Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[C:13](F)[CH:12]=1>CS(C)=O>[CH2:8]([O:7][C:5]([C:4]1[S:3][C:13]2[CH:12]=[C:11]([Br:10])[CH:18]=[CH:17][C:14]=2[CH:15]=1)=[O:6])[CH3:9]
Reactant: CCOC(=O)CS
Reactant: O=Cc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2ccc(Br)cc2s1
Reaction time: 0.17 h
Yield: 85.6 %

Procedure:
Sodium hydride (1.41 g, 35.32 mmol) is added to a round bottom flask and washed with hexanes (10 mL) twice. To the flask is added dimethyl sulfoxide (30 mL) and ethyl 2-mercaptoacetate (3.54 g, 29.43 mmol). The mixture is stirred for 10 minutes and 4-bromo-2-fluoro-benzaldehyde (4.78 g; 23.55 mmol) is added. The reaction mixture is stirred for 15 minutes and quenched with ice-water (100 g). The mixture is extracted with CH2Cl2 (50 mL×2). The combined organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified via flash chromatography eluting with 10% EtOAc/Hexanes. The appropriate fractions are combined and concentrated under reduced pressure to afford the title compound (5.75 g, 86%). 1H NMR (400 MHz, CDCl3): δ 8.00 (s, 1H), 7.99 (s, 1H), 7.75 (d, 1H), 7.48 (d, 1H), 4.38 (q, 2H), 1.39 (t, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7]([F:13])=[C:8]([F:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].C([Li])(CC)C.[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1.[Cl-].[NH4+]>CCCCCC.C1CCCCC1.C1COCC1.C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:30]2[CH2:31][CH2:32][CH:27]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([F:26])[C:20]=3[F:19])[CH2:28][CH:29]=2)=[C:8]([F:12])[C:7]=1[F:13])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(c2cccc(F)c2F)CC1
Reactant: CCCCOc1cccc(F)c1F
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(C2=CCC(c3cccc(F)c3F)CC2)c(F)c1F
Temperature: 30 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
3-Butoxy-1,2-difluorobenzene (s-18) (17.7 g) and THF (500 ml) were put in a reaction vessel under an atmosphere of nitrogen and cooled to −74° C. sec-Butyllithium (a 1.00 M solution in n-hexane and cyclohexane; 114 ml) was added dropwide thereto in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. Then, 4-(2,3-difluorophenyl)cyclohexanone (s-19) (20.0 g) dissolved in THF (100 ml) was added dropwise thereto in the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to come to 25° C. The reaction mixture was poured into a vessel containing an aqueous solution of ammonium chloride (3%; 200 ml) and ethyl acetate (200 ml), and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and the extraction was carried out. The combined organic phase was washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under the reduced pressure. p-Toluenesulfonic acid (4.1 g) and toluene (300 ml) were added to the residue and the mixture was heated to reflux for 2 hours, while distilled water was removed. After the reaction mixture had been cooled to 30° C., water (500 ml) and toluene (500 ml) were added to the mixture, and mixed with it. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction was carried out. The combined organic phase was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The solution was purified by column chromatography using silica gel as a stationary phase powder and a mixed solvent of toluene and heptane (1/1 by volume) as an eluent, and then by recrystallization from Solmix A-11 to give 1-butoxy-4-(4-(2,3-difluorophenyl)cyclohex-1-enyl)-2,3-difluorobenzene (s-20) (7.2 g). The yield based on the compound (s-18) was 20.