Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:12]1[C:11]([C:4]2[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:3]=2[O:2][CH3:1])=[C:19]2[C:14]([C:15]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:17]=[CH:18]2)=[N:13]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(OC)c1
Product: COc1cc(O)ccc1-c1c2cccc(C(F)(F)F)c2nn1Cc1ccccc1

Procedure:
Prepared according to Example 116 from 3-(2,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole and benzyl bromide.
Reaction SMILES: [C:1]([O:15]CC1C=CC=CC=1)(=[O:14])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH3:13]>CO.[Pd]>[C:1]([OH:15])(=[O:14])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH3:13]
Reactant: COCCOCCOCCOCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCCOCCOCCOCC(=O)O

Procedure:
Benzyl-3,6,9,12-Tetraoxatridecanoate (103, 5 mmol) is dissolved in methanol (50 ml) and 10% palladium on carbon is added (100 mg catalyst/mmol). The suspension. is shaken under 30 psi H2 until the starting material is consumed. The suspension is filtered through a short pad of Celite, washed thoroughly with methanol, and the solvent evaporated. The product is used directly without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH2:14][CH2:15][F:16])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][N:31]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:20])[C:6]([C:17]([OH:19])=[O:18])=[CH:7][N:8]3[CH2:14][CH2:15][F:16])=[CH:3][C:2]=2[F:1])[CH2:30]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(O)c1cn(CCF)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(CCF)c3c2F)C[C@H]1NC(=O)OC(C)(C)C
Yield: 62.8 %

Procedure:
A mixture of 6,7,8-trifluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.5 g) and DBU (0.27 g) was refluxed for an hour and then concentrated. The resulting residue was dissolved in chloroform and the solution was washed with 10% aqueous citric acid solution. After concentration of the chloroform layer, the resulting precipitate was triturated in water, and collected by filtration and washed with water, methanol and ether successively to give the title compound (0.51 g) as white powder, mp 217°-219° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][NH:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([N:35]([CH3:34])[C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CNC1CCCCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N(C)C4CCCCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and N-methylcyclohexylamine. ES-MS m/e (%): 482 (M+H+, 100).
Reaction SMILES: [C:1]([C:4](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[C:5]([O:7]CCC#N)=[O:6])(=O)[CH3:2].[NH2:22]/[C:23](/[CH3:49])=[CH:24]\[C:25]([O:27][CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][C:34]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:33][CH2:32]1)=[O:26].C(O)(=O)C>CC(O)C>[C:43]1([C:34]2([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][CH2:28][O:27][C:25]([C:24]3[CH:12]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=4)[C:4]([C:5]([OH:7])=[O:6])=[C:1]([CH3:2])[NH:22][C:23]=3[CH3:49])=[O:26])[CH2:36][CH2:35]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: C/C(N)=C/C(=O)OCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCC#N
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)=C(C)N1

Procedure:
8.1 g of 2-cyanoethyl 2-acetyl-3-(3-nitrophenyl)acrylate and 10.6 g of 3-(4,4-diphenylpiperid-1-yl)-propyl 3-aminocrotonate are heated at the boiling point under reflux in 120 ml of 2-propanol and 0.5 ml of glacial acetic acid for 4 hours. After most of the solvent has been distilled off and 2 portions of 50 ml of toluene each have been added, the residue is concentrated to dryness. The residue, which has foamed as a solid, is taken up in isopropanol, and diethyl ether is added to the clear solution until the resulting cloudiness first persists. After the mixture has been left to stand in a refrigerator, the starting compound crystallizes out in the form of fine platelets. m.p.: 158°-160° C.; yield: 14.3 g.
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(N(CC)CC)C.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>O1CCCC1>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30](=[O:31])[O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][CH2:5][N:4]2[CH2:1][C:2]#[CH:3])=[CH:9][CH:10]=1
Reactant: C#CCN1CCCc2ccc(O)cc21
Reactant: O=C=Nc1ccccc1Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCN1CCCc2ccc(OC(=O)Nc3ccccc3Br)cc21
Temperature: 35 °C

