Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[O:14])[C:9]=2[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=[O:35]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[C:9]=2[C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)=[CH:4][CH:3]=1.[OH2:35].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[C:9]=2[C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2n[nH]c(-c3ccc(F)cc3)c2-c2ccncc2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O
Product: O=C(c1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1)N1CCNCC1

Procedure:
A solution of 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]-1-piperazinecarboxylate (0.6349 g; 1.4077 mmol; prepared as set forth in step 2 of Example A-313) in methylene chloride (3.5 mL) and TFA (1.1 mL, 14.077 mmol) was stirred at room temperature under N2 for 2 hours. The solvents were removed under reduced pressure, and TFA was chased by methylene chloride and methanol. The resulting colorless oily residue was triturated with methanol. The resulting solid was collected by filtration and dried in a vacuum oven overnight to give the desired product 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]piperazine, monohydrate (0.7860 g, 96.4%). Anal. Calc'd for C19H18N5OF.2TFA.H2O: C, 46.24; H, 3.71; N, 11.72; Found: C, 45.87; H, 3.43; N, 11.45. MS (MH+): 352 (base peak).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([O:6][C:7]2[C:12]([C:13]3[CH2:14][CH2:15][O:16][CH2:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:3]1.[N:19]1[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[N:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:16]1[CH2:15][CH:14]=[C:13]([C:12]2[C:7]([O:6][CH:4]3[CH2:3][N:2]([C:25]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][N:21]=4)=[O:26])[CH2:5]3)=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:18][CH2:17]1
Reactant: C1=C(c2cccnc2OC2CNC2)CCOC1
Reactant: O=C(O)c1ccncn1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccncn1)N1CC(Oc2ncccc2C2=CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of 2-(azetidin-3-yloxy)-3-(3,6-dihydro-2H-pyran-4-yl)pyridine hydrochloride (see PREPARATION P26.1; 100 mg, 0.45 mmol), pyrimidine-4-carboxylic acid (55 mg, 0.45 mmol) and triethylamine (96.13 mg, 0.95 mmol) in CH2Cl2 (10 mL) was added 4-Dimethylaminopyridine (DMAP) (55 mg, 0.47 mmol) and propyl phosphonic anhydride (500 mg, 0.9 mmol). The reaction mixture was stirred at room temperature for overnight. Then the reaction mixture was concentrated and the crude product was purified by silica gel column chromatography to give the desired compound (48 mg, 0.16 mmol, yield 66%). [M+1]: 339. IC50 (uM): 0.99.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]1[CH2:23][O:22]1)([CH3:16])([CH3:15])[CH3:14]>CCO.O>[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]([OH:22])[CH2:23][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC[C@@H](O)CNc1ccc2c(c1)NC(=O)CS2
Yield: 82.9 %

Procedure:
A solution of 6-amino-4H-benzo[1,4]thiazin-3-one (10.68 g, 59.3 mmol; commercial) and (2R)-tert-butyl-dimethyl-(2-oxiranyl-ethoxy)-silane (first eluting compound of step C.i, 12.0 g, 59.3 mmol) in 9-1 EtOH/H2O (320 mL) was heated at 80° C. for 2 days. The mixture was concentrated under reduced pressure. Residual starting aniline could be removed by addition of Et2O/MeOH followed by filtration. The filtrate containing the product was concentrated under reduced pressure to afford the title intermediate as a brown oil (18.8 g, 83% yield) which was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C[N:11]([CH3:20])[C:12]1[CH:19]=[CH:18][C:15](C=O)=[CH:14][CH:13]=1.CO[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:18][CH:19]=3)[CH2:20][C:27]3[C:26](=[CH:25][CH:24]=[CH:23][CH:28]=3)[NH:29]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(N)cc1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: O=Cc1ccc(Cl)cc1
Product: Clc1ccc(C2Nc3ccccc3CN2c2ccccc2)cc1

Procedure:
2-(4'-chlorophenyl)-3-phenyl-1,2,3,4-tetrahydroquinazoline was prepared by the method of Example 1 but substituting 4-chlorobenzaldehyde for the 4-dimethylaminobenzaldehyde used in Example 1. The crude product had a melting point of 177° C. 0.5 g (0.0015 mol)of this compound and 0.18 g (0.005 mol) p-anisidine were fused together at 120 to 140° C. for about 1 hr. The product was the title compound as a white solid having a melting point of 116° C. This compound was imaged on CF paper, as described above, and gave an intense yellow coloration. The UV-visible spectrum of the coloured form of this compound showed peaks at 416 nm and 349 nm (relative intensity 0.98).
