Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C1CCN2C(=NCCC2)CC1.[C:46](Cl)(=[O:48])[CH3:47].CO>ClCCl>[C:46]([N:32]1[CH2:31][CH2:30][CH:29]([NH:28][C:26]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[C:9]5[O:13][CH2:12][O:11][C:10]=5[CH:14]=[CH:15][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:34][CH2:33]1)(=[O:48])[CH3:47]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[5-(Cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride from example D.f1 (486 mg; 1.0 mmol) and DBU (2.5 mmol) is dissolved in dry dichloromethane (5 mL). Acetyl chloride (1.1 mmol) is syringed into the reaction mixture at ice bath temperature. After addition the mixture is stirred at ambient temperature over night. Methanol (1 mL) is added and stirring is continued for two hours. The volatiles are evaporated. The residue is purified by reversed phase preparative HPLC. The collected product fraction is freeze-dried to yield the title compound as colorless solid.
Reaction SMILES: ClCC([NH:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([NH:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[O:18])([CH2:9]3)[CH2:7]1)[CH2:13]2)=O.NC(N)=S.C(O)C.[OH-].[Na+]>O.C(O)(=O)C>[NH2:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([NH:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[O:18])([CH2:9]3)[CH2:7]1)[CH2:13]2
Reactant: O=C(CCl)NC12CC3CC(C1)CC(NC(=O)c1ccccn1)(C3)C2
Agent: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: NC12CC3CC(C1)CC(NC(=O)c1ccccn1)(C3)C2
Temperature: 78 °C
Reaction time: 8 h
Yield: 102.6 %

Procedure:
To a 40 ml vial containing pyridine-2-carboxylic acid [3-(2-chloro-acetylamino)adamantan-1-yl]-amide (1.69 g, 4.85 mmol, from step 2) and thiourea (0.56 g, 7.4 mmol), was added ethanol (20.0 mL), and acetic acid (4.0 mL). The mixture was stirred at 78° C. overnight. The reaction solution was cooled to rt, poured into water (100 mL), and the pH of the solution was adjusted to 10-13 using 10 N aq. NaOH. The mixture was transferred into a separation funnel, extracted with DCM (3×150 mL). Combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to afford 1.35 g (95.4%) of crude title compound, pyridine-2-carboxylic acid (3-amino-adamantan-1-yl)-amide, as an oil, which became a colorless solid upon standing at room temperature. LC-MS (Gradient: acetonitrile in water, 10-85%, in 1.7 minutes with a cycle time of 2 min. Flow rate: 5.0 mL/min. Mobile phase additive: 30 mM of ammonium formate. Column: Inertsil® C8, 50×4.6 mm, 3 μm particle size (GL Sciences, Tokyo, Japan)): Retention time: 0.63 min; purity (UV254): 93%; ESI-MS m/z: 272 (M+H)+. It was used in the next step, amidation, without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].CCN(C(C)C)C(C)C.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:12]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=2)[C:6]([CH3:11])=[N:7]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1n[nH]c2cc(F)ccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)n1nc(C)c2ccc(F)cc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
