Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:17][OH:18])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH:23]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(=O)([O-])O.[Na+].ClCCCl>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:23][NH:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:17][OH:18])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: COc1ccc(C=O)cc1Cl
Reactant: CCOC(=O)c1sc(N2CCCC2CO)nc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(N2CCCC2CO)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 4-amino-5-ethoxycarbonyl-2-(2-hydroxymethyl-1-pyrrolodinyl)thiazole (prepared in the above (2)) 177 mg, 3-chloro-4-methoxybenzaldehyde 111 mg, acetic acid 78 mg and 1,2-dichloroethane 8 ml is added sodium triacetoxyborohydride 415 mg, and the mixture is stirred at room temperature for 6 hours. Further 3-chloro-2 5 4-methoxybenzaldehyde 111 mg and sodium triacetoxyborohydride 415 mg are added thereto, and the mixture is stirred at room temperature for 3 days. The reaction mixture is diluted with an aqueous sodium hydrogen carbonate solution and the organic layer is washed, dried and concentrated in vacuo. The residue is separated with reversed phase column chromatography and preparative thin-layer chromatography, and then triturated with ether to give 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-(2-hydroxymethyl-1-pyrrolodinyl)thiazole as crystals, 171 mg. mp 103.5–104.5° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:39]=[CH:38][CH:37]=[CH:36][C:7]=1[O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]3[CH:26]=[C:27]([CH:32]=[C:33]([CH3:35])[CH:34]=3)[C:28]([O:30]C)=[O:29])=[O:22])=[CH:17][N:16]=2)[CH2:10]1)[CH3:4]>C1COCC1>[CH2:3]([O:5][C:6]1[CH:39]=[CH:38][CH:37]=[CH:36][C:7]=1[O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][C:25]3[CH:26]=[C:27]([CH:32]=[C:33]([CH3:35])[CH:34]=3)[C:28]([OH:30])=[O:29])=[O:22])=[CH:19][N:20]=2)[CH2:10]1)[CH3:4]
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cc(C)cc(C(=O)OC)c3)cn2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cc(C)cc(C(=O)O)c3)cn2)C1
Temperature: 60 °C
Yield: 71.7 %

Procedure:
Aqueous 1N sodium hydroxide solution (1.2 mL, 1.2 mmol) was added to a solution of methyl (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-5-methylbenzoate (123 mg, 0.24 mmol) in THF (5 mL). The reaction mixture was heated to 60° C. for 48 hours, and then the volatiles were evaporated under reduced pressure. The remaining aqueous phase was washed with diethyl ether (10 mL). The aqueous phase was then adjusted to pH 3 with aqueous 1N HCl (1 mL), and then was extracted with EtOAc (2 times with 10 mL). The combined organic phases were washed with brine (2 times with 10 mL), dried over MgSO4, filtered, and concentrated to provide (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-5-methylbenzoic acid (84.4 mg, 60%). 1H NMR (500 MHz, CDCl3) δ 8.77 (br s, 2H), 7.84 (s, 1H), 7.81 (s, 1H), 7.41 (s, 1H), 7.00 (d, 1H), 6.95 (m, 1H), 6.87 (m, 2H), 6.48 (br s, 1H), 4.65 (d, 2H), 4.42 (m, 1H), 4.27 (m, 1H), 4.13 (m, 1H), 4.00 (m, 2H), 3.85 (m, 1H), 3.71 (m, 1H), 2.40 (s, 3H), 2.11 (m, 1H), 1.97 (m, 2H), 1.60 (m, 1H), 1.38 (t, 3H). MS (ES+) 491.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].Cl.[O:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][Cl:22])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:22].[O:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:1][C:2]2[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=2)[CH:7]=[O:8])[CH2:16][CH2:15]1
Reactant: ClCCN1CCOCC1
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(OCCN2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 95 %

Procedure:
5-hydroxy-2-nitrobenzaldehyde (1.00 g, 5.98 mmol) was dissolved in DMF (15.0 mL) and the solution was added with morpholinoethyl chloride hydrochloride (1.11 g, 5.98 mmol) and potassium carbonate (1.65 g, 12.0 mmol), followed by heating at 80° C. for 40 minutes. The reaction mixture was concentrated under reduced pressure, added with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (2.00 mL) and added with 4 mol/L hydrogen chloride-methanol solution (2.00 mL), followed by stirring at 0° C. The precipitated crystal was collected by filtration to obtain 5-(2-morpholinoethoxy)-2-nitrobenzaldehyde hydrochloride (1.80 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1>[Pd].C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)CCCc1ccc(F)cc1
Reaction time: 6 h
Yield: 97 %

