Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[CH3:11][NH2:12]>C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:12]/[CH3:11])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1F
Reactant: CN
Solvent: ClCCl
Product: C/N=C/c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 129 %

Procedure:
A mixture of 4-chloro-2-fluoro-benzoaldehyde (Matrix Sci, 3.17 g, 20.0 mmol) and methyl amine (2.0 M in THF, Aldrich, 15 mL, 15.0 mmol) in CH2Cl2 (20 mL) was stirred at rt overnight. The reaction mixture was concentrated and the residue was dried under reduced pressure to afford [[1-(4-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-methyl-amine (3.32 g, 97.0%) as colorless oil which was used in the next step without further purification.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[NH:5][CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]1([CH3:24])[CH3:23].FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[CH3:23][C:3]1([CH3:24])[CH2:2][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[NH:5][CH:4]1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: CC1(C)C(O)c2cc(C#N)ccc2NC1c1cccc([N+](=O)[O-])c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Cc2cc(C#N)ccc2NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.9 %

Procedure:
To a mixture of 4-hydroxy-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (25 g, 77 mmol) and triethylsilane (50 mL) at 25° C. was added trifluoroacetic acid (25 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(10% ethyl acetate/hexanes) to afford 3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (4 g, 16%) as a white solid: LC/MS m/e calcd for C18H17N3O2 (M+H)+: 308.36, observed: 308.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O-:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:23]([O-])=O.[OH-].[Na+]>CO>[NH2:23][C:3]1[CH:4]=[C:5]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CC1(C)Cc2cc(C(=O)[O-])ccc2NC1c1ccc(F)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(N)c1
Yield: 293.6 %

Procedure:
A mixture of 2-(4-fluoro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (0.5 g, 0.52 mmol) in methanol (10 mL) and 1 M aqueous sodium hydroxide solution (26 mL, 26 mmol) was heated to reflux for 3 h. LC-MS showed the reaction was complete. The solvent was removed in vacuo and the residue was acidified with 1 M hydrochloric acid solution to pH=6. The precipitated white solid was collected by filtration and washed with water, dried in vacuo to afford 0.48 g of 2-(3-amino-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid in quantitative yield.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([O:13]CC)=[O:12].[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)Cc1c(F)ccc(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1c(F)ccc(F)c1F
Yield: 98.5 %

Procedure:
Ethyl 2-(2,3,6-trifluorophenyl)acetate (16.2 g) is dissolved in ethanol (60 ml). The mixture is stirred and thereto is added 3N sodium hydroxide (200 ml), and the mixture is stirred at 70° C. for one hour. After cooling, 6N hydrochloric acid (120 ml) is added to the mixture. The resulting white powdery precipitates are dissolved by adding thereto diethyl ether. The diethyl ether layer is separated and dried over magnesium sulfate and then concentrated under reduced pressure to give 2-(2,3,6-trifluorophenyl)acetic acid (13.9 g), as white crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1.[Br:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][OH:34]>>[Br:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][O:34][CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1
Reactant: OCc1cccc(Br)c1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(COCc2cccc(Br)c2)n1
Yield: 61 %

Procedure:
As described for Example 157, 4-[2-chloromethyl-1-(4-nitro-phenyl)-1H-imidazol-4-yl]-5-methyl-3-phenyl-isoxazole (100 mg, 0.25 mmol), using 3-bromobenzyl alcohol instead of 3-chlorobenzyl alcohol, was converted to the title compound (84 mg, 61%) which was obtained as a light yellow gum. MS: m/e=545.3/547.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][CH:17]=[CH2:18])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:29](Br)[CH:30]=[CH2:31]>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:16][CH:17]=[CH2:18])[CH2:9][CH:10]([CH2:31][CH:30]=[CH2:29])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCN(CCC(=O)OCC)C(=O)OC(C)(C)C
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(CN(CC=C)C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 0 °C
Yield: 48.4 %