6-Fluoro-3-methyl-1H-indazole (2.79 g, 18.6 mmol) in CH2Cl2 (50 mL) was treated with acetic anhydride (2.8 g, 30 mmol), Hunig's base (5.2 mL, 30 mmol) and DMAP (0.2 g, 1.7 mmol). The mixture was stirred 1 h at 20° C., poured into water (100 mL) and extracted with CH2 Cl2 (2×100 mL). The extracts were dried (Na2SO4), concentrated and the residue recrystallised from hexane to give the title compound (3.41 g, 96%) as a white crystalline solid; mp 89°-91° C. (from hexane); 1H NMR (360 MHz, CDCl3) δ8.05 (dd, J=9.4, 2.2 Hz, 1H, indazole), 7.51 (dd, J=8.7, 5.1 Hz, 1H, indazole), 7.03 (dt, J=8.8, 2.2 Hz, 1H, indazole), 2.67 (s, 3H, Me), 2.49 (s, 3H, Ac); MS (CI+) m/e 193 (M+H+); Anal. calcd for C10 H9FN2O: C, 62.49; H, 4.72; N, 14.58. Found: C, 62.50; H, 4.79; N, 14.63.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][C:48]=1[O:49][CH3:50])[N:45]=[CH:44][CH:43]=[C:42]2[O:51][C:52]1[CH:58]=[CH:57][C:55]([NH2:56])=[CH:54][CH:53]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:37][O:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][C:48]=1[O:49][CH3:50])[N:45]=[CH:44][CH:43]=[C:42]2[O:51][C:52]1[CH:53]=[CH:54][C:55]([NH:56][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=2[Cl:1])=[CH:57][CH:58]=1
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)COc4ccc(Cl)cc4Cl)cc3)c2cc1OC
Yield: 71.4 %

Procedure:
2-(2,4-Dichlorophenoxy)acetic acid (310 mg) was added to chloroform (5 ml), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (403 mg), 1-hydroxybenzotriazole monohydrate (284 mg), and 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (498 mg) were added thereto. The mixture was then stirred with heating under reflux for 2 hr. A saturated aqueous sodium hydrogencarbonate solution was added to stop the reaction, and the reaction solution was extracted with chloroform, followed by washing with a saturated aqueous sodium hydrogencarbonate solution, 1 N hydrochloric acid, water, and saturated brine. The extract was then dried over sodium sulfate. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give N1-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-2-(2,4-dichlorophenoxy)acetamide (500 mg, yield 72%).
Reaction SMILES: C(NC(=O)NC1C=CC(C2N=C(N3CCOC[C@@H]3C)C3CCN(C(OC(C)(C)C)=O)CC=3N=2)=CC=1)C.Cl[C:38]1[N:39]=[C:40]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][C@@H:53]2[CH3:58])[C:41]2[CH2:46][N:45]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:44][C:42]=2[N:43]=1.[CH3:59][NH:60][C:61](=[O:82])[CH2:62][NH:63][C:64]([NH:66][C:67]1[CH:72]=[CH:71][C:70](B2OC(C)(C)C(C)(C)O2)=[CH:69][CH:68]=1)=[O:65]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:59][NH:60][C:61](=[O:82])[CH2:62][NH:63][C:64](=[O:65])[NH:66][C:67]1[CH:72]=[CH:71][C:70]([C:38]2[N:39]=[C:40]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][C@@H:53]3[CH3:58])[C:41]3[CH2:46][N:45]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:44][C:42]=3[N:43]=2)=[CH:69][CH:68]=1
Reactant: CNC(=O)CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NCC(=O)NC)cc3)nc(N3CCOC[C@@H]3C)c2C1
Yield: 46 %

Procedure:
Method as described for intermediate 5 using (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) and N-methyl-2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)acetamide as starting materials and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) as catalyst. The mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and solvent removed in vacuo. The residue was purified by prep HPLC (high pH) yielding the title compound (35 mg, 0.07 mmol, 46%).
