Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)[CH:3]=[N:2]1.Br[CH2:31][CH:32]1[CH2:34][CH2:33]1.O.[OH-].[Cs+].[ClH:38]>CN(C=O)C>[ClH:38].[ClH:38].[CH:32]1([CH2:31][N:1]2[CH:5]=[C:4]([CH2:6][N:7]3[C:15]4[C:10](=[C:11]([NH:16][C:17]([C:19]5[N:23]6[CH:24]=[CH:25][CH:26]=[CH:27][C:22]6=[N:21][CH:20]=5)=[O:18])[CH:12]=[CH:13][CH:14]=4)[C:9]([CH2:28][CH3:29])=[N:8]3)[CH:3]=[N:2]2)[CH2:34][CH2:33]1
Reactant: BrCC1CC1
Reactant: CCc1nn(Cc2cn[nH]c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: Cl
Agent: [Cs+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cnn(CC3CC3)c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
To a solution of N-(1-((1H-pyrazol-4-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (20 mg, 0.052 mmol; prepared according to Example 21, Step A) in dry DMF (0.5 mL) was added (bromomethyl)cyclopropane (7.0 mg, 0.052 mmol) and cesium hydroxide hydrate (8.7 mg, 0.052 mmol). The mixture was stirred at ambient temperature for 60 minutes. The mixture was filtered, washed with methanol and ethyl acetate, and concentrated under reduced pressure. The residue was purified using preparative thin layer chromatography on silica, eluting with 10% methanol in dichloromethane. The product was dissolved in a mixture of dichloromethane and methanol. Hydrogen chloride (0.52 mmol; 2M solution in diethyl ether) was added and the solvent was removed under reduced pressure, followed by high vacuum to give N-(1-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride (5.6 mg). MS (APCI), positive scan, m/z=440.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[C:4]([Br:15])[CH:3]=1.[CH2:16]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][C:29]=1[F:43])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[CH2:16]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[C:4]([Br:15])[CH:3]=2)=[CH:30][C:29]=1[F:43])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COCCOCOc1cc(Br)cc(Br)c1
Reactant: CC1(C)OB(c2ccc(OCCCOCc3ccccc3)c(F)c2)OC1(C)C
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOc1cc(Br)cc(-c2ccc(OCCCOCc3ccccc3)c(F)c2)c1

Procedure:
17.0 g (50.0 mmol) 1,3-dibromo-5-(2-methoxy-ethoxymethoxy)-benzene, 19.3 g (50.0 mmol) 2-[4-(3-benzyloxy-propoxy)-3-fluoro-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 41.3 g (150 mmol) sodium metaborate-tetrahydrate are suspended in 200 ml THF and 200 ml water and 1.6 g (2 mmol) palladium(dppf) are added. The mixture is heated overnight at reflux. After partial removal of the solvent and addition of 100 ml MTB ether, the mixture is acidified with 2M hydrochloric acid. The organic layer is separated and the aqueous layer is extracted three times with MTB ether. The combined organic layers are washed with sat. aq. sodium chloride solution, dried over sodium sulfate and the solvent is removed in vacuo. The crude product is filtered through silica gel with toluene/ethylacetate (7:3 to 1:1) to yield 4-(3-benzyloxy-propoxy)-3′-bromo-3-fluoro-5′-(2-methoxy-ethoxymethoxy)-biphenyl as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:30](=O)[CH3:31]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])/[C:11](=[CH:30]/[CH3:31])/[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC=O
Reactant: O=C1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C/C=C1\C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc2C1=O
Temperature: 0 °C
Yield: 88.8 %

