Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH2:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][S:37](Cl)(=[O:39])=[O:38]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH:28][S:37]([CH2:36][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[Cl:29])(=[O:38])=[O:39])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNS(=O)(=O)Cc4ccccc4Cl)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(4-aminomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and (2-chloro-phenyl)-methanesulfonyl chloride.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:14][CH2:15][C:16]([CH2:18][O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[O:17])(=[O:13])[CH:10]([CH3:12])[CH3:11].Cl>C(OCC)C>[C:9]([O:14][CH2:15][C:16]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([OH:17])[CH2:18][O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])(=[O:13])[CH:10]([CH3:12])[CH3:11]
Reactant: Brc1ccccc1
Reactant: CC(C)C(=O)OCC(=O)COC(=O)C(C)C
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)C(=O)OCC(O)(COC(=O)C(C)C)c1ccccc1
Temperature: -50 °C
Reaction time: 1 h
Yield: 108.6 %

Procedure:
Under an atmosphere of argon, 2 ml of diethyl ether was slowly added to 695 mg of magnesium turnings, and then thereto was added dropwise 4 g of bromobenzene dissolved in 10 ml of diethyl ether. The resulting liquid was stirred for 1 hour under refluxing and allowed to cool. That liquid was added dropwise to 50 ml of diethyl ether solution of 3.78 g of 1,3-diisobutyryloxyacetone which was previously cooled to -50° C. After the resulting liquid was stirred at -50° C. for 1 hour, a temperature thereof was gradually raised to room temperature. Then, the reaction mixture was added to 50 ml of 2N aqueous solution of hydrochloric acid at 5° C. or below, and an organic layer was separated and the aqueous layer was extracted twice with 50 ml of ethyl acetate. The organic layers were combined and washed three times with 1N aqueous solution of sodium hydroxide, washed twice with saturated aqueous solution with sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 5.5 g of the desired compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][OH:12].[H-].[Na+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C.O>[C:20]([O:19][C:17](=[O:18])[CH2:16][O:12][CH2:11][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[C:7]([CH3:8])[C:2]=1[Br:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1cc(C)c(Br)c(CO)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)c(Br)c(COCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A solution of (2-bromo-5-methoxy-3-methyl-phenyl)-methanol ((Example 192: step c) 0.800 g, 3.46 mmol) in DMF (10 mL) was cooled to 0° C. and treated with NaH (0.100 g of 95% dispersion, 4.15 mmol) and allowed to warm to room temperature 30 min. The mixture was then treated with tert-butyl bromoacetate (0.614 mL, 4.15 mmol) and stirred at room temperature 1 h. The reaction was diluted with water and extracted with EtOAc (2×125 mL). The combined organic layers were washed well with water (3×300 mL), dried over MgSO4, and concentrated in vacuo to afford the product (2-bromo-5-methoxy-3-methyl-benzyloxy)-acetic acid tert-butyl ester (1.19 g, 98%) as a yellow oil. 1H NMR (CDCl3): δ 6.967 (d, 1H, J=2.8 Hz), 6.745 (d, 1H, J=3.2 Hz), 4.683 (s, 2H), 4.086 (s, 2H), 3.794 (s, 3H), 2.380 (s, 3H), 1.496 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]([C:11]([OH:13])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH3:14][Si](C=[N+]=[N-])(C)C>CO.C(OCC)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: Nc1cc2c(cn1)C(C(=O)O)CC2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C1CCc2cc(N)ncc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-amino-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylic acid from Step F in methanol (10 mL) was treated dropwise with a solution of trimethylsilyl diazomethane in diethyl ether (2.0 M, 1.96 mL) at 0° C. After complete addition, the reaction warmed to room temperature and stirred 30 min, then was concentrated. The resulting residue was dried under high vacuum to afford methyl 3-amino-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylate. 1H NMR (500 MHz, CDCl3), δ 8.26 (s, 1H), 8.19 (s, 1H), 8.05 (br s, 2H), 4.00 (m, 1H), 3.75 (s, 3H), 3.01 (m, 1H), 2.83 (m, 1H), 2.44 (m, 1H), 2.32 (m, 1H); LC/MS (M+1)+=193.0;
Reaction SMILES: CC([Si](C(C)C)(C(C)C)[O:5][C:6]1[C:11]2[C:12]([CH3:16])([CH3:15])[CH2:13][O:14][C:10]=2[C:9]([CH3:17])=[CH:8][CH:7]=1)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:15][C:12]1([CH3:16])[C:11]2=[C:6]([OH:5])[CH:7]=[CH:8][C:9]([CH3:17])=[C:10]2[O:14][CH2:13]1
Reactant: Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)c2c1OCC2(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(O)c2c1OCC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
Tris(1-methylethyl)[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]silane (Intermediate 183, 3.6 g, 10.84 mmol) was dissolved in THF (36 mL) to obtain a dark yellow solution. TBAF (8.5 g, 32.5 mmol) was added and the reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with aqueous HCl, then aqueous NaHCO3 and finally brine. The organic solution was dried over Na2SO4 and evaporated to dryness and the residue was purified by flash chromatography on silica gel using cyclohexane to cyclohexane/ethyl acetate 95:5 as eluents affording the title compound (1.69 g) as colorless oil.
Reaction SMILES: [CH:1]1([NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=3)[CH3:17])[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO>[CH:1]1([NH:7][C:8]([CH:10]2[CH2:11][CH2:12][N:13]([CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=3)[CH3:17])[CH2:14][CH2:15]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(c1cccc([N+](=O)[O-])c1)N1CCC(C(=O)NC2CCCCC2)CC1
Solvent: CO
Product: CC(c1cccc(N)c1)N1CCC(C(=O)NC2CCCCC2)CC1
Temperature: 25 °C
Yield: 102.1 %