Reaction SMILES: [F:1][C:2]1[C:3]([S:24]([NH:27][C:28]2[S:32][N:31]=[CH:30][N:29]=2)(=[O:26])=[O:25])=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]3[C:21]4[CH2:20][C:19](=[O:22])[CH2:18][CH2:17][C:16]=4[CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:23]=1.C1COCC1.[BH4-].[Na+]>CO.O.CS(C)=O.C(O)(C(F)(F)F)=O>[F:1][C:2]1[C:3]([S:24]([NH:27][C:28]2[S:32][N:31]=[CH:30][N:29]=2)(=[O:25])=[O:26])=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]3[C:21]4[CH2:20][CH:19]([OH:22])[CH2:18][CH2:17][C:16]=4[CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:23]=1
Reactant: O=C1CCc2cccc(Cn3c(=O)oc4cc(S(=O)(=O)Nc5ncns5)c(F)cc43)c2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: O=c1oc2cc(S(=O)(=O)Nc3ncns3)c(F)cc2n1Cc1cccc2c1CC(O)CC2
Temperature: 25 °C

Procedure:
In a vial was added 5-fluoro-2-oxo-3-((7-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (19-5) (29 mg, 0.061 mmol), followed by anhydrous THF (1 mL), then NaBH4 (8 mg, 0.211 mmol). The reaction mixture was then capped (not under N2) & stirred at room temperature. Followed by LC/MS. The reaction mixture was diluted with MeOH/drops of H2O/DMSO/TFA (lot of bubbling), filtered (syringe filter), then purified (without workup) by reverse phase chromatography (5-75% MeCN/H2O; 0.1% TFA in AQ; 20 min gradient; Waters 30×150 mm Sunfire 5 micron C18 column); desired fractions concentrated (GENEVAC), then dissolved in MeOH/DCM & concentrated to yield 5-fluoro-3-((7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (21-1). HRMS [M+H] calculated; 477.0697, observed; 477.0705. 1H NMR (499 MHz, DMSO): δ 8.49 (s, 1H); 7.79 (d, J=5.5 Hz, 1H); 7.29 (d, J=9.6 Hz, 1H); 7.05-7.02 (m, 2H); 6.87-6.83 (m, 1H); 5.75 (s, 2H); 5.01-4.95 (m, 1H); 4.02-3.92 (m, 1H); 2.99-2.92 (m, 1H); 2.91-2.83 (m, 1H); 2.77-2.68 (m, 1H); 1.91-1.84 (m, 2H); 1.66-1.57 (m, 1H).
Reaction SMILES: C(O)C(N)(CO)CO.Cl.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[CH3:30][CH2:31][CH2:32][CH2:33][CH2:34][C@H:35]([OH:54])/[CH:36]=[CH:37]/[C@@H:38]1[C@@H:42]([CH2:43]/[CH:44]=[CH:45]\[CH2:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50])[C@H:41]2[O:52][O:53][C@@H:39]1[CH2:40]2.Cl.C(O)C(N)(CO)CO.CCCCC[C@H](O)/C=C/[C@H]1OC(O)C[C@H](O)[C@@H]1C/C=C\CCCC(O)=O>>[CH3:30][CH2:31][CH2:32][CH2:33][CH2:34][C@H:35]([OH:54])/[CH:36]=[CH:37]/[C@H:38]1[O:53][C@@H:39]2[O:52][C@@H:41]([CH2:40]2)[C@@H:42]1[CH2:43]/[CH:44]=[CH:45]\[CH2:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H]2C[C@H]1OO2
Agent: CCCCC[C@H](O)/C=C/[C@H]1OC(O)C[C@H](O)[C@@H]1C/C=C\CCCC(=O)O
Agent: Cl
Agent: NC(CO)(CO)CO
Product: CCCCC[C@H](O)/C=C/[C@H]1O[C@H]2C[C@H](O2)[C@@H]1C/C=C\CCCC(=O)O
Reaction time: 0.5 h

Procedure:
1 ml of a buffer (20 MM Tris-HCl buffer, 1 mM EDTA, pH 7.5) containing human blood platelet microsomes (50 μg protein/ml) and the test compound (final concentration 10−7M) was agitated, then incubated at 0° C. for 30 minutes. To this was added prostaglandin H2 (100 ng/2 μl). This was incubated at 23° C. for 3 minutes to cause a reaction. Next, 1M hydrochloric acid was added to make the solution acidic and stop the reaction, then this was neutralized by 1M Tris-Base and centrifuged at 3000 rpm for 20 minutes. The amount of the TxB2 in the supernatant was measured by the EIA method (Cayman Co. kit).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].F[C:38](F)(F)[C:39](O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCCCCC1CCN(C(OCC2C=CC=CC=2)=O)CC1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:24][CH:23]1[CH2:39][CH2:38][N:20]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:22]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Reactant: O=C(O)C(F)(F)F
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C(OCc1ccccc1)N1CCC(CCCCCBr)CC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 11 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetic acid salt (for example, as prepared for Intermediate 6) and phenylmethyl 4-(5-bromopentyl)-1-piperidinecarboxylate (for example, as prepared for Intermediate 35).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11](O)[CH3:12])=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1)[CH3:12]