Procedure:
To a solution of (S)-4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1 (2H)-one 1 (3.0 g, 10.3 mmol) in THF (50 mL) at −78 ° C was added LiHMDS (1.0 M, 12.4 mL, 12.4 mmol). The reaction mixture was stirred for 20 min before acetaldehyde (0.55 g, 0.70 mL, 12.41 mmol) was added. The reaction mixture was stirred and warmed to 0° C. over 2 h before being quenched with a saturated solution of NH4Cl (10 mL). The product was extracted with ethyl acetate, dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:7 to 1:5) to give (S,E)-4-(3,4-dichlorophenyl)-2-ethylidene-3,4-dihydronaphthalen-1(2H)-one 42 (2.9 g, 88%).
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[OH:1][CH2:2][C:3]1[N:25]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:7](=[O:9])[CH:8]=1
Reactant: NCc1ccccc1
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Solvent: O
Product: O=c1cc(CO)n(Cc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(hydroxymethyl)-5-(phenylmethoxy)-4H-pyran-4-one (10.5 g, 45.3 mmol) in benzylamine (40 ml) and water (60 ml) was refluxed for four hours and then stirred overnight at room temperature. The resulting precipitate was collected and washed thoroughly with water to give 9.17 g (28.6 mmol) of 2-(hydroxymethyl)-5-(phenylmethoxy)-1-(phenylmethyl)-4(1H)pyridinone (melting point 146°-147° C.) upon drying. The supernatant was diluted with water to a total volume of 450 ml, and after standing for one hour at room temperature, the resulting precipitate was collected to yield 2.47 g (7.69 mmol) of additional 2-(hydroxymethyl)-5-(phenylmethoxy)-1-(phenylmethyl)-4(1H)-pyridinone upon drying.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1.ClCCl>[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:12]([S:15]([N:1]([C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])[S:15]([C:12]2[CH:11]=[CH:10][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)(=[O:17])=[O:16])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1noc(N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
5-Amino-4-bromo-3-methylisoxazole (0.179 g, 1.0 mmol) was dissolved in dry pyridine (2 ml). 4-Biphenylsulfonyl chloride (0.509 g, 2.2 mmol) was added with stirring at ambient temperature. N,N-Dimethylaminopyridine (5 mg) was added, and stirring was continued at 50° C. for 16 h. The reaction mixture was diluted with dichloromethane (75 ml), washed with 1N HCl (2×50 ml) and the organic phase was dried over magnesium sulfate. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography using 8:2, hexanes/ethyl acetate, to give 0.390 g (60% yield) of N-(4-biphenylsulfonyl)-N-(4-bromo-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].[C:11](=N)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[C:2]([O:6][C:7](=[O:10])[CH2:8][N:9]=[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 91.5 %

Procedure:
A solution of glycine t-butyl ester hydrochloride (10 g, 59.65 mmol) in 250 mL of di-chloromethane is treated with benzophenoneimine (10.8 g, 59.6 mmol) at RT. After 16 h, the mixture is washed with brine, dried over anhydrous MgSO4 and concentrated to give benzhydrylideneaminoacetic acid t-butyl ester as a white solid (16.1 g, 91%).
Reaction SMILES: C(=N[OH:9])C1C=CC=CC=1.[H-].[Na+].[C:12]([C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]#[C:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH3:20])[C:15]([O:17]CC)=O)#[N:13]>CN(C=O)C.O1CCOCC1>[C:12]([C:14]1([CH3:20])[C:21]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]([OH:9])=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:15]1=[O:17])#[N:13]
Reactant: CCOC(=O)C#Cc1ccccc1C(C)(C#N)C(=O)OCC
Reactant: ON=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(O)c2ccccc2C(C)(C#N)C1=O
Reaction time: 0.5 h

Procedure:
A solution of benzaldehyde oxime (0.37 mL, 3.7 mmol) in dry DMF (4 mL) was added to a stirred suspension of NaH (0.16 mL, 3.7 mmol) in dry dioxane (50 mL) in a nitrogen atmosphere at room temperature. After 30 minutes, a solution of ethyl 3-(2-(2-cyano-1-ethoxy-1-oxopropan-2-yl)phenyl)propiolate (1.12 g, 3.7 mmol) was added in dry DMF (5 mL), and the solution was stirred overnight. The solvent was removed under vacuum, and water was added to the residue. The product was extracted with EtOAc. The organic layer was washed with water, dried with MgSO4, concentrated in vacuo, and purified by silica flash chromatography eluting with 0-30% EtOAc/hexane. MS (m/z)=272 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[NH:5][C:6]=1C(O)=O>CC(O)=O.Br>[Br:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[NH:5][CH:6]=1
Reactant: COc1ccc(-c2nc(Br)c(C(=O)O)[nH]2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(-c2nc(Br)c[nH]2)cc1
Reaction time: 8 h
Yield: 73.2 %