Procedure:
To a solution of ethyl N-(tert-butoxycarbonyl)-3-(2-propenylamino)propionate (1.12 g, 4.86 mmol) was added 1N solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (THF) (5.8 mL) and allyl bromide (1.46 mL, 17.0 mmol) successively at −78° C. The mixture was stirred at 0° C. for an hour, then quenched by a saturated aqueous NH4Cl solution and extracted with ethyl acetate. The extract was washed with water and brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of ethyl acetate and n-hexane (1:20) to give ethyl N-(tert-butoxycarbonyl)-2-(2-propenyl)-3-(2-propenylamino)propionate (0.7 g, 2.35 mmol, 48.4%) as a colourless oil.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.C[Si](C)(C)N[Si](C)(C)C.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1.[I-].[K+]>C(#N)C.S([O-])([O-])(=O)=O.[NH4+].[NH4+].O>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[C:3]2=[O:8])=[CH:21][CH:20]=1
Reactant: O=c1[nH]cccc1O
Reactant: ClCc1ccc(Cl)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: O=c1c(O)cccn1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
to a nitrogen purged 1-L round bottom flask equipped with a mechanical stirrer, upright condenser, and thermometer was charged 3-hydroxypyridin-2(1H)-one [2,3-dihydroxypyridine] (40.0 g, 0.36 mol, 1 equiv.) [CAS No. 16867-04-2], ammonium sulfate (2.4 g, 0.02 mol, 0.05 equiv.) and acetonitrile (200 mL, 5 parts v/w). The resulting suspension was stirred at room temperature. Hexamethyldisilazane (116.2 g, 0.72 mol, 2 equiv.) is added dropwise. The resulting suspension was heated to reflux for 4 hours. The solution was then cooled to room temperature followed by the addition of a solution of 4-chlorobenzyl chloride (63.8 g, 0.4 mol, 1.1 equiv.) in acetonitrile (40 mL, 1 part v/w). Potassium iodide (59.8 g, 0.36 mol, 1 equiv.) is then added. The solution was then brought to reflux for 16 hours. The solution was cooled to 5° C. and water (240 mL) was slowly added over 15 minutes. The reaction mixture was allowed to warm to room temperature and stirring was continued for 2 hours. The solution was filtered under vacuum and rinsed with water (360 mL). The filter cake is then washed with methyl tert-butyl ether (360 mL). The resulting green-brown solid is vacuum dried to afford 63.5 g (86.2%) of the desired product. 1H NMR (DMSO-d6) δ ppm 7.4 (d, 2H), 7.3 (d, 1H), 7.2 (d, 2H), 6.7 (d, 1H), 6.1 (t, 1H), and 5.1 (s, 2H).
Reaction SMILES: [CH2:1]([O:5][C:6]([CH:8]([NH:17][CH:18]1[CH2:24][S:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][N:20]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[C:19]1=[O:39])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([O:5][C:6]([CH:8]([NH:17][CH:18]1[CH2:24][S:23][CH:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:21][N:20]([CH2:31][C:32]([OH:34])=[O:33])[C:19]1=[O:39])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccccc2)CN(CC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccccc2)CN(CC(=O)O)C1=O

