Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH:3]=[C:4]([CH3:6])[CH3:5].BrC(C)(C)CC(F)(F)F.[N-:18]=[N+:19]=[N-:20]>CCOCC>[N:18]([C:4]([CH3:6])([CH3:5])[CH2:3][C:2]([F:8])([F:7])[F:1])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)=CC(F)(F)F
Agent: CC(C)(Br)CC(F)(F)F
Solvent: CCOCC
Product: CC(C)(CC(F)(F)F)N=[N+]=[N-]

Procedure:
The reaction mixture was distilled at ca. 65 mmHg pressure until 70 g of condensate had been collected; further distillate when examined by g.l.c. (2 m silicone, 50°) contained none of the required azide. The distillate was added to ice water (500 ml), shaken, and the lower organic layer (17.1 g) separated, shaken with an excess of aqueous sodium bicarbonate solution, then with water, and dried (Na2SO4). The washings were added to the ice-water layer, which was then extracted three times with ether. The combined ether extracts were washed with an excess of aqueous sodium bicarbonate solution, then with water and dried. The ether was removed to leave a residue of the azide concentrate (13.0 g). The azide was not isolated in the pure state, but as a precaution was handled diluted with ether, olefin and unchanged bromo-compound. The separated organic layer (17.1 g, above) by g.l.c. (2 m silicone, 50°) contained 1,1,1-trifluoro-3-methyl-2-butene (27%), 3-bromo-1,1,1-trifluoro-3-methylbutane (17%) and the azide. The product yields estimated by g.l.c. were 3-azide-1,1,1-trifluoro-3-methylbutane (10.0 g, 15%), 1,1,1-trifluoro-3-methyl-2-butene (27.5 g, 55%), and 3-bromo-1,1,1-trifuloro-3-methylbutane unreacted (4.4 g, 5%). The remaining material was partly accounted for as 1,1,1-trifluoro-3-methyl-2-butene in the ether distillate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C[Si]([C:19]#[N:20])(C)C>C(O)(=O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:8]2([C:19]#[N:20])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCCCC1
Reactant: Nc1cccnc1
Solvent: CC(=O)O
Product: N#CC1(Nc2cccnc2)CCCCC1
Reaction time: 0.25 h

Procedure:
1 g (10.6 mmol, 1.1 eq.) of 3-aminopyridine (starting material 1) is added to a solution of 1 ml (9.65 mmol, 1 eq.) of cyclohexanone (starting material 2) in 30 ml of acetic acid at 0° C. The solution is stirred for 15 minutes and 1.3 ml (9.75 mmol, 1 eq.) of trimethylsilyl cyanide are added. The reaction medium is stirred for 24 hours at room temperature. It is then poured gently into ice-cold ammonium hydroxide solution until the pH is basic, and is extracted with dichloromethane. The organic phases are combined and washed with water. They are dried over sodium sulfate. The residue is chromatographed on silica gel (50/50 heptane/ethyl acetate and then ethyl acetate). 1-(Pyridin-3-ylamino)cyclohexanecarbonitrile is obtained in the form of white crystals.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].[O-]S(C(F)(F)F)(=O)=O.F[N+:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[N+:1]([C:4]1[N:5]=[CH:6][N:7]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: F[n+]1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn(-c2ccccn2)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 4-nitro-1H-imidazole (0.5 g, 4.4 mmol) in DMF (15 ml) was cooled to 0° C. and treated with sodium hydride (0.23 g, 5.3 mmol). Stirring was continued at 0° C. for 1 h and subsequently cooled to −30° C. A solution of N-fluoropyridinium triflate (0.55 g, 2.2 mmol) in DMF (10 ml) was added within 5 min. After warming-up to ambient temperature, the reaction mixture was stirred at that temperature overnight. The crude product was obtained after extraction with ethyl acetate (2×100 ml), washing of the combined organic phases with 10% aqueous potassium bisulphate solution, water and brine and finally drying and solvent evaporation. This off-white solid material (0.33 g, 39%) was used without any further purification for the next step. MS: M=191.3 (M+H)+