Reactant: CC(O)c1ccnc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(Cl)c1ccnc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
To 1-Quinolin-4-yl-ethanol (1.4 g, 8.09 mmol) in 15 ml chloroform, thionyl chloride (1.8 ml, 20.2 mmol) was added dropwise over a five minute period at room temperature. Stirring was continued for 30 minutes after which the reaction mixture was cooled to 0° C. and quenched carefully by the addition of saturated aqueous NaHCO3 (20 ml). The chloroform layer was dried over sodium sulfate, filtered and concentrated. Column purification (hexane:ethyl acetate; 1.5:3.5) gave 1.54 g (100%) of the product as a syrup which was used as such for the subsequent step.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:23][CH2:24][CH3:25])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][CH3:31])(=[O:29])[CH:27]=[CH2:28]>CO>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]([CH2:24][CH3:25])[CH2:28][CH2:27][C:26]([O:30][CH3:31])=[O:29])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCNCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Reactant: C=CC(=O)OC
Solvent: CO
Product: CCN(CCC(=O)OC)Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)ethanamine (250 mg, 0.64 mmol, 1 equiv) was dissolved in CH3OH (1 mL). Then methyl acrylate (4 mL, 44 mmol, 70 equiv) was added to the mixture and stirred at r.t. for 16 h. The reaction was concentrated and purified by prep-TLC to give the title compound as a white solid (217 mg, 52%). (mobile phase: EA/PE=1:8). ESI-MS (M+1)+: 426.3, HPLC: 97.34%. 1H NMR (400 MHz, CDCl3) δ: 7.71˜7.60 (m, 3H), 7.44˜7.38 (m, 1H), 7.16˜7.09 (m, 2H), 4.30˜4.20 (m, 1H), 3.69 (s, 2H), 3.64 (s, 3H), 2.85 (t, 2H), 2.65˜2.46 (m, 4H), 2.31˜2.24 (m, 2H), 1.92˜1.85 (m, 2H), 1.49˜1.37 (m, 2H), 1.30˜1.10 (m, 3H), 1.05 (t, 3H), 0.89 (s, 9H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]O)=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2].[N+:46]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[S:55]([NH:58][CH2:59][C:60]([NH2:62])=[O:61])(=[O:57])=[O:56])([O-:48])=[O:47].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][N:58]([S:55]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=3[N+:46]([O-:48])=[O:47])(=[O:57])=[O:56])[CH2:59][C:60](=[O:61])[NH2:62])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:44])[CH3:45])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: NC(=O)CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN(CC(N)=O)S(=O)(=O)c3ccccc3[N+](=O)[O-])cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (98 mg) in tetrahydrofuran (2 mL) were added 2-(2-nitrobenzenesulfonylamino)acetoamide (40 mg), triphenylphosphine (45 mg) and diethyl azodicarboxylate (40% toluene solution, 0.1 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on silica gel (eluent: ethyl acetate-dichloromethane/methanol=10/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-[(4-{3-[N-(2-nitrobenzenesulfonyl)-N-(carbamoylmethyl)amino]propoxy}-2-methylphenyl)methyl]-1H-pyrazole (92 mg). This material was dissolved in acetonitrile (1 mL). To the solution were added cesium carbonate (0.14 g) and thiophenol (0.012 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give the title compound (57 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([CH3:16])=[N:11][C:10]=1[CH2:17][CH2:18][CH3:19].[CH:28]([O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([CH3:30])[CH3:29].N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:14](=[O:15])[N:13]([C:35]2[CH:36]=[CH:37][C:32]([O:31][CH:28]([CH3:30])[CH3:29])=[CH:33][CH:34]=2)[C:12]([CH3:16])=[N:11][C:10]=1[CH2:17][CH2:18][CH3:19]
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1nc(C)n(-c2ccc(OC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reaction time: 96 h
Yield: 40.8 %

Procedure:
A mixture of 3′-fluoro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 4-isopropoxyphenylboronic acid (1.1 g), copper(II) acetate (1.1 g), pyridine (1.2 mL), triethylamine (2.0 mL), molecular sieves 4 A (2.0 g) and dichloromethane (10 mL) was stirred for 4 days. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.56 g, 42%) as a colorless liquid.