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of 4-chloroaniline (25.51 g) and triethylamine (69.73 ml) in chloroform (350 ml) were added 2,2-dimethyl-propionyl chloride (25.32 g) over a 30 minutes period. The resulting solution was stirred at r.t. for 1 hour, then water was added and the mixture extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 35.8 g of product. M.p. 149-150° C.; Retention Time HPLC 2.83 min; MS (ES+) 212 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20](=[O:34])[C:21]([CH3:33])([CH3:32])[O:22][C:23]=4[C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[CH:15][CH:14]=3)[N:10]=2)[N:7]=1.C(NCC)C.[H][H]>CO.[OH-].[Pd+2].[OH-]>[N:10]1[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20](=[O:34])[C:21]([CH3:32])([CH3:33])[O:22][C:23]=3[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[CH:17][CH:18]=2)=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:7]2
Reactant: COc1ccc(C2=C(c3ccc(OCc4cn5nc(Cl)ccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCNCC
Product: COc1ccc(C2=C(c3ccc(OCc4cn5ncccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Palladium hydroxide (36 mg) was added to a solution of 4-(4-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (180 mg, 0.37 mmol) and diethyl amine (28 mg, 0.37) in methanol (25 ml) at RT under an atmosphere of nitrogen. The nitrogen atmosphere was exchanged for hydrogen and was stirred at RT for 2 h (the reaction was monitored by TLC). The compound was filtered through a bed of Celite® bed washing with methanol. The filtrate was concentrated under reduced pressure to afford 4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (160 mg, 96.7%,) as a white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.45 (s, 1H), 8.4 (s, 1H) 8.15 (d, 1H), 7.55 (d, 2H), 7.25 (d, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.25 (s, 2H) 3.8 (s, 3H), 1.25 (s, 6H). MS: [M+H]+: m/z=442.3. HPLC: (97.4%, Condition-A).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:11]=[CH:10][C:7]=1[CH:8]=O.[N+:22]([CH3:25])([O-:24])=[O:23].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.O>[F:5][C:6]1[CH:13]=[C:12]([CH:11]=[CH:10][C:7]=1/[CH:8]=[CH:25]/[N+:22]([O-:24])=[O:23])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(OCc2ccccn2)cc1F
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])/C=C/c1ccc(OCc2ccccn2)cc1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To an acetic acid (15.0 mL) solution of 2-fluoro-4-(pyridin-2-ylmethoxy)-benzaldehyde (1.07 g, 4.63 mmol) described in Manufacturing Example 95-1-1 were added nitromethane (1.41 g, 23.2 mmol) and ammonium acetate (714 mg, 9.26 mmol) under nitrogen atmosphere at room temperature, which was stirred for 2 hours at 100° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (1.20 g) as a crude product.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23](F)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][C:18]=1[C:30]#[N:31]>O1CCCC1>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([S:5][CH2:3][CH3:4])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][C:18]=1[C:30]#[N:31]
Reactant: CCS
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSc1cc2ncc(C#N)c(Nc3cc(OC)c(Cl)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To a mixture of sodium hydride (82 mg, 2.04 mmol) in 6 mL of tetrahydrofuran is added ethanethiol (77 mg, 1.12 mmol) in 6 mL of tetrahydrofuran. The reaction mixture is stirred at room temperature for 2 hours. A solution of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (200 mg, 0.51 mmol) in 7 mL of tetrahydrofuran is added via syringe and the reaction mixture is heated at 70° C. for 5 hours, then cooled to room temperature. The reaction volume is reduced by concentration in vacuo and then partitioned between ethyl acetate and water. The aqueous layer is extracted with additional ethyl acetate and the organic layers are combined and washed with water. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 10% to 30% ethyl acetate in hexane to provide 154 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-ethylsulfanyl-6-methoxy-3-quinolinecarbonitrile, mp 212-214° C.