Procedure:
A mixture of 1-(prop-2-ynyl)-1,2,3,4-tetrahydroquinolin-7-ol (400 mg, 2.14 mM) and triethylamine (0.6 mL) in dry tetrahydrofuran (THF, 5 mL) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 2-bromophenyl isocyanate (396 mg/ml, 3.21 mM) was added at once and then the reaction mixture was further stirred for 36 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chlorophorm-hexane (1:19) to afford 10c as solid. Yield: 540 mg, 65.61%.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24](I)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Sn](CCCC)(CCCC)[C:33]1[C:34]([CH3:38])=[N:35][O:36][CH:37]=1)CCC.C(N(CC)CC)C>O1CCOCC1.[Ag]=O>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:33]4[C:34]([CH3:38])=[N:35][O:36][CH:37]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Ic1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1conc1C
Agent: O=[Ag]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1nocc1-c1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1

Procedure:
(4-Benzyloxy-phenyl)-(6-iodoquinazolin-4-yl)-amine hydrochloride (0.35 g) in dioxan (10 ml) under nitrogen was treated with 4-tributylstannyl-3-methylisoxazole (prepapred according to the literature method: Heterocycles, (1996), 43(6), 1301-1304) (0.4 g), silver oxide (0.092 g), triethylamine (0.1 ml) and [1.4-bis(diphenylphosphino)butane]palladium (II) chloride (0.1 g) at 90° C. for 16 hours. The mixture was cooled, adsorbed onto silica and purified by chromatography. Trituration from hexane and filtration gave the title compound (0.20 g); δH [2H6]DMSO 9.78(1H, bs), 9.22(1H, s), 8.57(1H, s), 8.53(1H, s), 7.98(1H, d), 7.83(1H, d), 7.67(2H, d), 7.42(5H, m), 7.09(1H, d), 5.64(2H, s) 2.51 (3H, s); m/z (M+1)+ 409.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](Cl)=[N:26][CH:25]=1)=[O:23].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:24]([C:22]([O:21][CH3:20])=[O:23])=[CH:25][N:26]=3)=[CH:16][CH:17]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnc(Cl)c2ccccc12
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c2ccccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A suspension of N-[2-(4-chlorophenyl)ethyl]-4-hydroxy benzamide (605 mg) and 1-chloro-isoquinoline-4-carboxylic acid methyl ester (443 mg) and potassium carbonate (332 mg) in DMF (4 ml) was stirred at 60° C. for two hours. Ethyl acetate was added thereto, and the reaction solution was washed with water, and then washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (NH type silica gel, chloroform/n-hexane=50 to 80%) to give methyl 1-(4-{[2-(4-chlorophenyl)ethyl]carbamoyl}phenoxy)isoquinoline-4-carboxylate (782 mg) as a colorless solid.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=1)CBr>CN.CO.C(Cl)(Cl)Cl.CO>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=1)[CH2:7][CH2:6][NH2:3]
Reactant: Cc1cc(Br)cc(CBr)c1
Reactant: CCN(CC)CC
Agent: CN
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)cc(CCN)c1
Yield: 72.8 %

Procedure:
Triethylamine (3.62 g; 35.8 mmol) was dissolved in 40% solution of methylamine in methanol (100 ml). While the solution was stirred in an ice bath, 3-bromo-5-methylbenzyl bromide (9.44 g; 35.8 mmol) in chloroform/methanol (25 ml/25 ml) was added dropwise. After completion of the addition, the mixture was stirred for 72 hours at room temperature. Subsequently, the solvent was evaporated under reduced pressure, and the residue was taken up in 2N hydrochloric acid (100 ml), followed by washing with ether (100 ml). The aqueous layer was alkalinized with aqueous sodium hydroxide solution, and the mixture was extracted with chloroform (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=1:08→10:1), to thereby yield 5.58 g of the target compound as pale yellow oily matter (yield: 72.8%).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8]C(C)(C)C)[C@H:3]1[C:14]([O:16][CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:20]=1)[CH3:18])=[O:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:32][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:8])[OH:13])[C@H:3]1[C:14]([O:16][CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:20]=1)[CH3:18])=[O:15]
Reactant: CC(OC(=O)[C@@H]1[C@H](/C=C\C(=O)OC(C)(C)C)C1(C)C)c1cccc(Oc2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(OC(=O)[C@@H]1[C@H](/C=C\C(=O)O)C1(C)C)c1cccc(Oc2ccccc2)n1
Temperature: 0 °C
Yield: 96.3 %