Procedure:
0.12 g of isomer B of t-butyl α-[6-(1-butoxycarbonyl-3-phenylpropylamino)-5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl]acetate (prepared as described in Example 19 above) was subjected to de-t-butylation with trifluoroacetic acid in the manner described in Example 3, to give 78 mg of the title compound as an amorphous solid.
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]([CH3:11])[CH2:8][CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[C:12]1([CH3:32])[CH:17]=[CH:16][C:15]([S:18]([O:21]CC[C@@H](C)COC(C)(C)C)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[C:1]([O:5][CH2:6][C@H:7]([CH3:11])[CH2:8][CH2:9][OH:10])([CH3:3])([CH3:4])[CH3:2].[CH3:32][C:12]1[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H](C)COC(C)(C)C)cc1
Agent: C[C@H](CCO)COC(C)(C)C
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
Using the procedure of Example 8, (R)-(+)-4-tert. butoxy-3-methyl-1-butanol was converted into (R)-(+)-4-tert. butoxy-3-methyl-1-butanol p-toluenesulfonate which was isolated in 90% yield as a pale yellow oil.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[C@H:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][CH2:3]1>C(O)C.[C].[Pd]>[OH:1][C@@H:2]1[CH2:7][NH:6][C@H:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@H](O)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@H](O)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a solution of 67.2 g (200.4 mmol) of (2S,5S)-1-Benzyl 2-tert-butyl 5-hydroxypiperidine-1,2-dicarboxylate in ethanol (900 mL) was added 10.1 g of 10% palladium-carbon (water content ca. 50%), followed by vigorous stirring overnight at room temperature under hydrogen atmosphere. The catalyst of the mixture was filtered through Celite-pad to concentrate the filtrate, whereby 39.3 g of the title compound was afforded as a colorless solid (yield 97%). Enantiomeric excess: 99% ee or more (CHIRALPAK AD-H, 4.6×150 mm, UV 210 nm, diethylamine/hexane/ethanol=0.1/80/20, flow rate 1 mL/min., retention time 6.3 min.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:19]2[CH2:20][CH2:21][CH:16]([O:15][C:12]3[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=3)[CH2:17][CH2:18]2)=[CH:4][CH:3]=1
Reactant: c1cc(OC2CCNCC2)ccn1
Reactant: Brc1ccc(I)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Brc1ccc(N2CCC(Oc3ccncc3)CC2)cc1
Temperature: 110 °C
Yield: 50.9 %

Procedure:
2 g of 1-bromo-4-iodobenzene and 1.386 g of 4-(piperidin-4-yloxy)pyridine are placed in 35 ml of toluene and then 0.324 g of tris(dibenzylideneacetone)dipalladium(0), 0.245 g of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and 1.019 g of sodium tert-butoxide are added. The reaction medium is heated at 110° C. for 18 h. Ethyl acetate is subsequently added and the mixture is washed twice with water and once with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate and concentrated under reduced pressure. The crude product obtained is chromatographed on silica gel, elution being carried out with a gradient of a dichloromethane/methanol (99/1 to 98/2) mixture. 1.2 g of 4-[1-(4-bromophenyl)piperidin-4-yloxy]pyridine are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]2[CH2:22][O:21]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]2[C:26]=1[CH2:27][CH:28]([NH2:36])[CH2:29]2>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:21])[CH2:22][NH:36][CH:28]2[CH2:29][C:30]3[C:26](=[C:25]([O:24][CH3:23])[CH:33]=[CH:32][C:31]=3[O:34][CH3:35])[CH2:27]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccc2c([C@@H]3CO3)ccc(OCc3ccccc3)c2[nH]1
Reactant: COc1ccc(OC)c2c1CC(N)C2
Solvent: Cc1ccccc1
Product: COc1ccc(OC)c2c1CC(NC[C@H](O)c1ccc(OCc3ccccc3)c3[nH]c(=O)ccc13)C2
Temperature: 110 °C
Reaction time: 4 h