Reaction SMILES: [CH:1]1([O:7][C:8]2[O:9][C:10]([C:17]([NH:19][C:20]3[CH:21]=[N:22][C:23]([N:26]4[CH2:31][CH2:30]C(C5C=CC=CC=5)[CH2:28][CH2:27]4)=[CH:24][CH:25]=3)=[O:18])=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:38]1(CO)[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:6]1([CH2:1][O:7][C:8]2[O:9][C:10]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][N:12]([C:8]([O:9][CH:38]5[CH2:39][CH2:40][CH2:41][CH2:42]5)=[O:7])[CH2:28][CH2:27]4)=[N:22][CH:21]=3)=[O:18])=[C:11]([C:13]([F:14])([F:16])[F:15])[N:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(N2CCC(c3ccccc3)CC2)nc1)c1oc(OC2CCCCC2)nc1C(F)(F)F
Reactant: OCC1CCCC1
Product: O=C(Nc1ccc(N2CCN(C(=O)OC3CCCC3)CC2)nc1)c1oc(OCC2CCCC2)nc1C(F)(F)F

Procedure:
Compound 287 was prepared by the general procedure for compound 284, by using intermediates A-41 and cyclopentanemethanol as starting materials. 1H NMR (500 MHz, CDCl3) δ 8.20 (d, 1H, J=2.4 Hz), 8.07 (dd, 1H, J=9.2, 2.5 Hz), 7.23 (br s, 1H), 6.68 (d, 1H, J=9.1 Hz), 5.17 (m, 1H), 4.45 (d, 2H, J=9.1 Hz), 3.64-3.52 (m, 8H), 2.45 (m, 1H), 1.92-1.84 (m, 4H), 1.80-1.56 (m, 10H), 1.42-1.32 (m, 2H); LCMS (ESI) Rt=4.13 min, calcd for [M+1]+ 552.2. found 552.3.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][NH:11][C:12]2=[O:15])=[CH:7][N:6]=1)[CH3:3].C1C(=O)N([Cl:23])C(=O)C1>CC(O)=O>[Cl:23][C:14]1[C:5]([O:4][CH:2]([CH3:1])[CH3:3])=[N:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:15])[NH:11][CH2:10][CH2:9]2
Reactant: CC(C)Oc1cc2c(cn1)CCNC2=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CC(C)Oc1ncc2c(c1Cl)C(=O)NCC2
Temperature: 25 °C
Yield: 69.2 %

Procedure:
A solution of 7-(propan-2-yloxy)-3,4-dihydro-2,6-naphthyridin-1(2H)-one (112d, 75 mg, 0.36 mmol)) and NCS (498 mg, 3.64 mmol) in AcOH (3 mL) was heated at 100° C. for 4.5 hours. The reaction mixture was cooled to room temperature, AcOH was removed under vacuum and the residue was purified by column chromatography (0-80% ethyl acetate/heptanes) to give 8-chloro-7-(propan-2-yloxy)-3,4-dihydro-2,6-naphthyridin-1(2H)-one (112e, 60 mg, 68%) as a white solid.
Reaction SMILES: C(O)(=O)C.[C:5]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[N+:19]([O-])=O)([CH3:8])([CH3:7])[CH3:6]>CO.C(OCC)(=O)C.CCCCCC.[Zn]>[C:5]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[NH2:19])([CH3:8])([CH3:6])[CH3:7]
Reactant: COC(=O)c1ccc(C(C)(C)C)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(C)(C)C)c(N)c1
Reaction time: 0.67 h
Yield: 83.2 %

Procedure:
40 g of zinc powder and 8 ml of acetic acid were added to a solution of 22.7 g of methyl 4-t-butyl-3-nitrobenzoate (prepared as described in Preparation 4) in 400 ml of methanol, and the resulting mixture was stirred for 40 minutes. At the end of this time, a further 26.6 g of zinc powder were added (making a total amount of 66.6 g or 1.02 mmol). 20 ml of acetic acid were then added dropwise over a period of 1.5 hours to the mixture, and the resulting mixture was stirred for 2 hours. At the end of this time, the reaction mixture was diluted with a 10:1 by volume mixture of ethyl acetate and hexane, and the diluted mixture was filtered, using a Celite (trade mark) filter aid. The filtrate was concentrated by evaporation under reduced pressure, and the concentrate was dissolved in ethyl acetate. The resulting solution was washed twice with a saturated aqueous solution of ammonium chloride, once with a saturated aqueous solution of sodium hydrogencarbonate and once with water. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 150 g of silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 30:1 to 4:1 as the eluent, to give 16.5 g of the title compound as an oily substance, that is an 85% yield based on the starting material used in Preparation 4.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[S:11][C:10]=1[C:18]([OH:20])=[O:19])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:21](O)[CH:22]=[CH2:23].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([NH:8][C:9]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[S:11][C:10]=1[C:18]([O:20][CH2:23][CH:22]=[CH2:21])=[O:19])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(C)(C)C)sc1C(=O)O