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:11][CH3:12])=[N:4][CH:5]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.O>[CH2:15]([O:10][CH:8]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([S:11][CH3:12])=[N:4][CH:5]=1)[CH3:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CSc1ncc(C(C)O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncc(C(C)OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
3-Chloro-5-(1-hydroxyethyl)-2-methylthiopyridine (21.9 g, 0.108 mol) was dissolved with stirring in anhydrous DMF (250 mL) and 60% sodium hydride (5 g, 0.125 mol) added in portions. The mixture was stirred at room temperature for 30 minutes and benzyl bromide (17.6 g, 0.103 mol) added dropwise. The mixture was then stirred at room temperature for four hours, diluted with water (400 mL) and extracted three times with ethyl acetate (100 mL). The combined organic extracts were washed twice with water (200 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulphate, and evaporated to dryness. Purification of the residue by chromatography over silica (0-5% ethyl acetate:hexane) gave the desired product (25.0 g, 79%) as a pale yellow oil.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]([O-])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].CS(Cl)(=O)=O.N1C=CC=CC=1.[NH2:63][C@@H:64]1[C:95](=[O:96])[N:66]2[C:67]([C:79]([O:81][CH:82]([C:89]3[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=3)[C:83]3[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=3)=[O:80])=[C:68]([S:71][CH2:72][C:73]3[C:74](=[O:78])[O:75][CH2:76][CH:77]=3)[CH2:69][S:70][C@H:65]12>CN(C)C=O>[O:78]=[C:74]1[C:73]([CH2:72][S:71][C:68]2[CH2:69][S:70][C@@H:65]3[C@H:64]([NH:63][C:27](=[O:28])/[C:26](/[C:24]4[N:25]=[C:21]([NH:20][C:1]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[S:22][CH:23]=4)=[N:30]\[O:31][C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:95](=[O:96])[N:66]3[C:67]=2[C:79]([O:81][CH:82]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[C:89]2[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=2)=[O:80])=[CH:77][CH2:76][O:75]1
Reactant: O=C([O-])C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCC3=CCOC3=O)CS[C@H]12
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C1OCC=C1CSC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of sodium 2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetate (420 mg) in dimethylformamide (5 ml) was cooled to -50° C. whilst under an inert atmosphere. Methanesulphonyl chloride (0.047 ml) was added and the reaction stirred at -50° C. for 30 min. Pyridine (0.049 ml) was added followed by a solution of diphenylmethyl 7β-amino-3-(2,5-dihydro-2-oxofuran-3-ylmethylthio)ceph-3-em-4-carboxylate (300 mg) in dimethylformamide (3 ml) and the reaction was allowed to warm to 0° C. After stirring at 0° C. for 90 min the mixture was partitioned between ethyl acetate and water. The organic phase was separated and washed twice with water followed by saturated sodium bicarbonate and finally brine. After drying over magnesium sulphate and evaporation of solvent the residue was purified by chromatography on silica gel (Keiselgel, 2:3 ethyl acetate:hexane rising to 7:3 ethyl acetate:hexane). The title compound was isolated as a foam (422 mg). υmax (CH2Cl2) 3380, 1785, 1760 and 1725cm-1 ; δ H (CDCl3) 3.25 (1H, d, J 17.3Hz), 3.49-3.56 (3H, m), 4.68 (2H, s), 5.08 (1H, d, J 4.9Hz), 6.00 (1H, dd, J 8.8Hz, 4.9Hz), 6.44 (1H, s), 6.74 (1H, bs), 6.98 (1H, s), 7.12 (1H, s), 7.16-7.49 (41H, m). [mass spectrum: +ve ion (3NOBA, Na+) MNa+ 1170].
