Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]([NH:11][C@H:12]([C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]([OH:33])=[O:32])[C:26](=[O:34])[C@@H:25]1[CH2:35][C:36]([O:38][CH3:39])=[O:37])=[O:23])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:10])C1C=CC=CC=1>CO.[C].[Pd]>[C:14]([O:8][C:9]([NH:11][C@H:12]([C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]([OH:33])=[O:32])[C:26](=[O:34])[C@@H:25]1[CH2:35][C:36]([O:38][CH3:39])=[O:37])=[O:23])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)=[O:10])([CH3:19])([CH3:15])[CH3:13]
Reactant: COC(=O)C[C@H]1C(=O)N(CC(=O)O)CCN1C(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)O)CCN1C(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 185.3 %

Procedure:
In 300 ml of methanol was dissolved 19 g of (S)-4-(N-benzyloxycarbonyl-O-methyl-L-tyrosyl)-3-methoxycarbonylmethyl-2-oxopiperazine-1-acetic acid. To the solution was added 2.5 g of 10% palladium-carbon, and the mixture was stirred under hydrogen atomosphere for 1.5 hour. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in a mixture of 200 ml of water and 50 ml of 1,4-dioxane, to which was added 7.36 ml of triethylamine. To the mixture was added, under ice-cooling, 8.4 g of di-t-butyl dicarbonate. The reaction mixture was adjusted to pH 2 with 5% potassium hydrogensulfate, followed by extraction with ethyl acetate and drying over anhydrous sodium sulfate. The extract solution was concentrated under reduced pressure to give 16.5 g of the title compound in a crude state as a colorless powdery product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([NH:25][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1)[CH2:22][CH2:23][CH3:24]
Reactant: O=C(c1ccc(F)cc1)N1CCC[C@H]1CN1CCCC1
Reactant: CCCCN
Product: CCCCNc1ccc(C(=O)N2CCC[C@H]2CN2CCCC2)cc1

Procedure:
(4-Butylamino-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone is prepared from (4-Fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and n-butylamine in a manner substantially similar to Procedure A. MS (APCI+) 330 (MA-H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[C:13]([Cl:16])[CH:14]=2)[C:9](=[O:18])[N:8]([CH2:19][CH2:20][C:21]([OH:23])=O)[C:7]=1[CH2:24][N:25]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]1=[O:35])[CH2:2][CH2:3][CH3:4].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[C:13]([Cl:16])[CH:14]=2)[C:9](=[O:18])[N:8]([CH2:19][CH2:20][C:21](=[O:23])[N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[C:7]=1[CH2:24][N:25]1[C:26](=[O:35])[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]1=[O:34])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CCC(=O)O)c(=O)c2cc(Cl)c(Cl)cc12
Reactant: C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CCC(=O)N2CCCC2)c(=O)c2cc(Cl)c(Cl)cc12
Yield: 52.6 %