Procedure:
(R)-8-Benzyloxy-5-oxiranylcarbostyril (100 mg, 0.34 mmol), prepared from literature procedure (Beeley, Lee James; Dean, David Kenneth, PCT Int. Appl. WO 9525104) and 4,7-dimethoxy-indan-2-ylamine (66 mg, 0.34 mmol), prepared from literature procedure (Sindelar, R. D.; Mott, J.; Barfknecht, C. F.; Arneric, S. P.; Flynn, J. R.; Long, J. P.; Bhatnagar, R. K. J. Med. Chem. (1982), 25(7), 858-64), are dissolved in toluene (1 mL). The reaction mixture was heated to 110° C. and the solvent is allowed to evaporate. The residue is then stirred at 110° C. for 4 hours. The reaction is shown to be complete by TLC. The product is purified by flash column chromatography (silica, dichloromethane/methanol 20:1). TLC (silica, dichloromethane/methanol 25:1 Rf=0.10). ES+ MS m/e 487 (MH+).
Reaction SMILES: Cl.C(OC(=O)[N:8]([CH2:23][CH2:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([NH:33][C:34]([NH:36][C:37]2[CH:42]=[N:41][C:40]([C:43]#[N:44])=[CH:39][N:38]=2)=[O:35])=[CH:27][C:26]=1[Cl:45])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)(C)(C)C.C(OCC)C>O1CCOCC1.C(#N)C>[ClH:45].[Cl:45][C:26]1[C:25]([CH2:24][CH2:23][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=[CH:30][C:29]([O:31][CH3:32])=[C:28]([NH:33][C:34]([NH:36][C:37]2[CH:42]=[N:41][C:40]([C:43]#[N:44])=[CH:39][N:38]=2)=[O:35])[CH:27]=1
Reactant: COc1cc(CCN(Cc2ccc(N3CCN(C)CC3)cc2)C(=O)OC(C)(C)C)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CC#N
Product: COc1cc(CCNCc2ccc(N3CCN(C)CC3)cc2)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 155.6 %

Procedure:
A 3 N HCl solution in 1,4-dioxane (10 mL) was added to a stirred solution of tert-butyl-2-chloro-4-(3-(5-cyanopyrazin-2-yl)ureido)-5-methoxyphenethyl(4-(4-methylpiperazin-1-yl)benzyl)carbamate (0.5 g) in acetonitrile (50 mL) at 5° C. The reaction mixture was allowed to warm to room temperature and stirring continued for 1 hour. Diethylether (150 ml) was added and the precipitated solid collected by filtration. The solid was triturated with diethylether, methanol, diethylether then dried at reduced pressure to yield the title compound (0.35 g, 70%) as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]([Br:21])=[CH:19][N:18]([CH3:22])[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[Br:21][C:20]1[C:16]([C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:15])=[N:17][N:18]([CH3:22])[CH:19]=1
Reactant: Cn1cc(Br)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(Br)c(C(=O)N2CCNCC2)n1
Yield: 100.1 %

Procedure:
4-(4-Bromo-1-methyl-1H-pyrazole-3-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (800 mg, 2.14 mmol) from Step A and HCl in dioxane (4 N, 5.36 mL) was stirred at room temperature for 1 h. The solvent was removed under reduced pressure to afford the hydrochloride salt of the title compound (585 mg) as a light yellow solid. 1H NMR (Acetonitrile-d3, 400 MHz) δ 3.20-3.26 (m, 4H), 3.92 (s, 3H), 3.98-4.05 (m, 4H), 7.71 (s, 1H), 9.40-9.50 (bs, 2H). Exact mass calculated for C9H13BrN4O: 272.0. Found: LCMS m/z (%)=273.0 (M+H+79Br, 100%), 275.0 (M+H+81Br, 97%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:9][C:5]2[C:4]([O:10][CH3:11])=[N:3][C:2]([Cl:1])=[C:7]([Cl:8])[N:6]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: COc1nc(Cl)c(Cl)nc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: COc1nc(Cl)c(Cl)nc1NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6-dichloro-3-methoxy-2-pyrazinamine (0.1 g) and 4-chlorobenzenesulphonyl chloride (0.13 g). Yield 0.09 g.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:14]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: N#Cc1ccc(Br)c(C(F)(F)F)c1
Reactant: C1CCNC1
Product: N#Cc1ccc(N2CCCC2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared using an analogous method as described in Example 1.1, utilising 4-bromo-3-(trifluoromethyl)-benzonitrile and pyrrolidine (Fluka, Buchs, Switzerland), with a reaction temperature of 95° C.
Reaction SMILES: C(OC([N:11]1[CH2:18][C@H:17]2[C@:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:14][CH2:15][CH2:16]2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].CO>[C:23]([O:22][C:20]([NH:19][C:13]12[CH2:14][CH2:15][CH2:16][CH:17]1[CH2:18][NH:11][CH2:12]2)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@]12CCC[C@H]1CN(C(=O)OCc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC12CCCC1CNC2
Yield: 104.4 %

