Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[Cl:35][C:36]1[CH:41]=[C:40]([C:42]#[N:43])[CH:39]=[C:38](Cl)[N:37]=1>C1COCC1>[Cl:35][C:36]1[CH:41]=[C:40]([C:42]#[N:43])[CH:39]=[C:38]([O:8][C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([CH3:10])[C:6]=2[F:9])[N:37]=1
Reactant: Cc1ccc(Cl)c(O)c1F
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(Oc2cc(C#N)cc(Cl)n2)c1F
Reaction time: 0.25 h
Yield: 44.3 %

Procedure:
6-chloro-2-fluoro-3-methylphenol (4.73 g, 29.5 mmol) and 18-crown-6 (1.558 g, 5.90 mmol) were combined and treated with 20% potassium t-butoxide in THF (16.54 g, 29.5 mmol) in THF at 25° C. and stirred 15 min. 2,6-dichloro-4-pyridinecarbonitrile (5.1 g, 29.5 mmol) was added to the reaction mixture and stirred at ambient temperature for 4 days. A fine white precipitate was filtered off from the reaction mixture and washed with a small amount of DMSO. This material was partitioned between EtOAc and saturated aqueous NaHCO3, the phases separated, and the aqueous phase extracted twice with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated to dryness to give 2-chloro-6-[(6-chloro-2-fluoro-3-methylphenyl)oxy]-4-pyridinecarbonitrile (3.88 g, 13.06 mmol, 44.3% yield) as a white solid. The DMSO filtrate was treated with water and saturated aqueous NaHCO3 to give a purple precipitate that was filtered off, washed with water and air dried. This material was dissolved in DCM, dried over MgSO4, filtered and concentrated to dryness to give a purple solid. The residue was trituarated with EtOH, cooled in an ice bath, filtered and air dried to give a second batch of the desired product (3.65 g, 12.28 mmol, 41.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (d, J=0.82 Hz, 1H), 7.93 (d, J=0.73 Hz, 1H), 7.28-7.43 (m, 2H), 2.28 (d, J=1.74 Hz, 3H). LC-MS (ES+) m/z 296.95, 298.88 [M+H].
Reaction SMILES: FC(F)(F)[C:3]([O-:5])=[O:4].[CH:8]1([C@H:14]2[C:47](=[O:48])[N:46]3[CH2:49][C@@H:43]([CH2:44][C@H:45]3[C:50](=[O:67])[NH:51][C@:52]3([C:57](=[O:66])[NH:58][S:59]([C:62]4([CH3:65])[CH2:64][CH2:63]4)(=[O:61])=[O:60])[CH2:54][C@H:53]3[CH:55]=[CH2:56])[O:42][C:26]3=[N:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=4[C:34]([O:35][CH:36]4[CH2:41][CH2:40][NH2+:39][CH2:38][CH2:37]4)=[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[CH2:68][C@H:18]3[O:17][C:16](=[O:69])[NH:15]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[I-].[K+].Br[CH2:80][CH2:81][O:82][CH3:83]>CN(C=O)C.O>[CH:3]([O-:5])=[O:4].[CH:8]1([C@H:14]2[C:47](=[O:48])[N:46]3[CH2:49][C@@H:43]([CH2:44][C@H:45]3[C:50](=[O:67])[NH:51][C@:52]3([C:57](=[O:66])[NH:58][S:59]([C:62]4([CH3:65])[CH2:63][CH2:64]4)(=[O:61])=[O:60])[CH2:54][C@H:53]3[CH:55]=[CH2:56])[O:42][C:26]3=[N:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=4[C:34]([O:35][CH:36]4[CH2:37][CH2:38][NH+:39]([CH2:80][CH2:81][O:82][CH3:83])[CH2:40][CH2:41]4)=[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[CH2:68][C@H:18]3[O:17][C:16](=[O:69])[NH:15]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COCCBr
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CC[NH2+]CC1)O2)C(=O)NS(=O)(=O)C1(C)CC1
Reactant: O=C([O-])C(F)(F)F
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CC[NH+](CCOC)CC1)O2)C(=O)NS(=O)(=O)C1(C)CC1
Product: O=C[O-]
Temperature: 55 °C
Reaction time: 4 h

