Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][C:5]2[N:6]([C:8]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[F:18])=[N:9][N:10]=2)[N:7]=1.[CH2:23]([N:25]1[C:29]([CH2:30][OH:31])=[N:28][CH:27]=[N:26]1)[CH3:24].[H-].[Na+]>CN(C=O)C>[F:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[C:8]1[N:6]2[N:7]=[C:2]([O:31][CH2:30][C:29]3[N:25]([CH2:23][CH3:24])[N:26]=[CH:27][N:28]=3)[C:3]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: CCn1ncnc1CO
Reactant: CC(C)(C)c1cc2nnc(-c3c(F)cccc3F)n2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ncnc1COc1nn2c(-c3c(F)cccc3F)nnc2cc1C(C)(C)C

Procedure:
This compound was prepared from 6-chloro-3-(2,6-difluorophenyl)-7-(1,1-dimethylethyl)-1,2,4-triazolo[4,3-b]pyridazine and (2-ethyl-2H-1,2,4-triazol-3-yl)methanol following the procedure (sodium hydride, DMF) described in WO 98/04559. Data for the title compound: m.p. 182° C.; 1H NMR (400 MHz, CDCl3) δ1.39-1.45 (12H, m), 4.10-4.16 (2H, m), 5.46 (2H, s), 7.09-7.15 (2H, m), 7.52-7.59 (1H, m), 7.92 (1H, s), 8.00 (1H, s); MS (ES30) m/e 414 [MH]+; Anal. Found: C, 58.19; H, 5.05; N, 23.80%. C20H21F2N7O requires: C, 58.10; H, 5.12; N, 23.72%.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].IC>O.C(Cl)Cl.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[CH:6][N:7]=1
Reactant: Oc1ccc(F)nc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CI
Product: COc1ccc(F)nc1
Temperature: 100 °C

Procedure:
To a solution of 6-fluoropyridin-3-ol (75 g, 663 mmol) in DMF (265 mL, 663 mmol) were added potassium carbonate (59.7 g, 995 mmol) and iodomethane (108 g, 763 mmol). The resulting slurry was heated at 100° C. for 3 hours. The reaction was diluted with water (1000 mL) and poured into a separatory funnel containing diethyl ether (1000 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (4×500 mL). The combined organic layers were washed with water and then brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a yellow oil. This oil was diluted with 500 mL of DCM and concentrated to provide a yellow oil with a large amount of an off white precipitate. The mixture was filtered and the derived solid was washed well with DCM. The filtrate was concentrate to provide a mixture consisting of a yellow oil and an off white solid. The solid eas filtered, washing with DCM. Repeat this procedure again and then concentrated the filtrate to provide a yellow oil. The oil was taken up in 100 mL of ether and flashed through a plug of silica gel with 10:1 hexanes:ether to provide 2-fluoro-5-methoxypyridine as a yellow oil.
Reaction SMILES: C(C1C=CC(OC2C=CC=CC=2)=C(O)C=1)CCCCC.C(C1C=CC(OC2C=CC=CC=2)=C(OC)C=1)CCCCC.C[O:43][C:44]1[CH:49]=[C:48]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH:47]=[CH:46][C:45]=1[O:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>>[CH2:50]([C:48]1[CH:47]=[CH:46][C:45]([O:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[C:44]([OH:43])[CH:49]=1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]
Reactant: CCCCCCCCc1ccc(Oc2ccccc2)c(OC)c1
Agent: CCCCCCc1ccc(Oc2ccccc2)c(O)c1
Agent: CCCCCCc1ccc(Oc2ccccc2)c(OC)c1
Product: CCCCCCCCc1ccc(Oc2ccccc2)c(O)c1

Procedure:
The procedure as described above for synthesis of (5a) was used, except that compound (4a) was replaced with compound (4b). 1H NMR (300 MHz) (CDCl3) δ 7.43-6.72 (m, 8H), 5.58 (s, 1H), 2.66-2.61 (t, 2H), 1.71-1.66 (m, 2H), 1.39-1.35 (m, 10H), 0.99-0.95 (t, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:2]([NH:1][C:13]([NH:12][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=4)[N:22]=3)=[CH:17][CH:16]=2)=[S:14])[CH2:3][OH:4])=[CH:6][CH:7]=1
Reactant: NC(CO)c1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1)c1ccc(F)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-fluorophenyl)ethanol and 3-(4-isothiocyanatophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.4 g, 99%): 1H NMR (300 MHz, CDCl3) δ 8.07 (s, 1H), 7.67 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.6 Hz, 2H), 6.82-6.67 (m, 4H), 6.44 (q, J=7.7, 7.1 Hz, 4H), 6.33 (d, J=8.3 Hz, 1H), 5.09 (s, 1H), 3.44 (dd, J=10.9, 4.2 Hz, 1H), 3.32 (dd, J=11.2, 4.7 Hz, 1H); ESIMS m/z 502 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1>CCOC(C)=O.[Pd]>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: CC1(C)C=CC(=O)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CCC(=O)CC1
Reaction time: 3 h