Procedure:
A solution of rac-1-[1-(3-nitro-phenyl)-ethyl]-piperidine-4-carboxylic acid cyclohexylamide (375 mg, 1.04 mmol) in MeOH (15 mL) is treated with anhydrous stannous chloride (908 mg, 4.7 mmol). The mixture is heated at reflux overnight. The mixture is let to cool to RT and MeOH is evaporated under reduced pressure. Water (25 mL) is added to the residue, followed by saturated NaHCO3 solution (25 mL). The mixture is extracted twice with DCM (25 mL), the organic phases are washed with water (25 mL), brine (25 mL) and dried over MgSO4. The crude product (0.35 g, 99%) is isolated after evaporation under reduced pressure as a colorless oil: LC-MS A: tR=0.51 min; [M+H]+=330.31.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([C:18]3[CH2:19][CH2:20][S:21](=[O:25])(=[O:24])[CH2:22][CH:23]=3)=[C:13]([F:26])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:46][C:47]1NN=N[N:48]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.CO>[O:25]=[S:21]1(=[O:24])[CH2:20][CH:19]=[C:18]([C:14]2[C:15]([F:17])=[CH:16][C:11]([N:7]3[CH2:6][C@H:5]([CH2:4][N:1]4[N:2]=[N:3][C:47]([CH3:46])=[N:48]4)[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[F:26])[CH2:23][CH2:22]1
Reactant: Cc1nnn[nH]1
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2cc(F)c(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nnn(C[C@H]2CN(c3cc(F)c(C4=CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 56.7 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-(hydroxymethyl)-oxazolidin-2-one (WO 01/81350 A1) (0.50 g, 1.39 mmol), triphenylphosphine (0.55 g, 2.1 mmol), and 5-methyl-1H-tetrazole (0.18 g, 2.14 mmol) were dissolved in dry tetrahydrofuran (5 ml), and cooled on an ice-water bath. Diisopropylazodicarboxylate (0.41 ml, 2.58 mmol) was added dropwise and the mixture was stirred at 0° C. for 4 hours. Methanol (3 ml) was added, followed by evaporation of the solvent under reduced pressure and purification by flash column chromatography on silica gel with 10% acetonitrile in dichloromethane. The material obtained after chromatography was precipitated from dichloromethane with diethyl ether to give the title compound (0.335 g).
Reaction SMILES: CN1CCN=C1C1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:34])[CH:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])=CC=1.F[P-](F)(F)(F)(F)F.[N:42]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50]C=2N=N1>CN(C=O)C>[N:42]1[CH:46]=[CH:47][C:48]([N:13]2[CH2:10][CH2:11][CH:11]([CH2:10][NH:13][C:14](=[O:34])[CH:15]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[NH:16][C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)=[O:18])[CH2:12][CH2:14]2)=[CH:49][CH:50]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(C2=NCCN2C)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)NCC1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
To a solution of 2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (from EXAMPLE 84, 30 mg, 0.094 mmol), 4-[1-(pyridin-4-yl)piperidinyl]methylamine hydrochloride (36 mg, 0.19 mmol) and TEA (0.052 mL, 0.37 mmol) in DMF (3 mL), BOP (62 mg, 0.14 mmol) was added. After being stirred at room temperature for 2 h, the mixture was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (15 mg). MS 492.4 and 494.4 (M+H, Cl pattern).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30].[O:31]1[CH:36]=[CH:35][CH2:34][CH2:33][CH2:32]1>>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][O:31]1
Reactant: OCCCCCCCCCCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: BrCCCCCCCCCCCOC1CCCCO1
Reaction time: 8 h