Procedure:
To a solution of the product from Step 1, Example 236 (100 mg, 0.101 mmol) in DMF (3 mL) was added triethylamine (0.070 mL, 0.506 mmol), potassium iodide (3.36 mg, 0.020 mmol) and 2-bromoethylmethylether (42.2 mg, 0.303 mmol). The reaction was heated to 55° C. and stirred for 4 hours at which stage LCMS indicated no starting material. After cooling to room temperature, water was added and the reaction was extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (Na2SO4) and concentrated to give an oily residue, which was purified by HPLC (0 to 90% acetonitrile in water; with 0.1% HCOOH) to furnish the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17]>>[F:12][C:13]([F:25])([F:26])[C:14]1[CH:15]=[C:16]([NH:17][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=1
Reactant: Cc1ccc(O)c(C(=O)O)c1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 54.9 %

Procedure:
Using 5-methylsalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](O)=[O:5].B.C(O)(=O)C.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1c(F)cccc1F
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: OCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
A stirred solution of 25.0 g (0.158 mole) of 2,6-difluorobenzoic acid in 300 ml of diethyl ether was purged with nitrogen, and 20 ml of a 1 molar solution of borane in tetrahydrofuran was carefully added dropwise. The addition caused the reaction mixture to effervesce. When vigorous effervescence subsided, the reaction mixture was heated to reflux and an additional 170 ml of a 1 molar solution of borane (0.190 mole total) in tetrahydrofuran was added dropwise at a rate just sufficient to promote gentle reflux. Upon complete addition the reaction mixture was heated under reflux for an additional 1 hour, allowed to cool to ambient temperature and stand for 16 hours, then heated under reflux again for 1 hour. Acetic acid (11 ml, 0.19 mole) was added, then the reaction mixture was cooled in an ice-water bath and 100 ml of a saturated aqueous solution of ammonium chloride was added slowly. Upon complete addition the reaction mixture was stirred for 0.5 hour, then concentrated under reduced pressure to give a pasty residue. Diethyl ether was added and the mixture was washed with three portions of water, two portions of aqueous 10% sodium carbonate, two portions of water, and one portion of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 18.9 g of (2,6-difluorophenyl)methanol as a yellow oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].[NH:17]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C@@H:18]([C:31](ON1C(=O)CCC1=O)=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C=O)C.CO>[NH:17]([C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42])[C@@H:18]([C:31]([NH:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25]
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: N=C(N)NCCC[C@H](NC(=O)CN)C(=O)O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Yield: 97.4 %

Procedure:
8.8 Grams (20 mM) of H-Gly-Arg-CHA.2HCl was dissolved in 21.5 ml of DMF, to this solution was added 5.1 ml (40 mM) of NEM. To the mixture was further added with 9.6 g (20 mM) of Z-D-Lys(BOC)-OSu and reacted at room temperature for 18 hours. After the reaction was completed, the DMF was removed by evaporation under a reduced pressure and the residue obtained was dissolved in MeOH and reprecipitated in 1 liter of AcOEt. The crystals precipitated were collected by filtration and dried to obtain 14.9 g (97.4%) of Z-D-Lys(BOC)-Gly-Arg-CHA.HCl. Rf1 =0.50. Melting point: 207.5° C. (decomposed). [α]D20 -8.0 (C=0.5, MeOH)
Reaction SMILES: [CH2:1]([Li])[CH3:2].[CH3:4][O:5][C:6]1[CH:31]=[CH:30][CH:29]=[CH:28][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]2[CH2:26][CH3:27])=[CH:12][CH:11]=1)=[O:9].[Cl-].[NH4+]>O1CCCC1>[CH2:26]([CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][N:20]1[CH2:19][CH2:18][CH2:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]([C:7]2[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=2[O:5][CH3:4])([OH:9])[CH2:1][CH3:2])=[CH:15][CH:14]=1)[CH3:27]
Reactant: CCC1CCCCN1CCCOc1ccc(C(=O)c2ccccc2OC)cc1
Reactant: [Li]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC1CCCCN1CCCOc1ccc(C(O)(CC)c2ccccc2OC)cc1
Temperature: -15 °C

