Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[H-].[Na+].[CH2:16]([CH2:26]S([O-])(=O)=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=C.O>CS(C)=O>[CH2:24]([N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:26]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: C=CCCCCCCCCCS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.1 %

Procedure:
Theobromine (3.45 g, 19.2 mmol) was added to a suspension (30 ml) of sodium hydride (461 mg, 19.2 mmol) in dimethylsulfoxide. After 15 minutes, the 9-decenylmesylate (2.25 g, 11 mmol) was added and the reaction stirred for 18 hours at 25° C., then for 40 minutes at 100° C. The mixture was then poured into water (100 ml) and extracted with three 50 ml aliquots of dichloromethane. The combined organic portions were washed with saturated salt solution (60 ml) and dried over magnesium sulfate. Evaporating the solvent under vacuum left a white solid residue. Recrystallization of the residue in ether produced 3.40 g of 1-(9-decenyl)-3,7-dimethylxanthine (56% yield). 1-(9-Decenyl)-3,7-dimethylxanthine (3.2 g, 10.1 mmol), 4-methylmorpholine-N-oxide (1.41 g, 12 mmol), 3 drops of 2.5% osmium tetroxide solution in t-butanol, acetone (40 ml) and water (10 ml) were stirred for 24 hours. Following addition of 5 ml of a saturated solution of sodium dithionite and a further 15 minutes of stirring, the reaction mixture was extracted with four 50 ml aliquots of 25% ethanol/dichloromethane. The combined organic portions were dried over sodium sulfate. Evaporating the solvents left a white solid residue, which upon recrystallization in ethanol produced 3.3 g of 1-(9,10-dihydroxydecyl)-3,7-dimethylxanthine (93% yield). 1-(9,10-Dihydroxydecyl)-3,7-dimethylxanthine (2.11 g, 6 mmol), prepared above, was stirred with hydrogen bromide (3.58 ml, 4.85 g of a 30% solution in acetic acid, 18 mmol) for 90 minutes. The mixture was then added to a flask containing 40 ml aqueous sodium bicarbonate solution (5 g) and 50 ml dichloromethane. After 10 minutes of vigorous stirring the layers were separated and the aqueous portion washed with two 50 ml aliquots of dichloromethane. The organic portions were combined, dried over sodium sulfate, and evaporating the solvent produced 2.72 g of a yellow oil, inventive compound no. 1583 (100% yield).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH2:6]([O:8][P:9]([CH2:14][C:15]1[N:19]2[C:20]3[C:25]([NH:26][C:27](=[O:28])[C:18]2=[N:17][N:16]=1)=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:22][CH:21]=3)([O:11][CH2:12][CH3:13])=[O:10])[CH3:7]>S(=O)(=O)(O)O>[CH2:12]([O:11][P:9]([CH2:14][C:15]1[N:19]2[C:20]3[C:25]([NH:26][C:27](=[O:28])[C:18]2=[N:17][N:16]=1)=[CH:24][C:23]([C:29]([F:30])([F:32])[F:31])=[C:22]([N+:1]([O-:4])=[O:2])[CH:21]=3)([O:8][CH2:6][CH3:7])=[O:10])[CH3:13]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOP(=O)(Cc1nnc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n12)OCC
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOP(=O)(Cc1nnc2c(=O)[nH]c3cc(C(F)(F)F)c([N+](=O)[O-])cc3n12)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
Powdered potassium nitrate (1.82 g, 18 mmol) was added to a stirred solution of 1-[(diethoxyphosphoryl)methyl]-7-trifluoromethyl[1,2,4]triazolo [4,3-a]quinoxalin-4(5H)-one (3.7 g, 9.15 mmol) in 50 ml of conc. sulfuric acid at 0° C. The mixture was stirred at room temperature overnight, and quenched in ice/water (300 g). The aqueous phase was extracted with ethyl acetate (5×100 ml), and the combined organic extracts were dried with anhydrous sodium sulfate, and evaporated. The residue was triturated with ether to give 3.25 g (79%) of the title compound, m.p. 222°-228° C.; 1H-NMR (DMSO-d6): δ 1.20 (t, 6H), 4.10 (quint, 4H), 4.39 (d, 2H), 7.88 (s, 1H), 8.96 (s, 1H), 12.67 (br s, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[CH:21]=[CH:20][S:19][C:18]=3[C:22]([O:24]C)=[O:23])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].CO>O1CCCC1>[N:4]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[CH:21]=[CH:20][S:19][C:18]=3[C:22]([OH:24])=[O:23])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(N2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1sccc1NS(=O)(=O)c1ccc(N2CCOCC2)cc1
Temperature: 40 °C
Yield: 18 %

Procedure:
To a solution of 85 (306 mg; 0.8 mmol) in tetrahydrofuran (2.7 mL) were added aqueous sodium hydroxide (5.3 mL; 2N) and methanol (5.3 mL) sequentially. The reaction mixture was heated at 40° C. for 17 hours, allowed to cool to room temperature, and then extracted with aqueous sodium hydroxide (20 mL; 2N). The aqueous layer was washed with diethyl ether (30 mL×2), acidified with aqueous hydrochloric acid (40 mL; 6N), and extracted with dichloromethane (40 mL). The organic layer was washed with aqueous saturated sodium chloride (20 mL), dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting pale yellow solid was recrystallized from hot 80% ethyl acetate in hexane, to yield the title compound as a white solid (53 mg).
