Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=3)[C:17]([O:19]C)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Li+].O>C1COCC1>[N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=3)[C:17]([OH:19])=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC[C@@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC[C@@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)O)c1
Yield: 88.1 %

Procedure:
Methyl 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1R)-1-methyl-2-(methyloxy)ethyl]oxy}benzoate (1.06 g, 2.6 mmol) was dissolved in THF (24 mL) and methanol (8 mL) then 1N lithium hydroxide solution (3.12 mL) added, followed by the dropwise addition of water (10 mL). The resultant solution was stirred for 3 hours at RT, a further portion of 1N lithium hydroxide solution (1.3 mL), the reaction stirred a further 2 hours, then further 1N lithium hydroxide solution (0.6 mL) added and stirring continued for another hour. The organics were removed by evaporation under reduced pressure, the aqueous solution was washed with diethyl ether (10 mL) then acidified with 2N hydrochloric acid and extracted with ethyl acetate (3×20 mL). The combined organics were washed with water (10 mL), brine (10 mL) and evaporated to dryness under reduced pressure to give the desired compound as a white solid (887 mg).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:15]N1C(=O)C2=CC=CC=C2C1=O>C(#N)C1C=CC=CC=1>[O:15]=[C:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)Cc1ccccc1O2
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: N#Cc1ccccc1
Product: O=c1c2ccccc2oc2ccccc12
Temperature: 100 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
A mixture of 2 mmole of xanthene, 10 mole % of N-hydroxyphthalimide relative to xanthene, and 5 ml of benzonitrile was stirred for 20 hours at 100° C. under an oxygen atmosphere. The products in the reaction mixture were analyzed by gas chromatography, and, as a result, 9-oxoxanthene (yield not less than 99%) was formed.
Reaction SMILES: [H-].[Na+].[C:3]1([C@@H:9]([OH:24])[C@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>O1CCCC1>[C:30]([O:29][C:27]([CH2:26][O:24][C@H:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C@H:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: O[C@H](c1ccccc1)[C@@H](OC1CCCCO1)c1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CO[C@H](c1ccccc1)[C@@H](OC1CCCCO1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.9 %

Procedure:
To a suspension of sodium hydride (60% oil dispersion; 161 mg, 4.03 mmol) in dry tetrahydrofuran (9.6 ml) were added a solution of 8S (1.15 g, 3.84 mmol) and tert-butyl bromoacetate (681 μl, 4.61 mmol) in dry tetrahydrofuran (9.6 ml) at 0° C. After stirring for 18 h at rt, the reaction mixture was concentrated in vacuo. After addition of water, the product was extracted with ethyl acetate twice and the organic layer was dried over anhydrous sulfate. After concentration in vacuo, the residue was purified by silica gel chromatography (eluted with 10:1 hexane:AcOEt) to give 9S (1.17 g, 74%) as a white solid.
Reaction SMILES: [OH-].[Na+:2].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[O:13][CH:14]=1>O>[Na+:2].[Na+:2].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O-:21])=[O:20])[O:13][CH:14]=1.[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O-:21])=[O:20])[O:13][CH:14]=1
Reactant: O=C(O)CCCCc1nc(-c2ccccc2O)co1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CCCCc1nc(-c2ccccc2O)co1
Temperature: 25 °C
Yield: 107.8 %

Procedure:
Add a solution of NaOH (1.15 g, 28.75 mmol) in water (5 mL) to a suspension of 5-[4-(2-hydroxy-phenyl)-oxazol-2-yl]-pentanoic acid (compound of Example 6, 3.76 g, 14.38 mmol) in water (30 mL) and stir at room temperature. Heat to 50° C. for 1 h, filter hot. solution, concentrate, place in 50-60° C. vacuum oven overnight Scrape and crush solids, place in 50-60° C. vacuum oven for 60 hours to afford the title compound (4.39 g, 100%). MS (IS) 260 (M−1)−.
Reaction SMILES: C([Mg]Br)C.[CH3:5][C:6]1[N:11]=[C:10]2[NH:12][CH:13]=[CH:14][C:9]2=[CH:8][CH:7]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH3:5][C:6]1[N:11]=[C:10]2[NH:12][CH:13]=[C:14]([C:20]([C:19]3[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:17]([O:16][CH3:15])[CH:18]=3)=[O:21])[C:9]2=[CH:8][CH:7]=1
Reactant: Cc1ccc2cc[nH]c2n1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: CC[Mg]Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(C(=O)c2c[nH]c3nc(C)ccc23)cc(OC)c1OC
Reaction time: 1 h
Yield: 47.4 %