Procedure:
To 125 ml. of a 0.8 molar ethereal ethyl lithium solution a solution of 15.3 g. of 2-methoxy-4'-[3-(2-ethyl-piperid-1-yl)-propoxy]-benzophenone in 50 ml. of tetrahydrofuran is added dropwise, in argon atmosphere, with stirring at -15° C. The reaction mixture is stirred at room temperature for another two hours, whereupon it is decomposed with a saturated aqueous ammonium chloride solution under cooling. The aqueous phase is extracted with ether. The combined organic phases are washed with a saturated aqueous sodium chloride solution, and dried over anhydrous potassium carbonate. The solvent is distilled off under reduced pressure, and the residue is fractionated. 7.6 g. of the title compound are obtained. The physical characteristics of the product are identical with those given in Example 1.
Reaction SMILES: [C:1]([O:4][CH:5]([C:14]1[CH:18]([OH:19])[O:17][C:16](=[O:20])[CH:15]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:3])[CH3:2].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:19][CH:18]1[O:17][C:16](=[O:20])[CH:15]=[C:14]1[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCC(OC(C)=O)C1=CC(=O)OC1O
Solvent: c1ccncc1
Product: CCCCCCCCC(OC(C)=O)C1=CC(=O)OC1OC(C)=O
Reaction time: 20 h

Procedure:
A mixture of 4-(1-acetoxynonyl)-5-hydroxy-2(5H)-furanone (77.3 mg, 0.27 mmol), acetic anhydride (1/2 ml) and pyridine (1 ml) was stirred under argon at ca. 20° for 20h. After most of the solvent was removed under high vacuum (<40°), the residue was dissolved in ether (20 ml) and washed thoroughly with aqueous copper sulfate and water. Drying (magnesium sulfate) and evaporation gave a brown oil, which was flash chromatographed on silica using 30% ethyl ether/petroleum ether. Fractions with Rf 0.22 on evaporation afforded the title compound as a light yellow oil.
Reaction SMILES: [CH2:1]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[CH2:3][CH2:2]1.[C:13](=O)([O:16]C)[O:14][CH3:15].[H-].[Na+].Cl>CO>[O:5]=[C:4]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:12][CH2:1][CH2:2][CH:3]1[C:13]([O:14][CH3:15])=[O:16]
Reactant: COC(=O)OC
Reactant: O=C1CCCCc2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCCc2ccccc2C1=O
Temperature: 80 °C

Procedure:
A mixture of benzosuberone (8 g, 50 mmol) and neat dimethyl carbonate (45 mL) at ambient temperature under N2 was treated with NaH (60% in mineral oil, 4 g, 100 mmol) in 0.1 mL of dry MeOH, heated at 80° C. for 3 hours, cooled to ambient temperature, treated with 2 N HCl (55 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and concentrated to provide the title compound as an oil, as a 3:1 mixture of enol and keto forms of product by NMR spectroscopy. The NMR of the main enol form was: 1H NMR (CDCl3) δ 2.03-2.16 (m, 4H), 2.64 (m, 2H), 3.82 (s, 3H), 7.23 (m, 1H), 7.33 (m, 2H), 7.62 (m, 1H), 12.6 (bs, 1H). MS (M+H)+ m/z 219.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[NH:3]1.[CH2:14](Br)[C:15]#[CH:16]>>[CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[CH2:16][C:15]#[CH:14]
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: C#CCBr
Product: C#CCN1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Yield: 76 %