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:23])=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CS(C)=O>[CH3:17][C:16]1[O:15][C:14]([C:18]2[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[O:23])=[CH:20][CH:19]=2)=[N:13][C:12]=1[CH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(F)cc1
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(N2CCOCC2)cc1
Temperature: 130 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
A mixture of fluoride 48 (103 mg, 0.22 mmol) and morpholine (2 mL) in DMSO (1 mL) was stirred in a sealed tube at 130° C. for 16 h. The solvent was evaporated and the residue was suspended in ice/water (50 mL) for 1 h. The precipitate was filtered, washed with water (5 mL) and dried. The crude solid was purified by column chromatography, eluting with a gradient (0-10%) of MeOH/EtOAc, to give benzamide 50 (83 mg, 71%) as a white powder: mp (EtOAc) 208-210° C.; 1H NMR δ 9.23 (s, 1H, CONH), 8.57 (br s, 1H, H-2′), 8.47 (br d, J=4.5 Hz, 1H, H-6′), 8.00 (br d, J=8.5 Hz, 2H, H-2, H-6), 7.91 (br d, J=8.5 Hz, 2H, H-3, H-5), 7.74 (br d, J=7.8 Hz, 1H, H-4′), 7.54 (d, J=9.0 Hz, 2H, H-3″, H-5″), 7.37 (dd, J=7.8, 4.7 Hz, 1H, H-5′), 7.05 (d, J=9.0 Hz, 2H, H-2″, H-6″), 4.49-4.54 (m, 4H, CH2SO2, CH2N), 3.72 (br t, J=4.8 Hz, 4H, 2×CH2O), 3.27 (br t, J=4.8 Hz, 4H, 2×CH2N), 2.13 (s, 3H, CH3); 13C NMR δ 165.5, 157.8, 154.2, 149.7, 148.8, 148.0, 135.3, 135.1, 134.8, 129.7 (2), 128.8, 128.0 (2), 126.4, 126.0, 125.4 (2), 123.4, 113.3 (2), 65.6 (2), 53.2, 46.7 (2), 40.4, 9.6; MS m/z 533.7 (MH+, 100%). Anal. calcd for C28H28N4O5S: C, 63.14; H, 5.30; N, 10.52. Found: C, 62.94; H, 5.18; N, 10.51%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8][N:7]=1.[O:19]1[CH2:24][O:23][CH2:22][O:21][CH2:20]1.FC(F)(F)C(O)=O.C(OO)(C)(C)C>C(#N)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:20]2[O:21][CH2:22][O:23][CH2:24][O:19]2)=[N:8][N:7]=1
Reactant: Cc1cccc(Nc2nncc3ccccc23)c1
Reactant: C1OCOCO1
Agent: CC(C)(C)OO
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1cccc(Nc2nnc(C3OCOCO3)c3ccccc23)c1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
To a suspension of 9.6 g (40.8 mmol) 1-(3-methylanilino)phthalazine and 173 g 1,3,5-trioxane in 570 ml acetonitrile, 3.12 ml (40.8 mmol) trifluoroacetic acid, 11.0 ml (80% in tBuOOtBu; 87.4 mmol) tBuOOH and 190 mg (0.68 mmol) FeSO4·7 H2O are added, and the mixture stirred for 17 h at 80° C. The cooled reaction mixture is partly evaporated in the RE, diluted with EtOAc and water and adjusted to an alkaline pH with 1 N NaOH. The aqueous phase is separated off and twice extracted with EtOAc. The organic phases are washed twice with water and brine, dried (Na2SO4) and evaporated. Column chromatography (SiO2; EtOAc/toluene 1:3; applied as solution in dichloromethane/acetone 9:1) yields the title compound after crystallization with the addition of DIPE; m.p. 161° C.; DC (EtOAc/toluene 1:3) Rf=0.27; 1H-NMR (DMSO-d6) 9.27 (s, HN), 8.74 (m, 1H), 8.61 (m, 1H), 8.00 (m, 2H), 7.72 (s, 1H), 7.68 (d, 1H), 7.25 (t, 1H), 6.89 (d, 1H), 6.39 (s, 1H), 5.47 (d, 2H), 5.41 (d, 2H), 2.33 (s, 3H); FAB-MS (M+H)+=324; anal. calc.(C18H17N3O3) C, 66.86%; H, 5.30%; N, 13.00%; meas. C, 66.83%; H, 5.36%; N, 12.81%.
