at RT for 10 min, after which potassium fluoride (1.038 g, 17.87 mmol) was added. The mixture was stirred under a nitrogen atmosphere and heated at 90° C. for 12 h. The reaction mixture was filtered through a bed of Celite 545, rinsed with DCM and a small amount of MeOH. Following solvent removal, the residue was dispersed in DMSO/MeOH (1/1) and purified via reverse phase preparative HPLC to give the title compound (237 mg, 25%). [M+H] calc'd for C11H11ClN4O2, 267; found, 267.
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.[CH2:7]([O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14])[CH2:8][CH3:9].C(Cl)(Cl)[Cl:20]>C1(C)C=CC=CC=1.CCCCCC>[ClH:20].[CH2:7]([O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]([NH2:2])=[NH:14])[CH2:8][CH3:9]
Reactant: [NH4+]
Reactant: CCCOc1ccccc1C#N
Reactant: ClC(Cl)Cl
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCOc1ccccc1C(=N)N
Product: Cl
Temperature: 2.5 °C

Procedure:
21.41 g (400 ml) of ammonium chloride are suspended in 400 ml of toluene and cooled to 0-5° C. 200 ml of a 2 M solution of trimethylaluminum in hexane are added dropwise, and the mixture is stirred at room temperature until the evolution of gas has ceased. Following addition of 32.2 g (200 mmol) of 2-propoxybenzonitrile, the reaction mixture is stirred at 80° C. (bath) overnight. The cooled reaction mixture is, with ice-cooling, added to a suspension of 300 g of silica gel and 2.85 ml of ice-cooled chloroform and stirred for 30 minutes. The mixture is filtered off with suction and the filter cake is washed with the same amount of methanol. The solvent is distilled off under reduced pressure, the residue is triturated in 500 ml of a mixture of dichloromethane and methanol (9:1), the solid is filtered off and the mother liquor is concentrated. The residue is triturated with petroleum ether and filtered off with suction. This gives 22.3 g (52%) of product.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[N:12]([CH:13]2[C:21]3[C:16](=[C:17]([Cl:22])[CH:18]=[CH:19][CH:20]=3)[C:15](=[O:23])[C:14]2([CH3:25])[CH3:24])[CH:11]=[N:10][CH:9]=1)(C)(C)C.Cl.C(OCC)C>CO.C([O-])(O)=O.[Na+]>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[C:15](=[O:23])[C:14]([CH3:25])([CH3:24])[CH:13]2[N:12]1[C:8]([CH2:7][OH:6])=[CH:9][N:10]=[CH:11]1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cncn1C1c2cccc(Cl)c2C(=O)C1(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CC1(C)C(=O)c2c(Cl)cccc2C1n1cncc1CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-[5-(tert-butyl-dimethyl-silanyloxymethyl)-imidazol-1-yl]-7-chloro-2,2-dimethyl-indan-1-one (650 mg, 1.6 mmol) in methanol (20 mL) is added a 1N solution of HCl in diethyl ether (15 mL, 15 mmol). The reaction is permitted to stir for 30 minutes, at which time the reaction is cooled to 0° C. and diluted with saturated aqueous NaHCO3. The reaction mixture is then concentrated in vacuo to ca. one fourth of the original volume and diluted with ethyl acetate. The layers are separated and the aqueous layer is extracted two times with ethyl acetate. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The resulting residue is purified by silica gel flash chromatography (methanol-dichloromethane, 0:1 to 1:19) to furnish 7-chloro-3-(5-hydroxymethyl-imidazol-1-yl)-2,2-dimethyl-indan-1-one; 1H NMR (400 MHz, CD3OD) δ ppm 0.86 (s, 3 H), 1.41 (s, 3 H), 4.77 (dd, 2 H); 5.88 (s, 1 H), 7.01 (s, 1 H), 7.09 (s, 1 H), 7.45 (d, J=7.58 Hz, 1 H), 7.62 (d, J=7.83 Hz, 1 H), 7.74 (t, J=7.71 Hz, 1 H); HRMS: (ESI) m/z 291.0898 [(M+H)+: Calcd for C15H16N2O2Cl: 291.0900].
Reaction SMILES: O.[C:2]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])([CH3:5])([CH3:4])[CH3:3].Cl.[OH:19][C@@H:20]([CH2:50]O)[CH2:21][N:22]1[CH:26]=[CH:25][C:24]([NH:27]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:23]1.[CH:52](N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:2]([O:6][C:7](=[O:8])[NH:9][C@H:10]([C:15](=[O:17])[NH:27][C:24]1[CH:25]=[CH:26][N:22]([CH2:21][C:20]([OH:19])([CH3:50])[CH3:52])[N:23]=1)[CH2:11][CH:12]([CH3:13])[CH3:14])([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccn(CC(C)(C)O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.8 %

Procedure:
A solution of N-t-butoxycarbonyl-(L)-leucine mono-hydrate (2.81 g, 11.28 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 2.02 g, 13 mmol) in N,N-dimethylformamide (15 mL) was treated with N,N-diisopropylethylamine (3.5 mL, 20 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (8.84 g, 20 mmol) and stirred at room temperature for 12 h. At this time the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and a concentrated ammonium chloride solution. The layers were separated and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue purified by ISCO flash chromatography (RediSep silica 120 g, 20% to 80% ethyl acetate/hexanes) which afforded {(S)-1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-3-methyl-butyl}-carbamic acid t-butyl ester (4.15 g, 100%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][C:4]=1[O:9][CH3:10]
Reactant: COc1ccccc1OC
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)CCC(=O)O)cc1OC

Procedure:
The naphthalenes of formulas A and B are known to the art. Moreover, they can be prepared by conventional means. For example, 1,2-dimethoxybenzene is treated with succinic anhydride and aluminum chloride in a hydrocarbon solvent to afford 4-(3',4'-dimethoxyphenyl)-4-oxobutanoic acid. This is reduced by treatment with sodium borohydride, hydrogenolyzed by treating with palladium charcoal catalyst and hydrogen to furnish 4-(3',4'-dimethoxyphenyl) butanoic acid. The corresponding acid chloride is prepared such as by teatment with thionyl chloride, and the acid chloride is treated with aluminum chloride to afford 6,7-dimethoxy-1-tetralone. The tetralone is reduced and hydrogenolyzed by the means described above to furnish 6,7-dimethoxytetralin which is dehydrogenated by treating with palladium charcoal catalyst to afford 2,3-dimethoxy naphthalene. By utilizing 1-methyl-3-fluorobenzene in the above process, 6-methyl-8-fluoro-4-tetralone and 6-fluoro-8-methyl-4-tetralone (as intermediates) and 1-methyl-3-fluoro naphthalene and 1-fluoro-3-methyl naphthalene are prepared. The mixture of naphthalenes are separated by conventional means, such as vacuum distillation.
Reaction SMILES: C([O:4][C:5]1[C:42]([CH2:43][N:44]([CH2:53][C:54]([O:56]C(C)(C)C)=[O:55])[CH2:45][C:46]([O:48]C(C)(C)C)=[O:47])=[CH:41][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH:18]([C:37]([O:39][CH3:40])=[O:38])[C:19]3[CH:24]=[C:23]([I:25])[C:22]([O:26][C:27]4[CH:32]=[C:31]([I:33])[C:30]([OH:34])=[C:29]([I:35])[CH:28]=4)=[C:21]([I:36])[CH:20]=3)[CH:12]=2)=[O:10])=[CH:7][C:6]=1[CH2:61][N:62]([CH2:71][C:72]([O:74]C(C)(C)C)=[O:73])[CH2:63][C:64]([O:66]C(C)(C)C)=[O:65])(=O)C>FC(F)(F)C(O)=O.O>[C:64]([CH2:63][N:62]([CH2:61][C:6]1[CH:7]=[C:8]([CH:41]=[C:42]([CH2:43][N:44]([CH2:53][C:54]([OH:56])=[O:55])[CH2:45][C:46]([OH:48])=[O:47])[C:5]=1[OH:4])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH:18]([C:37]([O:39][CH3:40])=[O:38])[C:19]2[CH:24]=[C:23]([I:25])[C:22]([O:26][C:27]3[CH:32]=[C:31]([I:33])[C:30]([OH:34])=[C:29]([I:35])[CH:28]=3)=[C:21]([I:36])[CH:20]=2)[CH:12]=1)=[O:10])[CH2:71][C:72]([OH:74])=[O:73])([OH:66])=[O:65]
Reactant: COC(=O)C(Cc1cccc(C(=O)c2cc(CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)c(OC(C)=O)c(CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)c2)c1)c1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(Cc1cccc(C(=O)c2cc(CN(CC(=O)O)CC(=O)O)c(O)c(CN(CC(=O)O)CC(=O)O)c2)c1)c1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1

Procedure:
A solution of 630 mg of 21 in 5 mL of trifluoroacetic acid was stirred overnight, diluted with water and the solid which separated was collected and dried; yield 550 mg. The field desorption mass spectrum showed 22 (m/e1305) is present, as well as some material in which the methyl ester of the thyroxine has been hydrolyzed to the acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][OH:39]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:36][CH2:37][CH2:38][OH:39])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8]
Reactant: OCCCBr
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1OCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
4-(5,6-Dimethyl-[2,2′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol (compound 338) (45 mg) was suspended in N,N-dimethylformamide (5 ml), potassium carbonate (50 mg) and 3-bromo-1-propanol (0.03 ml) were added to the suspension, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (22 mg, yield 42%).
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.[ClH:15].CN(C)CCCN=C=NCC.C(O[C:34]1[CH:48]=[CH:47][C:37]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](O)=[O:45])=[CH:36][CH:35]=1)CCCCC.Cl>CN(C)C1C=CN=CC=1.CCOCC>[OH:3][C:2]1[CH2:4][O:5][C:6](=[O:7])[C:1]=1[C:44](=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:38][C:37]1[CH:47]=[CH:48][C:34]([Cl:15])=[CH:35][CH:36]=1
Reactant: CCCCCCOc1ccc(OCCCCCC(=O)O)cc1
Reactant: O=C1COC(=O)C1
Reactant: Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(CCCCCOc1ccc(Cl)cc1)C1=C(O)COC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 43 %

Procedure:
To a stirring solution of 554 mg (5.54 mmol) of tetronic acid in 20 mL of diemthylformamide is added 850 μL (6.09 mmol) of triethylamine and 220 mg (1.765 mmol) of 4-dimethylaminopyridine at 0° C. Next, 1.26 g (6.63 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.475 g (6.63 mmol) of 6-[4-(hexyloxy)phenoxy]hexanoic acid are added and the reaction mixture is stirred 2 days at room temperature. The reaction is acidified with 1.0N HCl and extracted three times with ether. The combined organic layers are dried over MgSO4 and concentrated in vacuo giving a yellow solid. Pure material is obtained by trituration in ether, filtering to give 774 mg (43%) of 4-hydroxy-3-[6-(4-chlorophenoxy)-1-oxohexyl]-2(5H)-furanone.
Reaction SMILES: N[C:2]1[CH:23]=[CH:22][C:5]([C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.C=O.[BH3-][C:27]#[N:28].[Na+].[C:30](O)(=O)C>C(#N)C.CCOCC>[CH3:30][N:28]([CH3:27])[C:2]1[CH:23]=[CH:22][C:5]([C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: Nc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: CN(C)c1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
0.1025 g (0.00033 mol) of 1-benzyl-piperidin-4-yl 4-amino-benzoate was dissolved in 5 ml of acetonitrile and treated with 0.4 ml (0.0053 mol) of formaldehyde (37%) and 0.113 g (0.001534 mol) of NaBH3CN. The pH was adjusted to 6 with glacial acetic acid and the reaction mixture was stirred at 50° for 1 hr. Subsequently, the mixture was diluted with 25 ml of ether, washed with saturated bicarbonate solution and saturated sodium chloride solution and the org. phase was dried over magnesium sulfate. After removing the solvent the residue was chromatographed over silica gel with dichloromethane/methanol (19:1). 0.078 g (70%) of 1-benzyl-piperidin-4-yl 4-dimethylamino-benzoate was obtained as white crystals; m.p. 103°.
Reaction SMILES: [I:1]C.Cl[CH2:4][CH2:5][N:6]1[C:10](=O)[NH:9][N:8]=[N:7]1.[C:12](=[O:15])([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[I:1][CH2:4][CH2:5][N:6]1[C:12](=[O:15])[N:9]([CH3:10])[N:8]=[N:7]1
Reactant: O=c1[nH]nnn1CCCl
Reactant: CI
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Cn1nnn(CCI)c1=O
Yield: 85 %

Procedure:
A mixture of 49 parts of iodomethane, 10.5 parts of 1-(2-chloroethyl)-1,4-dihydro-5H-tetrazol-5-one, 15 parts of sodium carbonate, 0.2 parts of potassium iodide and 240 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, 100 parts of water are added and the layers are separated. The aqueous phase is extracted with dichloromethane. The combined organic phases are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, yielding 15 parts (85%) of 1,4-dihydro-1-(2-iodoethyl)-4-methyl-5H-tetrazol-5-one as a residue.
Reaction SMILES: O[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:16])[CH:4]=1.[Br:17]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:17][CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:16])[CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)COc1ccc(CO)cc1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(CBr)cc1C
Yield: 54.1 %

Procedure:
To a solution of ethyl [4-(hydroxymethyl)-2-methylphenoxy]acetate (4.27 g, 19 mmol) in dry CH2Cl2 (150 mL) under nitrogen at 5° C., was added tetrabromomethane (6.91 g, 20.9 mmol) then triphenylphosphine (5.71 g, 21.8 mmol) portion wise over 0.5 h. The resultant mixture was then stirred for 16 h at room temperature. The solvents were removed in vacuo. Purification by Biotage™ chromatography (silica, 2×90 g) eluting with 30:1 cyclohexane:EtOAc afforded the title compound as a yellow solid (2.95 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH2:8][C:7]=2[CH:14]=1>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][C:9](=[O:13])[CH2:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2c(c1)CC(=O)NC=C2
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CC(=O)NCC2

Procedure:
First, 8-methoxy-1,3-dihydro-2H-3-benzazepin-2-one (56.8 g, 0.3 mol) (Mp: 190°-191° C.), dissolved in glacial acetic acid (600 ml), is hydrogenated in the presence of 10% palladium/charcoal (5 g) at 80° C. and at 5 bar for 12 hours. The catalyst is suction filtered and the acetic acid is distilled off in vacuo. The residue is mixed with water, neutralized with potassium carbonate, the precipitate obtained is suction filtered, washed with water and dried. Yield: 51.1 g. Mp: 160°-161° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:11](=[O:16])[NH:12][CH:13]2[CH2:15][CH2:14]2)=[N:8][O:9][CH:10]=1)=[O:5])C.[Li+].[OH-].C(OCC)C>C1COCC1.C(O)C>[CH:13]1([NH:12][C:11]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][N:8]=2)=[O:16])[CH2:14][CH2:15]1
Reactant: CCOC(=O)c1conc1C(=O)NC1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)c1conc1C(=O)NC1CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 3-(cyclopropylcarbamoyl)-isoxazole-4-carboxylic acid ethyl ester (600 mg, 2.68 mmol) in THF (7 ml) and ethanol (3 ml) was added LiOH (1M; 5.35 ml, 5.35 mmol) at 0-5° C. The mixture was stirred at 20° C. for 1 h, poured into 50 ml diethyl ether and extracted. The organic phase was washed with water. The combined aqueous phases were acidified with 1M HCl (6 ml) and extracted with dichloromethane. The organic layers were dried and evaporated to yield the product as yellow oil (464 mg, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:12]1[CH:17]=[CH:16][C:15](OS(C(F)(F)F)(=O)=O)=[CH:14][N:13]=1)[CH3:2].[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[CH:16][C:15]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:14][N:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH3:2]
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(OS(=O)(=O)C(F)(F)F)cn1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(-c2ccccc2)cn1
Yield: 86.2 %

Procedure:
Compound II (22 mg, 0.046 mmol), Pd(PPh3)4 (1.6 mg, 0.0014 mmol), phenylboronic acid (11.2 mg, 0.092 mmol) and potassium carbonate (9.5 mg, 0.07 mmol) were stirred in toluene (2 mL) at 90° C. in a sealed tube for 20 h. Then the reaction mixture was filtrated through celite and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (90:10 to 70:30) to furnish 16 mg of III in mixture with the starting material. MW: 403.52. LCMS (ES). found 404.2 [MH]+.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=O)=[CH:28][CH:27]=1)([O-:25])=[O:24].O>O1CCOCC1>[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](=[S:10])[NH2:32])=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Solvent: O
Product: NC(=S)c1ccc([N+](=O)[O-])cc1
Yield: 119.3 %

Procedure:
6.06 g (15 mmol) of Lawesson reagent is added to a solution of 4.15 g (25 mmol) of 4-nitrobenzamide in 100 ml of 1,4-dioxan. The reaction mixture is heated under reflux for two hours. After the solution has returned to ambient temperature, it is poured into 150 ml of water and extracted with 5 times 100 ml of ethyl acetate. The organic solution is dried over magnesium sulphate, filtered and concentrated under vacuum in order to produce a yellow oil which is purified on a silica gel column (eluant: heptane/ethyl acetate 1/1). The pure fractions are collected and concentrated under vacuum. 3.26 g of a yellow powder is obtained with a yield of 72%. Melting point: 165-167° C.