Procedure:
Compound 2a is synthesized from (4R,5S)-(+)-4-Methyl-5-phenyl-2-oxazolidinone (Aldrich) according to general procedure F using 15 mmol (1.79 g) propargyl bromide (Aldrich).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:16][C:17]#[N:18]>>[CH2:8]([N:9]1[CH2:10][CH2:11][N:12]([CH2:16][C:17]#[N:18])[CH2:13][CH2:14]1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCBr
Reactant: c1ccc(CCN2CCNCC2)cc1
Product: N#CCN1CCN(CCc2ccccc2)CC1

Procedure:
The title compound is synthesized by coupling of 4-Phenylethyl-piperazine (commercially available from ABCR GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+H=230.2: CtRet=4.20.
Reaction SMILES: [H-].[Na+].C[C@H]1CCC[C@@H](C)N1CC[NH:13][C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[C:22]1[O:23][C:24]2[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:25]=2[N:26]=1)=[O:15].I[CH:33]([CH3:35])[CH3:34]>CN(C)C=O>[CH:33]([O:31][C:29]1[CH:28]=[CH:27][C:25]2[N:26]=[CH:22][O:23][C:24]=2[CH:30]=1)([CH3:35])[CH3:34].[NH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[C:14]([NH2:13])=[O:15]
Reactant: CC(C)I
Reactant: C[C@@H]1CCC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2ccc(O)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2ncoc2c1
Product: NC(=O)C1CCCCN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium hydride as a 60% dispersion in oil (6 mg) was added to a solution of (2S)-N-2-[(cis)-2,6-dimethyl-1-piperidinyl]ethyl-1-(6-hydroxy-1,3-benzoxazol-2-yl)-2-piperidinecarboxamide (54.5 mg) [see Preparation 39] in dimethylformamide (2 ml) at 0° C. After 5 minutes 2-iodopropane (0.014 ml) were added. The reaction mixture was stirred at room temperature for 4 hours, after which time sodium hydride (3 mg) followed by 2-iodopropane (0.007 ml) was added. The mixture was stirred for a further 18 hours, after which time the solvent was removed and the residue partitioned between water and diethyl ether. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 97:3.5:0.5, by volume, dichloromethane/methanol/0.88 aqueous ammonia solution to afford (2S)-N-2-[(cis)-2,6-dimethyl-1-piperidinyl]ethyl-1-(6-isopropoxy-1,3-benzoxazol-2-piperidinecarboxamide (24 mg) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8](=[O:13])(=[O:12])[CH2:7][CH2:6][C:5]2=NNC(N)=S.S1C2C(=CC=CC=2)C(=[O:29])CC1.NNC(N)=S>CC1C=CC(S(O)(=O)=O)=CC=1.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8](=[O:13])(=[O:12])[CH2:7][CH2:6][C:5]2=[O:29]
Reactant: NC(=S)NN=C1CCS(=O)(=O)c2ccc(Br)cc21
Reactant: O=C1CCSc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NNC(N)=S
Solvent: CO
Product: O=C1CCS(=O)(=O)c2ccc(Br)cc21
Yield: 33 %

Procedure:
6-Bromo-1,1-dioxo-1-thiochroman-4-one thiosemicarbazone (23) Into a round bottom flask containing 0.198 g of the appropriate thiochroman-4-one (0.147 g, 0.534 mmol), 10 mL of anhydrous methanol were added and the solution was refluxed for about 15 minutes before adding thiosemicarbazide (0.0598 g, 0.657 mmol) and 1.4 mg of TsOH. After the reaction mixture was refluxed under nitrogen atmosphere for 10 h, a solid was formed which was filtered and, then purified by column chromatography (30% EtOAc/70% hex). 0.0618 g (0.178 mmol) of the product was obtained in a 33% yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.C(N(CC)CC)C.[NH2:23][CH2:24][C@H:25]([CH:42]([CH3:44])[CH3:43])[CH2:26][C@H:27]1[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[N:28]1[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].[OH-].[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH:23][CH2:24][C@H:25]([CH:42]([CH3:44])[CH3:43])[CH2:26][C@H:27]1[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[N:28]1[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:11]
Reactant: COCCCOc1ccccc1C(=O)O
Reactant: CC(C)[C@@H](CN)C[C@H]1COC(C)(C)N1NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H]1COC(C)(C)N1NC(=O)OC(C)(C)C)C(C)C
Reaction time: 1 h