Reaction SMILES: Cl[C:2]1[CH:24]=[C:23](Cl)[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:7].O=C1C(C(O)=O)=CC(C2C=CN=CC=2)=NN1.C(Cl)(=O)C(Cl)=O.[F:48][C:49]([F:59])([F:58])C1C=C(C=CC=1)CN>C(N(CC)CC)C.CN(C)C=O.ClCCl>[O:20]=[C:9]1[C:8]([C:6]([NH:5][CH2:4][C:3]2[CH:21]=[CH:22][CH:23]=[C:24]([C:49]([F:59])([F:58])[F:48])[CH:2]=2)=[O:7])=[CH:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:11][NH:10]1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1cc(-c2ccncc2)n[nH]c1=O

Procedure:
Working as in example 2 for the preparation of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide, but starting with 0.3 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid, 10 cm3 of dichloromethane, 0.02 cm3 of dimethylformamide, 0.12 cm3 of oxalyl chloride, 0.21 cm3 of 3-(trifluoromethyl)benzylamine and 0.19 cm3 of triethylamine, 0.22 g of 3-oxo-6-pyridin-4-yl-N-[3-(trifluoromethyl)benzyl]-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a cream-colored solid melting at 224° C.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.C([O:19][C:20](=[O:31])[C:21]#[C:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:10]([N:4]1[CH2:3][C:22]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)=[C:21]([C:20]([OH:31])=[O:19])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C#Cc1ccc(Cl)c(Cl)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1=C(c2ccc(Cl)c(Cl)c2)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At r.t., a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methyl amine (262.5 g, 1.06 mol) in CH2Cl2 (0.6 l) was added dropwise over 60 min to a solution of (3,4-dichloro-phenyl)-propynoic acid ethyl ester (172.0 g, 0.71 mol) and trifluoroacetic acid (5.4 ml, 0.07 mol) in CH2Cl2 (0.7 l). The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was then evaporated to dryness, and the residue was dissolved in dioxane (1.6 l). An aqueous solution of NaOH (1.0 l, 1.9 mol, 2.8 eq.) was added. The resulting emulsion was stirred at r.t. for 20 h, and the low boiling organic solvent was removed under vacuum. Water (2.0 l) was added, and the aqueous layer was separated and washed with TBME (2 times 1.2 l). The aqueous layer was then acidified to a pH value of 2.5 by addition of 25% HCl. The resulting suspension was then stirred overnight, and the white precipitate was filtered off, washed with water and ethanol and dried under high vacuum to yield 205.0 g (83%) of IIb as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][N:6]=[CH:5][C:4]=2[C:3]=1[C:11]([O:13][CH3:14])=[O:12].F[B-](F)(F)F.[CH3:20][O+](C)C>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:20])[N:7]=2)[C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: C[O+](C)C
Reactant: COC(=O)c1c(Br)ccc2[nH]ncc12
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Br)ccc2nn(C)cc12
Reaction time: 2.5 h
Yield: 72.2 %

Procedure:
To a solution of methyl 5-bromo-1H-indazole-4-carboxylate (4.50 g, 17.6 mmol) in ethyl acetate (176 mL) was added trimethyloxonium tetrafluoroborate (3.38 g, 22.9 mmol) at room temperature, and the mixture was stirred for 2.5 hr. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→30/70) to give the title compound (3.42 g, yield 73%).