Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[F-:15].[K+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([F:15])(=[O:13])=[O:12]
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)F)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
2--Chloro-5-nitro benzene sulphonylchloride (40 parts) was stirred in p-dioxane (48 parts) at room temperature. Potassium fluoride (10 parts) dissolved in water (35 parts) was added, and the mixture heated to 70° C. Stirred at 70° C. for 4 hours then cooled to room temperature and poured onto ice/water. Allowed to stand for 2 days then filtered off the precipitate and dried in air to yield the product 2-chloro-5-nitro benzene sulphonylfluoride (36 parts).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[NH:26][CH:25]=[CH:24]5)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C=O)C>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[N:26]([CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:25]=[CH:24]5)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1sc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1-c1ccccc1
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ccc2cc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)ccc21
Reaction time: 2 h

Procedure:
D2 (100 mg) was dissolved in DMF (1.2 ml), treated with K2CO3 (50 mg) then ethyl 3-bromopropionate (90 mg) and heated to 130° C. overnight. After this time LCMS showed the reaction to be incomplete so further ethyl 3-bromopropionate was added (45 mg) and stirring continued at 130° C. for 2 hours. LCMS showed no change so the reaction mixture was evaporated then partitioned between DCM and H2O. The organic layer was removed and the aqueous solution extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated to give the crude product (148 mg). This was purified on a silica cartridge (25+S), eluting with a 0 to 25% mixture of EtOAc in petroleum ether and then again on a 25+M cartridge with a 0 to 30% mixture of EtOAc in petroleum ether to give the title compound MF105672-144A3 (38 mg) as a white solid. δH (CDCl3, 400 MHz): 1.21 (3H, t), 2.85 (2H, t), 4.12 (2H, q), 4.50 (2H, t), 6.60 (1H, d), 7.21 (1H, d), 7.42-7.52 (6H, m), 7.91 (1H, s), 8.00 (1H, d), 8.46 (1H, s). MS (ES+): C26H20F3N3O3S requires 511; found 512 (MH+).
Reaction SMILES: C(=O)(O)O.[Cl:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]([NH2:21])=[NH:20])[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CN(C)/[CH:24]=[CH:25]/[C:26]([C:28]1[N:32]([CH:33]([CH3:35])[CH3:34])[C:31]([CH3:36])=[N:30][CH:29]=1)=O>>[Cl:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[N:21]=[C:26]([C:28]3[N:32]([CH:33]([CH3:35])[CH3:34])[C:31]([CH3:36])=[N:30][CH:29]=3)[CH:25]=[CH:24][N:20]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: N=C(N)Nc1ccc(N2CCOCC2)c(Cl)c1
Reactant: Cc1ncc(C(=O)/C=C/N(C)C)n1C(C)C
Agent: O=C(O)O
Product: Cc1ncc(-c2ccnc(Nc3ccc(N4CCOCC4)c(Cl)c3)n2)n1C(C)C

Procedure:
The title compound was prepared using the procedure described in Example 112, employing N-(3-chloro-4-morpholin-4-yl-phenyl)-guanidine carbonate (Method 17; 500 mg, 1.97 mmol), and (2E)-3-(dimethylamino)-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one (Method 24 of WO 03/076436; 363 mg, 1.64 mmol). Yield: 412 mg, 61% as a white solid. NMR: 1.42 (d, 6H), 2.47 (s, 3H), 2.90 (t, 4H), 3.72 (t, 4H), 5.60 (m, 1H), 7.02 (d, 1H), 7.10 (d, 1H), 7.40 (s, 1H), 7.54 (dd, 1H), 7.78 (d, 1H), 8.37 (d, 1H), 9.43 (s, 1H); m/z 413.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[Br:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31](CO)[CH:30]=[C:29]2[O:38][C:39]1[CH:44]=[CH:43][C:42]([S:45]([CH2:48][CH3:49])(=[O:47])=[O:46])=[CH:41][N:40]=1>O1CCCC1.O>[Br:25][C:26]1[CH:27]=[C:28]2[C:33]([CH:32]=[C:31]([CH2:20][Cl:24])[CH:30]=[C:29]2[O:38][C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH2:48][CH3:49])(=[O:46])=[O:47])=[CH:41][N:40]=2)=[CH:34][CH:35]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(CO)cc3ccc(Br)cc23)nc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCS(=O)(=O)c1ccc(Oc2cc(CCl)cc3ccc(Br)cc23)nc1
Temperature: 25 °C
Yield: 76 %