Reaction SMILES: [Br:1][C:2]1[C:3]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33]C(OC(C)(C)C)=O)[CH2:28]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[O:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.[ClH:48]>C(Cl)Cl.CCOCC>[ClH:48].[NH2:33][C@@H:29]1[CH2:30][CH2:31][CH2:32][N:27]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([CH:14]4[O:19][CH2:18][CH2:17][NH:16][CH2:15]4)=[O:13])[C:4]=23)[CH2:28]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CN(C(=O)OC(C)(C)C)CCO4)c23)C1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CNCCO4)c23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 2-(5-bromo-4-((R)-3-(tert-butoxycarbonylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylcarbamoyl)morpholine-4-carboxylate diastereomer #2 (80 mg, 0.13 mmol) in DCM (3 mL) at room temperature was treated with TFA (1 mL) The mixture was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was then purified by reverse phase HPLC (0-50% ACN in water). The product isolated was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give N-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)morpholine-2-carboxamide hydrochloride diastereomer #2 (44 mg, 64% yield). 1H NMR (400 MHz, D2O) δ 8.18 (s, 1H), 7.57 (s, 1H), 4.55-4.51 (m, 1H), 4.20-4.16 (m, 1H), 3.97-3.90 (m, 1H), 3.67-3.64 (m, 1H), 3.49-3.29 (m, 5H), 3.20-3.08 (m, 2H), 2.95-2.92 (m, 1H), 2.09-2.06 (m, 1H), 1.81-1.69 (m, 2H), 1.53-1.49 (m, 1H); LCMS (APCI+) m/z 423, 425 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH:3]([O:5][CH2:6][CH3:7])=O.[CH3:8][O:9]CC(OCC)=O.[NH2:16][C:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([S:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)=[CH:20][NH:19][N:18]=1.Cl>C(OCC)(=O)C.O.O1CCCC1>[OH:9][C:8]1[N:18]2[N:19]=[CH:20][C:21]([C:22]3[CH:23]=[CH:24][C:25]([S:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:26][CH:27]=3)=[C:17]2[N:16]=[CH:7][C:6]=1[O:5][CH3:3]
Reactant: Nc1n[nH]cc1-c1ccc(Sc2ccccc2)cc1
Reactant: CCOC=O
Reactant: CCOC(=O)COC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cnc2c(-c3ccc(Sc4ccccc4)cc3)cnn2c1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a tetrahydrofuran suspension of 480 mg of 60% sodium hydride, 2 ml of ethyl formate and 1.0 g of ethyl methoxyacetate were added under nitrogen atmosphere, and the mixture was stirred for 16 hours at room temperature. In succession, adding 1.0 g of 3-amino-4(4-phenylthiophenyl)pyrazole, the solution was stirred for 4 hours in reflux. After allowing to cool, water was added and the solution was neutralized with 10% hydrochloric acid. Removing water, ethyl acetate was added, and insoluble matter was filtered. The filtrate was washed in ethyl acetate and ether and dried, and the title compound was obtained (100 mg, 8%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:13]1[O:15][C@H:14]1[CH2:16]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O.[OH-].[Na+]>CN(C)C=O.CCCCCC.CCOCC>[CH2:16]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]#[N:10])[C@@H:14]1[O:15][CH2:13]1
Reactant: N#Cc1c(O)cccc1Cl