Reaction SMILES: O.[C@@H:2]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>CO>[CH3:22][N:23]([CH:25]=[N:15][C:14]1[C:13]2[N:12]=[CH:11][N:10]([C:19]=2[N:18]=[CH:17][N:16]=1)[C@@H:2]1[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1)[CH3:24]
Reactant: COC(OC)N(C)C
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Solvent: O
Solvent: CO
Product: CN(C)C=Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 50 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To a stirred solution of 2′-deoxyadenosine monohydrate 54 (1.00 g; 3.71 mmol) in methanol (43 mL), N,N-dimethylformamide dimethyl acetal (2.48 mL; 18.6 mmol) was added. The reaction was stirred at 50° C. for 16 h. After evaporation, CH2Cl2-hexane (1:1) was added. The white solid formed was then filtered, collected and washed by hexane to afford 55 as white solid (1.13 g; 99% yield): 1H NMR (400 MHz, CD3OD) δ 8.92 (s, 1H, CHN(CH3)2), 8.44 (s, 1H, 2-H), 8.43 (s, 1H, 8-H), 6.48 (dd, J=6.2, 7.8 Hz, 1H, 1′-H), 4.59 (m, 1H, 3′-H), 4.07 (m, 1H, 4′-H), 3.86 (dd, J=3.1, 12.2 Hz, 1H, one of 5′-H), 3.76 (dd, J=3.5, 12.2 Hz, 1H, one of 5′-H), 3.25 (s, 3H, one of NCH3), 3.24 (s, 3H, one of NCH3), 2.80-2.88 (ddd, J=5.9, 7.8, 13.5 Hz, 1H, one of 2′-H), 2.40-2.47 (ddd, J=2.8, 6.1, 13.4 Hz, 1H, one of 2′-H); 13C NMR (100 MHz, CD3OD) δ 161.0, 159.9, 152.8, 151.1, 142.8, 127.0, 89.7, 86.9, 72.9, 63.5, 41.5 (N(CHO 2) 35.3; HRMS (FAB+) calcd for C33H19O3N6 (M+H+): 307.1519. found: 307.1511.