Procedure:
After a solution of triphenylphosphine (330 mg, 1.26 mmol) and carbon tetrachloride (2 mL) in anhydrous tetrahydrofuran (6 mL) was stirred at room temperature for 10 minutes under a nitrogen atmosphere, [6-bromo-4-(5-ethanesulfonyl-pyridin-2-yloxy)-naphthalen-2-yl]-methanol (265 mg, 0.63 mmol) was introduced as a solid. The resulting mixture was heated at reflux for 4 hours, cooled to room temperature, then diluted with water (10 mL), and extracted with ethyl acetate (30 mL×2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (silica gel, 100-200 mesh, 5% ethyl acetate in petroleum ether) to afford 2-(7-bromo-3-chloromethyl-naphthalen-1-yloxy)-5-ethanesulfonyl-pyridine (210 mg, 76%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].Cl[CH:19]([F:21])[F:20]>CN(C)C=O>[F:20][CH:19]([F:21])[O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1
Reactant: FC(F)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC(F)F)cc1F
Temperature: 85 °C
Reaction time: 2 h

Procedure:
N,N-Dimethylformamide (15 mL) was added to 3-fluoro-4-nitrophenol (1.01 g, 6.43 mmol) and potassium carbonate (5.33 g, 38.6 mmol) in a 50 mL stainless steel reactor. The vessel was sparged briefly with CF2HCl, chilled with dry ice, and then chlorodifluoromethane (3.34 g, 38.6 mmol) was transferred into the reactor through a polypropylene tube. The mixture was stirred at 85° C. for 2 hours. The supernatant mixture was concentrated onto silica gel. Purification via flash chromatography (0-40% ethyl acetate/hexanes) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.28 (t, J=9.16 Hz, 1H), 7.51-7.57 (m, 1H), 7.50 (t, J=72.39 Hz, 1H), 7.21-7.29 (m, 1H)
Reaction SMILES: CS[C:3]1[C:4]2[CH:12]=[N:11][CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[NH:13]([C:3]1[C:4]2[CH:12]=[N:11][CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CSc1ncnc2ccncc12
Reactant: Nc1ccccc1
Solvent: CCO
Product: c1ccc(Nc2ncnc3ccncc23)cc1
Temperature: 0 °C
Yield: 16 %

Procedure:
A mixture of 4-methylthiopyrido[4,3-d]pyrimidine (174 mg, 0.97 mmol), and aniline (186.2 mg, 1.99 mmol) in EtOH (2 mL) is refluxed under N2 for 12 h. Cooling to 0° C. forms a solid which is filtered to yield 4-anilinopyrido-[4,3-d]pyrimidine (34.5 mg, 16%). 1H NMR (DMSO) δ 10.29 (1H, brs), 9.86 (1H, s), 8.82 (1H, d, J=5.8 Hz), 8.72 (1H, s), 7.85 (2H, d, J=7.5 Hz), 7.66 (1H, d, J=5.5 Hz), 7.45 (2H, t, J=8.0 Hz), 7.23 (1H, t, J=7.3 Hz).
Reaction SMILES: CCOC(C)=O.[CH3:7][C:8]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:9]=1[C:10]([NH:12][C:13]1[CH:14]=[N:15][CH:16]=[N:17][CH:18]=1)=[O:11].[H][H]>CO.[Pd]>[NH2:23][C:20]1[CH:21]=[CH:22][C:8]([CH3:7])=[C:9]([CH:19]=1)[C:10]([NH:12][C:13]1[CH:18]=[N:17][CH:16]=[N:15][CH:14]=1)=[O:11]
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cncnc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1C(=O)Nc1cncnc1

Procedure:
A 2 L high-pressure vessel was charged with Palladium 10% on carbon wet (50% water) and EtOAc (50 mL). 2-methyl-5-nitro-N-(pyrimidin-5-yl)benzamide 45 (18.79 g) was dissolved in methanol (400 mL) and added to the previous mixture. The reaction vessel was pressurized to 30 psi of H2 and mechanically stirred until the hydrogen intake stopped. The reduction of the nitro group was complete by LCMS and the mixture was filtered off through paper and glass paper. The crude 5-amino-2-methyl-N-(pyrimidin-5-yl)benzamide 46 was obtained as a yellow solid and used without further purification.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2]1.C1C(=O)N(Br)C(=O)C1.[C:18]([O:26]OC(=O)C1C=CC=CC=1)(=[O:25])C1C=CC=CC=1.C1C2C(=CC=CC=2)C=CC=1>CN(C=O)C>[CH2:4]([CH:3]1[CH2:2][O:26][C:18](=[O:25])[O:1]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: CCCCCCC1CO1
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccc2ccccc2c1
Solvent: CN(C)C=O
Product: CCCCCCC1COC(=O)O1
Yield: 87 %