Procedure:
A mixture of 4,4-dimethyl-2-cyclohexene-1-one (5.5 g) and 10% Pd/C (0.25 g, wet, Degussa type E101) in EtOAc (50 mL) was hydrogenated under 15 psi for 3 h at room temperature. The mixture was filtered through Celite and the filtrate was concentrated in vacuo affording the title compound as a colorless solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.07 (s, 6H), 1.65 (t, J=7 Hz, 4H), 2.35 (t, J=7 Hz, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:28]1[N:36]2[C:31]([C:32]([NH2:37])=[N:33][CH:34]=[N:35]2)=[CH:30][CH:29]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].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]>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:28]3[N:36]4[C:31]([C:32]([NH2:37])=[N:33][CH:34]=[N:35]4)=[CH:30][CH:29]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ncnn2c(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCc2ccc(-c3ccc4c(N)ncnn34)cc2C1
Temperature: 80 °C
Yield: 98.7 %

Procedure:
To a solution of 7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butylester (4 g, 11 mmol) and 7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (1.3 g, 6.1 mmol) in DME (133 mL) and 2 N Na2CO3 solution (26 mL) was added Pd(dppf)Cl2 (452 mg, 0.6 mmol). The reaction mixture was degassed with N2 for 15 min. The mixture was heated to 80° C. for 23 h. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The crude residue was purified by Biotage® to provide 2.20 g (55%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.9 (m, 2 H), 7.85 (d, 1 H), 7.2 (d, 1 H), 7.0 (d, 2 H), 4.5 (s, 2 H), 3.5 (t, 2 H), 2.8 (t, 2 H) 1.4 (s, 9 H); ES-MS m/z 366.05 [M+H]+, HPLC RT (min) 2.64.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=1.[CH2:16]([N:23]1[C:27]2=[C:28](Cl)[N:29]=[N:30][CH:31]=[C:26]2[CH:25]=[C:24]1[CH3:33])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN1CCCC1=O>[CH2:16]([N:23]1[C:27]2=[C:28]([O:13][CH2:12][C:11]3[CH:14]=[CH:15][C:8]([F:7])=[CH:9][CH:10]=3)[N:29]=[N:30][CH:31]=[C:26]2[CH:25]=[C:24]1[CH3:33])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OCc1ccc(F)cc1
Reactant: Cc1cc2cnnc(Cl)c2n1Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc2cnnc(OCc3ccc(F)cc3)c2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
32.65 g (291 mmol) of potassium tert-butoxide and 1.54 g (5.82 mmol) of [18]crown-6 (98% strength) are added successively to a solution of 21.8 g (173 mmol) of 4-fluorobenzyl alcohol in 150 ml of anhydrous N-methylpyrrolidone. This mixture is stirred at room temperature for 1 h. A solution of 15.0 g (58.2 mmol) of 1-benzyl-7-chloro-2-methylpyrrolo[2,3-d]pyridazine in 100 ml of anhydrous N-methylpyrrolidone is subsequently added dropwise in the course of 30 min. The mixture is stirred at room temperature for a further 15 min, then treated with 500 ml of ice-water and extracted with 3×400 ml of ethyl acetate. The organic extracts are washed with 3×300 ml of water and subsequently dried over magnesium sulfate. After concentration and crystallization from diisopropyl ether, 12.95 g (64%) of the title compound are isolated. M.p.: 127°-132° C.
Reaction SMILES: [O:1]=[C:2]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[CH2:3]1.[CH3:23][Mg]Cl.C1COCC1.[Cl-].[NH4+]>C1COCC1>[CH3:23][C:2]1([OH:1])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccccc12
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(C)(O)c1ccccc12
Reaction time: 1 h
Yield: 66.2 %

Procedure:
tert-Butyl 1-oxospiro[indane-3,4′-piperidine]-1′-carboxylate (0.202 g, 0.671 mmol) was dissolved in THF (3 mL), 3 mmol/L methylmagnesium chloride-THF solution (0.450 mL, 1.34 mmol) was added under ice-cooling, and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added dropwise to the reaction mixture, and the mixture was extracted several times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give the title compound (0.141 g, 66%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([N:26]=[C:27]=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:18]([NH:26][C:27](=[O:28])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10]2)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: O=C=NCCc1ccccc1
Product: O=C(NCCc1ccccc1)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (35.0 mg, 0.155 mmol) using the same procedure employed for Example 2 (2), but with phenethylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (22.0 mg, 38%) having the following characteristics.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]3[CH:23]=[N:22][NH:21][N:20]=3)[CH:15]=[CH:14][C:13]=2[C:12]2=[N:24][N:25](COCC[Si](C)(C)C)[C:26]([NH:27][CH:28]3[CH2:33][CH2:32][N:31]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:30][CH2:29]3)=[C:11]2[N:10]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O.N>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]3[CH:23]=[N:22][NH:21][N:20]=3)[CH:15]=[CH:14][C:13]=2[C:12]2[NH:24][N:25]=[C:26]([NH:27][CH:28]3[CH2:29][CH2:30][N:31]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:32][CH2:33]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(-c4cn[nH]n4)ccc32)c1NC1CCN(S(C)(=O)=O)CC1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(-c4cn[nH]n4)ccc23)CC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 10.8 %

Procedure:
116 mg of 5-(2,6-difluorophenyl)-N-[1-(methylsulphonyl)piperidin-4-yl]-7-(2H-1,2,3-triazol-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinolin-3-amine are introduced into 10 ml of DCM. After cooling to 0° C. using an ice bath, 1.1 ml of TFA are added and the mixture is stirred at RT for 5 h. It is concentrated under RP and the solid obtained is taken up in 60 ml of water, neutralized with 7.5M aqueous ammonia solution. It is extracted with ethyl acetate, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a DCM/methanol mixture (92.5/7.5 by vol.), to give 10 mg of 5-(2,6-difluorophenyl)-N-[1-(methylsulphonyl)piperidin-4-yl]-7-(2H-1,2,3-triazol-4-yl)-1H-pyrazolo[4,3-c]isoquinolin-3-amine (yellow solid). 1H NMR: 1.62-1.75 (m, 2 H) 2.10 (m, 2 H) 2.82-2.97 (m, 5 H) 3.57 (m, 2 H) 3.74-3.86 (m, 1 H) 6.04 (d, J=8.0 Hz, 1 H) 7.35 (t, J=8.0 Hz, 2 H) 7.63-7.75 (m, 1H) 8.13 (broad s, 1 H) 8.39 (broad d, J=8.6 Hz, 1 H) 8.45 (broad m, 1 H) 8.49 (d, J=8.6 Hz, 1 H) 12.77 (s, 1 H) 15.23 (broad m, 1 H).
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6]C=CC=1.N(CC1CC1)=[N+]=[N-].[C:18]([C:20]1[S:21][C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:23]([CH3:25])[N:24]=1)#[CH:19]>>[CH:2]1([CH2:1][N:8]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:23]([CH3:25])[N:24]=3)[N:10]=[N:9]2)[CH2:7][CH2:6]1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#Cc1nc(C)c(C(=O)OCC)s1
Agent: [N-]=[N+]=NCC1CC1
Product: CCOC(=O)c1sc(-c2cn(CC3CC3)nn2)nc1C
Yield: 70 %

Procedure:
Following the procedure as described in Example 2, making variations as necessary to replace benzylazide with (azidomethyl)cyclopropane to react with ethyl 2-ethynyl-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 70% yield: 1H NMR (300 MHz, CDCl3) δ 8.21 (s, 1H), 4.39-4.19 (m, 4H), 2.69 (s, 3H), 1.38-1.19 (m, 4H), 0.74-0.64 (m, 2H), 0.48-0.37 (m, 2H); MS (ES+) m/z 293.3 (M+1).
Reaction SMILES: FC1C([O:8][C:9](=O)[CH:10]([C:17]2[N:18]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[N:19]=[C:20]3[CH2:24][CH2:23][CH2:22][C:21]=23)[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=C(F)C(F)=C(F)C=1F.[CH3:37][O:38][C:39](=[O:48])[C:40]1[CH:45]=[CH:44][C:43]([NH2:46])=[C:42]([F:47])[CH:41]=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:37][O:38][C:39](=[O:48])[C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:9](=[O:8])[CH:10]([C:17]2[N:18]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[N:19]=[C:20]3[CH2:24][CH2:23][CH2:22][C:21]=23)[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:42]([F:47])[CH:41]=1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Reactant: COC(=O)c1ccc(N)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCC3)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 4.3, [2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-cyclohexyl-acetic acid pentafluorophenyl ester (example 4.2) was reacted with 4-amino-3-fluoro-benzoic acid methyl ester (CAS Reg. No. 185629-32-7) in the presence of DMAP in DMF to give the title compound as colorless oil. MS: m/e=510.2 [M+H+].
Reaction SMILES: Br[CH:2]1[S:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[SH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH:14]1[CH:15]=[C:10]([S:9][CH:2]2[S:6][C:5](=[O:7])[NH:4][C:3]2=[O:8])[N:11]=[CH:12][CH:13]=1
Reactant: O=C1NC(=O)C(Br)S1
Reactant: Sc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1NC(=O)C(Sc2ccccn2)S1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
To a solution of 5-bromo-thiazolidine-2,4-dione (28.24 g, 0.144 mol) and 2-mercaptopyridine [(II), 16.0 g, 0.144 moll] in dry THF (200 mL) at -78° C. was added lithium bis(trimethylsilyl)amide (1.0M in hexanes, 317 mL, 0.317 mol) dropwise over a 40 min period. After 30 min. the reaction mixture was warmed to room temperature. After an additional 3 hr, 10% HC1 was added to pH=1. The layers were separated and the aqueous phase was extracted with ethyl acetate (2×500 mL). The combined organic phase was washed with water (500 mL), brine (500 mL), dried (MgSO4) and concentrated to provide the title compound as a green solid (30.45 g, 93%): mp 118°-120 ° C.; NMR (DMSO, d 6): δ 12.35 (s, 1H, NH), 8.39 (d, J=5.3 Hz, 1H, PyrH), 7.69 (dd, J=7.3, 8.3 Hz, 1H, PryH), 7.42 (d, J=8.3 Hz, 1H, PyrH), 7.19 (dd, J=5.3,7.3 Hz, 1H, PyrH), 6.31 (s, 1H, CH), MS(EI): 226 (MI, 12%), 155 (10%), 79 (100%); Anal. (C8H6N2O2S2): C,H,N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[OH:11].Cl[Sn]Cl.C([O-])([O-])=O.[K+].[K+]>CCO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([OH:11])[CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1ccc(Cl)c(O)c1

Procedure:
2-Chloro-5-nitrophenol (3.06 g, 17.6 mmol) and SnCl2 (10.0 g, 52.8 mmol) in EtOH (120 mL) were heated for 10 h at 80° C. The reaction was treated with 1N K2CO3 (aq) and filtered through Celite. Most of the solvent was removed under vacuum. The crude was treated with saturated NaHCO3 and extracted with EtOAc twice. The organic layers were washed with water then brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield the title compound as a brown-green solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([OH:16])=O)=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C.CN1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:16])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:21]=2[C:22]([F:24])([F:23])[F:25])[O:11][N:10]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46820.8 %

Procedure:
3-(2-chloro-6-fluorophenyl)-5-(1-(3-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid (50 mg, 0.0001 mmol), Morpholine (9 mg, 0.0001 mmol), HOBt (14 mg, 0.0001 mmol) and EDCI (19 mg 0.00012 mmol) were dissolved in 1 mL dry DMF. N-Methylmorpholine (100 NL, 0.001 mmol) was added and the reaction mixture was stirred at room temperature overnight. Morpholine, HOBt, EDCI and N-Methylmorpholine were added again in the aforementioned ratios. The mixture was stirred at room temperature for 24 h. DMF was removed by evaporation. An aqueous solution of 5% citric acid was added. The precipitate was filtered and dried. The product (example B-35) was purified by pTLC (PE/EE 5/5) to give 26 mg of a yellow oil (yield 45%). Result of LC/MS MH+: 554.7; 1H NMR (CDCl3): 8.15 (1H, s, CH-pyraz.), 7.35-7.6 (6H, m, CH-arom), 7.15 (1H, t, CH-arom), 3.6 (4H, m, CH2-morpholine), 3.18 (4H, m, CH2-morpholine).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=1)(=[O:11])=[O:10].[Br-].[Br-].[Br-].[Al+3]>O>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=1)(=[O:11])=[O:10]
Reactant: COc1ccccc1S(=O)(=O)c1ccc(=O)[nH]n1
Agent: [Al+3]
Agent: [Br-]
Solvent: O
Product: O=c1ccc(S(=O)(=O)c2ccccc2O)n[nH]1
Temperature: 100 °C
Yield: 61.2 %

Procedure:
A mixture of 6-(2-methoxy-benzenesulfonyl)-2H-pyridazin-3-one (100 mg) and aluminum tri-bromide (2 g) was prepared and heated at 100° C. for two hours. The reaction mixture was cooled and water (10 mL) was added. The mixture was then extracted with chloroform. The organic extract was washed with water (2×10 mL), dried over anhydrous sodium sulfate and evaporated. The resulting residue was triturated with isopropyl ether and the resulting solid was collected by filtration to afford the title compound (61%, 58 mg), 1HNMR (CDCl3, 300 MHz), δ 7.0 (m, 3H), 7.6 (m, 2H), 7.8 (d, 1H).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]2[CH2:18][O:17][CH2:16]2)[CH:10]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>C1COCC1>[O:17]1[CH2:18][CH:15]([C:11]2[CH:10]=[C:9]([CH2:8][CH2:7][OH:6])[CH:14]=[CH:13][CH:12]=2)[CH2:16]1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(C2COC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: OCCc1cccc(C2COC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
9.0 g of tert-butyl-dimethyl-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-silane and 92.3 ml of a 1 N solution of tetra-n-butylammonium fluoride were dissolved in 200 ml of anhydrous THF. The mixture was stirred for 3 h at room temperature. Then the mixture was poured into 200 ml of a saturated aqueous solution of sodium hydrogencarbonate and extracted three times with 500 ml each of EA The combined organic layers were dried with magnesium sulfate and evaporated. The residue was purified by silica gel chromatography (HEP/EA gradient) to yield 4.9 g of the title compound.
Reaction SMILES: O=[C:2]1[CH:10]2[CH:5]([CH:6]=[CH:7][CH2:8][CH:9]2[C:11](OCC)=[O:12])[CH2:4][NH:3]1.[H-].C([Al+]CC(C)C)C(C)C.CO.COC(C)(C)C>O1CCCC1.O>[OH:12][CH2:11][CH:9]1[CH2:8][CH:7]=[CH:6][CH:5]2[CH:10]1[CH2:2][NH:3][CH2:4]2
Reactant: CCOC(=O)C1CC=CC2CNC(=O)C21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: OCC1CC=CC2CNCC21

Procedure:
5.2 g (25 mmol) of ethyl (1RS,2RS,6RS)-9-oxo-8-azabicyclo[4.3.0]non-4-ene-2-carboxylate (product A from Example K.2.) are dissolved in 50 ml of tetrahydrofuran under a nitrogen atmosphere and 130 ml of a 1.5 molar di(isobutyl)aluminium hydride solution (195 mmol) are subsequently added dropwise. The solution is heated under reflux for 16 h. After the reaction is complete, 60 ml of methanol, 30 ml of tert-butyl methyl ether and 10 ml of water are added dropwise successively and filtration with suction is then carried out in the presence of tonsil. The suction filter residue is stirred twice with a mixture of ethanol/conc. ammonia/water (10:1:1) and filtered off with suction once again. The combined filtrates are concentrated and the crude product is purified by chromatography (eluent: dichloromethanel-methanol/conc. ammonia 2:4:1).
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][NH:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[C:23](OCC)(=[O:27])[C:24]([O-])=[O:25].CC(C)([O-])C.[K+].Cl>C1COCC1>[F:22][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:24](=[O:25])[C:23]([OH:27])=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:10]2(=[O:12])=[O:11])=[CH:20][CH:21]=1
Reactant: O=S(=O)(Cc1ccccc1)NCc1ccc(OC(F)F)cc1
Reactant: CCOC(=O)C(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1C(O)=C(c2ccccc2)S(=O)(=O)N1Cc1ccc(OC(F)F)cc1
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 90.8 %

Procedure:
N-[4-(Difluoromethoxy)benzyl]-1-phenylmethanesulfonamide (0.6 g, 1.83 mmol) and ethyl oxalate (0.32 g, 2.20 mmol) were mixed in THF (4 mL, dry). Under an atmosphere of nitrogen, potassium tert-butoxide (0.27 g, 2.38 mmol) was added and the reaction mixture was heated in a microwave reactor at 150° C. for 10 mins and then at 150° C. for 5 mins. The mixture was then cooled in an ice-bath and HCl (10%, 1 mL) was added, pH˜1. The mixture was evaporated to remove THF and the residue was extracted with DCM (20 mL). The extract was dried (MgSO4) and evaporated to give the crude product (0.634 g). It was used in the next step without further purification.