Procedure:
A suspension of 9 (2.5 g, 0.008 mol) in AcOH (10 ml) and 48% HBr (40 ml) was heated at reflux for 15 hours. The solution was concentrated to dryness and stirred overnight with saturated NaHCO3. The suspension was filtered, the solids chromatographed on silica gel and eluted with 5% CH3OH--CHCl3 to yield 1.4 g (65%) of 11. An analytical sample was prepared by crystallization from CH3CN, m.p. 210°-212° C.
Reaction SMILES: [F:1][C:2]([F:24])([CH2:8][CH2:9][CH2:10][C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[C:3]([O:5]CC)=[O:4].[OH-].[Na+:26].O>CO>[F:1][C:2]([F:24])([CH2:8][CH2:9][CH2:10][C:11]([F:22])([F:23])[C:12]([F:20])([F:21])[C:13]([F:19])([F:18])[C:14]([F:15])([F:16])[F:17])[C:3]([O-:5])=[O:4].[Na+:26]
Reactant: CCOC(=O)C(F)(F)CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C([O-])C(F)(F)CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 99.2 %

Procedure:
Sodium 2,2,6,6,7,7,8,8,9,9,9-undecafluoro-nonanoate (60 g, 99% yield, formula above) was prepared from ethyl 2,2,6,6,7,7,8,8,9,9,9-undecafluorononanoate (61.5 g, 0.16 mol), sodium hydroxide (6.5 g, 0.163 mol), water (100 mL) and methanol (100 mL) according to the procedure of Example 7.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[S:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[O:14])[CH:9]=[CH:8][C:7]=1[OH:21])([O:3][CH2:4][CH3:5])=[O:2].[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O>[C:1]([C:6]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[S:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[O:14])[CH:9]=[CH:8][C:7]=1[O:21][CH2:22][CH:24]1[O:26][CH2:25]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: ClCC1CO1
Reactant: CCOC(=O)c1cc(NC(=O)c2ccc(C)s2)ccc1O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Product: CCOC(=O)c1cc(NC(=O)c2ccc(C)s2)ccc1OCC1CO1
Temperature: 110 °C

