Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[C:24]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1>>[C:24]1([O:18][CH2:17][CH2:16][C:13]2[N:14]([CH3:15])[C:10]([S:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)=[C:11]([CH:19]([CH3:21])[CH3:20])[N:12]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1
Reactant: COC1=CCCCCCCCCCC1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Product: CC(C)c1nc(CCOC2=CCCCCCCCCCC2)n(C)c1Sc1cc(Cl)cc(Cl)c1
Yield: 82 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the enol ether with 1-methoxycyclododecene (982 mg, 5 mmol) in the same manner as the example 41 to give the compound 49 (418 mg, 82%). Mp 96-102° C. PMR (CDCl3 -0.1% d5 -Py): δH1.24 (6 H, d, J 7 Hz, (CH3)2C), 3.11 (2 H, t, J 6.2 Hz, CH2 -Im), 3.10 (1 H, m, (CH3)2CH), 3.51 (3 H, s, NCH3), 3.96 (2 H, t, J 6.2 Hz, OCH2), 4.36 (1 H, t, J 7.8 Hz, =CH), 6.80 (2 H, d, J 1.6 Hz, arom-H), 7.10 (1 H, t-like, arom-H). IR(KBr)cm-1 : 3434, 3057, 1702, 1662, 1566, 1558, 1469, 1409, 1378, 1235, 1130. Elementary analysis (for C27H38N2Ocl2S) Calcd. : C, 63.64% H, 7.52% N, 5.50% S, 6.29% Cl, 13.91% Found: C, 64.48% H, 7.69% N, 5.10% S, 6.03% Cl, 12.85%
Reaction SMILES: Br[C:2]([CH3:13])([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].FC1C=CC([C:21](=[O:25])C(C)C)=CC=1.C[O-].[Na+]>CO>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([O:25][CH3:21])[C:2]([CH3:13])([CH3:12])[O:4]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)c1ccc(F)cc1
Reactant: CC(C)(Br)C(=O)c1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC1(c2ccc(F)cc2)OC1(C)C

Procedure:
39.22 g (0.16 mol) of 2-bromo-1-(4-fluorophenyl)-2-methylpropan-1-one, prepared by brominating 1-(4-fluorophenyl)-2-methylpropan-1-one analogously to European Patent Application No. 3,002, are dissolved in 50 ml of methanol. 23.5 g (0.176 mol) of methanolic 30% strength sodium methylate solution are added dropwise at room temperature. The methanol is then distilled off, and the residue is taken up with diethyl ether. The salt is filtered off, and the ether solution is concentrated. The liquid crude product is further reacted as described hereinafter without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)=[C:5]([F:21])[CH:4]=1)=[CH2:2].B1C2CCCC1CCC2.[OH-:31].[Na+].OO>C1COCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][OH:31])=[CH:4][C:5]=2[F:21])=[CH:11][C:12]=1[C:17]([F:20])([F:18])[F:19]
Reactant: [OH-]
Reactant: C=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)phenyl 4-ethenyl-2-fluorophenyl ether (4.0 g, 12.63 mmol) in THF (13 mL) was added dropwise 9-BBN (50.5 mL, 25.3 mmol) at 0° C. The reaction mixture was stirred at room temperature for overnight, then mixed with NaOH (25.3 mL, 76 mmol) and H2O2 (7.74 mL, 76 mmol). The mixture was stirred at 55° C. for 4 h, quenched by Na2SO3, and extracted with EA (100 mL×3). Organic phases were collected, combined, dried with anhydrous Na2SO4, and concentrated to provide the title compound (4.02 g, 95% yield). LCMS: rt=4.6 min, [M+H+]=334
Reaction SMILES: C(O/[CH:4]=[CH:5]\[C:6]1[C:11]([C:12]#[N:13])=[CH:10][N:9]=[C:8]([S:14][CH3:15])[N:7]=1)C.BrN1C(=O)CCC1=O.[NH2:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=1>O1CCOCC1.O>[CH3:31][C:30]1[C:25]2[N:26]([C:5]([C:6]3[C:11]([C:12]#[N:13])=[CH:10][N:9]=[C:8]([S:14][CH3:15])[N:7]=3)=[CH:4][N:24]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cccnc1N
Reactant: CCO/C=C\c1nc(SC)ncc1C#N
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1COCCO1
Product: CSc1ncc(C#N)c(-c2cnc3c(C)cccn23)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31.6 %