Reaction SMILES: [CH:1]12[NH:9][CH:5]([C:6](=[O:8])[CH2:7]1)[CH2:4][O:3][CH2:2]2.C([O-])([O-])=O.[K+].[K+].[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17]>CC#N>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:9]1[CH:5]2[C:6](=[O:8])[CH2:7][CH:1]1[CH2:2][O:3][CH2:4]2)(=[O:27])=[O:26])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: O=C1CC2COCC1N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CC2COCC1N2S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of compound 108b (100 mg), TEA (102 mg), K2CO3 (207 mg, 1.5 mmol, 3.0 eq) and 2-nitro-benzenesulfonyl chloride (222 mg) in MeCN (10 mL) was stirred at room temperature for 10 h. Then the solvent was removed in vacuo, the residue was purified by silica gel (EA/PE=1:3) to give 8-(2-nitrophenyl)sulfonyl-3-oxa-8-azabicyclo[3.2.1]octan-6-one 108c as a white solid, 100 mg. MS: calc'd (MH+) 313, measured (MH+) 313.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:37]([CH3:39])[CH3:38])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34](O)=O)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.[C:46]([C:50]1[CH:51]=[C:52]([NH2:57])[C:53]([NH2:56])=[CH:54][CH:55]=1)([CH3:49])([CH3:48])[CH3:47].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:46]([C:50]1[CH:55]=[CH:54][C:53]2[NH:56][C:34]([CH2:33][CH2:32][CH:30]3[CH2:31][CH:28]([N:27]([CH2:26][C@@H:18]4[C@H:19]5[O:23][C:22]([CH3:24])([CH3:25])[O:21][C@H:20]5[C@H:16]([N:13]5[C:9]6[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]7[CH:40]=[CH:41][C:42]([O:44][CH3:45])=[CH:43][C:3]=7[O:2][CH3:1])[C:8]=6[CH:15]=[CH:14]5)[CH2:17]4)[CH:37]([CH3:38])[CH3:39])[CH2:29]3)=[N:57][C:52]=2[CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanoic acid (490 mg, 0.79 mmol) and 4-tert-butylbenzene-1,2-diamine (155 mg, 0.946 mmol) in N,N-Dimethylformamide (8.1 ml) was treated with N,N-Diisopropylethylamine (0.453 ml, 2.60 mmol) dropwise followed by N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (449 mg, 1.18 mmol) in one portion. The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated under high vacuum and the residue was partitioned between 50 ml EtOAc and 50 ml 1/1 H2O/sat NaHCO3. The aqueous phase was extracted with 30 ml EtOAc and the combined organic phase was washed with 30 ml portions of H2O and brine. The organic phase was dried over Na2SO4, filtered and concentrated to give a glass/stiff foam. The crude material was purified by flash chromatography (SiO2, eluting with 4% 7N N NH3 in CH3OH/CH2Cl2) to give the desired intermediate as a mixture of amide regioisomers (400 mg). A solution of intermediate (0.40 g) in Acetic acid (15 ml) was heated at 65° C. for 2.5 h, the reaction mixture was cooled and placed under high vacuum to remove the acetic acid. The residue was taken up in 60 ml CH2Cl2 and washed with 40 ml portions of sat NaHCO3 and 2% Na2CO3 solution. The organic phase was dried over Na2SO4, filtered and concentrated to yield a glass/stiff foam. The material was placed on high vacuum and used directly in the next step (380 mg)
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[H-].[Na+].[CH3:7][O:8][C:9]1[C:10]([CH3:32])=[C:11]([C:18]([C:20]2[CH:21]=[CH:22][C:23]3[NH:28][C:27](=[O:29])[O:26][C:25](=[O:30])[C:24]=3[CH:31]=2)=[O:19])[N:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2>CN(C=O)C>[CH3:7][O:8][C:9]1[C:10]([CH3:32])=[C:11]([C:18]([C:20]2[CH:21]=[CH:22][C:23]3[N:28]([CH2:3][CH:2]=[CH2:1])[C:27](=[O:29])[O:26][C:25](=[O:30])[C:24]=3[CH:31]=2)=[O:19])[N:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2
Reactant: COc1c(C)c(C(=O)c2ccc3[nH]c(=O)oc(=O)c3c2)n2ccccc12
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)oc(=O)c2cc(C(=O)c3c(C)c(OC)c4ccccn34)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
0.5 ml (5.71 mmol) of allyl bromide and 0.19 g (4.28 mmol) of sodium hydride at 60% are added, under an inert atmosphere at ambient temperature, to 1 g (2.85 mmol) of 6-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]-2H-3,1-benzoxazine-2,4(1H)-dione in 15 ml of DMF. The reaction medium is stirred for 2 hours at ambient temperature and then concentrated under reduced pressure. After the addition of ice to the residue, the precipitate formed is filtered off, rinsed with water, and dried under reduced pressure at 50° C. overnight. 0.773 g of a yellow solid is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7]([OH:14])=[C:6]([NH:15][S:16]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])(=[O:18])=[O:17])[CH:5]=1.Br[CH2:30][CH2:31]Br>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:13])[F:12])[C:7]2[O:14][CH2:31][CH2:30][N:15]([S:16]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[O:26][CH3:27])(=[O:18])=[O:17])[C:6]=2[CH:5]=1)=[O:28]
Reactant: BrCCBr
Reactant: COC(=O)c1cc(NS(=O)(=O)c2cc(Cl)ccc2OC)c(O)c(C(F)(F)F)c1
Product: COC(=O)c1cc2c(c(C(F)(F)F)c1)OCCN2S(=O)(=O)c1cc(Cl)ccc1OC

Procedure:
The title compound, MS (ISP)=569.0 (M−H)−, was produced in analogy with example 36, steps 1-4. Step 1 was performed using 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-5-trifluoromethyl-benzoic acid methyl ester (example 40, step 2) and 1,2-dibromoethane, yielding 4-(5-chloro-2-methoxy-benzenesulfonyl)-8-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 2 to afford 4-(5-chloro-2-methoxy-benzenesulfonyl)-8-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 4-aminobenzoate in step 3 to produce 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 4.