Procedure:
In a flask, the mixture of 35 g of 2-carbethoxy 4-(5-methyl-2-thiophene carboxamido)phenol and 175 ml of epichlorohydrin, is heated to 110° C., then 2.9 g of benzyltrimethylammonium chloride are introduced. The reaction mixture is then heated to reflux for 30 mins., then cooled. Once the temperature of the medium has dropped again to 50° C., 200 ml of water are added and the mixture is stirred strongly. After decantation, the aqueous phase is extracted twice with ether and the organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. The residue hardens in ether. After three washings in 50 ml of isopropylic ether, 30 g of 1-[2-carbethoxy 4-(5-methyl 2-thiophene carboxamido)phenoxy]2,3-epoxy propane are obtained in the form of white crystals melting at 109° C.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH3:7])[C:3](O)=[O:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:41]([C@H:43]1[C@H:48]([NH:49][C:50]2[C:51]3[N:52]([CH:59]=[C:60]([C:62]4[CH:63]=[N:64][N:65]([CH3:67])[CH:66]=4)[CH:61]=3)[N:53]=[CH:54][C:55]=2[C:56]([NH2:58])=[O:57])[CH2:47][CH2:46][NH:45][CH2:44]1)[CH3:42]>CN(C=O)C>[CH2:41]([C@H:43]1[C@H:48]([NH:49][C:50]2[C:51]3[N:52]([CH:59]=[C:60]([C:62]4[CH:63]=[N:64][N:65]([CH3:67])[CH:66]=4)[CH:61]=3)[N:53]=[CH:54][C:55]=2[C:56]([NH2:58])=[O:57])[CH2:47][CH2:46][N:45]([C:3](=[O:4])[C@@H:2]([OH:1])[CH2:6][CH3:7])[CH2:44]1)[CH3:42]
Reactant: CC[C@H](O)C(=O)O
Reactant: CC[C@@H]1CNCC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(C)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@@H]1CN(C(=O)[C@@H](O)CC)CC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(C)c3)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
To a solution of (S)-2-hydroxybutanoic acid (3.54 mg, 0.034 mmol) in DMF (181 μl) were added DIEA (28.5 μl, 0.163 mmol) and HATU (25.9 mg, 0.068 mmol). After 15 minutes, 4-(((3R,4R)-3-ethylpiperidin-4-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (10 mg, 0.027 mmol) was added. The reaction was stirred at room temperature for 3 hrs. The product mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified via preparative HPLC (Column: Waters XBridge C18, 19×200 mm, 5-μm). The collected fractions were combined and dried via centrifugal evaporation to yield the title compound (7.9 mg, 0.017 mmol, 64.0% yield) as a white solid. 1H NMR (500 MHz, 1:1 Chloroform-d/Methanol-d4) δ 8.12-8.09 (m, 1H), 7.77 (d, J=2.5 Hz, 1H), 7.72 (d, J=3.5 Hz, 2H), 6.92-6.88 (m, 1H), 4.42-4.34 (m, 2H), 4.24-4.13 (m, 1H), 3.95 (s, 3H), 3.12-3.03 (m, 1H), 2.41-2.34 (m, 1H), 1.84-1.73 (m, 2H), 1.70-1.58 (m, 3H), 1.43-1.32 (m, 1H), 1.06-0.97 (m, 7H). LCMS (Method K) m/z 454.249 ([M+H]+). HPLC (Method F) Rt: 1.12 min.
Reaction SMILES: [Cl:1]Cl.ClC(SS[C:9]([O:30][CH2:31][C:32]([F:39])([N+:36]([O-:38])=[O:37])[N+:33]([O-:35])=[O:34])([O:20][CH2:21][C:22]([N+:27]([O-:29])=[O:28])([N+:24]([O-:26])=[O:25])[F:23])[O:10][CH2:11][C:12]([N+:17]([O-:19])=[O:18])([N+:14]([O-:16])=[O:15])[F:13])(Cl)Cl>ClCCCl>[F:13][C:12]([N+:17]([O-:19])=[O:18])([N+:14]([O-:16])=[O:15])[CH2:11][O:10][C:9]([Cl:1])([O:30][CH2:31][C:32]([F:39])([N+:36]([O-:38])=[O:37])[N+:33]([O-:35])=[O:34])[O:20][CH2:21][C:22]([F:23])([N+:27]([O-:29])=[O:28])[N+:24]([O-:26])=[O:25]
Reactant: O=[N+]([O-])C(F)(COC(OCC(F)([N+](=O)[O-])[N+](=O)[O-])(OCC(F)([N+](=O)[O-])[N+](=O)[O-])SSC(Cl)(Cl)Cl)[N+](=O)[O-]
Reactant: ClCl
Solvent: ClCCCl
Product: O=[N+]([O-])C(F)(COC(Cl)(OCC(F)([N+](=O)[O-])[N+](=O)[O-])OCC(F)([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]
Reaction time: 8 h

Procedure:
Dry chlorine gas was passed for 2 hrs into a solution of 81.0 g (0.124 mole) of tris(2-fluoro-2,2-dinitroethoxy)methyl trichloromethyl disulfide in 300 ml of dry 1,2-dichloroethane at 60°-65° C. The solution was allowed to stand at ambient temperature overnight before the volatiles were removed with a stream of nitrogen and heating at 60°-65° C. The cooled residue was stirred with 300 ml of dry hexanes to give tris(2-fluoro-2,2-dinitroethyl)chloroorthoformate as an insoluble white solid. The hexanes solution was decanted from the solid which was washed with hexanes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([I:13])[N:7]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]/[C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[CH:10][CH:9]=[C:8]([I:13])[N:7]=1
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Reactant: COC(=O)CCc1nc(I)ccc1O
Product: COC(=O)CCc1nc(I)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 68.6 %