Procedure:
The solution of 2.99 g of 2-(3-methoxypropoxy)benzoic acid [179992-98-4] and 3.95 ml of triethylamine in 60 ml of dichloromethane is cooled to 15° C. and admixed with 3.70 g of bis-(2-oxo-3-oxazolidynyl)phosphinoyl chloride. The mixture is stirred over 1 hour and subsequently admixed with the solution of 2.22 g of tert-butyl 4(S)-(2(S)-aminomethyl-3-methylbutyl)-2,2-dimethyloxazolidine-3-carbamate in 3 ml of dichloromethane and 0.703 g of 4-dimethylaminopyridine, and stirred overnight. The reaction mixture is poured onto 1M NaOH and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a slightly yellowish oil. Rf=0.29 (1:1 EtOAc-heptane); Rt=5.49 (gradient I).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][C:18]3[O:22][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:20][C:19]=3[CH3:29])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)C.[Li+].[OH-].O.Cl>CCO.C1COCC1>[CH3:29][C:19]1[N:20]=[C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:22][C:18]=1[CH2:17][CH2:16][O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C@H:6]([CH2:5][C:4]([OH:30])=[O:3])[CH2:7][CH2:8]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3oc(-c4ccccc4)nc3C)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nc(-c2ccccc2)oc1CCOc1ccc2c(c1)CC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
Ethyl{(1S)-5-[2-(4-methyl-2-phenyl-1,3-oxazol-5-yl)ethoxy]-2,3-dihydro-1H-inden-1-yl}acetate (0.135 g, 0.33 mmol) was dissolved in EtOH (6 mL) and LiOH (0.024 g, 1.0 mmol) was added. Water (3 mL) was added and THF was added until the cloudy solution became clear. The resulting mixture was stirred overnight at rt. HCl (2 N) was added to adjust the pH to 2, then extracted three times with ethyl acetate. The organic layers were combined, dried, and concentrated to give {(1S)-5-[2-(4-methyl-2-phenyl-1,3-oxazol-5-yl)ethoxy]-2,3-dihydro-1H-inden-1-yl}acetic acid (0.039 g, 30.6% yield) as colorless oil. ES-MS m/z 378.2 ((MH)+); HPLC RT (min.) 3.22; 1H NMR (Acetone-d6) δ 8.1 (s br 1H) 8.0-7.95 (m, 2H), 7.52-7.43 (m, 3H), 7.15 (d, 1H), 6.81 (s, 1H), 6.73 (d, 1H), 4.27 (t, 2H) 3.47-3.40 (m, 1H), 3.18 (t, 2H), 2.90-2.68 (m, 3H), 2.41-2.29 (m, 2H), 2.18 (s, 3H), 1.77-1.68 (m, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH:5](C(OC(C)(C)C)=O)[C@H:6]([C:17]([OH:19])=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[CH3:27]O>>[ClH:3].[CH3:27][O:19][C:17](=[O:18])[C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)[NH2:5]
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Product: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.49 ml of thionylchloride and 25 ml of methanol were mixed, cooled by dry-ice-acetonitrile bath and 2 g of Boc-Phe(4-NO2)-OH was added thereto. After stirring it for 1 hour and removing the bath, the solution was warmed up till room temperature and further stirred for 2.5 hours. The reaction solvent was concentrated under reduced pressure to obtain 1.83 g of the intended compound as white powder.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[N:4][C:3]=1[CH2:19][N:20]([CH3:30])[C:21]([C:23]1[C:24]([CH3:29])=[N:25][O:26][C:27]=1[CH3:28])=[O:22].[C:31]([Cu])#[N:32].[C-]#N.[K+]>CN(C=O)C.CCOC(C)=O>[C:31]([C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[N:4][C:3]=1[CH2:19][N:20]([CH3:30])[C:21]([C:23]1[C:24]([CH3:29])=[N:25][O:26][C:27]=1[CH3:28])=[O:22])#[N:32]
Reactant: N#C[Cu]
Reactant: Cc1noc(C)c1C(=O)N(C)Cc1nc(NC(=O)NCc2cccc(F)c2)sc1Br
Agent: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1C(=O)N(C)Cc1nc(NC(=O)NCc2cccc(F)c2)sc1C#N