Procedure:
A solution of 3-[4-butoxy-6,7-dichloro-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-oxo-2(1H)isoquinolinyl]propionic acid (1.03 g, 2.4 mmol), pyrrolidine (0.20 ml, 2.4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.46 g, 2.4 mmol) and 1-hydroxybenzotriazole (0.37 g, 2.4 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from tetrahydrofuran-diisopropyl ether to give 2-[[4-butoxy-6,7-dichloro-1-oxo-2-[3-oxo-3-(1-pyrrolidinyl)propyl]-1,2-dihydro-3-isoquinolinyl]-methyl]-1H-isoindole-1,3(2H)-dione (0.72 g, 66.1%) as crystals.
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[C:13]1([C:19]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@H:27]3[C@H:23]([CH2:24][N:25]([C:28](=O)[CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH3:37])[CH2:26]3)[C:22](=[O:39])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH3:46].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[NH:46]=[C:28]([N:25]1[CH2:24][C@H:23]2[C@H:27]([C:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:20][CH2:21][C:22]2=[O:39])[CH2:26]1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37]
Reactant: N
Reactant: COc1ccccc1CC(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COc1ccccc1CC(=N)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Triethyloxonium tetrafluoroborate (4 g) is added to a solution of (3aR,7aR)-7,7-diphenyl-2-[(2-methoxyphenyl)acetyl]perhydro-4-isoindolone (7.7 g) in anhydrous dichloromethane (13 cc). The reaction mixture is left stirring for 20 hours at room temperature; the mixture is then cooled to -15° C. and thereafter a 5.4N ethanolic solution (2.6 cc) of ammonia is added. The reaction mixture is allowed to return to room temperature and stirring is continued for 5 hours and a half. The reaction mixture is treated with 10% strength aqueous potassium carbonate solution (20 cc); the precipitate formed is drained and washed with dichloromethane (10 cc). The organic phases are combined, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in acetonitrile (10 cc); the crystals obtained are drained, washed with acetonitrile (5 cc) and with isopropyl ether (10 cc) and dried. They are then chromatographed on a column of Pechiney CBT1 neutral alumina gel (diameter 4.5 cm, height 28 cm), eluting with a mixture (200 cc) of 1,2-dichloroethane and methanol (98:2 by volume) and then with a mixture of 1,2-dichloroethane and methanol (90:10 by volume) and collecting 25-cc fractions. Fractions 8 to 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in acetonitrile (10 cc); the crystals obtained are drained and dried. (3aR,7aR)-2-[1-Imino-2-(2-methoxyphenyl)ethyl]-7,7-diphenylperhydro-4-isoindolone (1.6 g), m.p. 190° C., is obtained; [α]D20 =-254° (c=1, methanol).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][C:13]=1[C:14]#[C:15][CH3:16])(C)(C)C.C1CCN2C(=NCCC2)CC1>CO.O>[CH3:16][C:15]1[NH:7][C:8]2=[CH:9][N:10]=[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=[C:13]2[CH:14]=1
Reactant: CC#Cc1cc(-c2ccccc2)ncc1NC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Solvent: O
Product: Cc1cc2cc(-c3ccccc3)ncc2[nH]1
Temperature: 60 °C
Reaction time: 24 h
Yield: 99.6 %

Procedure:
A solution of (6-phenyl-4-prop-1-ynylpyridin-3-yl)carbamic acid tert-butyl ester (670 mg, 2.17 mmol) in a mixture of 33 mL of methanol and 11 mL of water was treated with DBU (2.0 mL, 13.4 mmol). The resulting mixture was heated at 60° C. After 24 hours, the mixture was concentrated in vacuo, 50 mL of water was added, the mixture was sonicated, and the resulting solid was filtered. The solid was dried over P2O5 in vacuum to give 450 mg of the title product as a yellow solid (99% yield), which was used without further purification.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:6][C@H:7]([NH:27][C:28](=[O:30])[CH3:29])[C@H:8]([OH:26])[CH2:9][NH:10][C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Br[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].CC(C)([O-])C.[K+].C1COCC1.OP([O-])(O)=O.[K+]>CC(C)=O.C(OCC)(=O)C>[ClH:1].[ClH:1].[CH2:36]([O:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:6][C@H:7]([NH:27][C:28](=[O:30])[CH3:29])[C@H:8]([OH:26])[CH2:9][NH:10][C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CC(=O)N[C@@H](Cc1cc(O)cc(F)c1)[C@H](O)CNC1(c2cccc(C(C)C)c2)CCCCC1
Reactant: CCCCCCBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCCCCOc1cc(F)cc(C[C@H](NC(C)=O)[C@H](O)CNC2(c3cccc(C(C)C)c3)CCCCC2)c1
Yield: 125 %