Procedure:
Ethylmagnesium bromide (3.0 M solution in diethyl ether, 0.43 mL) was added to a mixture of 6-methyl-1H-pyrrolo[2,3-b]pyridine (0.127 g, 0.969 mmol) and anhydrous zinc chloride (0.263 g, 1.94 mmol) in dry CH2Cl2 (20 mL) over 10 min at room temperature. The suspension was stirred for 1 h and then a solution of 3,4,5-trimethoxybenzoyl chloride (0.335 g, 1.45 mmol) in dry CH2Cl2 (10 mL) was added dropwise over 5 min. After 1 h, aluminum chloride (0.129 g, 0.969 mmol) was added. The resulting thick mixture was vigorously stirred for 5 h. The reaction was quenched with water (10 mL) and extracted with CH2Cl2 (20 mL). The organic layer was dried over anhydrous MgSO4 and concentrated to give a brown oil, which was further purified on a silica gel column (MeOH:CH2Cl2=1:25) to give compound 8 (0.150 g, 48%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:16]2[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.Cl.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38]1[NH:42][N:41]=[C:40]([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[N:39]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(Cl)(Cl)Cl>[C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:16]2[CH:23]=[CH:22][C:19]([CH2:20][N:46]3[CH2:47][CH2:48][CH:43]([C:40]4[NH:39][C:38]([C:34]5[S:33][CH:37]=[CH:36][CH:35]=5)=[N:42][N:41]=4)[CH2:44][CH2:45]3)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1csc(-c2nc(C3CCNCC3)n[nH]2)c1
Reactant: O=Cc1ccc(-c2nc3ccccn3c2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: c1ccc(-c2c(-c3ccc(CN4CCC(c5nnc(-c6cccs6)[nH]5)CC4)cc3)nc3ccccn23)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 0.120 g (0.402 mM) of 4-(3-phenylimidazo[1,2-a]pyridin-2-yl)benzaldehyde in 5 mL of THF is added triethylamine (2 eq). The reaction mixture is stirred for 5 minutes. To this solution is added 4-[5-(thiophen-2-yl)-1H-1,2,4-triazol-3-yl]piperidine dihydrochloride (Intermediate I) (1.5 eq) followed by acetic acid (2.5 eq). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH(OAc)3 (6 eq) over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained is taken up in chloroform and washed with water, dried and concentrated. The crude is purified on a flash column chromatography to obtain the desired compound.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17]([C:19]1([CH3:22])[CH2:21][CH2:20]1)=[O:18])=[O:4].[OH-].[Li+]>>[CH:14]1([CH2:13][S:10]([C@H:8]2[CH2:7][N:6]([C:17]([C:19]3([CH3:22])[CH2:20][CH2:21]3)=[O:18])[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]2)(=[O:11])=[O:12])[CH2:15][CH2:16]1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1C(=O)C1(C)CC1
Agent: [Li+]
Agent: [OH-]
Product: CC1(C(=O)N2C[C@H](S(=O)(=O)CC3CC3)C[C@H]2C(=O)O)CC1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-cyclopropylmethanesulfonyl-1-(1-methyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:27]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)=[CH2:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:32]1[CH:33]=[CH:34][C:29](/[CH:27]=[CH:28]/[C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([N:13]4[CH2:17][CH2:16][C@@:15]5([C:21]6[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=6[C:19](=[O:26])[O:18]5)[CH2:14]4)=[O:12])[CH2:9][CH2:10]3)=[CH:4][CH:3]=2)=[CH:30][CH:31]=1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(Br)cc4)CC3)C2)c2ccccc21
Reactant: C=Cc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(/C=C/c5ccncc5)cc4)CC3)C2)c2ccccc21