Procedure:
A mixture of 3-(4-fluorobenzoyl)propanoic acid (42.3 g, 0.22 mol) and 10% Palladium on carbon (3 g) in acetic acid (250 mL) was hydrogenated at 50 psi and 25° C. for 6 h. The mixture was filtered and concentrated in vacuo. The residue was distilled at 0.02 mm Hg and the product crystallized to give 4-(4-fluorophenyl)butyric acid as a white solid (97%). m.p., 44°-46.2° C. (lit. J. Chem. Soc. 89, 386, 1967; m.p., 45.5°-46.5° C.).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2([CH3:26])[O:19][C:18]3=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]3[CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.C(Cl)(=O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)Cl>[CH3:26][C:15]1([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:5])[CH2:9][CH2:10]2)[O:19][C:18]2=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]2[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC1(CN2CCN(C(=O)c3ccccc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
A mixture of 2-(4-tert-butoxycarbonylpiperazin-1-yl)methyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 306 (142 mg, 0.39 mmol), trifluoroacetic acid (1 ml) and methylene chloride (1 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (2 ml). To the mixture, triethylamine (2 ml, 14.35 mmol) was added. To the solution, benzoyl chloride (54 μl, 0.46 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with methylene chloride, washed with a saturated sodium hydrogencarbonate solution, water and a saturated saline solution in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was treated with diethyl ether to afford [4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]phenylmethanone (72 mg, yield 50%) as a yellow powder.
Reaction SMILES: [OH:1][CH:2]([CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([OH:15])[CH2:10]2.[CH2:21]=O.[ClH:23]>C(O)C>[ClH:23].[CH:18]([N:17]1[CH2:16][CH:2]([CH2:3][O:4][C:5]2[C:6]3[CH2:7][CH2:8][CH:9]([OH:15])[CH2:10][C:11]=3[CH:12]=[CH:13][CH:14]=2)[O:1][CH2:21]1)([CH3:20])[CH3:19]
Reactant: CC(C)NCC(O)COc1cccc2c1CCC(O)C2
Reactant: C=O
Agent: Cl
Solvent: CCO
Product: CC(C)N1COC(COc2cccc3c2CCC(O)C3)C1

Procedure:
A solution of 5.58 g. (0.02 mole) of 1,2,3,4-tetrahydro-5-[2-hydroxy-3-(isopropylamino)propoxy]-2-naphthol in 30 ml. of 99% ethanol is treated with 4 ml. of 33% formalin and heated under reflux for 12-16 hours. The solution is acidified with hydrochloric acid in ethanol and the oxazolidine hydrochloride precipitated by the addition of ether.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([CH3:25])[C:10]([C@@H:12]1[CH2:16][C@@H:15]([F:17])[CH2:14][N:13]1C(OC(C)(C)C)=O)=[O:11]>C(Cl)(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:17][C@H:15]1[CH2:14][NH:13][C@H:12]([C:10]([N:9]([CH3:25])[CH3:8])=[O:11])[CH2:16]1
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](F)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)[C@@H]1C[C@@H](F)CN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
10.5 mL of trifluoroacetic acid was added under ice cooling to a 25 mL chloroform solution of 3.50 g of the compound obtained in step 1-2b, after which the reaction mixture was stirred for 3 hours at room temperature. The solvent was then distilled off under reduced pressure, which gave 7.27 g of residue (yellow oily substance). This compound was used in the following reaction without being purified.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=[O:5].Cl[Si:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.[I-].[Na+]>C(#N)C>[CH3:9][Si:8]([CH3:11])([CH3:10])[O:5][CH:4]=[CH:3][C:2]([CH3:6])=[CH2:1]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)=CC=O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(C)C=CO[Si](C)(C)C