Procedure:
A 5 mL volumetric flask was charged with 1.5 mL of 1,2-epoxyoctane (1a, 10 mmol), 89 mg of NBS (0.5 mmol), 0.12 g of benzoyl peroxide (0.5 mmol), and 0.13 g of naphthalene (1.0 mmol). The volumetric flask was filled to the mark with anhydrous DMF (2 M). An 8 mL, stainless steel Harvard Apparatus syringe was filled with the solution and then attached to the flow apparatus (syringe pump). The flow apparatus itself was set up as described above. After approximately 4 tR's (˜2 h), a sample was taken using the 6-way valve. The sample was analyzed by GC and 1H NMR. GC analysis indicated 96% conversion whereas 1H NMR analysis indicated a yield of 87% of the title compound 2a. IR (neat): 2928, 2859, 1788, 1384, 1165, 1059, 774 cm−1. 1H NMR (400 MHz, CDCl3): δ 4.67 (qd, J=7.5, 5.5 Hz, 1H), 4.50 (t, J=8.1 Hz, 1H), 4.04 (dd, J=8.3, 7.3 Hz, 1H), 1.79-1.73 (m, 1H), 1.68-1.61 (m, 1H), 1.45-1.27 (m, 10H), 0.86 (t, J=6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 155.1, 77.1, 69.4, 33.9, 31.5, 28.8, 24.3, 22.5. HRMS (DART) m/z calcd for C9H20NO3 [M+NH4]+: 190.1438. Found: 190.1438.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]([F:40])([F:39])[O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][OH:36])=[CH:33][CH:32]=1.O>CN(C)C=O>[N:13]1([C:4]2[N:3]=[C:2]([O:36][CH2:35][C:34]3[CH:37]=[CH:38][C:31]([O:30][C:29]([F:28])([F:39])[F:40])=[CH:32][CH:33]=3)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: OCc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1OCc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 53.2 %

