Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]1([C:30]([CH3:33])([CH3:32])[CH3:31])[O:10][CH:9]2[CH:11]([OH:29])[CH:12]([N:14]3[C:18]4[N:19]=[C:20]([N:23]=[CH:24][N:25]([CH3:27])[CH3:26])[N:21]=[CH:22][C:17]=4[S:16][C:15]3=[O:28])[O:13][CH:8]2[CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:38]([O:37][C:35](=[O:36])[O:29][CH:11]1[CH:9]2[O:10][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:30]([CH3:33])([CH3:32])[CH3:31])[O:6][CH2:7][CH:8]2[O:13][CH:12]1[N:14]1[C:18]2[N:19]=[C:20]([N:23]=[CH:24][N:25]([CH3:27])[CH3:26])[N:21]=[CH:22][C:17]=2[S:16][C:15]1=[O:28])([CH3:40])[CH3:39]
Reactant: CC(C)OC(=O)Cl
Reactant: CN(C)C=Nc1ncc2sc(=O)n(C3OC4CO[Si](C(C)(C)C)(C(C)(C)C)OC4C3O)c2n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)OC(=O)OC1C2O[Si](C(C)(C)C)(C(C)(C)C)OCC2OC1n1c(=O)sc2cnc(N=CN(C)C)nc21
Reaction time: 5 h
Yield: 50.9 %

Procedure:
N′-[3-(2,2-Di-tert-butyl-7-hydroxy-tetrahydro-furo[3,2-d][1,3,2]dioxasilin-6-yl)-2-oxo-2,3-dihydro-thiazolo[4,5-d]pyrimidin-5-yl]-N,N-dimethyl-formamidine (1.83 g, 3.68 mmol) was dissolved in DCM (18.4 mL) and DMAP (450 mg, 3.68 mmol) was added. Isopropyl chloroformate (7.37 mL, 1 M in toluene, 7.37 mmol) was added over 12 h via syringe pump. The reaction was stirred an additional 5 h following addition then concentrated in vacuo. The residue was submitted to flash chromatography (50-100% EtOAc-Hex) yielding 1.09 g (51%) of 14 as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.61 (1H, s), 8.60 (1H, s), 6.27 (1H, t, J=7.4 Hz), 6.10 (1H, d, J=7.9 Hz), 5.06 (1H, t, J=6.9 Hz), 4.61 (1H, septet, J=6.1 Hz), 4.49 (1H, t, J=10.5 Hz), 4.30-4.36 (1H, m), 3.93 (1H, dd, J1=5.3 Hz, J2=10.8 Hz), 3.14 (3H, s), 3.03 (3H, s), 1.14 (3H, d, J=6.2 Hz), 1.04 (3H, d, J=5.4 Hz), 1.04 (3H, s), 1.00-1.03 (18H, m)8.61 (1H, s), 8.60 (1H, s), 6.27 (1H, t, J=7.4 Hz), 6.10 (1H, d, J=7.9 Hz), 5.06 (1H, t, J=6.9 Hz), 4.61 (1H, septet, J=6.1 Hz), 4.49 (1H, t, J=10.5 Hz), 4.30-4.36 (1H, m), 3.93 (1H, dd, J1=5.3 Hz, J2=10.8 Hz), 3.14 (3H, s), 3.03 (3H, s), 1.14 (3H, d, J=6.2 Hz), 1.04 (3H, d, J=5.4 Hz), 1.04 (3H, s), 1.00-1.03 (18H, m). [M+H]+ @ m/z 583.0.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([N:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1)[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]([N:18]1[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]1)[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(COCc2ccccc2)c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(C(COCc2ccccc2)N2CCNCC2)cc1
Yield: 92.9 %