Reaction SMILES: Cl[P:2]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:6])[O:3][CH2:4][CH3:5].[NH2:17][CH:18]1[CH2:23][S:22][C@H:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:19]1=[O:36].C(N(CC)CC)C>C(Cl)Cl>[CH2:4]([O:3][P:2]([NH:17][CH:18]1[CH2:23][S:22][C@H:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:19]1=[O:36])([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])[CH3:5]
Reactant: CCOC(=O)CN1C(=O)C(N)CS[C@@H]1c1ccccc1
Reactant: CCOP(=O)(Cl)CCCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1C(=O)C(NP(=O)(CCCCc2ccccc2)OCC)CS[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of the crude chloro(4-phenylbutyl)phosphinic acid, ethyl ester (2.6 mmole), dry methylene chloride (9.0 ml.) and (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester (0.72 g., 2.4 mmole) at 0° (ice bath) in an argon atmosphere is treated dropwise with triethylamine (0.44 ml., 1.3 eq.) in methylene chloride (2 ml.) over 5 minutes. After 30 minutes, the ice bath is removed and the reaction mixture is stirred at room temperature for 16 hours. The mixture is diluted with ethyl acetate and washed successively with saturated sodium bicarbonate, 5% potassium bisulfate, brine, dried (MgSO4), and evaporated. The residue (1.5 g.) is chromatographed on silica (80 g.) eluting with hexane/acetone (2:1) to give 1.0 g. of (R)-dihydro-5-[[ethoxy(4-phenylbutyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester as an oil after evaporation. TLC (hexane/acetone, 2:1) single spot at Rf =0.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[CH3:12].[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1Cl
Temperature: 75 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
1-Chloro-4-fluoro-2-methyl-5-nitrobenzene (D22) (1.5 mmol, 284 mg) in dimethylformamide (5 mL) was treated under argon at room temperature with 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1.5 mmol, 300.5 mg, 1 eq) and diisopropylethylamine (1.5 mmol, 194 mg, 1 eq) then stirred at 75° C. overnight. The mixture was concentrated under reduced pressure, treated with 10% Na2CO3 aqueous solution and extracted twice with ether. Organics were combined, dried on MgSO4 and concentrated under reduced pressure to give the title compound as a clean orange solid (1.46 mmol, 539 mg, 97% yield). M−H=368.16.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:13]=2)O1.Br[C:22]1[S:23][CH:24]=[C:25]([C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[O:28])[N:26]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:33][S:30]([NH:29][C:27]([C:25]1[N:26]=[C:22]([C:9]2[CH:10]=[N:11][N:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:13]=2)[S:23][CH:24]=1)=[O:28])(=[O:31])=[O:32]
Reactant: CC1(C)OB(c2cnn(-c3cccnc3)c2)OC1(C)C
Reactant: CS(=O)(=O)NC(=O)c1csc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CS(=O)(=O)NC(=O)c1csc(-c2cnn(-c3cccnc3)c2)n1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Under argon, 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]pyridine (0.1 g, 0.37 mmol), 2-bromo-N-(methylsulphonyl)-1,3-thiazole-4-carboxamide (0.105 g, 0.37 mmol) and tetrakis(triphenylphosphine)palladium (0.013 g, 0.011 mmol) were added to a mixture, degassed by means of argon, of sodium carbonate solution in water (1.5 ml, 2 M/L) and acetonitrile (3.8 ml). The reaction mixture was stirred at 70° C. for 16 h. After cooling, the reaction mixture was poured onto water and extracted with dichloromethane. The organic phase was dried over sodium sulphate and the solvent was removed under reduced pressure. The residue was subsequently stirred with diethyl ether and filtered off with suction. This gave 0.23 g (97% of theory) of 6-[1-(pyridin-3-yl)-1H-pyrazol-4-yl]pyridine-2-sulphonamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:24]1(Br)[CH2:28][CH2:27][CH2:26][CH2:25]1.O>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrC1CCCC1
Reactant: O=Cc1ccc(OCc2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: O=Cc1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A stirred solution of 4-benzyloxy-3-hydroxybenzaldehyde (60.9 g; that is prepared as described in Reference Example 36) in dry dimethylformanide (270 mL) under nitrogen is treated portionwise with potassium carbonate (79.5 g). After stirring at room temperature for 45 minutes, it is treated with cyclopentyl bromide (34.3 mL), and the resulting suspension is heated at 60° C. for 8 hours. After cooling, the solution is evaporated to low bulk under reduced pressure, to give an oil. This oil is treated with water (250 mL) and diethyl ether (300 mL), and the aqueous layer is washed with further quantities of diethyl ether (2×50 mL). The combined ethereal extracts are washed with brine (1×50 mL) and with water (3×50 mL), dried over magnesium sulfate and evaporated. The resulting residue is crystallized from methanol, to give 4-benzyloxy-3-cyclopentyloxybenzaldehyde (79 g), m.p. 55-56° C. [Elemental analysis: C,77.1; H,6.9%; calculated: C,77.0; H,6.8%].