Reactant: C=CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=CCOC(=O)c1sc(C(C)(C)C)cc1NC(=O)OC(C)(C)C
Yield: 66 %

Procedure:
To a solution of 3-(N-carbo-tert-butoxyamino)-5-tert-butylthiophene-2-carboxylic acid (0.20 g, 0.67 mmol), allyl alcohol (0.042 g, 0.73 mmol, 1.1 equiv) and DMAP (0.008 g, 0.07 mmol, 10 mol %) in CH2Cl2 (2 mL) was added EDCI.HCl (0.14 g, 0.73 mmol, 1.1 equiv). The CH2Cl2 mixture was stirred at room temp. for 3 d, diluted with CH2Cl2, washed with a 1N HCl solution (5 mL) and a saturated NaHCO3 solution (5 mL), dried (Na2SO4), and concentrated under reduced pressure to afford allyl 3-(N-carbo-tert-butoxyamino)-5-tert-butylthiophene-2-carboxylate (0.15 g, 65%) as a colorless oil: TLC (50% CH2Cl2/hexane) Rf0.63; 1H NMR (CDCl3) δ1.37 (s, 9H), 1.50 (s, 9H), 4.74 (ddd, J=5.5, 1.5, 1.5 Hz, 2H), 5.26 (dd, J=10.3, 1.5 Hz, 1H), 5.37 (dd, J=17.3, 1.5 Hz, 1H), 5.87-5.98 (m, 1H), 7.68, 9.35; 13C NMR (CDCl3) δ28.2 (3C), 31.8 (3C), 35.2, 64.9, 80.8, 104.9, 116.4, 118.1, 132.0, 145.6, 152.1, 164.0, 164.4
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:19]C(C2CCNCC2)=N[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:31]=[C:32]=[N:33]CCCN(C)C.C1C=CC2N(O)N=NC=2C=1.ONC(N)=N>CN(C=O)C.O>[NH2:33][C:32]1[N:22]=[C:18]([C@@H:13]2[CH2:12][CH2:11][C@@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:19][N:31]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2c2nnc(C3CCNCC3)o2)N1OCc1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: N=C(N)NO
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Nc1noc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)n1
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
A solution of (2S,5R)-6-(benzyloxy)-2-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (2.0 g, 7.25 mmol), EDCI (1.53 g, 7.98 mmol) and HOBT (1.08 g, 7.98 mmol) in DMF (15 mL) was stirred at rt for 0.5 h. 1-Hydroxyguanidine (0.653 g, 7.98 mmol) was then added and the reaction mixture was stirred for an additional 0.5 h. The resulting solution was treated under microwave at 100° C. for 1.5 hrs. The mixture was poured into water and extracted with EtOAc (2×). The combined organic layers were then washed with water (20 mL), and saturated sodium chloride (20 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (2:1 EtOAc/petroleum ether) to give (2S,5R)-2-(3-amino-1,2,4-oxadiazol-5-yl)-6-(benzyloxy)-1,6-diaza-bicyclo[3.2.1]octan-7-one (1.0 g, 44%). (ESI-MS (EI+, m/z): 316 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=[O:22])[C:13]2[CH:18]=[N:17][N:16]([CH2:19][CH2:20][CH3:21])[C:14]=2[N:15]=1)[CH3:2].[Cl:23][S:24](O)(=[O:26])=[O:25]>C(OCC)C>[Cl:23][S:24]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:10]2[NH:11][C:12](=[O:22])[C:13]3[CH:18]=[N:17][N:16]([CH2:19][CH2:20][CH3:21])[C:14]=3[N:15]=2)[CH:6]=1)(=[O:26])=[O:25]
Reactant: O=S(=O)(O)Cl
Reactant: CCCn1ncc2c(=O)[nH]c(-c3ccccc3OCC)nc21
Solvent: CCOCC
Product: CCCn1ncc2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
6-(2-Ethoxyphenyl)-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 1; 0.5 g, 0.0017 mol) was added portionwise to stirred chlorosulphonic acid (3 ml) at 0° C. and the resulting solution stirred at room temperature for 14 hours. The reaction mixture was then added dropwise to ice/water (20 g) and the aqueous solution thus obtained was extracted with dichloromethane (4×30 ml). The combined extracts were dried (Na2SO4) and the solvent evaporated under vacuum to give a white solid; trituration was diethyl ether (50 ml) gave the title compound (0.67 g, 100%), m.p. 177-180° C., which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]=2[O:19][CH3:20])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:27]([O:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:26]([C:44]([F:47])([F:46])[F:45])=[CH:25][CH:24]=1>>[C:40]([O:39][C:37]([O:36][C:27]1[C:26]([C:44]([F:45])([F:46])[F:47])=[CH:25][CH:24]=[C:23]([CH2:22][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]=3[O:19][CH3:20])=[CH:6][CH:7]=2)[C:28]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:38])([CH3:41])([CH3:42])[CH3:43]