Procedure:
To 0.40 mmol of hydrochloride 11 in 3 mL of acetone is added 0.29 mL (2.1 mmol) of 1-bromohexane. The mixture is heated to reflux, and 0.6 mL of a 1 M solution of potassium t-butoxide in THF (0.6 mmol) is added. After 1.2 h the mixture is cooled and aqueous 1 N KH2PO4 and ethyl acetate are added. The organic phase is washed twice with 1 N NaHCO3 and once with brine, dried over Na2SO4, and concentrated. Chromatography over silica gel, eluting with 7%–9& methanol (containing 1% of NH4OH) in CH2Cl2, affords a colorless oil. Treatment with ethereal HCl produces 147 mg (0.25 mmol, 64%) of hydrochloride 12 as a white solid: 1H NMR (CDCl3+CD3OD drop) δ 7.45 (s, 1H), 7.37 (m, 2H), 7.27 (m, 1H), 6.50 (s, 1H), 6.43 (m, 2H), 3.98 (m, 1H), 3.88 (m+t, J=6.5 Hz, 3H), 2.93 (m, 2H), 2.63 (m, 4H), 2.38 (m, 1H), 2.09 (m, 2H), 1.89 (s, 3H), 1.75 (m, 4H), 1.59 (m, 1H), 1.43–1.32 (m, 10H), 1.27 (d, J=7 Hz, 6H), 0.90 (t, J=7 Hz, 3H); MS (CI) m/z 541.5 (MH+).
Reaction SMILES: [CH3:1][S:2][C:3]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22](O)=[O:23])=[CH:10][CH:9]=1)([CH3:7])[C:4]([OH:6])=[O:5]>C(O)(=O)C>[CH3:1][S:2][C:3]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:15](=[O:25])[C:16]3=[CH:21][CH:20]=[CH:19][CH:18]=[C:17]3[C:22]2=[O:23])=[CH:12][CH:13]=1)([CH3:7])[C:4]([OH:6])=[O:5]
Reactant: CSC(C)(C(=O)O)c1ccc(NC(=O)c2ccccc2C(=O)O)cc1
Solvent: CC(=O)O
Product: CSC(C)(C(=O)O)c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Yield: 96.6 %

Procedure:
α-Methylthio-α-(p-(o-carboxybenzoylamino)phenyl)propionic acid (146 mg) was dissolved in 1 ml of acetic acid, and the solution was heated under reflux for 3 hours. Acetic acid was removed under reduced pressure to afford 134 mg of α-methylthio-α-(p-phthalimidophenyl)propionic acid as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH2:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([SH:24])[CH:21]=[CH:22][CH:23]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:15][S:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[CH:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=1
Reactant: C=C(C(=O)OCC)c1ccc(OC)cc1
Reactant: COc1cccc(S)c1
Product: CCOC(=O)C(CSc1cccc(OC)c1)c1ccc(OC)cc1

Procedure:
A process for preparing a compound of formula (6): ##STR120## characterized in that a compound of formula (1): ##STR121## is reacted with oxalic acid diethyl ester and sodium hydride to produce a compound of formula (2): ##STR122## the resulting compound of formula (2) is reacted with 3-methoxybenzenethiol represented by the formula: ##STR123## to produce a compound of formula (3): ##STR124## the resulting compound of formula (3) is reacted with hydrochloric acid to produce a compound of formula (4): ##STR125## the compound of formula formula (4) is then cyclized to produce a compound of formula (5): ##STR126## and the compound of formula (5) is reacted with methyl iodide in the presence of lithium diisopropylamide to produce the compound of formula (6).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH:10]([OH:36])[CH2:11][NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:29]([O:31]C(C)(C)C)=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)(C)(C)C.CCOCC.[ClH:46]>C(O)(=O)C>[ClH:46].[NH2:8][C@@H:9]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH:10]([OH:36])[CH2:11][NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:29]([OH:31])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NCC(O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NCC(O)[C@@H](N)CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-[N-[(3S)-3-[[(t-butyloxy)carbonyl]amino]-2-hydroxy-5-methylhexyl]-L-phenylalanyl-L-leucine, t-butyl ester (845 mg, 1.5 mmol) in 22 ml of 1.3N hydrogen chloride in acetic acid was allowed to stir at room temperature for 2 hours. The resultant thick white slurry was evaporated to dryness in vacuo. The residue was dissolved in water and the solution was microfiltered and concentrated in vacuo to give a white gummy residue. Trituration with ether afforded 698 mg of the title compound as a fine white powder, melting point 179°-203° C. (with decomposition). The 13C-NMR spectrum was consistent with an approximately 2:1 mixture of alcohol isomers.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][C:12]([O:14]CC)=[O:13])=[N:8][CH:9]=1)(=[O:3])[CH3:2].CO.O.[OH-].[Li+]>C1COCC1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CNc1ccc(C(C)=O)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(NCC(=O)O)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.2 %