Procedure:
10 g of 4-[(Z)-2-ethoxyvinyl]-2-(methylthio)-5-pyrimidinecarbonitrile (synthesized according to the method disclosed in International Publication WO2006/025567, pages 90-91) was dissolved in a mixed solvent of 150 mL of 1,4-dioxane and 30 mL of water and then 8.04 g of N-bromosuccinimide was added thereto under an ice-cold condition, and the mixture was stirred for 1.5 hours at room temperature. To the reaction solution, 4.89 g of 2-amino-3-picoline was added, and the mixture was further stirred for 2.5 hours. 200 mL of water was added to the reaction solution to extract with 2 L of a mixed solvent of chloroform and methanol (mixing ratio: 9/1). The organic layer was washed with water, and dried over anhydrous magnesium sulfate. Thereafter, the insolubles were filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in a small amount of chloroform and solidified with hexane to obtain 4.02 g of 4-(8-methylimidazo[1,2-a]pyridin-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile [1-6] (hereinafter, referred to as the compound [1-6]) as a light brown solid.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].O>CN(C)C=O>[C:1]1(=[O:11])[N:5]([CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: COC(=O)CCCC#CCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCC#CCN1C(=O)c2ccccc2C1=O
Yield: 44.1 %

Procedure:
A mixture or potassium phthalimide (2.31 g) and methyl 7-bromohept-5-ynoate (3.0 g) in dimethylformamide (35 ml) was heated at 110° C. for 4.5 hours. The cooled solution was poured into water (75 ml) and the pH of the solution was adjusted to 6. The resulting solution was extracted with ether (4×200 ml) and the combined ether extracts were dried over magnesium sulphate, the solvent was removed and the residue was chromatographed on silica gel eluted with chloroform to give the title compound (1.56 g) m.p. 62°-63° C.
Reaction SMILES: I[C@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1.O>CN(C=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C@@H:2]2[CH2:6][CH2:5][O:4][CH2:3]2)=[CH:16][CH:15]=1
Reactant: I[C@H]1CCOC1
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(S[C@@H]2CCOC2)cc1
Reaction time: 8 h

Procedure:
To a suspension of (3S)-3-iodotetrahydrofuran [prepared according to the method outline in US2006004018] (1.2 g, 6.061 mmol) and K2CO3 (1.675 g, 12.12 mmol) in DMF (12.00 mL) at ambient temperature was added 4-bromobenzenethiol (1.146 g, 6.061 mmol). The resulting suspension was stirred at this temperature overnight. Water was added and then the aqueous layer extracted with DCM (×3). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the sub-title compound as a clear oil which was used directly in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:30])[N:5]([CH2:6][CH2:7][C:8]2[C:9](=[O:24])[NH:10][C:11](=[O:23])[N:12]([C@@H:14]3[O:22][CH2:21][C@@H:19]([OH:20])[C@@H:17]([OH:18])[C@H:15]3[OH:16])[CH:13]=2)[C:4](=[O:25])[C:3]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]12.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl-].[NH4+]>N1C=CC=CC=1.ClCCl>[C:31]([O:16][C@@H:15]1[C@H:17]([OH:18])[C@H:19]([OH:20])[CH2:21][O:22][C@H:14]1[N:12]1[CH:13]=[C:8]([CH2:7][CH2:6][N:5]2[C:4](=[O:25])[C:3]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]3[C:1]2=[O:30])[C:9](=[O:24])[NH:10][C:11]1=[O:23])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1cn([C@@H]2OC[C@@H](O)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(O[C@@H]1[C@H](O)[C@H](O)CO[C@H]1n1cc(CCN2C(=O)c3ccccc3C2=O)c(=O)[nH]c1=O)c1ccccc1
Temperature: -70 °C
Reaction time: 0.58 h
Yield: 60597.3 %

Procedure:
10.6 g (0.025 mmol) of 5-(2-phtalimidoethyl)-1-(β-D-ribopyranosyl)uracil were dissolved in 20 ml of pyridine in a heated and argon-flushed 1 l four-necked flask and mixed with 200 ml of dichloromethane. The mixture was cooled to −70° C., 3.82 ml (0.033 mmol) of benzoyl chloride in 5 ml of pyridine and 20 ml of dichloromethane were slowly added dropwise with cooling and the mixture was stirred at −70° C. for 35 min. The reaction mixture was poured onto 600 ml of cooled ammonium chloride solution and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, dried and concentrated to dryness in vacuo. Chromatography on silica gel (ethyl acetate/heptane 1:1) yielded 7.9 g (60%) of 1-(2′-O-benzoyl-β-D-ribopyranosyl)-5-(2-phtalimidoethyl)uracil.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[C:36]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)([CH3:39])([CH3:38])[CH3:37]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:43]4[CH2:44][CH2:45][N:40]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:41][CH2:42]4)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:31][C:32]([F:35])([F:34])[CH2:33]2)=[O:29])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: CC(C)(C)N1CCNCC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Product: CC(C)(C)N1CCN(c2ccc(S(=O)(=O)[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)[C@H](C(=O)N4CC(F)(F)C4)C3)c(C(F)(F)F)c2)CC1

Procedure:
The title compound was prepared in analogy to Example 127 using (1R,2R,4R)-2-(3,3-Difluoro-azetidine-1-carbonyl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 118) and 1-tert-butyl-piperazine. Light yellow foam. MS (EI): 646.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([O:12]C)=O)=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[CH2:14]([NH2:17])[CH2:15][NH2:16]>>[NH2:1][C:2]1[C:3]([C:10]([NH:16][CH2:15][CH2:14][NH2:17])=[O:12])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: NCCN
Reactant: COC(=O)c1nc(Cl)c(N)nc1N
Product: NCCNC(=O)c1nc(Cl)c(N)nc1N
Reaction time: 72 h
Yield: 59 %

Procedure:
A mixture of 2.0 g (10.0 mmol) of methyl 3,5-diamino-6-chloropyrazine-2-carboxylate and 13.5 g (22.6 mmol) of ethylene diamine was allowed to stand for 3 days at ambient temperature. The excess amine was evaporated and the residue was crystallized from ethanol. There was obtained 1.38 g (5.9 mmol, 59%) of 3,5-diamino-6-chloro-N-(2-aminoethyl)pyrazine-2-carboxamide: mp 173°-174° C.
Reaction SMILES: [CH:1]([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])=[CH2:2].C([OH:11])=C.[Br:12][CH2:13][C:14](Br)=[O:15]>CN(C)C=O>[CH:1]([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])=[CH2:2].[Br:12][CH2:13][C:14]([O-:15])=[O:11]
Reactant: C=CO
Reactant: O=C(Br)CBr
Agent: C=CN1CCCC1=O
Solvent: CN(C)C=O
Product: O=C([O-])CBr
Reaction time: 1 h

Procedure:
A solution containing 330 mg of 1-vinyl pyrrolidone/vinyl alcohol copolymer (VI) in 8 mL of dry dimethyl formamide was taken in a two-neck round-bottomed flask and connected to nitrogen. The other neck was capped with a septum stopper. The flask was cooled in an ice bath. To the flask 0.25 mL of bromoacetyl bromide dissolved in 2 mL of DMF was added dropwise with a syringe through the septum stopper. The reaction was allowed to proceed at room temperature for 1 hour in the dark. The precipitation of the reaction mixture in 15-fold diethyl ether for 5 times yielded 270 mg of 1-vinyl pyrrolidone/bromoacetate copolymer (VII). A test of alkylating agents using 4-(p-nitrobenzyl)pyridine was positive indicating the presence of alkyl bromide in the copolymer (5). C-13 NMR (CD3OD) : 19.2, 27.4, 32.5, 33.7-37.1, 43.6-45.5, 48.2-48.9, 70.0-71.5, 168.6, 177.7. Elemental Analysis: found (Calcd): C, 40.05 (43.5); H, 4.87 (5.11); Br, 30.97 (28.94); N, 5.43 (5.07).
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](C(OC)=O)=[CH:16][C:15]([CH2:22][OH:23])=[N:14]2)=[CH:9][CH:8]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH:17]=[CH:16][C:15]([CH2:22][OH:23])=[N:14]2)=[CH:11][CH:12]=1
Reactant: COC(=O)c1cc(CO)nn1-c1ccc(OC)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc(-n2ccc(CO)n2)cc1
Temperature: 25 °C
Yield: 176 %