Procedure:
A 10% palladium-carbon catalyst (about 50% wet, 114 mg) was added to a solution of (−)-(1R*,5S*)-3-benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-3-azabicyclo[3.3.0]octane (569 mg, 1.579 mmol) in methanol (30 mL), and the mixture was stirred in a hydrogen atmosphere at room temperature for two hours. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure to give crude 1-(tert-butoxycarbonylamino)-3-azabicyclo[3.3.0]octane (373 mg) as a colorless transparent gummy solid.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH2:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:23][C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:25].C(=O)([O-])O.[Na+]>C(#N)C>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][C:24]([CH2:23][N:12]2[CH2:13][CH2:14][N:9]([CH2:8][C:7]3[CH:6]=[C:5]([O:4][CH3:3])[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=3)[CH2:10][CH2:11]2)=[O:25])=[CH:28][CH:29]=1
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: COc1ccc(OC(=O)CCl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(OC(=O)CN2CCN(Cc3cc(OC)c(OC)c(OC)c3)CC2)cc1

Procedure:
A mixture of 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (prepared by the method disclosed in Belgian Pat. No. 560,330) (50 g), 4-methoxyphenyl chloroacetate (prepared by the method disclosed in U.S. Pat. No. 3,657,318) (33 g), sodium hydrogen carbonate (49 g) and acetonitrile (700 ml) is stirred at 60° C. for 3 hours. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure to give crude 1-[(4-methoxyphenoxy)carbonylmethyl]-4-(3,4,5-trimethoxybenzyl)piperazine (free base) (60 g) as an oily substance. This crude free base (60 g) is dissolved in a mixture of water (200 ml) and acetonitrile (50 ml) and thereto is added fumaric acid of about 2 moles (41 g) to 1 mole of the free base, and the mixture is heated. After the reaction mixture is allowed to cool at room temperature, the precipitated crystals are separated by filtration and recrystallized from a mixture of water and acetonitrile to give 1-[(4-methoxyphenoxy)carbonylmethyl]-4-(3,4,5-trimethoxybenzyl)piperazine difumarate monohydrate (73.5 g) as colorless crystals.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[C:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37]S(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:37][CH2:36][CH2:35][C:33]3[N:34]=[C:30]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[O:31][C:32]=3[CH3:48])=[CH:11][CH:12]=2)[C:4]([OH:23])=[O:3])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)cc2)C(=O)O)cc1

Procedure:
Standard Procedure (B) was utilized to prepare the title compound from 2-(4-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C@H:3]([NH:8][C@H](C1C=CC=CC=1)C)[C:4]([NH:6][CH3:7])=[O:5]>CO.[Pd]>[CH3:7][NH:6][C:4](=[O:5])[C@H:3]([C:2]([CH3:18])([CH3:17])[CH3:1])[NH2:8]
Reactant: CNC(=O)[C@@H](N[C@@H](C)c1ccccc1)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CNC(=O)[C@@H](N)C(C)(C)C
Yield: 98.5 %

Procedure:
A solution of 12.4 g (50 mmol) of (S)-3,3,N-trimethyl-2-[(S)-1-phenylethylamino]-butyramide in 206 ml of methanol was hydrogenated in a 380 ml autoclave in the presence of 1.2 g of 5 percent Pd/C at 50° C. and under a pressure of 4 bar for 6 hours. After pressure release the catalyst was filtered off and the filtrate was evaporated to dryness. There were obtained 7.1 g (98.5%) of (S)-N-methyl-tert-leucinamide as white crystals, 99.2% e.e.