Procedure:
To a solution of the product of step 1 (1.1 gm, 5.3 mmoles) in a mixture of THF (12 ml), methanol (4 ml) and water (4 ml), lithium hydroxide (444 mg, 10.6 mmoles) was added and the reaction mixture was stirred at ambient temperature for 4 hours. The solvents were evaporated under reduced pressure. The residue was dissolved in water, acidified with 1N HCl and evaporated in vacuum. The residue was diluted with ethyl acetate, stirred for 30 min and filtered. The filtrate was concentrated in vacuum to yield 1.0 gm (98%) of title product as off white solid.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:13]=[O:14])[CH:11]=[O:12])=[CH:6][CH:5]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:13][OH:14])[CH2:11][OH:12])=[CH:8][CH:9]=1
Reactant: O=CC(C=O)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCC(CO)c1ccc(Br)cc1
Reaction time: 1.5 h
Yield: 66.3 %

Procedure:
Sodium borohydride (433 mg, 11.5 mmol) was added slowly to a solution of 2.0 g (8.81 mmol) of 2-(4-bromophenyl)malonaldehyde in tetrahydrofuran (20 ml) under ice cooling, and the mixture was stirred for 1.5 hr. A saturated aqueous sodium hydrogencarbonate solution was added thereto. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was removed by distillation, and the residue was then purified by column chromatography on silica gel (hexane:ethyl acetate=1:1 to 1:4) to give 1.35 g (yield 66%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C([Li])CCC.CON(C)[C:28](=[O:30])[CH3:29].[Cl-].[NH4+]>O1CCCC1.CCCCCC.[Cl-].[Na+].O>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:5]2[N:6]=[CH:7][C:2]([C:28](=[O:30])[CH3:29])=[CH:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1ccc(CNc2ccc(Br)cn2)cc1
Reactant: CON(C)C(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(NCc2ccc(C(F)(F)F)cc2)nc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
(5-Bromo-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-amine (17, 3.00 g, 9.06 mmol, prepared as described in Example 10, Scheme 12) was dissolved in tetrahydrofuran (80 mL). The reaction was cooled at −78° C. under an atmosphere of argon. 2.5 M n-butyllithium in hexane (10.9 ml) was added. The reaction was stirred at −78° C. for 60 minutes. N-Methoxy-N-methylacetamide (1.93 mL, 18.1 mmol) was added to the reaction, which was allowed to warm to room temperature. The reaction was poured into 1M ammonium chloride and brine and extracted with ethyl acetate. The organic portions were dried with anhydrous sodium sulfate, filtered and the filtrate was adsorbed onto silica. The mixture was purified by silica gel chromatography (ethyl acetate:hexanes) to provide the desired compound as an oil that crystallized to a white solid (620, 1.328 g, 50%), consistent with the compound structure by 1H-NMR and MS(ESI): [M+H+]+=295.3.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:43])[NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:39]=[CH:38][C:24]([CH2:25][N:26]([CH2:34][CH2:35][O:36][CH3:37])C(=O)OC(C)(C)C)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)[CH2:3][CH2:2]1.Cl.O1CCOCC1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:39]=[CH:38][C:24]([CH2:25][NH:26][CH2:34][CH2:35][O:36][CH3:37])=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)=[O:43])[CH2:3][CH2:2]1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
To a solution of 112 (560 mg, 0.923 mmol) in DCM (10 mL) was added 4.0M HCl in dioxane (0.923 mL, 3.69 mmol) and the reaction mixture was stirred at RT for 2 hours. The mixture was diluted with saturated NaHCO3 solution and the layers were separated. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. The resultant solid was triturated with Et2O to afford title compound 113 (350 mg, 75% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.69 (s, 1H), 8.48 (d, J=5.48 Hz, 1H), 8.00 (s, 1H), 7.82 (d, J=8.41 Hz, 1H), 7.70 (m, 1H), 7.44 (d, J=8.22 Hz, 1H), 7.36 (t, J=9.19 Hz, 1H), 7.19 (m, 1H), 6.56 (m, 2H), 3.75 (s, 2H), 3.39 (t, J=5.67 Hz, 2H), 3.22 (s, 3H), 2.64 (t, J=5.67 Hz, 2H), 2.53 (m, 1H), 0.63 (m, 2H), 0.41 (m, 2H). MS (m/z)=507.5 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]1)=[O:13].Br[CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]#[C:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:31][CH:30]=1>>[CH3:24][O:23][C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([NH:14][C:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[O:1][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]#[C:38][CH2:39][O:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:31][CH:30]=2)[C:6]([O:8][CH3:9])=[O:7])=[O:13])[CH2:16]1)=[O:22]
Reactant: COC(=O)c1ccc(O)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Reactant: BrCCCc1ccc(OCC#CCOc2ccccc2)cc1
Product: COC(=O)c1ccc(OCCCc2ccc(OCC#CCOc3ccccc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 22 from the (+)-B-enantiomer of methyl 4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate (see Example IX, method 2) and 1-(3-bromopropyl)-4-[(4-phenoxybut-2-yn-1-yl)oxy]benzene.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=O)[CH2:12][C:13](=O)[CH3:14])=[CH:7][CH:6]=1.O>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([CH3:14])[N:3]=[N:2][C:16]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[CH:7][CH:6]=1
Reactant: NN
Reactant: CSc1ccc(C(=O)C(CC(C)=O)c2ccc(Cl)cc2)cc1
Solvent: CCO
Solvent: O
Product: CSc1ccc(-c2nnc(C)cc2-c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 7 h
Yield: 64.4 %