Procedure:
In the same way as that described in Example 8, Step 4 using 1-[2-benzyloxy-1-(4-fluorophenyl)ethyl]-4-(tert-butyloxycarbonyl)piperazine (1.58 g, 3.8 mmol), trifluoroacetic acid (5 mL) and CH2Cl2 (50 mL). The piperazine (1.11 g, 92%) was isolated as a colourless oil. 1H NMR (250 MHz, CDCl3) δ2.36-2.57 (4H, m), 2.84-2.89 (4H, m), 3.49-3.54 (1H, m), 3.65 (1H, dd, J=9.9 and 5.4 Hz), 3.79 (1H, dd, J=9.9 and 5.8 Hz), 4.47 (2H, s), 6.99 (1H, dd, JHA-HB =8.7 Hz and JHA-F =8.7 Hz), 7.20-7.35 (7H, m). MS (ES+) (315, M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O)[CH3:24]>>[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8])[CH3:24]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: CCOc1ccccc1B(O)O
Product: CCOc1ccccc1-c1cc(-c2cnc3c(F)c(C(C)(C)O)ccn23)ccc1F
Yield: 5 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 2-ethoxybenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(2′-ethoxy-2-fluorobiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (6 mg, 5%): m/z (ES+) 409 [MH+].
Reaction SMILES: [CH3:1][C:2]1([C:10]([OH:12])=[O:11])[NH:6][CH:5]([C:7]([OH:9])=[O:8])[CH2:4][S:3]1.N[CH:14]([C:17](O)=[O:18])CS>>[C:17]([N:6]1[CH:5]([C:7]([OH:9])=[O:8])[CH2:4][S:3][C:2]1([CH3:1])[C:10]([OH:12])=[O:11])(=[O:18])[CH3:14]
Reactant: CC1(C(=O)O)NC(C(=O)O)CS1
Reactant: NC(CS)C(=O)O
Product: CC(=O)N1C(C(=O)O)CSC1(C)C(=O)O
Yield: 44 %

Procedure:
By an operation similar to that in Synthetic Example 16 and using 2-methylthiazolidine-2,4-dicarboxylic acid synthesized from DL-cysteine by a method similar to that in Reference Example 1, N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid (cis form) was obtained as an amorphous substance (yield 44%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:41])[CH2:37][C:38]([NH2:40])=[O:39])=[CH:31][CH:30]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[C:38]([CH2:37][N:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=3[F:22])=[CH:14][CH:15]=2)=[O:5])=[N:34][CH:33]=1)[CH3:41])(=[O:39])[NH2:40]
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: CN(CC(N)=O)Cc1ccc(N)nc1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN(C)CC(N)=O)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 22 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 2-[(6-amino-pyridin-3-ylmethyl)-methyl-amino]-acetamide (Step 118.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 22 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 523.1 [M+H]+; tR=3.53 min (System 1); TLC: Rf=0.16 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)=[CH:9][C:10]=2[Cl:12])[CH:5]=[CH:4][C:3]=1[OH:21].B(Br)(Br)Br>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)=[CH:9][C:10]=2[Cl:12])[CH:5]=[CH:4][C:3]=1[OH:21]
Reactant: COc1ccc(-c2cc(Cl)c3c(Cl)c(O)ccc3c2)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2cc(Cl)c3c(Cl)c(O)ccc3c2)cc1