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#Cc1c(Cl)cccc1OC[C@H]1CO1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3-Chloro-2-cyanophenol (0.55 g, 3.58 mmol) was dissolved in 10 mL of dimethylformamide, and the solution cooled to 0° C. Sodium hydride (0.158 g, 3.94 mmol 60% in oil), washed with hexane and dimethylformamide, was added to cooled solution over a period of one minute. After stirring for 10 minutes at room temperature, (2R)-(−)-glycidyl 3-nitrobenzenesulfonate was added and stirred 16 hours. The reaction was poured into ether and dilute sodium hydroxide. The ether layer was separated and the aqueous layer extracted once more with ether. The combined ether extracts were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 0.7 g of (R)-3-chloro-2-cyanophenyl glycidyl ether.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[F:18][C:19]([F:35])([F:34])[O:20][C:21]1[CH:33]=[CH:32][C:24]([CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1>>[F:34][C:19]([F:18])([F:35])[O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:2][C:3]([NH:5][C@@H:6]3[CH2:11][O:10][C:9]4=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]4[CH2:7]3)=[O:4])[CH2:28][CH2:27]2)=[CH:32][CH:33]=1
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Reactant: FC(F)(F)Oc1ccc(CC2CCNCC2)cc1
Product: O=C(CN1CCC(Cc2ccc(OC(F)(F)F)cc2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 62.1 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(4-(trifluoromethoxy)benzyl)piperidine (259 mg, 1.0 mmol) as crude materials, 150 mg title compound was generated and yield was 62%.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:17])[C:14]([OH:16])=O)=[CH:11][C:5]=2[O:4][CH2:3]1.[O:18]([CH:25]1[CH2:30][CH2:29][N:28](C)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:32](OCC)C>>[O:16]=[C:14]([N:28]1[CH2:27][CH2:26][CH:25]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:30][CH:29]1[CH3:32])[C:13]([NH:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2](=[O:1])[CH2:3][O:4][C:5]=2[CH:11]=1)=[O:17]
Reactant: O=C1COc2cc(NC(=O)C(=O)O)ccc2N1
Reactant: CN1CCC(Oc2ccccc2)CC1
Reactant: CCOCC
Product: CC1CC(Oc2ccccc2)CCN1C(=O)C(=O)Nc1ccc2c(c1)OCC(=O)N2

Procedure:
The title compound is prepared from N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-oxalamic acid (Example 53b) and 4-phenoxy-methyl-piperidine [DE 254 999 (1977)] according to the method described in Example 1c. Melting Point: 215-217° C. (diethylether)
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=CC=2)=[N:4][NH:5][CH:6]=1.Br[CH:14]([CH2:20][CH2:21][CH3:22])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16].ClC(C)C(N(C)C)=[O:26]>>[O:26]1[CH:10]=[CH:11][CH:12]=[C:7]1[C:3]1[C:2]([CH3:1])=[CH:6][N:5]([CH:14]([CH2:20][CH2:21][CH3:22])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[N:4]=1
Reactant: CCCC(Br)C(=O)N(C)C
Reactant: CC(Cl)C(=O)N(C)C
Reactant: Cc1c[nH]nc1-c1ccccc1
Product: CCCC(C(=O)N(C)C)n1cc(C)c(-c2ccco2)n1

Procedure:
Following the procedure of Example 1, but substituting 3-(2-furyl)-4-methylpyrazole for 4-methyl-3-phenylpyrazole and 2-bromo-N,N-dimethylvaleramide for 2-chloro-N,N-dimethylpropionamide there was obtained 3-(2-furyl)-N,N,4-trimethyl-α-propylpyrazole-1-acetamide having a melting point of 107°-109° C.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=O.[N+]([O-])(O)=O.[O:19]([CH2:23][CH2:24][NH2:25])[N+:20]([O-:22])=[O:21].C(OC(C)C)(C)C>>[O:19]([CH2:23][CH2:24][NH:25][C:8](=[O:10])[CH2:7][O:6][C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([N:2]([CH3:1])[CH3:14])[CH:4]=1)[N+:20]([O-:22])=[O:21]
Reactant: NCCO[N+](=O)[O-]
