Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@:14]([F:27])([C:16]3[N:20]([CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([O:28][Si](C(C)(C)C)(C)C)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CCOCC.CO>[CH2:1]([N:8]1[C@@H:13]2[C@:14]([F:27])([C:16]3[N:20]([CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([OH:28])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOCn1nnnc1[C@]1(F)C[C@@]2(c3ccccc3)[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1N2Cc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COCCOCn1nnnc1[C@]1(F)C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.4 %

Procedure:
A mixture of (1R*,2R*,5S*,6S*)-8-benzyl-2-(tert-butyldimethylsilyloxy)-6-fluoro-6-[1-(2-methoxyethoxymethyl)-1H-tetrazol-5-yl]-1-phenyl-8-azabicyclo[3.2.1]octane (Description 44a; 4.5 g, 7.7 mmol), 1 M solution of hydrogen chloride in ether (30 ml) and methanol (50 ml) was stirred at room temperature for 90 minutes. The reaction mixture was treated with saturated aqueous NaHCO, and extracted into ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 20-80%) to give the title compound (2.5 g, 70%).
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9]([N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].NN>C(O)C.O1CCCC1>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](N)C1
Reaction time: 8 h

Procedure:
To a mixture of (±)-cis-2-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-isoindole-1,3-dione (1.03 g, 2.98 mmol) (from Example 10b supra) in ethanol/tetrahydrofuran (2:1, 20 mL) was added anhydrous hydrazine (1.2 mL, 38.90 mmol) (Aldrich). After stirring overnight the reaction mixture was filtered. The solids were washed with diethyl ether (approx. 30 mL) and the combined filtrate was concentrated. The residue was treated with diethyl ether again (approx. 30 mL) and the resulting mixture was filtered again and concentrated to give (±)-cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamine as a colorless oil. (Yield 570 mg, 88%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][NH:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:32]=[CH:33][C:28]([C:26]([NH:25][CH3:24])=[O:27])=[CH:29][CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Product: CNC(=O)c1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 48 mg, 0.129 mmol) and 4-(N-methylaminocarbonyl)phenylboronic acid (ABCR, Karlsruhe, Germany, 27 mg, 0.153 mmol) to give the title compound as a white solid. (HPLC: tR 2.40 min (Method A); M+H=427 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.54-8.48 (m, 1H), 8.19-8.15 (m, 1H), 8.13-8.07 (m, 1H), 7.98-7.89 (m, 3H), 7.61-7.53 (m, 3H), 3.94 (s, 3H), 3.57 (s, 3H), 2.79 (d, 3H), 1.95 (s, 3H))
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([OH:4])[CH3:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:17][C:18]1[C:19]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([CH:35](OC)OC)[CH:29]=2)=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>C1(C)C=CC=CC=1>[Cl:17][C:18]1[C:19]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([CH:35]3[O:4][CH:2]([CH3:3])[CH2:1][O:5]3)[CH:29]=2)=[N:20][CH:21]=[C:22]([C:24]([F:26])([F:27])[F:25])[CH:23]=1
Reactant: COC(OC)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: CC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1COC(c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc2Cl)O1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
2.0 g of 1,2-propanediol and 100 mg of p-toluenesulfonic acid were added to 3.2 g of 3-chloro-2-(4-chloro-3-dimethoxymethylphenyl)-5-trifluoromethylpyridine in 100 ml of anhydrous toluene. The mixture was then refluxed for two hours and stirred at 23° C. for 16 hours. Extraction was carried out first with 50 ml of a 10% by weight sodium bicarbonate solution and then three times with 80 ml of water each time, after which the organic solution was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel with cyclohexane/ethyl acetate (10:1). Yield: 3.1 g (94%) of a colorless oil (1:1 mixture of diastereomers);
Reaction SMILES: [H-].[Na+].C(OP([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.O=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>C1COCC1>[CH2:15]([O:14][C:12](=[O:13])[C:11](=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)[CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h