Reaction SMILES: O.S.[Na].[N:4]([CH2:7][C:8]1[N:18]=[C:11]2[N:12]=[C:13]([CH3:17])[CH:14]=[C:15]([SH:16])[N:10]2[N:9]=1)=[N+]=[N-].[C:19]1([C:25]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[O:29][C:28]3[CH:30]=[CH:31][C:32]([C:34](ON4C5C=CC=CC=5N=N4)=[O:35])=[CH:33][C:27]=3[O:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[SH:16][C:15]1[N:10]2[N:9]=[C:8]([CH2:7][NH:4][C:34]([C:32]3[CH:31]=[CH:30][C:28]4[O:29][C:25]([C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[O:26][C:27]=4[CH:33]=3)=[O:35])[N:18]=[C:11]2[N:12]=[C:13]([CH3:17])[CH:14]=1
Reactant: O=C(On1nnc2ccccc21)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Reactant: Cc1cc(S)n2nc(CN=[N+]=[N-])nc2n1
Agent: S
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(S)n2nc(CNC(=O)c3ccc4c(c3)OC(c3ccccc3)(c3ccccc3)O4)nc2n1
Yield: 86.2 %

Procedure:
A dried solution of 2.0 g of sodium hydrogen sulphide monohydrate (drying agent molecular sieve 4 Å) in 100 ml of dimethylformamide is treated with 2.2 g of 2-azidomethyl-5-methyl[1.2.4]triazolo[1,5-a]pyrimidine-7-thiol and stirred until the evolution of gas has finished (about 15 minutes). Thereupon, 4.35 g of 1H-benzotriazol-1-yl 2,2-diphenyl-1,3-benzodioxol-5-carboxylate are added and the reaction mixture is stirred at room temperature for 20 hours and at 45° C. for 24 hours. The solvent is evaporated in a high vacuum, the residue is taken up in 200 ml of ethyl acetate and 200 ml of water and stirred in an ice bath for 30 minutes. The resulting precipitate is filtered off under suction, washed with water and ethyl acetate and dried in a vacuum at 40° C. The yellow product is dissolved in 100 ml of methanol, a small amount of insoluble material is removed by filtration and the filtrate is concentrated to dryness. The residue in 100 ml of acetonitrile is heated at reflux on a steam bath for 1 hour. After cooling in an ice bath the product is filtered off under suction and dried. There are obtained 4.25 g of N-[(7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidin-2-yl)methyl]-2,2-diphenyl-1,3-benzodioxol-5-carboxamide as a yellow solid of melting point 267°-271° C. (dec.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17]O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:39].CO>CN(C)C(=O)C.ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][Br:39])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1C[C@H](CO)[C@@H](O)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)N(C)C
Product: O=C(OCc1ccccc1)N1C[C@H](CBr)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
(3R,4R)-(1-Benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl)methanol (503 mg) and triphenylphosphine (577 mg) were dissolved in N,N-dimethylacetamide (10 mL) While this solution was chilled in an ice water bath, carbon tetrabromide (730 mg) in dichloromethane (2 mL) was added dropwise. After the reaction mixture was stirred at room temperature for 5 hours, methanol (1 mL) was added and the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with saturated brine (2×10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluant: ethyl acetate: hexane=2:1) to give (3S,4R)-1-benzyloxycarbonyl-3-bromomethyl-4-hydroxypyrrolidine as a milky white syrup (503 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18](=[O:28])[C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[CH:16]=[CH:17][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:38])C=1>ClCCl>[CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:38])[C:5]2[CH:14]=[C:15]([C:18](=[O:28])[C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CC1(C)CC(c2ccccn2)c2cc(C(=O)c3ccc([N+](=O)[O-])cc3)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C(=O)c3ccc([N+](=O)[O-])cc3)ccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