Reactant: CN(C)c1cccc(OCC(=O)O)c1
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: CN(C)c1cccc(OCC(=O)NCCO[N+](=O)[O-])c1
Yield: 49.7 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.83 g of 3-dimethylaminophenoxyacetic acid and 0.60 g of nitroxyethylamine nitrate, 0.50 g of the title compound was obtained as pale yellow acicular prisms (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [CH2:1]([N:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:23][CH2:24][CH2:25][CH2:26][Si:27]([O:32][CH3:33])([O:30][CH3:31])[O:28][CH3:29]>>[Cl-:23].[CH3:29][O:28][Si:27]([O:32][CH3:33])([O:30][CH3:31])[CH2:26][CH2:25][CH2:24][N+:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:12]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: CCCCCCCCCCN(C)CCCCCCCCCC
Product: CCCCCCCCCC[N+](C)(CCCCCCCCCC)CCC[Si](OC)(OC)OC
Product: [Cl-]
Temperature: 110 °C

Procedure:
In a 12-liter 3-neck round bottom reaction flask equipped with stirrer, thermometer and condenser was placed 4746 grams (15.2 moles) of didecylmethylamine and 3160.7 grams (15.9 moles) 3-chloropropyltrimethoxysilane. The solution was stirred with heating at 110° C. under a nitrogen atmosphere for 48 hours. The dark yellow/orange liquid was then placed under vacuum (5 torr), and approximately 135 mls. residual 3-chloropropyltrimethoxysilane was removed. The remaining product was then added slowly to 7750 grams of methanol with stirring to produce a product containing 50% active material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[C:21]([O:23][CH3:24])=[O:22])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:35].[Mg+2]>ClCCl.CO>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[C:21]([O:23][CH3:24])=[O:22])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:9])=[O:35]
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: COC(=O)c1scc(-c2ccccc2)c1-c1ccc(SC)c(F)c1
Agent: [Mg+2]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1scc(-c2ccccc2)c1-c1ccc(S(C)=O)c(F)c1
Reaction time: 1 h
Yield: 81 %

Procedure:
The methyl 3-[3-fluoro-4-(methylthio)phenyl]-4-phenyl-2-thiophenecarboxylate (5.00 g, 13.9 mmol) was dissolved in dichloromethane (100 mL) and methanol (30 mL). Magnesium monoperoxyphathalate hexahydrate (MMPP)(3.78 g of 80%, 7.6 mmol) was added in five equal portions at one minute intervals. The resulting heterogeneous solution was stirred for 1 hour. Additional MMPP (600 mg, 1.6 mmol) was added and the solution stirred for 15 min. The reaction was complete and solution extracted with saturated sodium bicarbonate (2×100 mL). The organic layer was dried over sodium sulfate and solvent removed at reduced pressure. Methyl 3-[3-fluoro-4-(methylsulfinyl)phenyl]-4-phenyl-2-thiophenecarboxylate was isolated by crystallization from dichloromethane and hexanes. (81% yield): Mp 164.0-164.1° C. 1H NMR (CDCl3/300 MHz) 7.75 (t, 1H, J=7.7 Hz), 7.53 (s, 1H), 7.15-7.26 (m, 3H), 6.94-7.40 (m, 3H), 3.90 (s, 3H), 2.85 (s, 3H). ESHRMS m/z 375.0536 (calcd for M+H, 375.0525).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:14]([OH:17])(=O)[CH3:15].C1(NC2C3[S:45][CH2:44][CH2:43][C:27]=3[N:28]=[C:29](N3CCN(C4C=CC=CC=4)CC3)[N:30]=2)CCCCC1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:29]3[N:30]=[C:14]([OH:17])[C:15]4[S:45][CH2:44][CH2:43][C:27]=4[N:28]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: c1ccc(N2CCN(c3nc4c(c(NC5CCCCC5)n3)SCC4)CC2)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CC(=O)O
Solvent: O
Product: Oc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1SCC2