Procedure:
To a solution of ethyl 4-chloro-2-(2,3-dihydro-1H-indol-1-yl)-5-pyrimidinecarboxylate (520 mg, 1.72 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (829 mg, 6 mmol) and 4-(trifluoromethoxy)benzyl alcohol (384 mg, 2 mmol) and the mixture was stirred at 100° C. for 18 h. The reaction mixture was allowed to cool to room temperature and water was added, which was followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the residue was applied to silica gel column chromatography and eluted with hexane-ethyl acetate (4:1) to give the title compound (420 mg, 53%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8]Br.[CH:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[C:16]([SH:21])[CH:17]=[CH:18]2)=[CH:13][CH:12]=1.C(N(CC)CC)C>C(OCC)C>[CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:21][C:16]1[CH:17]=[CH:18][C:19]2[C:14](=[CH:13][CH:12]=[CH:11][CH:20]=2)[CH:15]=1
Reactant: Sc1ccc2ccccc2c1
Reactant: COC(=O)C=CC=CCBr
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)C=CC=CCSc1ccc2ccccc2c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of 6-bromo-hexa-2,4-dienoic acid methyl ester (1.57 g, 7.66 mmol) and 2-thionaphthol (1.35 g, 8.42 mmol) in diethyl ether (40 mL) was added dropwise triethylamine (1.40 mL, 10.0 mmol) under an atmosphere of argon. The mixture was stirred for one hour 20° C. and filtered. The filtrate was washed saturated aqueous sodium hydrogen carbonate (25 mL), demineralised water (25 mL) and brine (25 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a yellow oil that was purified by column chromatography (9:1 to 8:2 40-60° C. petroleum ether:diethyl ether). Recrystallisation from diethyl ether/petroleum ether afforded the title compound (1.9 g, 88%) as a white solid, mp 73-75° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3[C:10](=[O:29])[N:11]([C:20]4[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=4)[CH:12]([C:13]4[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=4)[C:8]=3[C:7]([CH3:30])=[N:6]2)[CH2:2]1.[CH2:31](Cl)Cl.CO>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]2[C:8]3[C:7]([CH3:30])=[N:6][N:5]([CH:3]4[CH2:2][N:1]([CH3:31])[CH2:4]4)[C:9]=3[C:10](=[O:29])[N:11]2[C:20]2[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=2)=[CH:14][CH:15]=1
Reactant: ClCCl
Reactant: Cc1nn(C2CNC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Solvent: CO
Product: Cc1nn(C2CN(C)C2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared using an analogous procedure to that described in Step 139.2 using 1-(azetidin-3-yl)-4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 138.2). tR: 0.61 min (LC-MS 2); ESI-MS: 438.1 [M+H]+ (LC-MS 2); Rf=0.29 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83-1.96 (m, 6H) 2.33 (s, 3H) 3.35 (s, 3H) 3.45-3.59 (m, 2H) 3.66-3.78 (m, 2H) 4.97-5.10 (m, 1H) 6.07 (s, 1H) 7.26 (d, J=8.60 Hz, 2H) 7.33-7.42 (m, 3H) 7.71 (d, J=2.74 Hz, 1H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[C:44]([O:43][C:42](=[O:48])[NH:41][C@H:38]1[CH2:37][CH2:36][C@@H:35]([NH:34][C:31]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:14]=3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[C:20]=2[CH3:30])=[O:33])[CH2:40][CH2:39]1)([CH3:47])([CH3:45])[CH3:46]
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c7) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:69]1([NH:74][CH2:75][CH2:76][C:77]#[N:78])[CH2:73][CH2:72][CH2:71][CH2:70]1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[N:74]([CH2:75][CH2:76][C:77]#[N:78])[CH:69]2[CH2:73][CH2:72][CH2:71][CH2:70]2)[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N#CCCNC1CCCC1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC#N)C2CCCC2)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 146.2 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.100 g), TBTU (0.080 g) and HOBt (0.034 g) in DMF (3 ml) was added DIPEA (0.087 ml) followed by 3-(cyclopentylamino)propionitrile (0.035 g) after 15 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was washed with water and extracted with ethyl acetate. The organic layer was dried with brine and MgSO4, filtered and concentrated to give the title compound (0.190 g) as a brown oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:25]=[CH:24][C:15]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:14][CH:13]=1.C([O-])(C)(C)C.[K+]>CS(C)=O>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:25][CH:24]=1)(=[O:17])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(c1ccccc1)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1

Procedure:
The product (770 mg) is obtained according to the method of stage 1 of Example 4, by using 1.5 mL of 2-fluoro-nitrobenzene and 4.2 g of 4-aminobenzophenone in the presence of 2.54 g of potassium tert-butanolate in 40 mL of DMSO.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]([N:12]2[C:16]([C:17](O)=[O:18])=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:20])[O:3]1.C(Cl)(=O)C(Cl)=O.O[NH:29][C:30](=[NH:32])[CH3:31]>ClCCl.C(Cl)(Cl)Cl>[CH3:21][C:2]1([CH3:1])[CH:11]([N:12]2[C:16]([C:17]3[O:18][N:32]=[C:30]([CH3:31])[N:29]=3)=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:20])[O:3]1
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C(=O)O
Reactant: CC(=N)NO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1noc(-c2cncn2C2c3ccccc3C(=O)OC2(C)C)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3-(3,3-Dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carboxylic acid (0.538 g, 1.88 mmol) (Example 23) is dissolved in dichloromethane (4 mL) and cooled to 0° C. Oxalyl chloride (0.41 mL, 4.702 mmol) is added and the cooling bath is removed. The mixture is stirred at room temperature for 3 h. The reaction mixture is concentrated in vacuo. The residue obtained is redissolved in chloroform and N-hydroxyacetamidine (0.181 g, 2.44 mmol) is added. The reaction mixture is stirred at reflux for 72 h. The mixture is cooled to room temperature, washed with saturated solution of sodium bicarbonate and is extracted with dichloromethane. The organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (hexane-ethyl acetate, 3:7) to give dimethyl-4-[5-(3-methyl-[1,2,4]oxadiazol-5-yl)-imidazol-1-yl]-isochroman-1-one as a white solid; MS (ESI) m/z 325.0 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.26 (s, 3 H), 1.61 (s, 3 H), 2.55 (s, 3 H), 6.94 (s, 1 H), 7.56 (d, J=7.1 Hz, 1 H), 7.63 (s, 1 H), 7.72 (td, J=7.6, 1.3 Hz, 1 H), 7.80 (td, J=7.6, 1.3 Hz, 1 H), 8.01 (s, 1 H), 8.30 (dd, J=7.8, 1.3 Hz, 1 H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[NH2:7][S:8]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])(=[O:10])=[O:9].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.C(Cl)Cl>[NH2:7][S:8]([CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(=[O:10])=[O:9]
Reactant: BrCc1ccccc1
Reactant: NS(=O)(=O)CCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NS(=O)(=O)CCCC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 27 %