Procedure:
Example: A mixture of 3,5-dimethyl-isoxazole-4-carboxylic acid {5-bromo-2-[3-(3-fluoro-benzyl)-ureido]-thiazol-4-ylmethyl}-methyl-amide (Ex. 151) (100 mg, 0.2 mmol), CuCN (180 mg, 2.0 mmol) and KCN (13 mg, 0.2 mmol) in DMF (1 mL) was heated to 120 C for 5 hours. Upon cooling the mix was diluted with EtOAc (50 mL), filtered, washed with brine, dried and evaporated. Flash chromatography afforded 3,5-dimethyl-isoxazole-4-carboxylic acid {5-cyano-2-[3-(3-fluoro-benzyl)-ureido]-thiazol-4-ylmethyl}-methyl-amide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[N:14]=[C:13]1[N:8]([CH2:9][CH2:10][CH2:11][O:12]1)[C:7]2=[O:16].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH:28]3[CH2:30][CH2:31][CH:25]2[CH2:26][NH:27]3)=[CH:20][CH:19]=1.C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[NH:14][C:13](=[O:12])[N:8]([CH2:9][CH2:10][CH2:11][N:27]1[CH2:26][CH:25]3[CH2:31][CH2:30][CH:28]1[CH2:29][N:24]3[C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)[C:7]2=[O:16]
Reactant: O=c1c2cccc(Cl)c2nc2n1CCCO2
Reactant: Fc1ccc(N2CC3CCC2CN3)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]c2c(Cl)cccc2c(=O)n1CCCN1CC2CCC1CN2c1ccc(F)cc1
Temperature: 120 °C
Yield: 32.8 %

Procedure:
8-Chloro-3,4-dihydro-2H-1-oxa-4a,9-diaza-anthracen-10-one (0.35, 1.49 mmol), 2-(4-Fluoro-phenyl)-2,5-diaza-bicyclo[2.2.2]octane (HCl salt) (0.30g, 1.24 mmol), triethylamine (0.21 ml, 1.49 mmol), p-toluene sulfonic acid (0.036 g, 0.187 mmol) were combined in dimethyl acetamide (2 ml) and heated at 120° C. for 15 hours. The reaction was cooled to room temperature, diluted with H2O (200 mL) and extracted with ethyl acetate (3×100 mL). The pooled organic layers were washed with water (3×200 mL),dried over magnesium sulfate, and concentrated to a brown semi-solid. Silica gel flash chromatography using 5% methanol/chloroform as the eluent yielded 8-Chloro-3-{3-[5-(4-fluoro-phenyl)-2,5-diaza-bicyclo[2.2.2]oct-2-yl]-propyl}-1H-quinazoline-2,4-dione (0.18 g, 32.7%) as an light brown solid Maleate salt was formed by dissolving the solid in hot ethyl acetate (5 ml) and maleic acid (0.57 g, 1.2 eq) in ethyl acetate (4 ml) was added. Upon cooling the white solid was filtered to yield the maleate salt (0.12 g) which had the following properties: Mp. 186-188° C.; 1H NMR DMSO-d6 δ: 11.04 (brds, 1H), 9.40 (brd s, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.20 (t, J=7.9 Hz, 1H), 6.68 (brds, 2H), 6.02 (s, 2H), 4.11 (brds, 1H), 4.02-3.92 (m, 2H), 3.80-3.52 (m, 3H), 3.44-3.17 (m, 4H), 2.18-1.65 9m, 6H). IR(KBr): Analysis calculated for C23H24ClFN4O2* C4H4O4: C, 56.40; H, 4.91; N, 9.74;