Procedure:
A mixture of POPd1 catalyst (CombiPhos Catalysts, Inc) (2 mg), (1R)-1′-{[1-(4-bromophenyl)cyclopropyl]-carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (15 mg, 0.036 mmol), 4-vinylpyridine (19 mg, 0.18 mmol), potassium carbonate (5.5 mg, 0.04 mmol) in N,N-dimethylformamide (0.3 ml) was microwave irradiated at 135° C. for 30 minutes. Then the desired product was obtained from the mixture by prep-HPLC followed by chiral HPLC (13 mg, 82%). LCMS: m/z 437.2 (M+H)+; 459.2 (M+Na)+.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]1=[O:25])C.[OH-].[Li+]>C(O)C.O>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:26])=[O:3])[C:7](=[O:25])[CH:8]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)CN1CCN(C(=O)OC(C)(C)C)C(c2ccccc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)O)C(=O)C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 101B (0.77 g, 2.12 mmol) in ethanol/water (1:3, 30 mL) was added lithium hydroxide (0.26 g, 6.37 mmol), and the reaction mixture was stirred at ambient temperature overnight. Then the mixture was concentrated and partitioned in cold 1 N HCl/methylene chloride. The organic layer was separated, dried over MgSO4 and concentrated to yield the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.86 (s, 1H), 7.35 (m, 5H), 5.47 (s, 1H), 4.09 (dd, 2H), 3.90 (d, J=15.26 Hz, 1H), 3.53 (m, 1H), 3.28 (m, 1H), 1.40 (s, 9H); MS/DCI 352 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7](Br)[N:6]=1)=[O:4].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C(N(CC)CC)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[Fe+2]>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([C:14]2[O:13][CH:17]=[CH:16][CH:15]=2)[N:6]=1)=[O:4]
Reactant: OB(O)c1ccco1
Reactant: COC(=O)c1nc(Br)cnc1N
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1nc(-c2ccco2)cnc1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
A mixture of Pd(OAc)2 (146 mg, 0.7 mmol) and 1,1-bis(diphenylphosphino)ferrocene (478 mg, 0.9 mmol) in DMF (65 ml) under an argon atmosphere was stirred at 50° for 15 min and cooled to rt. The reaction mixture was evacuated, then flushed with argon. 3-Amino-6-bromopyrazine-2-carboxylic acid methyl ester (5.0 g, 21.5 mmol), 2-furanboronic acid (2.65 g, 23.7 mmol) and triethylamine (4.3 ml) were added. The reaction mixture was again evacuated, then flushed with argon. The mixture was heated at 90° overnight. After cooling to rt, the black mixture was concentrated to dryness. The residue was dissolved in dichloromethane (800 ml), washed with water, dried over MgSO4, filtered and evaporated. The crude product was purified by silica gel chromatography using a n-heptane/EtOAc gradient for elution, providing the title compound as yellow solid (2.84 g, 60%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][N:13]=2)[N:5]2[CH:20]=[C:21]([C:23]([O:25]CC)=[O:24])[N:22]=[C:4]2[CH:3]=1.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([NH:11][CH2:10][CH2:9][NH:8][C:6]2[N:5]3[CH:20]=[C:21]([C:23]([OH:25])=[O:24])[N:22]=[C:4]3[CH:3]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([C:29]([F:40])([F:39])[F:28])=[CH:31][CH:32]=3)[N:7]=2)=[N:13][CH:14]=1)#[N:19]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cn2c(NCCNc3ccc(C#N)cn3)nc(Cl)cc2n1
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(C(F)(F)F)cc3)cc3nc(C(=O)O)cn23)nc1

Procedure:
In analogy to the preparation of Example 109, the desired product is prepared by Pd-catalysed coupling starting from ethyl 7-chloro-5-({2-[(5-cyanopyridin-2-yl)amino]ethyl}amino)-imidazo[1,2-c]pyrimidine-2-carboxylate (Example 59A) and [4-(trifluoromethyl)phenyl]boronic acid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]#[C:4][C:5]([F:11])([F:10])[C:6]([F:9])([F:8])[F:7].ClC1(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl.[F-].[F-].[F-].[Cl-:28].[Cl-:29].[Sb+5].ClC1C(F)(F)C(F)(F)C(F)(F)C=1Cl>>[Cl:28][C:3](=[C:4]([Cl:29])[C:5]([F:10])([F:11])[C:6]([F:8])([F:7])[F:9])[C:2]([F:12])([F:13])[F:1]
Reactant: [Cl-]
Reactant: FC(F)(F)C#CC(F)(F)C(F)(F)F
Agent: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Agent: FC1(F)C(Cl)=C(Cl)C(F)(F)C1(F)F
Agent: [F-]
Product: FC(F)(F)C(Cl)=C(Cl)C(F)(F)C(F)(F)F

Procedure:
For example, a process for synthesizing perfluoro-2-pentyne is described in J. Am. Chem. Soc., vol. 76, p 611 (1954) wherein hexachlorocyclopentadiene is treated with antimony trifluorodichloride to synthesize 1,2-dichloro-3,3,4,4,5,5-hexafluorocyclopentene; and, 2,3-dichloro-1,1,1,4,4,5,5,5-octafluoro-2-pentene as produced as a by-product in this synthetic process is dechlorinated with zinc to give perfluoro-2-pentyne. This process has a problem such that an antimony pentahalide, which is troublesome to handle, must be used for obtaining the raw material (i.e., 2,3-dichloro-1,1,1,4,4,5,5,5-octafluoro-2-pentene), and the yield of perfluoro-2-pentyne is low.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][N:5]2[CH:11]=1.[CH2:12]([CH:14]([C:17]1[C:18]2[N:19]([C:24](I)=[C:25]([CH3:27])[N:26]=2)[N:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:15][CH3:16])[CH3:13]>>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][N:5]2[C:11]=1[C:24]1[N:19]2[N:20]=[C:21]([CH3:23])[CH:22]=[C:17]([CH:14]([CH2:12][CH3:13])[CH2:15][CH3:16])[C:18]2=[N:26][C:25]=1[CH3:27]
Reactant: Cc1cn2cccc(C)c2n1
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C)cccn34)c(C)nc12
Yield: 64.6 %

Procedure:
Using a procedure analogous to Example 16B, 2,8-dimethyl-imidazo[1,2-a]pyridine (J. Chem. Soc. 1951; 2411, 2415), (0.30 g, 2.06 mmol) and 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.71 g, 2.06 mmol) give the title compound (0.48 g, 1.33 mmol, 65%). 1H NMR (CDCl3): δ 0.92 (t, J=7.5 Hz, 3H), 0.93 (t, J=7.5 Hz, 3H), 1.81-1.95 (m, 4H), 2.41 (s, 3H), 2.44 (s, 3H), 2.45 (s, 3H), 2.70 (s, 3H), 3.35-3.43 (m, 1H), 6.65 (t, J=6.6 Hz, 1H0, 6.72 9s, 1H), 7.03 (d, J=6.6 Hz, 1H), 7.40 9d, J=6.6 Hz, 1) ppm. ES-MS (m/z): calcd for C22H27N5 (M+H)+: 362.5. found: 362.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][CH:40]=1)[CH2:27][NH:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:23][C:24]2[CH:40]=[CH:39][CH:38]=[C:26]([CH2:27][NH:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:30])[CH:25]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: Nc1cccc(CNC(=O)Nc2ccccc2)c1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Nc4cccc(CNC(=O)Nc5ccccc5)c4)cc3)c2)o1

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-{3-[(3-phenylureido)methyl]phenyl}-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and N-(3-aminobenzyl)-N′-phenylurea using method J. NMR; δH [2H6]—DMSO 10.36,(1H, b), 8.57,(1H, s), 8.06,(2H, d), 7.90,(1H, dd), 7.78,(2H, m), 7.69,(1H, dd), 7.57,(3H, m), 7.39,(3H, m), 7.21,(2H, m), 7.05,(1H, d), 6.62,(1H, t), 4.31,(2H, d), 2.57,(3H, s), 2.33,(3H, s). LCMS; retention time 3.55 min, MH+ 518.
Reaction SMILES: FC1C(F)=C(F)C=CC=1O.BrCCCCCCCCCO.[F:22][C:23]1[C:39]([F:40])=[C:38]([F:41])[CH:37]=[CH:36][C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35].FC1C(F)=C(F)C=CC=1OCCCCCCCCC(O)=O.Cl.Cl.[CH2:65]([O:72][C:73](=[O:81])[CH2:74][C@@H:75]([NH2:80])[CH2:76][N:77]([CH3:79])[CH3:78])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>>[CH2:65]([O:72][C:73](=[O:81])[CH2:74][C@@H:75]([NH:80][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:24]1[CH:36]=[CH:37][C:38]([F:41])=[C:39]([F:40])[C:23]=1[F:22])[CH2:76][N:77]([CH3:78])[CH3:79])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: OCCCCCCCCCOc1ccc(F)c(F)c1F
Agent: Cl
Agent: O=C(O)CCCCCCCCOc1ccc(F)c(F)c1F
Agent: OCCCCCCCCCBr
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCOc1ccc(F)c(F)c1F

Procedure:
The title compound, m/e=433.5 ([M+H]+), was produced in analogy with example 18, steps 1 to 4. Thus, 2,3,4-trifluorophenol was alkylated in step 1 with 9-bromo-1-nonanol, leading to 9-(2,3,4-trifluoro-phenoxy)-nonan-1-ol, which was oxidized in step 2 to 9-(2,3,4-trifluoro-phenoxy)-nonanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-[9-(2,3,4-trifluoro-phenoxy)-nonanoylamino]-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([O:6][C:7]([C@@H:9]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=C)[N:10]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:8])[CH3:5].[BH4-].[Na+]>CO.C(Cl)Cl>[CH2:4]([O:6][C:7]([C@@H:9]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:1])[N:10]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:8])[CH3:5]
Reactant: O=[O+][O-]
Reactant: C=CCC1CC[C@@H](C(=O)OCC)N1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)[C@@H]1CCC(CCO)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Ozone was passed at −78° C. through a solution of 1.00 g of 169 (3.53 mmol) in a mixture of 12 ml of MeOH and 6 ml of CH2Cl2 until the solution turned blue. The reaction was subsequently terminated and excess ozone removed by purging with oxygen. Thereafter, 270 mg of NaBH4 (7.06 mmol, 2 eq.) was added and the mixture stirred overnight to allow warming to RT. After checking completion of the reaction by means of TLC (EE/CH 1:1), the batch was concentrated and the remaining residue taken up in 60 ml of CH2Cl2 and 40 ml of half-conc. NaCl solution. The aqueous phase was extracted with 3×20 ml of CH2Cl2, the combined organic phases were dried over MgSO4 and concentrated. The residue was purified using silica gel column chromatography (EEICH 1:1) to obtain 691 mg (2.40 mmol, 68%) of alcohol 170 as a mixture of epimers (colorless oil).
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2.[C:19](Cl)(=[O:27])[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl.C(N(CC)CC)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][N:2]([CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2)[C:19](=[O:27])[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)CCN1CCSc2cc([N+](=O)[O-])ccc21
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCN1CCSc2cc([N+](=O)[O-])ccc21)C(=O)Oc1ccccc1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
To a stirred solution of N,N-dimethyl-2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethanamine (100 mg, 0.374 mmol) in dichloromethane (5 mL) under argon was added phenyl carbonochloridate (0.094 mL, 0.748 mmol). The resulting mixture was stirred at room temperature. A precipitate was observed, and triethylamine (3 drops) was added to aid dissolution (reaction turned clear). The mixture was then stirred over the weekend. The clear yellow mixture was then diluted with water and sodium carbonate and then extracted with dichloromethane (3×). The combined organics were dried, filtered, concentrated, and then chromatographed in ethyl acetate, giving the desired product (139 mg, 100%). 1H NMR (DMSO-d6) δ 7.84-7.74 (m, 2H), 7.39-7.31 (m, 2H), 7.23-7.16 (m, 1H), 7.03-6.93 (m, 3H), 3.85-3.78 (m, 3H), 3.73-3.65 (m, 2H), 3.55-3.50 (m, 1H), 3.09, 2.97 (2s, 3H), 3.09-3.05 (m, 2H); MS-EI: (m/z, %) 373 (M+, 4), 209 (31), 179 (100), 151 (28).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1.Cl>N1C=CC=CC=1.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:12][C:13]([OH:15])=[O:14])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: O=C(O)CC(=O)O
Reactant: Cc1ccc(C=O)cc1C
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: O
Product: Cc1ccc(C=CC(=O)O)cc1C
Temperature: 50 °C

Procedure:
A suspension of 3,4-dimethylbenzaldehyde (15.000 g; 111.793 mmol) and malonic acid (22.103 g; 212.410 mmol) in pyridine (85 ml) was heated to 50° C., under nitrogen. Then piperidine (8.5 ml; 86.079 mmol) was added dropwise (over 5 minutes) and the resulting suspension was heated to 75° C. for 2 h. The reaction mixture was cooled to 0° C., and poured into an ice-cooled solution of concentrated hydrochloric acid (12 N; 96 ml) in water (1200 ml). The precipitated colorless product was filtered off, and washed with water (3×100 ml). Remaining water was evaporated under reduced pressure, then under HV to give the dried product 3-(3,4-dimethyl-phenyl)-acrylic acid as a colorless solid (19.230 g; 98%). LC-MS: tR=0.88 min; [M+H]+: no ionisation.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Cl[C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[NH:10][CH:11]=[N:12]2.[N-:17]=[N+:18]=[N-:19].[Li+]>CS(C)=O>[NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[N:17]([C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[NH:10][CH:11]=[N:12]2)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1ncnc2nc[nH]c12
Agent: O=C1CCCN1
Agent: [Li+]
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1ncnc2nc[nH]c12

Procedure:
The 6-chloropurine pyrrolidone (1 mmol) is treated with lithium azide (2 mmol) in dimethyl sulfoxide (2 ml) at 30°-100° C. for several h. At the end of this time the mixture is evaporated under reduced pressure, dissolved in chloroform, washed with 10% sodium bicarbonate, and the organic layer dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica using a gradient of methanol in chloroform (0-25%).