Temperature: 180 °C
Reaction time: 16 h
Yield: 96.1 %

Procedure:
1.9 g (9.66 mmol) of 1-(4-chlorophenyl)piperazine is placed in 0.55 mL (9.62 mmol) of glacial acetic acid and heated to 180° C. in the heating block. 0.800 g (3.73 mmol) of 2-ethylsulfanyl-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (I) is added, then the mixture is left to stand for 1.5 hours at 180° C. and 16 hours at ambient temperature. Then the reaction mixture is combined with water and treated in the ultrasound bath. The precipitate is suction filtered, washed, and dried. 1.25 g of product II is obtained and used further in the crude state.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:13]=[C:8]([C:4]2[CH:3]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=3)[CH:7]=[CH:6][CH:5]=2)[N:9]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-trifluoromethyl-phenyl)-6-methyl-pyrimidine (example E.47) (0.175 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.021 g, 10%). MS (ISP) 408.3 [(M+H)+]; mp 290° C.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:35])[N:22]=[CH:23][C:24]=3[CH:25]([CH3:27])[CH3:26])=[CH:14][C:13]=2[CH3:36])=[CH:8][CH:7]=1.[OH-].[Na+]>O.C1COCC1.CO>[Cl:34][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:35])[C:28]=1[N:21]1[C:20]([CH2:19][O:18][C:15]2[CH:16]=[CH:17][C:12]([C:9]3[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:37])=[O:2])=[CH:7][CH:8]=3)=[C:13]([CH3:36])[CH:14]=2)=[C:24]([CH:25]([CH3:27])[CH3:26])[CH:23]=[N:22]1
Reactant: COC(=O)C=Cc1ccc(-c2ccc(OCc3c(C(C)C)cnn3-c3c(Cl)cccc3Cl)cc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1-c1ccc(C=CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
A mixture of 3-{4′-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2′-methyl-biphenyl-4-yl}-acrylic acid methyl ester (510 mg, 0.928 mmol), 5 N sodium hydroxide (928 μL, 4.64 mmol), methanol (15 mL) and THF (12 mL) is stirred overnight at room temperature. The reaction mixture is diluted with water and most of the THF and methanol is evaporated. The remaining aqueous portion is washed with ether and the ether layer is discarded. The aqueous layer is acidified with 1 N HCl and extracted with ether. The combined ether layers are washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The residue is purified using flash chromatography with 5% MeOH/CH2Cl2 and triturated in ether-hexane to give 146 mg (30%) of the title compound. ES/MS m/e (35Cl) 521.3 (M+1)
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:8]=[CH:9][N:10]=1.Cl[CH2:23][C:24]1[N:25]=[C:26]([CH:29]=[CH:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([F:42])([F:41])([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[O:27][CH:28]=1.O>CN(C=O)C>[F:40][S:37]([F:38])([F:39])([F:41])([F:42])[C:34]1[CH:35]=[CH:36][C:31](/[CH:30]=[CH:29]/[C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:21][C:18]3[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:7]4[CH:8]=[CH:9][N:10]=[C:6]4[CH2:5][CH2:4][OH:3])=[CH:20][CH:19]=3)[N:25]=2)=[CH:32][CH:33]=1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(S(F)(F)(F)(F)F)cc3)n2)cc1
Reaction time: 0.25 h
Yield: 46.7 %

Procedure:
14 mg (0.50 mmol) 95% sodium hydride were given to a solution of 130 mg (0.50 mmol) 4-{4-[2-(2-Hydroxyethyl)-imidazol-1-yl]-butyl}-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 10 ml water the resulting precipitate was filtered, dried and purified by chromatography on silica (ethyl acetate/methanol 8:1) to give 133 mg (47%) amorphous material.