Procedure:
Hydrazine hydrate (72 mg, 1.44 mmol) was added to a solution of 4-(4-chlorophenyl)-5-[4-(methylthio)phenyl]pentane-2,5-dione (317 mg, 0.953 mmol) in ethanol (6 ml), and the resulting mixture was stirred for 7 hours at a bath temperature of 80° C. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed successively with water and brine, and was then dried over anhydrous sodium sulfate. The solvent was distilled off and the residue (320 mg) was dissolved in chloroform. The thus-obtained solution was stirred at room temperature for 7 hours to conduct air oxidation. The solvent was distilled off and the residue (296 mg) was separated and purified by preparative thin-layer chromatography on silica gel (developing solvent: chloroform), whereby the title compound was obtained as a pale yellow oil (200.5 mg, 64.3%).
Reaction SMILES: Cl.[CH3:2][O:3][N:4]1[CH2:9][CH2:8][C:7](=[CH:10][O:11]C)[CH2:6][CH2:5]1>C1COCC1>[CH3:2][O:3][N:4]1[CH2:9][CH2:8][CH:7]([CH:10]=[O:11])[CH2:6][CH2:5]1
Reactant: COC=C1CCN(OC)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CON1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Concentrated hydrochloric acid (7 mL) was added to a solution of 1-methoxy-4-methoxymethylene-piperidine (9.2 g, 58 mmol) in THF (100 mL), and the mixture was stirred at room temperature for 4 h. The organic solvent was removed under reduced pressure, and the reaction mixture was partitioned between methylene chloride and water. The separated organic layer was dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel. Yield: 7.5 g of 1-methoxy-piperidine-4-carbaldehyde as an oil.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C2C=CC=CC=2)C=CC=CC=1>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %), 2-di-tert-butylphosphino)biphenyl (6.0 mg, 0.02 mmol, 2.0 mol %), phenylboronic acid (183 mg, 1.5 mmol), potassium fluoride (174 mg, 3.0 mmol), and 1-chloro-4-nitrobenzene (158 mg, 1.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) was added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL), filtered through celite, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 196 mg (98%) of the title compound.
Reaction SMILES: [H-].[Na+].[CH:3]([O:5][CH3:6])=[O:4].[F:7][C:8]([F:22])([F:21])[C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](OC)=[O:18])=[CH:11][N:10]=1>COCCOC>[OH:18]/[CH:17]=[C:16](/[CH2:15][C:12]1[CH:11]=[N:10][C:9]([C:8]([F:22])([F:21])[F:7])=[N:14][CH:13]=1)\[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)CCc1cnc(C(F)(F)F)nc1
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)/C(=C\O)Cc1cnc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of NaH (360 mg, 9.00 mmol) in DME (20 mL) was added a solution of methyl formate (0.254 mL, 4.10 mmol) and methyl 3-[2-(trifluoromethyl)-5-pyrimidinyl]propanoate (800 mg, 3.42 mmol) in DME (20 mL) at 0° C. The mixture was stirred at room temperature overnight, and quenched with MeOH. Purification via reverse phase flash chromatography afforded the title compound (730 mg, 2.78 mmol, 82% yield) as yellow solid. LCMS: rt=2.03 min, [M+H+]=263.