Procedure:
A 100-mL 3-neck round-bottom flask was charged with anhydrous THF (20 mL) and 60% dispersion sodium hydride (0.574 g, 14.35 mmol) and placed under nitrogen atmosphere. At ambient temperature, ethyl 2-(diethoxyphosphoryl)propanoate (3.42 g, 14.35 mmol) was added to the suspension via syringe over a period of 5 min and the mixture stirred for 30 min. The resulting clear mixture was treated with a solution of tert-butyl 4-oxopiperidine-1-carboxylate (2.2 g, 11.04 mmol) in anhydrous THF (5 mL) and the reaction continued at ambient temperature for 1 h. At the conclusion of this period, the mixture was quenched with saturated NH4Cl solution and the mixture was then extracted with EtOAc (3×50 mL). The extract was washed with brine, dried (MgSO4) and concentrated to give the crude product. The crude product was purified by flash chromatography using an 80 g silica gel gradient elution from 20:1 Hex/EtOAc to 6:1 Hex/EtOAc. The fractions containing the product were pooled and concentrated on a rotary evaporator to give tert-butyl 4-(1-ethoxy-1-oxopropan-2-ylidene)piperidine-1-carboxylate as a colorless liquid. 1H-NMR (500 MHz, CDCl3) δ ppm 4.18 (2 H, q, J=7.15 Hz), 3.43 (4 H, dt, J=23.71, 5.88 Hz), 2.61 (2 H, t, J=5.77 Hz), 2.33 (2 H, t, J=5.77 Hz), 1.86 (3 H, s), 1.45 (9H, s), 1.26-1.31 (3H, m, J=7.15 Hz).
Reaction SMILES: C([S@@]([NH:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[F:17])[CH2:10][C@H:9]1[C:18]([O:20][C:21](C)(C)C)=[O:19])=O)(C)(C)C.Cl.CO>>[NH2:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[F:17])[CH2:10][C@H:9]1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CC(C)(C)OC(=O)[C@@H]1Cc2cccc(F)c2[C@H]1N[S@@](=O)C(C)(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1Cc2cccc(F)c2[C@H]1N
Reaction time: 1 h
Yield: 85 %

Procedure:
To 12 mg of tert-butyl (1S,2R)-1-{[(S)-tert-butylsulfinyl]amino}-7-fluoroindane-2-carboxylate (compound of Preparation Example 113a) was added 0.4 ml of a 10% hydrogen chloride/methanol solution, followed by stirring for 1 hour under ice-cooling. To the reaction mixture was added 1 ml of a 10% hydrogen chloride/methanol solution, followed by stirring at 50° C. for 6 hours. After leaving to be cooled, the solvent was evaporated under reduced pressure, and then to the obtained residue were added a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 6 mg of methyl (1S,2R)-1-amino-7-fluoroindane-2-carboxylate.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][CH2:10][OH:11])=[C:4]([O:12]C)[CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[F:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([OH:12])=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=1
Reactant: COc1cc(F)c(F)cc1CCO
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: OCCc1cc(F)c(F)cc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.7 %

Procedure:
To a solution of 2-(4,5-difluoro-2-methoxyphenyl)ethanol (800 mg, 4.25 mmol) in DCM (25 mL) at 0° C. was added 1M BBr3 (17.01 mL, 17.01 mmol) solution and the resulting mixture was allowed to warm to room temp and stir for 4 h. Then, water (dropwise) was added and after the bubbling stops mixture was diluted with DCM and washed with water, dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (5-70%, EtOAc/hexane) to afford 4,5-difluoro-2-(2-hydroxyethyl)phenol (450 mg, 2.58 mmol, 60.8% yield) as clear viscous oil. 1H NMR (500 MHz, CDCl3) δ 6.93-6.84 (m, 1H), 6.75 (dd, J=11.5, 7.1 Hz, 1H), 4.03-3.96 (m, 2H), 2.85 (t, J=5.2 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[C:26]1([C:32]2[O:33][C:34]([C:40](F)(F)F)=[C:35]([C:37](O)=[O:38])[N:36]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:37]([C:35]4[N:36]=[C:32]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[O:33][C:34]=4[CH3:40])=[O:38])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C)cn3)cc2C1=O
Yield: 43 %

Procedure:
The compound of example 654 was prepared analogous to the compound of example 640 by reaction of compound of example 392 with 2-phenyl-5-(trifluoromethyl)oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]12([S:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:14][C@H:15]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:16]1>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][N:17]2[CH2:18][CH2:19][CH:15]([NH:14][S@:11]([C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)=[O:12])[CH2:16]2)=[CH:23][CH:24]=1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: O=S(Cl)C12CC3CC(CC(C3)C1)C2
Product: O=[S@](NC1CCN(CCc2ccc(F)cc2)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
1-Adamantanesulfinyl chloride and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanesulfinamide.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].[NH2:21][NH2:22]>CO>[NH:21]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)(=[O:14])=[O:13])[NH2:22]
Reactant: COC(=O)c1ccc(F)c(S(=O)(=O)N2CCOCC2)c1
Reactant: NN
Solvent: CO
Product: COC(=O)c1ccc(NN)c(S(=O)(=O)N2CCOCC2)c1
Temperature: 65 °C
Yield: 64.1 %