Reaction SMILES: C1(O)C=CC=CC=1.[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.[OH:14][C:15]1[CH:31]=[CH:30][C:18]([CH:19]=[C:20]2[C:25](=[O:26])[O:24][C:23]([CH3:28])([CH3:27])[O:22][C:21]2=[O:29])=[CH:17][CH:16]=1>ClCCl.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[CH3:27][C:23]1([CH3:28])[O:24][C:25](=[O:26])[C:20](=[CH:19][C:18]2[CH:30]=[CH:31][C:15]([O:14][CH:13]3[CH2:12][CH2:11][CH2:10][CH2:9][O:8]3)=[CH:16][CH:17]=2)[C:21](=[O:29])[O:22]1
Reactant: C1=COCCC1
Reactant: CC1(C)OC(=O)C(=Cc2ccc(O)cc2)C(=O)O1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Oc1ccccc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(=Cc2ccc(OC3CCCCO3)cc2)C(=O)O1

Procedure:
Protection of the phenol with dihydropyran was carried out based on the method given in Miyashita et al. (1977) J. Org. Coed. 42: 3772. Compound 1.1 (500 g, 2 mol) was dissolved in dichloromethane (4 L). 3,4-Dihydro-2H-pyran (250 g, 3 mol) was added to the suspension followed by PPTS (5 g, 20 mmol). The reaction mixture heated to a gentle reflux (3.5 h). HPLC showed ˜90% completion of the reaction. The reaction was concentrated under reduced pressure to ˜2 L of volume. 1 L of acetone was added, and 2 L of solvent was removed under reduced pressure. 1 L of acetone was added, and 1 L of solvent was removed under reduced pressure. 0.5 L of acetone was added, and 0.5 L of solvent was removed under reduced pressure. The resulting slurry of very fine, light yellow crystals was filtered and rinsed sequentially with two 500 mL portions of acetone. The product was dried in a vacuum oven at 50° C. until no further solvent collected in the traps. Compound 52.1 (528 g) was obtained as fine, light yellow crystals. 1H NMR(400 MHz)(DMSO-d6) δ 8.29 (s, 1H); 8.18 (d, 2H, J=8.9 Hz); 7.13 (d, 2H, J=8.9 Hz); 5.67 (m, 1H); 3.70 (m, 1H); 3.60 (m, 1H). 1.9-1.5 (m, 12H). MS ESI (pos.) m/e: 355.1 (M+Na).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)(=O)=O)=CC=1.BrCC1CCCCO1.[O:26]1[CH2:30][C:29]2([C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][C:31]2=[O:39])[C:28]2[CH:40]=[C:41]3[C:46](=[CH:47][C:27]1=2)[CH2:45][CH2:44][CH2:43][CH2:42]3>>[O:14]1[CH2:15][CH2:16][CH2:17][C@@H:13]1[CH2:12][N:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29]2([CH2:30][O:26][C:27]3[CH:47]=[C:46]4[C:41](=[CH:40][C:28]2=3)[CH2:42][CH2:43][CH2:44][CH2:45]4)[C:31]1=[O:39]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCCC3
Agent: BrCC1CCCCO1
Product: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc3c(cc12)CCCC3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1-[(2R)-tetrahydrofuran-2-ylmethyl]-5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1′H)-one was obtained (80%) as a colorless solid: mp 139-141° C.; 1H NMR (300 MHz, CDCl3) δ 7.32-7.27 (m, 1H), 7.15-7.01 (m, 3H), 6.66 (s, 1H), 6.41 (s, 1H), 4.88 (dd, J=8.9, 0.9 Hz, 1H), 4.63 (dd, J=8.9, 2.5 Hz, 1H), 4.32-4.24 (m, 1H), 4.00-3.69 (m, 4H), 2.75-2.71 (m, 2H), 2.54 (br s, 2H), 2.10-1.86 (m, 3H), 1.78-1.69 (m, 5H); 13C NMR (75 MHz, CDCl3) δ178.0, 158.6, 142.9, 138.8, 132.4, 130.0, 128.6, 126.5, 123.6, 123.4, 123.2, 110.1, 109.5 79.7, 76.9, 68.2, 57.9, 44.6, 29.9, 29.2, 29.0, 25.6, 23.2, 23.0; MS (ES+) m/z 375.9 (M+1).