Procedure:
3-methyl-2-butenal is reacted with chlorotrimethylsilane using the method of P. Cazeau et al., Tetrahedron 43, 2075-2088 (1987), in acetonitrile containing triethylamine and anhydrous sodium iodide at 40°-45° to yield 1-trimethylsilyloxy-3-methyl-1,3-butadiene 2;
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.CC(C)(C)C=[N:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1.[ClH:32]>>[ClH:32].[NH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:26]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(C)(C)C=NC1CCNC1
Agent: Cl
Product: NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1

Procedure:
If, for example, 1-cyclopropyl-6,7,8-trifluoro1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted with 3-(2,2-dimethylpropylideneamino)-pyrrolidine and the reaction product is treated with hydrochloric acid, 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid hydrochloride is obtained.
Reaction SMILES: [Li]CCCC.[CH3:6][Si:7]([CH3:12])([CH3:11])[C:8]#[C:9][CH3:10].Cl[CH2:14][C:15]1[N:19]([CH3:20])[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]=1>C1COCC1>[CH3:20][N:19]1[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]=[C:15]1[CH2:14][CH2:10][C:9]#[C:8][Si:7]([CH3:12])([CH3:11])[CH3:6]
Reactant: CC#C[Si](C)(C)C
Reactant: Cn1c(CCl)nc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(CCC#C[Si](C)(C)C)nc2ccccc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 22.4 %

Procedure:
n-BuLi (1.35 mL, 3.39 mmol, 2.5 M) was added to a solution of trimethyl-prop-1-ynyl-silane (0.55 mL, 3.69 mmol) in THF (1 mL) at −78° C. After 2 hours, a solution of 2-chloromethyl-1-methyl-1H-benzoimidazole (556 mg, 3.08 mmol) in THF (8 mL) was added to the reaction mixture at −78° C. then the reaction mixture was stirred for 30 min. at −78° C. and 1 hour at room temperature and was quenched with water. The aqueous phase was extracted with DCM. The organic phase was washed with water, dried over MgSO4, filtered and evaporated to yield 1-methyl-2-(4-trimethylsilanyl-but-3-ynyl)-1H-benzoimidazole (178 mg, 0.69 mmol, 23%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][N:20]=[N+]=[N-])[O:16][C:15]2=[O:23])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]1>CO.C(OCC)(=O)C.[Pd]>[NH2:20][CH2:19][C@@H:17]1[O:16][C:15](=[O:23])[N:14]([C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]3)=[C:2]([F:1])[CH:3]=2)[CH2:18]1
Reactant: Cc1cn(-c2ccc(N3CC(CN=[N+]=[N-])OC3=O)cc2F)nn1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cn(-c2ccc(N3C[C@H](CN)OC3=O)cc2F)nn1
Reaction time: 4 h
Yield: 55.6 %

Procedure:
3-[3-Fluoro-4-(4-methyl-1,2,3-triazol-1-yl)phenyl]-5-(azidomethyl)-oxazolidin-2-one (Intermediate 17) (2.0 g, 6.30 mmol) was dissolved in methanol/ethyl acetate (50 ml, 1:1) and hydrogenated over palladium on carbon (10%, 0.2 g) at room temperature and normal pressure for 4 hours. The resulting mixture was filtered through the celite and concentrated under reduced pressure to give 1.02 g of the title compound as a solid, which was used without further purification in the next step.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]([S:16][CH3:17])=[S:15])[CH2:10][CH2:9]1)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:2][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]([S:16][CH3:17])=[S:15])[CH2:10][CH2:9]1
Reactant: CSC(=S)N1CCN(Cc2ccccc2[N+](=O)[O-])CC1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CSC(=S)N1CCN(Cc2ccccc2N)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
To a mixture of 4 ml of conc. hydrochloric acid and 4 ml of ethanol was added 622 mg (2.0 mmol.) of methyl 4-(2-nitrobenzyl)-1-piperazinecarbodithioate. The mixture was chilled withice, and then to this chilled mixture was dropwise added under stirring a solution of 2.7 g (12 mmol.) of SnCl2.2H2O in 5 ml of ethanol for 15 min. After the addition was complete, the mixture was further stirred at room temperature for 2 hours. Ethanol was distilled off under reduced pressure, and to the residue were added 10 ml of water and 10 ml of ethyl acetate. The resulting mixture was made alkaline by addition of saturated aqueous sodium hydrogen carbonate solution. Precipitated insolubles were removed by filtration. The organic filtrate was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. The residue was crystallized from ether, and collected by filtration, yielding 436 mg of the desired compound as a white crystallineproduct, m.p. 110°-113.5° C., yield 77.6%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[C:4]([CH3:13])[CH:3]=1.B1(C=C)OB([CH:20]=[CH2:21])OB(C=C)O1.C1C=CN=CC=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C(OCC)C.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>[CH2:9]([N:8]([CH2:11][CH3:12])[C:6]1[CH:5]=[C:4]([CH3:13])[CH:3]=[C:2]([CH:20]=[CH2:21])[N:7]=1)[CH3:10]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: CCN(CC)c1cc(C)cc(Cl)n1
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: c1ccncc1
Solvent: CCOCC
Solvent: COCCOC
Product: C=Cc1cc(C)cc(N(CC)CC)n1
Temperature: 80 °C
Reaction time: 15 h
Yield: 29.5 %

Procedure:
To a solution of (6-chloro-4-methyl-pyridin-2-yl)-diethyl-amine (5.35 g, 26.9 mmol) in DME (75 mL), 2,4,6-trivinylcyclotriboroxane pyridine complex (6.48 g, 26.9 mmol, prepared according to F. Kerins, D. F. O'Shea J. Org. Chem. 67 (2002) 4968-4971) followed by 2 M aq. K2CO3 solution (25 mL) is added. The solution is degassed and put under argon before Pd(PPh3)4 (560 mg, 0.485 mmol) is added. The mixture is stirred for 15 h at 80° C. Another portion of Pd(PPh3)4 (560 mg, 0.485 mmol) is added, and stirring is continued for 6 h. The mixture is cooled to rt, diluted with diethyl ether and washed with sat. aq. NaHCO3. The org. extract is dried over MgSO4, filtered and concentrated. The remaining yellow oil is purified by prep. HPLC to give diethyl-(4-methyl-6-vinyl-pyridin-2-yl)-amine (1.51 g) as a colourless oil; LC-MS: tR=0.68 min, [M+1]+=191.05. 1H NMR (CDCl3): δ 1.20 (t, J=7.0 Hz, 6H), 2.25 (s, 3H), 3.56 (q, J=7.0 Hz, 4H), 5.32 (dd, J=10.5, 2.3 Hz, 1H), 6.23 (dd, J=17.1, 2.0 Hz, 1H), 6.23 (s, 1H), 6.36 (s, 1H), 6.65 (dd, J=17.3, 10.5 Hz, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([Si:7]([CH3:33])([CH3:32])[O:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([NH2:21])[CH:15]=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[N:13]=1)([CH3:6])([CH3:5])[CH3:4].[C:34]([C:38]1[C:39]([Cl:47])=[C:40]([C:44](Cl)=[O:45])[N:41]([CH3:43])[N:42]=1)([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[C:3]([Si:7]([CH3:33])([CH3:32])[O:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([NH:21][C:44]([C:40]2[N:41]([CH3:43])[N:42]=[C:38]([C:34]([CH3:36])([CH3:35])[CH3:37])[C:39]=2[Cl:47])=[O:45])[CH:15]=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:30])([F:31])[F:29])[N:13]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1nc(-c2ccccc2C(F)(F)F)cc(N)c1[N+](=O)[O-]
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Nc1cc(-c2ccccc2C(F)(F)F)nc(OCCO[Si](C)(C)C(C)(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 60% sodium hydride in mineral oil (120 mg, 3.00 mmol) in THF (10 mL) at 0° C. was added 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-ylamine (458 mg, 1.00 mmol, prepared as described in the previous step) slowly. The resulting mixture was warmed to room temperature and then stirred for 1 h under Ar. 5-tert-Butyl-4-chloro-2-methyl-2H-pyrazole-3-carbonyl chloride (259 mg, 1.10 mmol, prepared as described in Example 1, STEP C) was added and the resulting mixture was stirred for 3 h under Ar. After quenching with saturated aqueous NH4Cl solution (5 mL), the mixture was treated with EtOAc (100 mL) and washed with H2O, brine and dried with Na2SO4. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (0:100-10:90 EtOAc/hexanes) yielded 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-yl]-amide as a white solid. 1H-NMR (400 MHz, CD3OD) δ: 10.10 (s, 1H), 8.33 (s, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.62-7.70 (m, 1H), 7.52-7.62 (m, 2H), 4.51-4.61 (m, 2H), 4.11 (s, 3H), 3.94-4.01 (m, 2H), 1.42 (s, 9H), 0.89 (s, 9H), 0.07 (s, 6H). Mass Spectrum (LCMS, ESI pos.) Calculated For C29H37ClF3N5O5Si: 656.2 (M+H), Measured: 656.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])=[CH:16][CH:17]=1
Reactant: Clc1ccc(Br)cc1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc(Cl)cc2)C1=O
Yield: 63.6 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474 mmol) was reacted with 1-bromo-4-chloro-benzene (162 mg, 0.8474 mmol), 1,4-dioxane (5 mL), copper iodide (16.142 mg, 0.08474 mmol), trans-1,2-diamino cyclohexane (29.108 mg, 0.2542 mmol) and potassium carbonate (234.3 mg, 1.6948 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform) afforded 155 mg of the product (63.78% yield).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[C:8]([CH2:14][CH2:15][C:16]([OH:18])=O)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]>C(Cl)(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]([CH2:14][CH2:15][C:16]([Cl:3])=[O:18])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CCC(=O)O)cc1Br
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCC(=O)Cl)cc1Br

Procedure:
A solution of 102.4 g (0.86 mol) of thionyl chloride is added to a solution of 51.8 g (0.2 mol) of 3-(3-bromo-4-methoxyphenyl)propanoic acid in 700 ml of chloroform. The mixture is heated at reflux for 4 hours, and the solvent is then evaporated off. 53 g are obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:7][S:8]([OH:11])(=O)=[O:9].[O:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1>>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[S:8]([Cl:7])(=[O:11])=[O:9]
Reactant: O=S(=O)(O)Cl
Reactant: c1ccoc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ccco1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 8.3 %

Procedure:
Phosphorus pentachloride (15.29 g, 73.44 mmol) was added portionwise (caution, foaming) over 5 min at 0° C. to chlorosulfonic acid (21.39 g, 183.6 mmol) and the resulting solution was stirred at 0° C. for 10 min. Then, furan (5.0 g, 73.44 mmol) was added in one portion and the resulting dark suspension was stirred at 0° C. for 15 min during which time foaming occurred and subsided. The reaction mixture was then poured onto ice and the resulting suspension was extracted with CH2Cl2 (150 mL). The organic extract was filtered through a pad of celite, washed with brine and dried over MgSO4. The solvent was removed in vacuo to provide 2-furansulfonyl chloride as a black oil (1.01 g, 7.9%). 1H-NMR (DMSO-d6, 400 MHz) δ 7.4 (d, 1H); 6.38 (d, 1H); 6.35 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])[CH:11]([CH3:13])O.S([O-])(=O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[I-].[K+].CN(C)C=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:11]([CH3:13])[C:10]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=[CH:3][CH:4]=1)=[O:7]
Reactant: CCCCOC(=O)C(C)O
Reactant: O=Cc1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCCCOC(=O)C(C)Oc1ccc(C=O)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 82.4 %

Procedure:
6.1 g of 4-hydroxybenzaldehyde, 12.3 g of (-)-butyl lactate-mesylate ([α]D25 =-49.1°), 4 g of sodium carbonate, 0.2 g of potassium iodide and 100 g of dimethyl formamide, were mixed, and the mixture was stirred at 100° C. for 5 hours and then cooled to room temperature. The reaction mixture was subjected to liquid separation with an addition of toluene and water. The organic layer was washed twice with water, and after distilling off toluene, subjected to distillation under reduced pressure, whereby 10.3 g of (+)-butyl 2-(4-formylphenoxy)propionate was obtained as a colorless transparent liquid. The boiling point was from 135° to 140° C./0.1 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[CH3:14]>[Pd].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[CH3:14]
Reactant: COC(=O)/C=C/c1ccc(F)c(C)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(F)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(E)-Methyl 3-(4-fluoro-3-methylphenyl)acrylate (1.3 g, 6.7 mmol) was dissolved into 58 mL MeOH and to it added 10% Pd/C (750 mg). The solution was saturated with H2 and then stirred for 3 h at room temperature under an atmosphere of hydrogen balloon. The mixture was filtered through a bed of Celite and rinsed with ethyl acetate. The solvent was removed under reduced pressure and the crude product used directly in the next step without further purification.