Procedure:
To a solution of of (2′-tert-butylaminosulfonyl-[1,1′]-biphen-4-yl)amine (1.44 g, 4.73 mmol) in 40 mL of methylene chloride at ambient temperature was added trimethylaluminum (14.2 mL of a 2.0 M solution in toluene, 28.4 mmol) dropwise. The resulting solution was allowed to stir until no more gas evolution was observed (˜15 min). To this solution was added 1-[(4-methoxy)phenyl]-3-(hydroxymethyl)-5-(methoxycarbonyl)pyrazole (1.24 g, 4.73 mmol) in 10 mL of methylene chloride. The resulting solution was stirred at 40° C. for 16 h and then was cooled to ambient temperature and quenched by the addition of saturated aq NH4Cl. After diluting with ethyl acetate, the organic layer was washed with 10% aq HCl, saturated aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo. The solid residue was recrystallized from hexanes/ethyl acetate to afford 1.7 g (68%) of the title compound. LRMS (ES+): 557.1 (M+Na)+.
Reaction SMILES: [CH2:1]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][O:5]1)[CH:2]=[CH2:3].[OH2:16].[OH-].[Na+].OO>C1COCC1>[C:10]1([C:4]2([CH2:1][CH2:2][CH2:3][OH:16])[CH2:9][CH2:8][CH2:7][CH2:6][O:5]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O
Reactant: C=CCC1(c2ccccc2)CCCCO1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCCCC1(c2ccccc2)CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-allyl-2-phenyltetrahydro-2H-pyran (700 mg, 3.46 mmol) in THF (7 mL) at 0° C. was added 1M borane tetrahydrofuran complex (1.730 mL, 1.730 mmol) dropwise, and the mixture was stirred overnight at room temperature. After cooling to 0° C., water (0.07 ml) was added to destroy the excess borane. After stirring for mins, 3M NaOH (0.42 mL, 1.260 mmol) was added and stirred for 10 mins. Then 30% H2O2 (0.42 mL, 4.11 mmol) was added and the cooling bath was removed. It was refluxed for 1.5 hrs and cooled to room temperature. It was extracted with EtOAc (2×), and the combined extracts were washed with brine, dried over Na2SO4 and evaporated to give 3-(2-phenyltetrahydro-2H-pyran-2-yl)propan-1-ol as oil. 1H NMR (400 MHz, CCl3D) δ ppm 7.11-7.44 (5H, m), 3.66-3.81 (2H, m), 3.48-3.59 (2H, m), 2.22-2.37 (2H, m), 1.35-1.89 (8H, m).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[CH2:10][C@@H:11]([NH:22][C:23](OC(C)(C)C)=O)[C:12]([NH:14][C@@H:15]([CH2:20][OH:21])[C:16]([OH:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[C:38]1([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:43]=[CH:42][C:41]([CH:44]2[CH2:48]C(OC)O[CH:45]2OC)=[CH:40][CH:39]=1>ClCCCl>[CH2:1]([O:8][C:9](=[O:30])[CH2:10][C@@H:11]([N:22]1[CH:23]=[CH:45][C:44]([C:41]2[CH:42]=[CH:43][C:38]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:39][CH:40]=2)=[CH:48]1)[C:12]([NH:14][C@@H:15]([CH2:20][OH:21])[C:16]([OH:19])([CH3:17])[CH3:18])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)C(C)(C)O
Reactant: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)[C@H](CO)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Yield: 11 %

Procedure:
According to the procedure described in Example 1(c) for N-(8-oxo-4-oxa-1,7-diazatricyclo-[9.6.1.012,17 ]-octa-deca-11(18),12,14,16-tetraen-9S-yl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-t-butoxycarbonylamino-N-(2-hydroxy-1(S)-hydroxymethyl-2-methyl-propyl)succinamic acid benzyl ester was deprotected with trifluoroacetic acid. The crude amine salt and 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 1(a)) were condensed in anhydrous 1,2-dichloroethane with trifluoroacetic acid to give in 11% yield 3(R)-[3-(biphenyl4-yl)-1H-pyrrol-1-yl]-N-[2-hydroxy-1(S)-(hydroxymethyl)-2-methylpropyl]succinamic acid benzyl ester as an amorphous solid. 1H NMR (acetone-d6): δ 7.67-7.61 (m, 6H), 7.48 (t, 2H, J=7.7 Hz), 7.39 (t, 1H, J=1.8 Hz), 7.37-7.27 (m, 6H), 7.09 (bd, 1H, J=9.2 Hz), 6.96 (t, 1H, J=2.6 Hz), 6.53 (dd, 1H, J=1.7, 2.8 Hz), 5.35 (t, 1H, J=7.4 Hz), 5.11 (s, 2H), 3.81-3.62 (m, 3H), 3.39 (dd, 1H, J=6.8, 16.4 Hz), 3.12 (dd, 1H, J=7.7, 16.6 Hz), 1.24 (s, 3H), 1.21 (s, 3H). Anal. Calculated for C32H34N2O5 : C, 72.98; H, 6.51; N, 5.32. Found: C, 72.83; H, 6.60; N, 5.24.
Reaction SMILES: S(O[CH2:12][CH2:13][CH:14]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15]1)(C1C=CC(C)=CC=1)(=O)=O.[OH:23][C:24]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[OH:23][C:24]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:29][CH2:28][N:27]([CH2:12][CH2:13][CH:14]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:26][CH2:25]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2Cc3ccccc3O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: OC1(c2ccccc2)CCN(CCC2Cc3ccccc3O2)CC1
Reaction time: 48 h