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]([O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([CH3:26])[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[CH:30][CH:29]=[C:28]([O:27][CH:24]([CH3:26])[CH3:25])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CC(C)Oc1cccc(B(O)O)c1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cccc(OC(C)C)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-isopropoxyphenylboronic acid (Aldrich, Buchs, Switzerland) to give the title compound as a white solid. (HPLC: tR 2.95 min (Method A); M+H=428 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.19-8.16 (m, 1H), 8.09-8.05 (m, 1H), 7.94-7.89 (m, 1H), 7.57-7.54 (m, 1H), 7.39-7.33 (m, 1H), 7.10-7.06 (m, 1H), 6.94-9-6.90 (m, 2H), 4.68 (hp, 1H), 3.92 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H), 1.30 (t, 6H))
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23]>>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[O:10][CH3:11])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: COc1ccc(I)c(OC)c1
Product: COc1ccc(-c2ccc(C(C)=O)cc2[N+](=O)[O-])c(OC)c1

Procedure:
By methods analogous to 2'described in Example 1 (a) and (b), 4-iodo-3-methoxy anisole and 4'-bromo-3'-nitroacetophenone were reacted to give the novel intermediate 4-acetyl-2',4'-dimethoxy-2-nitrobiphenyl, m.p. 129° - 131°C. which was converted to the novel intermediate 4acetyl-2-amino-2;40 ,4'-dimethoxybiphenyl, m.p. 149° - 151°C. This (15.7 g.) was diazotized and the diazonium solution added slowly to a solution of cuprous chloride (7.5 g.) in 4N hydrochloric acid (70 ml.) at 0°C. The mixture was warmed to room temperature over 1 hour and then heated for a further hour on a steam bath. The solution was cooled and made alkaline (pH14) with 18N caustic soda. The product was extracted with methylene chloride, the extract dried and the solvent evaporated off to give a brown oil which was extracted with ether. The ether was evaporated and the residual oil distilled and the distillate recrystallised from isopropanol to give the novel intermediate 4-acetyl-2-chloro-2',4'-dimethoxybiphenyl m.p. 115° - 118°C. By methods analogous to those described in Example 1 (d) and 1 (e) this was converted to crude 2-(2-chloro-2',4'-dimethoxy-4-biphenylyl)propionaldehyde and thence to the novel intermediate 2-(2-chloro-2',4'-dimethoxy-4-biphenylyl) propionic acid, obtained as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[C:15]3[N:10]([N:11]=[C:12]([O:27]C)[CH:13]=[CH:14]3)[N:9]=2)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=3)=[C:15]3[N:10]([N:11]=[C:12]([OH:27])[CH:13]=[CH:14]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(-c3ccc(S(C)(=O)=O)cc3)c(-c3ccc(F)cc3)nn2n1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3nc(O)ccc23)cc1
Temperature: 200 °C
Yield: 38.4 %

Procedure:
A mixture of 2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-6-methoxy-pyrazolo[1,5-b]pyridazine (321 mg) and pyridine hydrochloride (1.4 g) was heated to and at 200° C. in a sealed vessel (Reactivial™) for 3 hours. The cooled reaction was poured into water (20 ml), and extracted with ethyl acetate (3×30 ml). The combined organic extracts dried (MgSO4), filtered and evaporated in vacuo to give a solid which was triturated with diethyl ether to give the title compound as a beige solid (119 mg).