Procedure:
The title compound was prepared by reacting 1,8-dichloro-6-(4-methoxyphenyl)-2-naphthol (0.12 g, 0.38 mmol) with boron tribromide (0.75 mL of 1N solution, 0.75 mmol) according to method D to yield 0.10 (86%) of which was further purified by reverse phase preparative HPLC to yield the title compound as a white solid: mp 172–174° C. (dec.); 1H NMR (DMSO-d6): δ 6.89 (2H, d, J=8.54 Hz), 7.36 (1H, d, J=8.90 Hz), 7.65 (2H, d, J=8.56 Hz), 7.88–7.91 (2H, m), 8.10 (1H, d, J=1.63 Hz), 9.69 (1H, s), 10.64 (1H, s); MS (ESI m/z 303/305/307 (M−H)−. Anal. for C16H10Cl2O2.0.25 H2O Calc'd: C,62.98 H, 3.30 Found: C,61.80 H, 3.08
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH2:23][CH3:24])[NH:10][C:11](=[O:14])[C:12]=1[NH2:13].[N:25]#[C:26]Br.O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[CH2:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:9]1[N:8]=[C:7]2[C:12](=[N:13][C:26]([NH2:25])=[N:6]2)[C:11](=[O:14])[N:10]=1)[CH2:23][CH3:24]
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCOc1ccccc1C1=NC(=O)C2=NC(N)=NC2=N1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A partial solution of 4,5-diamino-2-(2-propoxyphenyl)-pyrimidin-6-one sulphate (1.1 g), cyanogen bromide (0.33 g), and sodium acetate trihydrate (0.42 g) in 50% aqueous ethanol (44 ml) was stirred at room temperature for 2 hours then allowed to stand overnight. The stirred mixture was then heated in a water bath (temperature 65° C.) for 3 hours, extra cyanogen bromide (0.05 g) added, and the mixture heated for a further 2 hours. The suspension was subjected to partial evaporation under reduced pressure then ammonium hydroxide was added to pH 5. The crude product was collected by filtration and recrystallised from acetonitrile to give the pure title compound, 0.6 g, m.p. 322°-335° C. dec. (after melting ca. 200° C.).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[N:21][C:22]=3[NH2:24])[N:17]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:24][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:17]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:16]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[C:23]=12
Reactant: Nc1ncnc2c1c(-c1ccc(OCc3ccccc3)cc1)nn2C1CCCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ncnc2c1c(-c1ccc(O)cc1)nn2C1CCCC1
Temperature: 80 °C
Yield: 99.8 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.47 g, 6.41 mmol, 1 equiv), Pd black (0.341 g, 3.20 mmol, 0.5 equiv), and ammonium formate (2.02 g, 32 mmol, 5 equiv) in ethanol (50 mL) was heated at 80° C. for 4 h. The reaction mixture was allowed to cool to ambient temperature and the resulting solids were removed by filtration through a pad of Celite with the aid of EtOH (300 mL). The filtrate was concentrated to give a pale yellow solid which was purified by washing with CH2Cl2 (200 mL) to afford 4-(4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol as a white solid (1.89 g, 6.4 mmol): 1H NMR (d6 DMSO, 400 MHz): δ H 8.22 (1H, s), 7.45 (2H, d, J=8.5 Hz), 6.92 (2H, d, J=8.5 Hz), 5.17-5.24 (1H, m), 2.01-2.10 (4H, m), 1.87-1.90 (2H, m), 1.67-1.70 (2H, m). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 13.13 min. MS: MH+ 296.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=1.[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17].C(Br)C>>[CH2:16]([O:15][P:14]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=1)([O:18][CH2:19][CH3:20])=[O:21])[CH3:17]
Reactant: CCOP(OCC)OCC
Reactant: BrCc1cc(-c2ccccc2)no1
Solvent: CCBr
Product: CCOP(=O)(Cc1cc(-c2ccccc2)no1)OCC

Procedure:
5-Bromomethyl-3-phenylisoxazole (7.14 g, 30 mmol) and triethyl phosphite (10.4 ml, 60 mmol) were heated at 150° C. until no more ethyl bromide distilled, then the temperature maintained for a further 1 h. The mixture was then distilled under reduced pressure to give 5-diethylphosphonomethyl-3-phenylisoxazole bp 190°-192° C. at 0.5 mm Hg (8.15 g, 27.6 mmol, 92%); νmax (film) 2980, 2900, 1605, 1580, 1465, 1440, 1410, 1250, 1160, 1020, 970, 770, 690, 670 cm-1 ; δH (CDCl3) 1.30 (6H, t, J 7 Hz, OCH2CH3), 3.45 (1H, d, JH-P 22 Hz, CH2 -P), 4.10 (4H, m, OCH2CH3), 6.55 (1H, d, J 3 Hz, CH-4), 7.40 (3H, m, Ph), 7.65 (2H, m, Ph); δC (CDCl3) 16.3, 16.4 (OCH2CH3), 24.7, 26.9 (CH2 -P), 62.8, 62.9 (OCH2CH3), 101.5, 101.6 (C-4), 126.8 128.9, 130.0 (Ph), 162.8 (C-3), 164.3, 164.4 (C-2).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[CH:3]=1.C(B(CC)[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)C.CN(C=O)C>O>[I:8][C:4]1[CH:3]=[C:2]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Ic1cccc(I)c1
Reactant: CCB(CC)c1cccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Ic1cccc(-c2cccnc2)c1

Procedure:
A solution of 1,3-diiodobenzene (1.10 g, 3.3 mmol), 3-(diethylboryl)pyridine (0.48 g, 3.3 mmol), tetrakis(triphenlyphosphine)palladium(0) (0.010 g, 0.0086 mmol) potassium carbonate (0.922 g, 6.64 mmol), in mixed solvent of 3 mL DMF and 1 mL water, was heated at 150° C. for 5 minutes under microwave irradiation. The reaction mixture was quenched with H2O (30 mL), then extracted with EtOAc (3×30 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude purified by liquid chromatography on silica gel using an ISCO single channel system (Hexane/EtOAc=9/1 to 1/9) to afford 3-(3-iodophenyl)pyridine as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:20])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:26](Cl)([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[N:11]([CH3:20])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(C(=O)OCc2ccccc2)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4,5-di-(4-chlorophenyl)-1-methylimidazole (0.25 gm, 0.825 mmol) from Step B in THF (5 mL) cooled to −70° C. in a dry ice/acetone bath was added via syringe n-butyl lithium (1.6 N in hexanes, 0.62 mL, 1.0 mmol). The reaction was stirred at −70° C. for 30 min and then a solution of CBZ-Cl (0.42 mL, 1.65 mmol) in THF (2 mL) was added rapidly. The reaction was warmed to rt over 1 hr. The reaction was poured into an aq. sodium bicarbonate solution and then extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by flash chromatography (15% ethyl acetate in hexanes) to provide the title compound as a white solid. HPLC/MS: 437 (M+1), 439 (M+3); Rt=4.37 min.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:13][C:12]3[C:11]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[C:10]([CH3:21])[CH:9]=[C:8]([CH3:22])[C:7]=3[C:5]=2[N:6]=1.[C:23]1([CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:30][CH2:31]I)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH:29]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:30][CH2:31][S:1][C:2]2[S:3][C:4]3[CH2:13][C:12]4[C:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[C:10]([CH3:21])[CH:9]=[C:8]([CH3:22])[C:7]=4[C:5]=3[N:6]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ICCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1c(C)cc(C)c2c1Cc1sc(S)nc1-2
Product: Cc1cc(C)c2c(c1OCC(=O)O)Cc1sc(SCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 55 %

Procedure:
Using ethyl [(2-mercapto-4,6-dimethyl-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and 3,3-diphenylpropyl iodide, the procedure of Example 21 was otherwise repeated to synthesize the title compound. Yield 55%.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:36][CH2:35][C:12]2([C:16](=[O:17])[N:15]([C:18]3[CH:23]=[N:22][C:21]([N:24]4[CH2:28][CH2:27][C@H:26]([N:29]5[CH2:33][CH2:32][CH2:31][C@@H:30]5[CH3:34])[CH2:25]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[CH3:34][C@H:30]1[CH2:31][CH2:32][CH2:33][N:29]1[C@H:26]1[CH2:27][CH2:28][N:24]([C:21]2[N:22]=[CH:23][C:18]([N:15]3[CH2:14][CH2:13][C:12]4([CH2:35][CH2:36][NH:9][CH2:10][CH2:11]4)[C:16]3=[O:17])=[N:19][CH:20]=2)[CH2:25]1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2cnc(N3CCC4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)cn2)C1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CCCN1[C@H]1CCN(c2cnc(N3CCC4(CCNCC4)C3=O)cn2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 123.2 %

Procedure:
Hydrochloric acid in dioxane (0.5 mL) was added to 2-[5-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyrazin-2-yl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (0.0185 g, 0.038 mmol) and stirred at room temperature for 3 hours. Reaction mixture was then concentrated under vacuum to afford 0.018 g (96%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][NH:3]1.CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.CS(O[CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54]/[C:53]/1=[CH:58]\[C:59]([O:61][CH3:62])=[O:60])(=O)=O>CN(C)C=O>[CH3:62][O:61][C:59](/[CH:58]=[C:53]1/[CH:52]([N:3]2[C:2](=[O:1])[CH:7]=[CH:6][C:5]([C:8]3[C:9]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)=[N:4]2)[CH2:57][CH2:56][CH2:55][CH2:54]/1)=[O:60]
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Reactant: COC(=O)/C=C1\CCCCC1OS(C)(=O)=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C1\CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a solution of 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (271 mg) in N,N-dimethylformamide (6 ml) was added potassium tert-butoxide (111 mg) and 18-crown-6 (24.8 mg) at 5° C. To this solution was added a solution of (E)-1-methylsulfonyloxy-2-methoxycarbonylmethylenecyclohexane (467 mg) in N,N-dimethylformamide (2 ml) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour and then heated at 110 to 125° C. for 7 hours. The reaction mixture was poured into ice water (30 ml) and extracted with ethyl acetate (20 ml×2). The combined extracts were washed with water (20 ml) and brine (20 ml), dried over anhydrous magnesium sulfate, and evaporated in vacuo. The crude material was purified by column chromatography on SiO2 using a mixture of dichloromethane and ethyl acetate (20:1) as an eluant to give colorless crystals of (E)-3-[2-(2-methoxycarbonylmethylenecyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (191.4 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH:20][C:21]([C:23]3([NH2:27])[CH2:26][O:25][CH2:24]3)=[O:22])[CH3:19])=[C:14]([F:28])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4].[F:29][C:30]([F:36])([F:35])[CH2:31][C:32](O)=[O:33]>>[CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH:20][C:21]([C:23]3([NH:27][C:32](=[O:33])[CH2:31][C:30]([F:36])([F:35])[F:29])[CH2:24][O:25][CH2:26]3)=[O:22])[CH3:19])=[C:14]([F:28])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4]
Reactant: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(N)COC2)c(F)c1
Reactant: O=C(O)CC(F)(F)F
Product: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(NC(=O)CC(F)(F)F)COC2)c(F)c1

Procedure:
The title compound was prepared in analogy to example 1 using intermediate 4 instead of intermediate 1 and 3,3,3-trifluoropropionic acid instead of 3-fluoro-5-(trifluoromethyl)benzoic acid and was obtained as white solid. 515.2 [M−H]−.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)=[O:9])[CH:4]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(F)cc1)c1cccnc1
Reaction time: 8 h

Procedure:
To a stirred and cooled (ice-bath) mixture of 88 parts of nicotinoyl chloride hydrochloride in 400 parts of fluorobenzene are added portionwise 165 parts of aluminium chloride at a temperature between 5° and 10° C. Upon completion, the cooling-bath is removed and the mixture is stirred and refluxed for 6 hours. The reaction mixture is allowed to stand overnight at room temperature and is then poured onto a mixture of crushed ice and hydrochloric acid. After cooling, the layers are separated. The aqueous phase is extracted three times with ether. The combined organic layers are discarded and the aqueous phase is alkalized with a 40% sodium hydroxide solution. The product is extracted several times with chloroform. The extracts are washed twice with water, dried and evaporated. The residue is dissolved in ether. The solution is filtered from insoluble matter and the filtrate is allowed to crystallize upon dilution with petroleumether at -20° C, yielding p-fluorophenyl 3-pyridyl ketone; mp. 74.5° C.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].N1C=CN=C1.[CH2:10]([CH:13]1[CH2:18][CH2:17][CH:16]([CH:19]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[C:29]([F:31])[C:28]([NH2:32])=[C:27]([F:33])[CH:26]=3)[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)[CH2:11][CH3:12]>ClCCl>[F:31][C:29]1[CH:30]=[C:25]([CH:22]2[CH2:21][CH2:20][CH:19]([CH:16]3[CH2:17][CH2:18][CH:13]([CH2:10][CH2:11][CH3:12])[CH2:14][CH2:15]3)[CH2:24][CH2:23]2)[CH:26]=[C:27]([F:33])[C:28]=1[N:32]=[C:1]=[S:2]
Reactant: CCCC1CCC(C2CCC(c3cc(F)c(N)c(F)c3)CC2)CC1
Reactant: S=C(Cl)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCCC1CCC(C2CCC(c3cc(F)c(N=C=S)c(F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.9 ml of thiophosgene are added dropwise over the course of 30 minutes at 15-25° C. to 18.4 g of imidazole in 150 ml of dichloromethane, and the mixture is stirred at RT for a further 2 hours. 15.8 g of 4-(4′-n-propylbicyclohexyl-4-yl)-2,6-difluorophenylamine (prepared as described in Examples 1a-1e) are subsequently added, and the mixture is stirred at RT for 24 hours. Conventional work-up gives 4′-(3,5-difluoro-4-isothiocyanatophenyl)-4-n-propylbicyclohexyl having the following properties: C 65 N 225.5 1; Δε 16.0; Δn 0.1990.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH:12]([CH3:14])[NH:11][CH:10]([CH3:15])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH:12]([CH3:14])[N:11]([S:24]([C:19]3[CH:20]=[CH:21][C:22]([Cl:23])=[C:17]([Cl:16])[CH:18]=3)(=[O:26])=[O:25])[CH:10]([CH3:15])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CC1CN(c2ncccc2Cl)CC(C)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1CN(c2ncccc2Cl)CC(C)N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
1-(3-chloropyridin-2-yl)-3,5-dimethylpiperazine (370 mg, 1.644 mmol) was dissolved in anhydrous dichloromethane (6 mL) added with 3,4-dichlorobenzene sulfonyl chloride (509 mg, 1.97 mmol) and diisopropylethylamine (0.72 mL, 4.11 mmol). The reaction mixture thus prepared was stirred overnight at room temperature. The reaction was complete as determined by TLC. It was purified via flush column chromatography to afford 4-(3-chloropyridin-2-yl)-1-[(3,4-dichlorophenyl)sulfonyl]-2,6-dimethylpiperazin in 13% yield (110 mg) as a sticky solid.