Procedure:
A mixture of 5.649 g of the product of Step A, 0.5 g of p-toluene sulfonic acid and 70 ml of toluene was refluxed until gas evolution ceased and the mixture was cooled to 0° C. and filtered. The filtrate was evaporated to dryness under reduced pressure to obtain 4.741 g of (RS)1-(6-phenoxy-2-pyridyl)-ethyl(1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-hydroxy-1-propenyl]-cyclopropane-carboxylate.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:29]([O:12][C:11](=[O:13])[C@H:10]([CH3:14])[CH2:9][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid (prepared using the procedure described in WO 2008083967) (1.0 g, 2.61 mmol) and benzyl bromide (468 mg, 2.74 mmol) in DMF (15 mL) is added potassium carbonate (541 mg, 3.91 mmol) and the mixture is stirred at room temperature for 2 hours. Water is added and the mixture is extracted with ethyl acetate. The combined organic layers are washed with water and dried over magnesium sulfate. The solvent is removed under reduced pressure and the residual oil is purified by column chromatography using heptane/EtOAc (4:1) to furnish (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid benzyl ester.
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH3:5][C:3]1[CH2:2][C:1](=[O:7])[N:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:17]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: NNc1ccccc1
Solvent: CCO
Product: CC1=NN(c2ccccc2)C(=O)C1
Reaction time: 3 h
Yield: 65 %

Procedure:
Into 50 ml of ethanol, 13.0 g of ethyl acetoacetate and 10.8 g of phenylhydrazine were added, and the mixture was refluxed under stirring for 3 hours. After left to cool, the precipitated crystals were filtered and recrystallized from ethanol to obtain 11.3 g of 3-methyl-1-phenyl-2-pyrazolin-5-one (Compound No. 1) as colorless crystals.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].CCN=C=NCCCN(C)C.[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][C:34](O)=[O:35]>C(Cl)Cl>[O:8]=[C:3]1[CH2:4][CH2:5][C:6](=[O:7])[N:2]1[O:1][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH3:20]
Reactant: COCCOCCOCCOCCCC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: COCCOCCOCCOCCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
N-hydroxysuccinimide (0.55 g, 4.8 mmol) and EDCI (1.15 g, 6.0 mmol) were dissolved in CH2Cl2 (7 mL). Then 4-{2-[2-(2-Methoxy-ethoxy)-ethoxy]-ethoxy}-butyric acid (0.940 g, 3.8 mmol), dissolved in CH2Cl2 (2 mL), was added. Reaction stirred overnight at room temperature. Crude reaction was diluted with CH2Cl2 (21 mL), washed 1M HCl (30 mL), H2O (30 mL), dried MgSO4, and evaporated to dryness. Column chromatography (Silica, ethyl acetate) afforded 4, a clear oil (0.556 g, 43% yield).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5]1([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=2)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.O>CN(C=O)C>[N:1]([CH2:17][C:16]1[CH:19]=[CH:20][C:13]([C:11]([CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:12])=[CH:14][CH:15]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1ccc(CBr)cc1)C1CCCCC1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(C(=O)C2CCCCC2)cc1
Temperature: 90 °C
Yield: 37.6 %

Procedure:
Add sodium azide (441 mg, 6.785 mmol) to a stirred solution of 4-(cyclohexanecarbonyl)-benzyl bromide (954 mg, 3.393 mmol) in anhydrous DMF (20 mL) and heat the mixture to 90° C. for 2 h. Cool the mixture to room temperature, add water and extract the aqueous solution with diethyl ether. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1) to give the desired intermediate as oil (310 mg, 38%).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:18][CH:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:26][CH:19]([CH3:18])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: CC(O)c1ccccc1
Product: CC(OC(=N)N1Cc2ccccc2-c2ccccc2C1)c1ccccc1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6carbonitrile and α-methylbenzyl alcohol, there is obtained α-methylbenzyl 5,7-dihydro-6H-dibenz[c,e]-azepine-6-carboximidate as a resin, mass spectrum m/e: [M+ 342 (5), 237 (60), 194 (100), 105 (63);
Reaction SMILES: [N:1]([CH:4]1[CH:8]2[O:9][CH2:10][CH:11]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])[CH:7]2[O:6][CH2:5]1)=[N+]=[N-]>CO.[OH-].[OH-].[Pd+2]>[NH2:1][CH:4]1[CH:8]2[O:9][CH2:10][CH:11]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])[CH:7]2[O:6][CH2:5]1
Reactant: [N-]=[N+]=NC1COC2C1OCC2N1C(=O)c2ccccc2C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NC1COC2C1OCC2N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(6-azidohexahydrofuro[3,2-b]furan-3-yl)isoindoline-1,3-dione (crude product from above step) in MeOH (70 mL) was added 10% Pd(OH)2/C (240 mg, 0.17 mmol). The mixture was stirred at room temperature overnight under H2 atmosphere. The mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product. The residue was used for the next step without further purification.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17](O)=[O:18])=[C:13]([F:20])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].F[P-](F)(F)(F)(F)F.[N:28]1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C=O)C>[N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([NH2:28])=[O:18])=[C:13]([F:20])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C(=O)O)c(F)c2)C(=O)O1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C(N)=O)c(F)c2)C(=O)O1
Yield: 88 %