Procedure:
Pyridine toluene 4-sulphonate (1,0 g, 4,0 mmol) and 11-Bromo-1-undecanol (10,0 g, 400 mmol) were dissolved in dry CH2CH2 (200 ml) at ambient temperature, and 3,4-dihydro-2H-pyrane (5,0 g, 60 mmol) was added. The reaction mixture was stirred overnight. The crude product was purified by flash chromatography on silica gel eluted with CH2Cl2. The yield of 11-Bromo-1(tetrahydro-2-pyranyloxy)undecane was 10,7 g (80%).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[NH:7]([C:8]1[S:9][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=S)Nc1ccccc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(Nc2ccccc2)n1

Procedure:
A mixture comprising 8.6 g of phenylthiourea, 10 g of ethyl bromopyruvate and 100 ml of ethanol was heated under reflux for 3 hours, and the reaction mixture was then concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crystals which formed were collected by filtration. washed with benzene, and then recrystallized from ethanol, giving the desired compound as pale yellow prismatic crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH:39]([CH3:41])[CH3:40])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH:39]([CH3:40])[CH3:41])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1ccccc1OC(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2OC(C)C)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 29.9 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.20 g, 0.006 mol) in N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (3.76 g, 0.029 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2-isopropoxy-phenoxy)-but-2-enoic acid ethyl ester (2.00 g, 0.006 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2-isopropoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (0.720 g, 28%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:16])([F:15])[CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:10][C:11]([F:16])([F:15])[CH2:12][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: OCCC(F)(F)F
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(OCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 39.1 %

Procedure:
To a stirred solution of 4-hydroxybenzaldehyde (0.36 g, 2.93 mmol), 3,3,3-trifluoropropanol (0.5 g, 4.39 mmol) and triphenylphosphine (1.15 g, 4.39 mmol) in dry THF (10 ml) at 0° C. under an atmosphere of argon was added dropwise diisopropylazodicarboxylate (0.89 g, 4.39 mmol). On completion of the addition, the reaction mixture was stirred at room temperature for 60 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (4:1 Hexane/EtOAc) to give the title compound (0.25 g, 46%) as a colourless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][O:34][C@H:33]([CH2:37]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>CC(N(C)C)=O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][O:34][C@H:33]([CH2:37][O:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: COc1cccc(CCc2ccccc2O)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(CCc2ccccc2OC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)c1
Yield: 92.3 %

Procedure:
Following a procedure similar to that described in Example 40(a), 1.14 g of 2-[2-(3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 20), 0.560 g of potassium t-butoxide and 1.86 g of (S)-4-t-butoxycarbonyl-2-(p-toluenesulfonyloxymethyl)morpholine were reacted in 25 ml of dimethylacetamide. The mixture was then worked up as described in Example 40(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.97 g (yield 92%) of the title compound as a colorless oil.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>>[CH:18]1([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:28][CH2:27][CH2:25][OH:26])=[O:24])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: NCCO
Reactant: COC(=O)c1ccc(OCc2c(C3CCCCC3)noc2C)nc1
Product: Cc1onc(C2CCCCC2)c1COc1ccc(C(=O)NCCO)cn1
Yield: 10 %

Procedure:
As described for example 31e, 6-(3-cyclohexyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (708 mg, 1.5 mmol) was converted, using ethanolamine instead of isopropylamine, to the title compound (55 mg, 10%) which was obtained as a light yellow oil after purification by chromatography (silica, 0 to 5% methanol in dichloromethane). MS: m/e=360.4 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][CH:4]([C:27]1([C:30]#[N:31])[CH2:29][CH2:28]1)[N:5]1[CH:9]=[C:8]([C:10]2[C:11]3[CH:18]=[CH:17][N:16](COCC[Si](C)(C)C)[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[N:6]1)#[N:2].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[C:1]([CH2:3][CH:4]([C:27]1([C:30]#[N:31])[CH2:29][CH2:28]1)[N:5]1[CH:9]=[C:8]([C:10]2[C:11]3[CH:18]=[CH:17][NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[N:6]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4(C#N)CC4)c3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCC(n1cc(-c2ncnc3[nH]ccc23)cn1)C1(C#N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
1-{2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}cyclopropanecarbonitrile (48 mg, 0.11 mmol) was stirred in a mixture of DCM (3 mL) and TFA (2 mL) for 3 hours. The solvents were removed in vacuo and the residue was re-dissolved in THF (3 mL). 6N NaOH (2 mL) was added and the resulting mixture was stirred at ambient temperature for 3 hours. The crude reaction mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded product (20 mg, 43%).
Reaction SMILES: [CH3:1][C@H:2]([N:11]1[CH2:15][CH2:14][C@H:13]([NH:16]C(=O)OCC2C=CC=CC=2)[C:12]1=[O:27])[C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]>[Pd].C(O)C>[NH2:16][C@H:13]1[CH2:14][CH2:15][N:11]([C@@H:2]([CH3:1])[C:3]([N:5]2[CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)=[O:4])[C:12]1=[O:27]
Reactant: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](N)C1=O
Reaction time: 16 h
Yield: 95.7 %