Procedure:
Methyl 4-fluoro-3-(morpholinosulfonyl)benzoate (30 mg, 0.099 mmol) was added to hydrazine (4.44 mg, 0.138 mmol) in methanol (8 mL) and refluxed for 5 h at 65° C. The reaction was monitored by TLC. Upon completion of the reaction and cooling, the solvent was removed by vacuum, and the compound was purified by column chromatography affording the title compound (20 mg). 1H NMR (400 MHz, CD3OD): δ 8.15 (d, 1H, J=2.0 Hz), 8.03 (dd, 1H, J=2.4 & 9.2 Hz), 7.48 (d, 1H, J=9.2 Hz), 3.86 (s, 3H), 3.67 (m, 4H), 3.04 (m, 4H). ESI-MS: 316.1 [M+H]+.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[O:9]=[C:10]1[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=[C:12]([C:19]([F:22])([F:21])[F:20])[NH:11]1>C1(C)C=CC=CC=1>[CH3:3][N:4]([CH:6]=[N:18][C:16]([C:15]1[C:10](=[O:9])[NH:11][C:12]([C:19]([F:20])([F:22])[F:21])=[CH:13][CH:14]=1)=[O:17])[CH3:5]
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1ccc(C(F)(F)F)[nH]c1=O
Solvent: Cc1ccccc1
Product: CN(C)C=NC(=O)c1ccc(C(F)(F)F)[nH]c1=O

Procedure:
0.87 g (7.28 mmol) of N,N-dimethylformamide dimethyl acetal was added to 1.00 g (4.85 mmol) of 2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide in 5 ml of toluene, and the mixture was heated under reflux for 4 h. After cooling, the resulting precipitate was filtered off with suction and dried: 0.5 g (39% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@@H:12]3[O:32][C@H:31]([CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C@@H:22]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C@H:13]3[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1.C([Sn](CCCC)(CCCC)[C:47]1[S:48][CH:49]=[CH:50][N:51]=1)CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:47]3[S:48][CH:49]=[CH:50][N:51]=3)=[CH:9][N:8]([C@@H:12]3[O:32][C@H:31]([CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C@@H:22]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C@H:13]3[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(I)c3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(-c3nccs3)c3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 100 °C
Reaction time: 48 h
Yield: 88.6 %