Procedure:
A solution of 5-(S)-azidomethyl-3-[4′-carboxy-3′-fluorophenyl-]oxazolidine-2-one (3.2 g, 11.4 mmol; prepared as described in Example 3), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (6.5 g, 17.1 mmole) and N,N′-diisopropylethylamine (5.9 g, 7.9 ml , 45.6 mmol) in DMF (12 ml) was stirred at room temperature for 20 min. Ammonium chloride (1.2 g, 22.8 mmol) was added, and the reaction mixture was stirred at r. t. overnight. Most of the solvent was removed under vacuum, and the residue taken up in ethyl acetate and washed twice with 3% aq. citric acid and brine. Organic layer was dried (Na2SO4) and concentrated under vacuum. Crude material was purified by silica gel chromatography eluting with 15% methanol in ethyl acetate to afford a white crystalline product (2.8 g, 91%). HPLC Rt=4.7, MS (m/z): [M+H]+=280.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[N:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[N:15]=1.[C:22](=[O:24])=[O:23].Cl>C1COCC1>[Cl:13][C:14]1[N:19]=[C:18]([Cl:20])[C:17]([C:22]([OH:24])=[O:23])=[C:16]([Cl:21])[N:15]=1
Reactant: O=C=O
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1c(Cl)nc(Cl)nc1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 49 %

Procedure:
To a solution of diisopropylamine (23.42 mL, 164 mmol) in THF (200 mL) was slowly added butyllithium (100 mL, 160 mmol) at −78° C. The mixture was stirred at −78° C. for 15 min. To this mixture was slowly added a solution of 2,4,6-trichloropyrimidine (20.06 g, 109 mmol) in THF (50 mL) at −78° C. The mixture was stirred for 1 h. Dry ice was added and the mixture was stirred at RT for 1 h. To the mixture was added 1N HCl, which was subsequently extracted with EtOAc. The organic layers were basified with aqueous NaHCO3, and washed with EtOAc. The aqueous layer was then acidified with 1N HCl, and extracted with EtOAc. The organic layers were washed with 1N HCl, water, and brine, were dried over anhydrous MgSO4, and then filtered. The filtrate was concentrated under reduced pressure. The residue was washed with hexane to give the desired product as a pale brown solid (12.28 g, 49%). 1H NMR (500 MHz, CDCl3) δ ppm 7.65 (br s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:19]=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][CH2:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccccc2n1CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.5 g (2.6 mmol) of 1H-Indole-2-carboxylic acid ethyl ester was dissolved in DMF and 116 mg (2.9 mmol) of sodium hydride (60% dispersion in mineral oil) was added. The solution was stirred for 30 min at room temperature, then cooled to −78° C. A solution of 0.82 g (2.6 mmol) of toluene-4-sulfonic acid 2-(4-chloro-phenyl)-ethyl ester in DMF was added to this cooled solution. The solution was warmed to RT and was stirred for 16 h. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and the solution was washed once with saturated aqueous sodium bicarbonate, once with water, and once with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with a gradient of n-heptane/ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH2:35][CH3:36])([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:28]4([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:22]([CH3:34])[CH:21]=3)[CH2:18][CH3:19])=[CH:13][CH:12]=2)[CH:10]=1.[H][H]>CO.[C].[Pd]>[CH3:1][O:2][C:3](=[O:37])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([CH2:35][CH3:36])([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]4([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:22]([CH3:34])[CH:21]=3)[CH2:18][CH3:19])=[CH:15][CH:16]=2)[CH:10]=1
Reactant: [H][H]
Reactant: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(C#CC2(O)CCCC2)c(C)c1
Agent: [Pd]
Solvent: CO
Product: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(CCC2(O)CCCC2)c(C)c1
Yield: 79.4 %

Procedure:
10% palladium carbon (16 mg) was added to a solution of [5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 148-(1); 16.4 mg, 0.033 mmol) in methanol (0.2 mL), and the mixture was stirred in a hydrogen atmosphere for 19 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give the title compound (13.1 mg, 79%).