Procedure:
Cs2CO3 (0.51 eq) was added to a solution of 4-(aminosulfonyl)butanoic acid (1 M) in DMF. After 1 h, benzyl bromide (1 eq) was introduced and the reaction left to stir overnight before diluting with DCM and filtering. The filtered liquor was concentrated in vacuo, the residue taken up in DCM and washed with saturated aqueous NaHCO3, water and brine, before being dried over Na2SO4, filtered and concentrated in vacuo. Trituration of the residue with Et2O afforded the title compound as a white solid (27%). (ES+) m/z 280 (M+Na)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][N:12]([CH2:15][C:16](=[O:17])[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:20][CH:19]=2)[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1cnc(OCc2ccccc2)cc1=O)c1ccc(CBr)cc1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: O=C(Cn1cnc(OCc2ccccc2)cc1=O)c1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 52 mg (0.13 mmol) 6-benzyloxy-3-[2-(4-bromomethyl-phenyl)-2-oxo-ethyl]-3H-pyrimidin-4-one (preparation 20b) in 2.00 mL of DMF is added 42 μL (0.50 mmol) pyrrolidine. The reaction mixture is stirred 30 min at RT and is directly purified by HPLC (Waters Xbridge; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 0:100).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.[CH2:12]([Zn]CC)C.IC(I)C.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[CH2:12]1[C:2]2([CH2:11][CH2:10][C:5]3([O:6][CH2:7][CH2:8][O:9]3)[CH2:4][CH2:3]2)[CH2:1]1
Reactant: CC[Zn]CC
Reactant: C=C1CCC2(CC1)OCCO2
Agent: CC(I)I
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: C1COC2(CCC3(CC3)CC2)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 8-methylene-1,4-dioxa-spiro[4.5]decane (6.0 g, 39 mmol, prepared according to a literature procedure (K. C. Nicolaou, R. L. Magolda, D. A. Claremon, J. Am. Chem. Soc. 102 (1980) 1404-1409)) in toluene (10 mL), a solution of diethyl zinc (100 mL, 1 M in hexane) is added at −40 to −20° C. The mixture is stirred for 10 min before diiodoethane (53.6 g, 200 mmol) is added dropwise over a period of 20 min. The reaction is warmed to rt and stirring is continued for 18 h. The reaction mixture is poured onto ice-cooled sat. aq. NH4Cl solution and extracted twice with diethyl ether. The combined organic extracts are washed with sat. aq. Na2S2O3 and water, dried over Na2SO4, filtered and the solvent of the filtrate is evaporated to give 7,10-dioxa-dispiro[2.2.4.2]dodecane (12.35 g) as a colourless liquid containing approx. 20% of toluene (product volatile).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C@H:4]1[CH2:6][O:5]1.[CH2:15](I)[CH:16]=[CH2:17]>C1(C)C=CC=CC=1.[Ag-]=O>[CH2:17]([O:1][CH2:2][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[C@H:4]1[CH2:6][O:5]1)[CH:16]=[CH2:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)[C@H]1CO1
Reactant: C=CCI
Agent: O=[Ag-]
Solvent: Cc1ccccc1
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)[C@H]1CO1
Temperature: 65 °C
Reaction time: 15 h

Procedure:
To a solution of tert-butyl(S)-2-hydroxy-1-((S)-oxiran-2-yl)ethylcarbamate (0.125 g, 0.6 mmol; see: Kurokawa, N.; Ohfune, Y. Tetrahedron 1993, 49, 6195) in toluene (6 mL), was added allyliodide 0.3 mL, 3 mmol) followed by silver(I) oxide (0.7 g, 3 mmol). The solution was stirred at 65° C. in a darkened hood for a period of 15 h. The mixture was then cooled to ambient temperature, filtered through Celite, washed with CH2Cl2, and conc. in vacuo. Purification on SiO2 (10-20% EtoAc/Hexanes) gave the title compound as a yellow oil.