Procedure:
An argon purged mixture of the compound 4 from Step 1 (544 mg, 0.74 mmol), 2-(tributylstannyl)thiazole (554 mg, 1.48 mmol) and PdCl2(PPh3)2 (22 mg, 0.03 mmol) in DMF (3 ml) was stirred at 100° C. for 48 h. Volatiles were evaporated under diminished pressure, the residue was co-evaporated with water (3×), twice with MeOH, twice with hexane and then co-evaporated with silica from hexane. Column chromatography on silica (hexanes then hexanes/AcOEt, 10:1→6:1) afforded title compound 5 as foam (454 mg, 89%). 1H NMR (500.0 MHz, CDCl3): −0.36, −0.10, 0.11, 0.13, 0.17 and 0.18 (6×s, 6×3H, CH3Si); 0.74, 0.95 and 0.99 (3×s, 3×9H, (CH3)C); 3.79 (dd, 1H, Jgem=11.4, J5′b,4′=2.7, H-5′b); 3.96 (dd, 1H, Jgem=11.4, J5′a,4′=3.2, H-5′a); 4.11 (ddd, 1H, J4′,5′=3.9, 2.7, J4′,3′=1.8, H-4′); 4.23 (dd, 1H, =4.7, J3′,4′=1.8, H-3′); 4.55 (dd, 1H, J2′,1′=6.9, J2′,3′=4.7, H-2′); 5.96 (bs, 1H, NHaHb); 6.31 (d, 1H, J1′,2′=6.9, H-1′); 7.21 (d, 1H, J5,4=3.4, H-5-thiazolyl); 7.72 (d, 1H, J4,5=3.4, H-4-thiazolyl); 7.74 (s, 1H, H-6); 8.26 (s, 1H, H-2); 9.79 (bs, 1H, NHaHb). 13C NMR (125.7 MHz, CDCl3): −5.35, −5.33, −5.19, −4.65, −4.61 and −4.47 (CH3Si); 17.82, 18.13 and 18.57 (C(CH3)3); 25.61, 25.86 and 26.15 ((CH3)3C); 63.37 (CH2-5′); 73.03 (CH-3′); 76.26 (CH-2′); 86.28 (CH-4′); 87.01 (CH-1′); 100.52 (C-4a); 112.19 (C-5); 116.76 (CH-5-thiazolyl); 122.24 (CH-6); 141.71 (CH-4-thiazolyl); 151.57 (C-7a); 151.94 (CH-2); 157.52 (C-4); 163.53 (C-2-thiazolyl). MS (ESI) m/z 692 (M+H), 714 (M+Na). HRMS (ESI) for C32H58N5O4SSi3 [M+H] calcd: 692.3512. found: 692.3512.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[O:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34]2[NH:38][CH:37]=[N:36][N:35]=2)[CH2:29][CH2:28]1>>[O:18]=[C:17]1[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:10][CH:11]=2)=[C:22]([CH2:23][CH2:24][CH3:25])[N:35]2[N:36]=[CH:37][N:38]=[C:34]2[N:33]1[CH:30]1[CH2:29][CH2:28][O:27][CH2:32][CH2:31]1
Reactant: c1nnc(NC2CCOCC2)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2ncnn12
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 44.5 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1 g) and N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.25 g) was stirred at 250° C. for 15 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.3 g, 44%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:9]=1[CH3:10])=O.CC(C[AlH]CC(C)C)C>O1CCCC1.C(Cl)Cl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([C:8]2[C:9]([CH3:10])=[C:5]([CH2:3][OH:2])[S:6][CH:7]=2)(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: COC(=O)c1scc(S(=O)(=O)c2ccc(Cl)cc2)c1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(S(=O)(=O)c2ccc(Cl)cc2)csc1CO
Reaction time: 3 h
Yield: 86.7 %

Procedure:
A solution of 4-(4-Chloro-benzenesulfonyl)-3-methyl-thiophene-2-carboxylic acid methyl ester (992 mg, 3.00 mmol) in dry tetrahydrofuran (20 mL) and dry CH2Cl2 (10 mL) was cooled to 0° C. under N2, and DIBAL-H (9.0 mL, 9.0 mmol, 1 M solution in toluene) was added. After 3 hours, another portion of DIBAL-H (4.5 mL, 4.5 mmol) was added, and stirring was continued for another 2 hours. The reaction was quenched by the addition of saturated Rochelle salt solution (30 mL), and the mixture was stirred for 1 hour at room temperature. The phases were separated, the aqueous phase was extracted with EtOAc (2×50 mL) and the pooled organic layers were dried over Na2SO4 and evaporated in vacuo. The product was purified by chromatography on silica gel on a FlashMaster system using as eluent heptane/ethyl acetate (linear gradient elution from 1:0 to 6:4). Fractions containing the product were pooled and evaporated in vacuo to yield the desired compound (788 mg, 87%). LC-MS: (m/z)=285.2 (M−H2O+H+), calcd for C12H10ClO2S2: 284.9805, tR=2.45 min. 1H NMR (CDCl3): 1.84 (t, J=5.7 Hz, 1 H), 2.20 (s, 3 H), 4.73 (d, J=5.7 Hz, 2 H), 7.49 (d, J=8.5 Hz, 2 H), 7.84 (d, J=8.5 Hz, 2 H), 8.18 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][CH2:10][O-:11].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH2:10][CH3:9])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
5-Bromo-2-chloro-pyrimidine (5.0 g, 25 mmol) is dissolved in ethanol (55 mL) and sodium ethylate (1.81 g, 26.6 mmol) is added in portions. The reaction mixture is stirred for 15 hours at ambient temperature. When the reaction is complete, the solvent is evaporated off, water (200 mL) is added, and then the reaction mixture is extracted with dichloromethane (2×100 mL). The organic phase is dried over Na2SO4, and then evaporated to dryness to yield 5-bromo-2-ethoxy-pyrimidine.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([C:17]2[C:25]3[C:20](=[N:21][C:22]([C:29]4[CH:30]=[CH:31][C:32]([F:39])=[C:33]([CH:38]=4)[C:34]([O:36][CH3:37])=[O:35])=[CH:23][C:24]=3[C:26](=[O:28])[NH2:27])[N:19](C3CCCCO3)[N:18]=2)[CH:14]=[CH:15][CH:16]=1)=[O:10])C1C=CC=CC=1>S(=O)(=O)(O)O>[C:26]([C:24]1[CH:23]=[C:22]([C:29]2[CH:30]=[CH:31][C:32]([F:39])=[C:33]([C:34]([O:36][CH3:37])=[O:35])[CH:38]=2)[N:21]=[C:20]2[NH:19][N:18]=[C:17]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[C:9]([OH:10])=[O:8])[C:25]=12)(=[O:28])[NH2:27]
Reactant: COC(=O)c1cc(-c2cc(C(N)=O)c3c(-c4cccc(C(=O)OCc5ccccc5)c4)nn(C4CCCCO4)c3n2)ccc1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(-c2cc(C(N)=O)c3c(-c4cccc(C(=O)O)c4)n[nH]c3n2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 119.3 %