Reactant: COC(=O)Cc1cccc(-c2ccc(O)cc2)c1OC
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Product: COC(=O)Cc1cccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OC(=O)OC(C)(C)C)c3C(=O)OC(C)(C)C)cc2)c1OC

Procedure:
According to a method similar to Example (2-3), from methyl (4′-hydroxy-2-methoxy-1,1′-biphenyl-3-yl)acetate (792 mg, 2.91 mmol) obtained in Example (114-1) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (1.32 g, 2.91 mmol) obtained in Example (28-5), tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[({2′-methoxy-3′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]-3-(trifluoromethyl)benzoate was obtained as a yellow oil (1.20 g, yield: 64%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][CH:48]=1)(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].[F-].[K+].O>C1(C)C=CC=CC=1>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[N:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:14]=[C:13]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=4)[N:12]=3)[CH:10]=2)=[N:49][CH:48]=1)(=[O:45])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (Example G.1) (0.265 g, 0.41 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.115 g, 0.45 mmol), tetrakis(triphenyl-phosphine)palladium (0.028 g, 0.024 mmol) in toluene (5 mL) was heated under reflux conditions for 15 h. The mixture was poured into saturated potassium fluoride solution (5 mL), water (20 mL) was added and the water layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield N-tert-butyl-2-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.081) as a light brown solid. Mp 281° C.
Reaction SMILES: C([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>Cl.O>[NH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: CCOC(=O)N1CCN(CCCCNC(C)=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)N1CCN(CCCCN)CC1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
6 g of ethyl 4-(4-acetamidobutyl)-piperazine-1-carboxylate were dissolved in a mixture of 12 ml of conc. hydrochloric acid and 24 ml of water and the solution was refluxed for 5 hours. The solution was then cooled to room temperature and made alkaline with potassium carbonate. The mixture was extracted 3 times with 100 ml of chloroform and the combined extracts were dried over MgSO4 and evaporated to dryness to obtain 4 g (79% yield) of ethyl 4-(4-aminobutyl)-piperazine-1-carboxylate in the form of a pale yellow oil which slowly solidified.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[N:25]([S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])[C:24]([Si](C(C)(C)C)(C)C)=[N:23][CH:22]=1.O>CN(C)C=O>[CH3:28][N:27]([CH3:29])[S:26]([N:25]1[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[CH:22][N:23]=[CH:24]1)(=[O:30])=[O:31]
Reactant: CN(C)S(=O)(=O)n1c(CCCCCCCBr)cnc1[Si](C)(C)C(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)n1cncc1CCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 92.9 %

Procedure:
Potassium phthalimide (1.67 g, 9.00 mmol) was added to a solution of the product from step b (2.10 g, 4.50 mmol) in dry N,N-dimethylformamide (10 ml), under an atmosphere of argon. The mixture was stirred and heated at 100° C. for 18 h and allowed to cool to room temperature. Water (75 ml) was added and the mixture extracted with dichloromethane (3×40 ml). The combined extracts were evaporated, the residue dissolved in ethyl acetate (75 ml) and the solution washed five times with brine. The solvent was evaporated and the residue purified by flash column chromatography (silica; ethyl acetate), from which the product was isolated as a yellow oil (1.75 g, 93%).