Procedure:
A mixture of benzyl (3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-ylcarbamate (20 g), 10% palladium on carbon (2 g) and ethanol (1.31) was stirred under an atmosphere of hydrogen for 16 h. The reaction mixture was filtered through Celite™ and the filtrate was concentrated under reduced pressure to give the title compound (12.3 g) as a pale white oil.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[NH:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:30]=[CH:31][CH:32]=1)[O:17][CH2:18][C:19]1[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=1[C:21](Cl)=[N:22][O:23][CH3:24]>CCOCC>[Cl:13][C:14]1[CH:15]=[C:16]([CH:30]=[CH:31][CH:32]=1)[O:17][CH2:18][C:19]1[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=1[C:21]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)=[N:22][O:23][CH3:24]
Reactant: CON=C(Cl)c1ccccc1COc1cccc(Cl)c1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CON=C(c1ccccc1COc1cccc(Cl)c1)n1ccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.3 %

Procedure:
N,N-Dimethylformamide (3 ml) and 60% sodium hydride (0.16 g, 3.9 mmol) were added to imidazole (0.27 g, 3.9 mmol), and the mixture was stirred at room temperature for 10 minutes. Then, 2-(3-chlorophenoxymethyl)-α-methoxyiminobenzyl chloride (0.40 g, 1.3 mmol) was added, and the mixture was stirred at 110° C. for 2 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was washed with brine (80 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 1-[2-(3-chlorophenoxymethyl)-α-methoxyiminobenzyl]imidazole (0.29 g, 65.3%) as colorless crystals. mp. 96.5-97.5° C.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[C:16]([CH2:19][NH:20][C@H:21]([C:25]([OH:27])=[O:26])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][C:5]1=2)#[N:2].[C:28](Cl)(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32]>ClCCl.C(N(C(C)C)CC)(C)C>[C:1]([CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[C:16]([CH2:19][N:20]([C:28](=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32])[C@H:21]([C:25]([OH:27])=[O:26])[CH:22]([CH3:23])[CH3:24])[CH:17]=[CH:18][C:5]1=2)#[N:2]
Reactant: CCCCC(=O)Cl
Reactant: CC(C)[C@H](NCc1ccc2c(c1)CCc1ccccc1N2CC#N)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCC(=O)N(Cc1ccc2c(c1)CCc1ccccc1N2CC#N)[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
Compound 40-b (1.2 g) was dissolved in a mixture of 30 ml of dichloromethane and 0.6 ml of diisopropylethylamine, and 0.4 ml of valeryl chloride was added to the solution under ice cooling, followed by stirring at room temperature for 5 hours. Then, ice was added thereto, and the mixture was stirred for some time. The mixture was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (5/1)] to give 1.4 g (96%) of the product as a yellow oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[C:15]([OH:20])=[N:16][O:17][C:18]=1[CH3:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)=[O:60])[CH2:55][CH2:56][CH3:57]>CN(C=O)C>[CH2:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][N:64]([C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][C:14]2[C:15]([OH:20])=[N:16][O:17][C:18]=2[CH3:19])[CH2:63][CH2:62]1)=[O:60])[CH2:55][CH2:56][CH3:57]
Reactant: CCCCOC(=O)N1CCNCC1
Reactant: Cc1onc(O)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](Cc2c(O)noc2C)NC(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
To a solution of 110 mg (S)-2-tert-Butoxycarbonylamino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)-propionic acid in 2 ml DMF were added 0.07 ml DIPEA, 107 mg HATU and 50 mg Piperazine-1-carboxylic acid butyl ester. After stirring for 2 h the reaction mixture was concentrated, diluted with DCM and washed with aqueous LiCl (4%). The crude product obtained was used without further purification. Yield: 146 mg.