134 mg of 3,4-dihydro-2,2-dimethyl-6-(4-nitrobenzoyl)-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 15 ml of dichloromethane and 72 mg of m-chloroperbenzoic acid were added. The mixture was stirred at room temperature overnight. After washing in succession with sodium bisulphite solution and sodium bicarbonate solution the organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/methanol (4:1) for the elution. The residue was recrystallized from isopropanol to give 50 mg of 2-[3,4-dihydro-2,2-dimethyl-6-(4-nitrobenzoyl)-2H-1-benzopyran-4-yl]pyridine N-oxide of melting point 209°-211° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:6]2[N:7]([C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=2)[N:8]=1.N1C=CC=CC=1.[CH3:36][O:37][C:38](Cl)=[O:39]>ClCCl>[CH2:12]([C:9]1[N:7]2[N:8]=[C:3]([CH2:2][NH:1][C:38]([O:37][CH3:36])=[O:39])[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=3)[C:6]2=[CH:11][CH:10]=1)[CH3:13]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)CCCCc1c(CN)nn2c(CC)ccc2c1-c1cncc(C)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CCCCc1c(CNC(=O)OC)nn2c(CC)ccc2c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a solution of ethyl 5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (80 mg) and pyridine (1 mL) in dichloromethane (2 mL) was added methyl chloridocarbonate (34.8 mg) under ice-water cooling and the mixture was stirred at ambient temperature for 2 hours. After evaporation of solvent, the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-[7-ethyl-2-{[(methoxycarbonyl)amino]methyl}-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (70 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.F[C:20]1[CH:21]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:24][CH:25]=1.O>CN(C)C=O>[CH3:3][N:4]1[CH2:5][CH2:6][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[N:11]=2)[CH2:8][CH2:9]1
Reactant: Fc1cccc(C(F)(F)F)c1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(c2nn(-c3cccc(C(F)(F)F)c3)c3ccccc23)CC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 17.7 %

Procedure:
To a stirred suspension of 4.9 g of a 50% oil dispersion of sodium hydride in 60 ml of dimethylformamide was added dropwise a solution a 10.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole in 80 ml of hot dimethylformamide. The reaction mixture was stirred for 1 hr and then 15.2 g of 3-fluorobenzotrifluoride was added. The reaction was heated at 90° C. for 22 hrs, cooled and poured into water. The aqueous mixture was extracted with ether. The ethereal extracts were dried over anhydrous magnesium sulfate and concentrated to give an oil. The oil was flash chromatographed (silica gel, diethylamine-ethyl acetate (1:9)). Evaporation of the appropriate fractions followed by recrystallization twice from hexane yielded 2.96 g (18%) of product, mp 103°-105° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]3[O:19][CH:18]=[C:17](Br)[C:16]=3[CH:21]=1)=[O:11])[CH2:2]2.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH3:35][Si:36]([C:39]#[CH:40])([CH3:38])[CH3:37]>O1CCOCC1.CCOC(C)=O.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]3[O:19][CH:18]=[C:17]([C:40]#[C:39][Si:36]([CH3:38])([CH3:37])[CH3:35])[C:16]=3[CH:21]=1)=[O:11])[CH2:2]2
Reactant: C#C[Si](C)(C)C
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc2occ(Br)c2c1
Agent: Cl[Pd]Cl
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: N#Cc1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1coc2ccc(C(=O)N[C@H]3CN4CCC3CC4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzofuran-5-carboxamide (350 mg, 1.0 mmol) is combined with bis(benzonitrile)palladium dichloride (57 mg, 0.15 mmol), cuprous iodide (19 mg, 0.10 mmol), tri(t-butyl)phosphine (658 μL, 0.325 mmol), trimethylsilylacetylene (170 μL, 1.2 mmol), and DIA (168 μL, 1.2 mmol) in dioxane (3 ml) in a dry flask under nitrogen. The reaction is stirred overnight at RT, is diluted with EtOAc (25 ml), is washed with 1:1:0.1 NaCl/water/conc. NH4OH (4×25 ml), and the organic layer is dried (K2CO3). The volatiles are removed in vacuo and the residue is chromatographed over 30 g silica gel (230-400 mesh) eluting with 7% MeOH/CHCl3+1% conc. NH4OH. The appropriate fractions are combined and concentrated to afford 268 mg (73%) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-[(trimethylsilyl)ethynyl]-1-benzofuran-5-carboxamide as a pale foam. HRMS (ESI) calcd for C21H26N2O2SI+H: 367.1841, found 367.1852 (M+H)+.