Procedure:
The mixture of 4.6 g of 2-(2-tosyloxyethyl)-2,3-dihydrobenzofuran, 2.64 g of 4-hydroxy-4-phenylpiperidine, 10 g of anhydrous sodium carbonate and 100 ml of 4-methyl-2-pentanone is relfuxed for 48 hours. It is filtered, evaporated and the residue recrystallized from isopropanol-petroleum ether, to yield the 2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-2,3-dihydrobenzofuran melting at 107°.
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1I)[CH2:2][CH2:3][CH3:4].[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:22]=1[NH2:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1.[Cu]>[CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:23][C:22]1[C:21]([Cl:20])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:28])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: CCCCN(CCCC)C(=O)Cc1ccccc1I
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CCCCN(CCCC)C(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Yield: 81.1 %

Procedure:
A mixture of 3.5 g (0.0095 mole) of N,N-di-n-butyl-o-iodophenylacetamide, 1.70 g (0.0105 mole) of 2,6-dichloroaniline, 1.46 g (0.0104 mole) of anhydrous potassium carbonate, 1.0 g of copper powder and 1.0 g of cuprous iodide was reacted in 53 ml of xylene for 45 hours. After completion of the reaction, the post treatment was carried out in the same manner as in Example 12 to obtain 3.14 g of N,N-di-n-butyl-o-(2,6-dichloroanilino)phenylacetamide in the form of a colorless needle having a melting point of 66° to 68° C. (after recrystallization from methanol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:14]([O:16]C)=O)[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:19][NH2:20]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1([C:14]([NH:19][NH2:20])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C(=O)NN)CCCC1

Procedure:
Methyl 1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylate and hydrazine monohydrate were reacted in methanol under heating to obtain 1-[(tert-butoxycarbonyl)amino]cyclopentanecarbohydrazide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:20]=[C:13]([C:14]([O:16][CH:17](Cl)[CH3:18])=[O:15])[C:12]([OH:21])=[CH:11][CH:10]=1.[C:22](=[O:27])([O-:26])[O:23][CH2:24][CH3:25].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:20]=[C:13]([C:14]([O:16][CH:17]([O:27][C:22]([O:23][CH2:24][CH3:25])=[O:26])[CH3:18])=[O:15])[C:12]([OH:21])=[CH:11][CH:10]=1
Reactant: CC(Cl)OC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: CCOC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)OC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 25 °C

Procedure:
To a solution of 1-chloroethyl 5-(2,4-difluorophenyl)salicylate (5.0 g) in about 40 ml of DMF is added portionwise 3.0 g of sodium ethyl carbonate. The reaction is stirred at room temperature and then concentrated in vacuo. The concentrate is partitioned between ether/ethyl acetate and acidified water. The organic layer is separated and the aqueous layer is again extracted with ether, the organic layers are pooled and washed with water followed by drying and concentration to the crude product. After further purification by chromatography as described in Example 1, the product is crystallized from hexane to afford pure 1-(ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)salicylate.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[CH:15]=[C:16]([Cl:30])[C:17]([CH3:29])=[C:18]([C:27]#[N:28])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:30][C:16]1[C:17]([CH3:29])=[C:18]([C:27]#[N:28])[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:15]=1
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1C#N
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c1C#N
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (41 mg, 0.21 mmol), 6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-carbonitrile (50 mg, 0.2 mmol), and N,N-diisopropylethylamine (0.060 mL, 0.35 mmol) in isopropyl alcohol (0.7 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C21H17ClFN6 (M+H)+: m/z=407.1. found: 407.1.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:20][C:15]1[CH:14]=[C:13]([C@H:11]2[CH2:12][NH:8][CH2:9][C@@H:10]2[C@@H:21]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH3:22])[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(Cl)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CNC[C@@H]1c1ccc(F)c(Cl)c1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
To a solution of 6-{(S)-1-[(3R,4S)-1-benzyl-4-(3-chloro-4-fluoro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile-48 mg (0.11 mmol) dissolved in toluene (1 mL) were added 47 mg (0.33 mmol) of 1-chloroethyl chloroformate and 43 mg (0.33 mmol) of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (5 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 28 mg (72%) of the title compound as a light yellow oil. ES-MS m/e: 346.1 (M+H+).