Procedure:
Methyl 5-[3-{3-[(benzyloxy)carbonyl]phenyl}-4-carbamoyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-2-fluorobenzoate (1.0 g/1.64 mmol) is dissolved in 6.8 mL of concentrated sulphuric acid. The solution is stirred at ambient temperature for 30 min and then run into ice-cold water and stirred for 30 min. The precipitate obtained is filtered off, washed with water and dissolved in EtOAc/MeTHF (50/50). The solution is washed with water and with a saturated aqueous solution of NaCl, dried over sodium sulphate, filtered and concentrated to dryness. The solid is taken up with a mixture of DCM/methanol, filtered and dried under vacuum to give 0.85 g of a beige powder (yield: 85%).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]#[N:21])=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>CCCCCC>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2([C:20]#[N:21])[CH2:6][CH2:5][CH2:4][CH2:3]2)=[CH:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#CCc1cn(Cc2ccccc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: N#CC1(c2cn(Cc3ccccc3)c3ccccc23)CCCC1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium hydride (60%, 2.26 g, 56 mmol) was added a solution of 1-benzyl-1H-indol-3-ylacetonitrile in DMSO-ether (10 MI: 80 mL) dropwise and the mixture was stirred for 5 hours at 20° C. Water and hexane were added. Solid was collected by filtration and washed with water and hexane to give 1-(1-benzyl-1H-indol-3-yl)cyclopentanecarbonitrile (5.3 g). MS (ES): 301 (MH+).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][S:29](=[O:32])[CH2:28][CH2:27]1>>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([N:26]3[CH2:31][CH2:30][S:29](=[O:32])[CH2:28][CH2:27]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1CCNCC1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(SCc3ccccc3)c2n1
Product: O=S1CCN(c2nc(N3CCOCC3)c3ncnc(SCc4ccccc4)c3n2)CC1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzylthio-2-chloro-4-morpholino-pyrimido[5,4-d]pyrimidine melting point: 159°-161° C.) and thiomorpholine-1-oxide.
Reaction SMILES: [C:1]([C:9]1[C:10]([NH:16][C:17](=[O:20])[CH2:18]Cl)=[CH:11][N:12]([CH3:15])[C:13]=1[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:21].[K+]>C(O)C>[C:1]([C:9]1[C:10]([NH:16][C:17](=[O:20])[CH2:18][I:21])=[CH:11][N:12]([CH3:15])[C:13]=1[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Cc1c(C(=O)c2ccccc2)c(NC(=O)CCl)cn1C
Agent: [K+]
Solvent: CCO
Product: Cc1c(C(=O)c2ccccc2)c(NC(=O)CI)cn1C

Procedure:
N-(4-benzoyl-1,5-dimethyl(1H)pyrrol-3-yl)2-chloroacetamide (0.741 mole) and potassium iodide (1.62 mole) were refluxed in ethanol (3400 ml) for 5 hours with stirring. The reaction mixture was then cooled, the inorganic salts were filtered off and the solvent was evaporated under vacuum. The obtained residue was purified by washing first with water and then with cold ethanol. M.p. 135°-137° C. Yield 87%.