Procedure:
Under the conditions of example 1 D, 850 mg of 3-(3-hydroxy-6-iodo-2-pyridyl)-propionic acid methyl ester is reacted with 612 mg of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene, worked up, and the crude product is chromatographed on silica gel with hexane/0-5% ethyl acetate. 773 mg of 3-{6-iodo-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester is obtained as colorless oil.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][N:25]=[C:26]([C:33]3[N:37]([CH3:38])[N:36]=[N:35][N:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:18]=2)C(=O)OC(C)(C)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([CH2:7][CH2:8][NH:9][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][N:25]=[C:26]([C:33]3[N:37]([CH3:38])[N:36]=[N:35][N:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1nnnc1C(=NOCc1cccc(N(CCC2CCCCC2)C(=O)OC(C)(C)C)n1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nnnc1C(=NOCc1cccc(NCCC2CCCCC2)n1)c1ccccc1
Yield: 79.6 %

Procedure:
To a stirred solution of tert-butyl (2-cyclohexylethyl){6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate (0.252 g, 0.413 mmol, 1 eq.) in 5 ml of dry DCM, was added TFA (1.41 g, 12.39 mmol, 30 eq.) in one portion. The reaction was refluxed for 5 hrs. Then the solvent and excess TFA were evaporated. The residue was neutralised with TEA and purified by chromatography on silica gel to give N-(2-cyclohexylethyl)-6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine (0.138 g, 76% yield) as a viscous oil.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[OH:19].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[O:19][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1ncccn1
Reactant: COc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1Oc1ncccn1
Temperature: 80 °C
Reaction time: 72 h
Yield: 77.4 %

Procedure:
According to Scheme 3 Step 1 Method B: 2-Bromopyrimidine (1.26 mmol, 211 mg) was added to a suspension of 2-methoxy-4-nitrophenol (1.15 mmol, 200 mg), Cs2CO3 (1.41 mmol, 460 mg) in DMF (3 mL). The reaction mixture was stirred at 80° C. for 3 days. The reaction mixture was quenched with water. The aqueous phase was extracted with AcOEt. The organic phase was washed with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was washed with a solution of NaOH 3M and dried to obtain 2-(2-methoxy-4-nitrophenoxy)pyrimidine (0.89 mmol, 220 mg, 78%) as a solid. The product was used without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:5]=1[CH2:6][NH:7][C:8]([C:10]1[CH:24]=[CH:23][C:13]2[CH2:14][CH:15]3[CH:20]([CH3:21])[C:19]([CH3:22])([C:12]=2[CH:11]=1)[CH2:18][CH2:17][NH:16]3)=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][CH2:39][CH2:40]Br>C(#N)C>[CH3:2][O:3][C:4]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:5]=1[CH2:6][NH:7][C:8]([C:10]1[CH:24]=[CH:23][C:13]2[CH2:14][C@@H:15]3[C@H:20]([CH3:21])[C@:19]([CH3:22])([C:12]=2[CH:11]=1)[CH2:18][CH2:17][N:16]3[CH2:40][CH2:39][O:38][CH3:37])=[O:9]
Reactant: COc1ccc(CNC(=O)c2ccc3c(c2)C2(C)CCNC(C3)C2C)c(OC)c1
Reactant: COCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CC[C@@]2(C)c3cc(C(=O)NCc4ccc(OC)cc4OC)ccc3C[C@@H]1[C@@H]2C
Temperature: 65 °C
Yield: 85.5 %

Procedure:
A mixture of 2R,6R,11R)-N-(2,4-dimethoxybenzyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide hydrochloride (400 mg, 0.93 mmol), potassium carbonate (385 mg, 2.78 mmol), and bromoethyl methyl ether (142 mg, 1.02 mmol) in acetonitrile (15 mL) was heated at 65° C. overnight. Further bromoethyl methyl ether was added (70 mg, 0.50 mmol) and the to reaction heated at 65° C. for 24 hours. The reaction mixture was allowed to return to ambient temperature before partitioning between ethyl acetate (100 mL) and water (100 mL). The organic phase was dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave (2R,6R,11R)-N-(2,4-dimethoxybenzyl)-3-(2-methoxyethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide (360 mg, 86% yield); LC/MS (M+H)+=453.2.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4]1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>C1COCC1.C(OC(=O)C)C>[Si:10]([O:8][CH:5]1[CH2:6][CH2:7][CH:3]([OH:9])[CH2:4]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCC(O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
Sodium Hydride (3.77 g, 0.094 mol, 60% in mineral oil) was added to a solution of 1,3-cyclopentanediol (9.62 g, 0.094 mol) in 100 mL of THF. A slight generation of gas was observed. After stirring at room temperature for 1 h, tert-butyldimethylsilyl chloride (14.2 g, 0.094 mol) was added and the mixture was stirred at room temperature over night. The reaction mixture was diluted with 500 mL of ethylacetate and washed with 125 mL of 10% K2CO3, brine, and dried over Na2SO4. The solution was concentrated and dried in vacuo to give 20.3 g of crude product as a colorless oil. Further purification over SiO2 using a gradient elution 5% EtOAc/hexanes to 10% EtOAc/hexanes provided the desired compound as a colorless oil (7.1 g, 35% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[OH:24].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:2]([O:24][C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Cc1cccc(C)c1O
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCCCCCCCOc1c(C)cccc1C
Yield: 99.3 %

Procedure:
The product was generated via general protocol A using 1-bromotetradecane (44.7 mL, 0.147 mol), 2,6-dimethylphenol (20.0 g, 0.162 mol), K2CO3 (81.3 g, 0.588 mol) and CH3CN (150 mL). Yielded 46.5 g (99.3%) of a yellow/orange liquid. 1H NMR (CDCl3, 400 MHz) δ: 7.01 (d, 4J=7.3 Hz, 2H, Ar—H), 6.91 (t, 3J=6.8 Hz, 3H, Ar—H), 3.76 (t, 3J=6.7 Hz, 2H, OCH2), 2.28 (s, 6H, Ar—CH3), 1.81 (p, 3J=7.1 Hz, 2H, OCH2CH2), 1.50 (p, 3J=7.4 Hz, 2H, OCH2CH2CH2), 1.36-1.27 (m, 22H), 0.89 (t, 3J=6.9 Hz, 3H, CH2CH3). 13C NMR (CDCl3, 100 MHz) δ: 156.08, 130.95, 128.71, 123.54, 77.32, 77.00, 76.68, 72.28, 31.93, 30.44, 29.70, 29.68, 29.66, 29.63, 29.57, 29.37, 26.16, 22.69, 16.26, 14.12.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[S:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=1)C.C(O[CH:19](OCC)[N:20]([CH3:22])[CH3:21])C>>[CH3:1][O:3][C:4](=[O:15])[C:5]([C:6]1[S:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=1)=[CH:19][N:20]([CH3:22])[CH3:21]
Reactant: CCOC(=O)Cc1nnc(C(F)(F)F)s1
Reactant: CCOC(OCC)N(C)C
Product: COC(=O)C(=CN(C)C)c1nnc(C(F)(F)F)s1

Procedure:
3.05 g (13.5 mmol) 5-(trifluoromethyl)-1,3,4-thiadiazol-2-ylacetic acid ethyl ester [for preparation see DE 42 40 168-A1] are heated in 6.9 ml (40.5 mmol) dimethylformamide diethyl acetal overnight at 100° C. After cooling, the mixture is concentrated and the residue is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient).