Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[S:12][CH2:13][CH2:14][OH:15].O=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[F:11][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]([NH:1][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[C:3]([S:12][CH2:13][CH2:14][OH:15])[CH:4]=1
Reactant: Nc1cc([N+](=O)[O-])c(F)cc1SCCO
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])c(F)cc2SCCO)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a stirred solution of 2-(2-amino-5-fluoro-4-nitrophenylthio)ethanol (434 mg, 1.869 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (372 mg, 1.869 mmol) in dichloroethane (10 mL) and acetic acid (0.321 mL, 5.61 mmol) was added sodium triacetoxyborohydride (594 mg, 2.80 mmol). The resulting mixture was stirred at room temperature. After 1 hour, additional tert-butyl 4-oxopiperidine-1-carboxylate (372 mg, 1.869 mmol) was added, followed by additional sodium triacetoxyborohydride (594 mg, 2.80 mmol). After a further 3 hours, more tert-butyl 4-oxopiperidine-1-carboxylate (372 mg, 1.869 mmol) was added followed by more sodium triacetoxyborohydride (594 mg, 2.80 mmol). The reaction mixture was stirred overnight. The mixture was then quenched with 1 N NaOH (10 mL), water (20 mL), and saturated sodium carbonate (20 mL). The organic products were then extracted with dichloromethane (3×20 mL). The combined organics were dried, filtered, concentrated, and then chromatographed using 1:3 ethyl acetate:hexanes on silica gel to give the desired product (710 mg, 91%). 1H NMR (DMSO-d6) δ 7.45 (d, J=12.0 Hz, 1H), 7.23 (d, J=6.6 Hz, 1H), 5.08 (t, J=5.4 Hz, 1H), 5.02 (d, J=8.1 Hz, 1H), 3.96-3.84 (m, 2H), 3.69-3.55 (m, 5H), 2.99-2.83 (m, 2H), 1.92-1.83 (m, 2H), 1.45-1.18 (m, 11H); ESI-MS (m/z, %): 360 (100), 128 (30).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[C:5](=[CH:10][C:11]([CH2:14][N:15]2[C:23](=[O:24])C3C(=CC=CC=3)C2=O)=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[OH2:27].NN>CO>[CH3:1][O:2][C:3](=[O:26])[C:4]1[C:5](=[CH:10][C:11]([CH2:14][NH:15][C:23]([O:24][C:4]([CH3:5])([CH3:13])[CH3:3])=[O:27])=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1C(=O)OC
Reactant: O
Agent: NN
Solvent: CO
Product: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The compound (909 mg) obtained in Example 7-2 was suspended in methanol (22 ml). Hydrazine monohydrate (0.13 ml) was dropped in this suspension and the whole was refluxed under heating for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and then the residue was subjected to extraction with chloroform. The organic layer was washed with water and then with a saturated saline solution, followed by drying with anhydrous sodium sulfate. The residue obtained by distilling the solvent off was dissolved in DMF (15 ml) and added with triethylamine (0.54 ml) and di-t-butyldicarbonate (851 mg), followed by stirring at room temperature for 15 hours. After the solvent was distilled off, the residue was subjected to extraction with chloroform. The organic layer was washed with water and a saturated saline solution and then dried with anhydrous sodium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (779 mg) as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[C:12](=O)([O:16]CC)[O:13][CH2:14][CH3:15].[H-].[Na+].C(O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH2:10][C:12]([O:13][CH2:14][CH3:15])=[O:16]
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 56 %

Procedure:
To a solution of 2′,4′-Dichloroacetophenone (1.50 g, 7.93 mmol) in diethyl carbonate (24.0 mL, 198 mmol) at 0° C. was slowly added NaH (60% suspension in mineral oil, 0.657 g, 16.4 mmol). The mixture was then stirred at 80° C. for 90 minutes. The mixture was cooled to room temperature and then poured into an ice cold solution of 2.0 mL acetic acid in 56 mL water. The layers were separated and the aqueous phase was extracted with ether 3 times. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (1.16 g, 56%). LCMS: (FA) ES+, 262. 1H NMR (400 MHz, d1-chloroform) δ (2 sets of signals, keto and enol): 12.49 (s, 1H), 7.61-7.29 (m, 2 sets of 3H), 5.57 (s, 1H), 4.28 (q, J=7.28 Hz, 2H), 4.19 (q, J=7.28 Hz, 2H), 4.02 (s, 2H), 1.34 (t, J=7.03 Hz, 3H), 1.25 (t, J=7.03 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:14]=2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.Cl[C:39]1[O:40][C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=1>CN(C)C=O>[O:40]1[C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=[C:39]1[N:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22])[CH:14]=1)[CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=1
Reactant: COc1ccc(OCCCNCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Reactant: Clc1nc2ccccc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(OCCCN(Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)c2nc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-3-(4-methoxyphenoxy)propyl-3-tert-butyldimethylsilyloxybenzylamine (1.9 g, 5.0 mmol) was dissolved in N,N-dimethylformamide (3.0 mL). Subsequently, N,N-diisopropylethylamine (768 mg, 5.9 mmol) was added dropwise thereto. To the solution, 2-chlorobenzoxazole (912 mg, 5.94 mmol) was added. The mixture was stirred for 15 minutes at room temperature, and then stirred overnight at 70° C. The resultant mixture was extracted with ethyl acetate, followed by washing the organic layer with brine, drying over anhydrous sodium sulfate, and concentration under reduced pressure. The resultant mixture was subjected to purification by silica gel column chromatography (n-hexane/ethyl acetate=10/1), whereby the target compound was obtained (1.9 g, 73%).
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:34][C:35]#[N:36].O>C1COCC1>[OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:34][C:35]#[N:36])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: N#CCBr
Reactant: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(OCC#N)cc1
Yield: 52.6 %

Procedure:
To the phenol prepared in example 91 (608 mg, 1.5 mmol) in THF (20 mL) at 0° C. was addded sodium hydride (66 mg of a 60% dispersion in oil, 1.66 mmol). After ten minutes bromoacetonitrile (199 mg, 1.66 mmol) was added. The suspension was stirred at room temperature whereupon another portion of bromoacetonitrile (360 mg, 3 mmol) was added and stirring continued until the reaction was complete by TLC. Water (50 mL) was added to the reaction and the two layers separated. The aqueous phase was extracted with ether (2×40 mL) and the combined organic phases dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 10% MeOH/CHCl3 to provide 350 mg (53%) of product. Anal. Calcd for C27H30N3O3: C, 67.56; H 6.30; N, 8.75. Found: C, 67.39; H, 6.51; N, 8.49.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:16]=2)[CH2:9]1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:16]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nc(-c3ccccc3O)nc3ccccc23)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Oc1ccccc1-c1nc(N[C@@H]2CCCNC2)c2ccccc2n1
Reaction time: 24 h
Yield: 39.6 %

Procedure:
Crude (R)-3-[2-(2-hydroxy-phenyl)-quinazolin-4-yl-amino]-piperidine-1-carboxylic acid tert-butyl ester (˜1.0 mmol) was dissolved in methanol (4 mL) and 4M HCl in dioxane (10 mL) was added. After stirring for 24 hours the solution was concentrated and purified by ion exchange chromatography on SCX-2 Isolute acidic resin (5 g), eluting with methanol and then 1 M ammonia in methanol. Further purification by silica column chromatography, eluting with 20% methanol in dichloromethane, gave the title compound as a yellow solid (0.127 g, 40%).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]3[C:43](=[CH:44][CH:45]=2)[C:42](=[O:46])[N:41]([CH2:47][C:48]([F:51])([F:50])[F:49])[CH2:40]3)O1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:37]3[CH:38]=[C:39]4[C:43](=[CH:44][CH:45]=3)[C:42](=[O:46])[N:41]([CH2:47][C:48]([F:51])([F:50])[F:49])[CH2:40]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Reactant: CC1(C)OB(c2ccc3c(c2)CN(CC(F)(F)F)C3=O)OC1(C)C
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CN(CC(F)(F)F)C5=O)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethyl)isoindolin-1-one. LCMS (M+H)+=505.0.
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[N:21][NH:22]2)=[CH:18][CH:17]=1>>[NH:22]1[C:23]2[C:19](=[CH:18][CH:17]=[C:16]([NH:15][C:12](=[O:13])[CH2:11][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)[CH:24]=2)[CH:20]=[N:21]1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc2cn[nH]c2c1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1ccc2cn[nH]c2c1
Yield: 22 %

Procedure:
Prepared according to the method of Example 1b) from 1-adamantaneacetyl chloride (0.2 g) and 6-aminoindazole (0.13 g) to give the title compound as a white solid (0.064 g).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:9]=1[CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18]>O1CCCC1>[O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:9]=1[CH2:10][NH:11][C:17](=[O:18])[NH:16]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1c(N)cccc1Oc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1NCc2c(cccc2Oc2ccccc2)N1
Temperature: 25 °C

Procedure:
The product of example 2b above, 2-phenoxy-6-aminobenzyl amine, (0.22 g 1.03 mol) was dissolved in dry tetrahydrofuran (8 mL) and stirred under argon at room temperature. 1,1′-Carbonyldiimidazole (0.2 g, 1.24 mmol) dissolved in dry tetrahydrofuran (2 mL) was added and the mixture stirred at room temperature. The solvent was evaporated in vacuo, to give the crude product which was flash chromatographed on silica gel eluted wit 0–10% methanol in methylene chloride to give the title compound as a white amorphous solid. mp 278–280° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[CH:11][C:10]([C:20]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH:39]=3)=[CH:7][CH:6]=2)[N:9]=[C:10]([C:20]([OH:29])([C:21]([F:22])([F:24])[F:23])[C:25]([F:26])([F:27])[F:28])[CH:11]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: OC(c1cc(-c2ccccc2Cl)n(-c2ccc(Br)cc2)n1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3nc(C(O)(C(F)(F)F)C(F)(F)F)cc3-c3ccccc3Cl)cc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
A mixture of 2-[1-(4-bromophenyl)-5-(2-chlorophenyl)-1H-pyrazol-3-yl]-1,1,1,3,3,3-hexafluoro-propan-2-ol (100 mg, 020 mmol), 3-methanesulfonyl-phenylboronic acid (48 mg, 0.24 mmol), K2CO3 (83 mg, 0.60 mmol), Cl2Pd(dppf).DCM (16 mg, 10 mol %) and H2O (0.2 mL) in dioxane (2 mL) was sparged with Argon for 5 min and then heated at 80° C. as a sealed flask. After 3 h the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 0:100 to 50:50) to give the title compound (94 mg, 82%) as a white solid. 1H-NMR (DCM-d2): δ 8.12 (m, 1H), 7.92 (m, 1H), 7.87 (m, 1H), 7.67 (m, 1H), 7.61 (d, 2H), 7.33-7.47 (m, 6H), 6.74 (s, 1H), 5.25 (s, 1H), 3.07 (s, 3H); MS(ES): 575 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:19](=[O:26])[CH2:20][C:21](OCC)=[O:22])=[C:10]([C:15]([O:17][CH3:18])=[O:16])[N:11]2[CH3:14])=[CH:7][CH:6]=1>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[Cl:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:19](=[O:26])[CH2:20][C:21]([N:2]([CH3:3])[CH3:1])=[O:22])=[C:10]([C:15]([O:17][CH3:18])=[O:16])[N:11]2[CH3:14])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CC(=O)c1c(C(=O)OC)n(C)c2cc(Cl)ccc12
Reactant: CNC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1c(C(=O)CC(=O)N(C)C)c2ccc(Cl)cc2n1C
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A stream of gaseous dimethylamine is passed into a mixture of 15 g (44.4 mmol) of ethyl 3-[6-chloro-2-(methoxycarbonyl)-1-methyl-1H-indol-3-yl]-3-oxo-propanoate, obtained in step 2.1., and 0.2 g (1.63 mmol) of 4-(N,N-dimethyl)aminopyridine in 100 ml of toluene. Immediately a condenser, surmounted by a balloon flask, is fitted and the solution is stirred at 100° C. under low pressure for 20 h. The mixture is cooled to ambient temperature and concentrated under reduced pressure and the residue is chromatographed on a silica gel column (eluent: cyclohexane/dichloromethane: 50/50, then dichloromethane/ethyl acetate: 100/0 to 0/100). This gives 3.8 g of a yellow solid which is recrystallized from a dichloromethane/ethyl acetate mixture.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:18][CH:17]([CH:19]([OH:23])[CH:20]([CH3:22])[CH3:21])[CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:18][CH:17]([CH:19]([OH:23])[CH:20]([CH3:22])[CH3:21])[CH2:16]1
Reactant: CC(C)C(O)C1CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(O)C1CNC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 88.8 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of 3-(1-hydroxy-2-methylpropyl)azetidine-1-carboxylic acid tert-butyl ester (0.84 g, 3.66 mmol) in dichloromethane (12 mL). The resulting reaction mixture was stirred at RT for 40 min. The solvents were reduced in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The solvents were reduced in vacuo to afford 1-Azetidin-3-yl-2-methylpropan-1-ol as a white solid (0.42 g, 88%). 1H NMR (400 MHz, CDCl3): δ 3.63-3.62 (3 H, m), 3.53-3.51 (2 H, m), 2.88-2.87 (1 H, m), 1.62-1.62 (1 H, m), 0.89 (6 H, dd, J=6.84, 4.72 Hz)
Reaction SMILES: Br.[NH2:2][C:3]1[N:4]=[C:5]([Br:8])[S:6][CH:7]=1.N1C=CC=CC=1.[C:15]([O-])(=[O:17])[CH3:16].[Na+]>C(OC(=O)C)(=O)C>[C:15]([NH:2][C:3]1[N:4]=[C:5]([Br:8])[S:6][CH:7]=1)(=[O:17])[CH3:16]
Reactant: Nc1csc(Br)n1
Reactant: CC(=O)[O-]
Agent: Br
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1csc(Br)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4-Amino-2-bromothiazole hydrobromide (52 g, 0.2 m) was suspended in acetic anhydride (200 ml.) then treated dropwise with pyridine (100 ml.), maintaining the temperature at 0° C. by means of an ice bath. After the addition was complete, the reaction mixture was stirred for 2 hours at room temperature then poured onto 20% aqueous sodium acetate (2 1.) The solution was cooled, filtered and the precipitate washed with water (2 × 200 ml.). The product was air dried and recrystallised from acetone to give 4-acetamido-2-bromo-thiazole (35 g, 80%). m.p. 165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[Li].[CH:12]1([CH:17]=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1>[CH:12]1([CH:17]([C:7]2[C:2]([Cl:1])=[N:3][C:4]([S:9][CH3:10])=[N:5][C:6]=2[Cl:8])[OH:18])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=CC1CCCC1
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: [Li]
Solvent: C1CCOC1
Product: CSc1nc(Cl)c(C(O)C2CCCC2)c(Cl)n1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
4,6-Dichloro-2-methylsulfanyl-pyrimidine (8.0 g, 41.01 mmol) was dissolved in 500 mL dry THF and cooled to −78° C. Lithium diusopropylamine (36.9 mL of 2.0 M solution in hexanes) was added dropwise, and the reaction mixture was stirred for 20 minutes at −78° C. Cyclopentane-carboxaldehyde (8.05 g, 82.02 mmol was added, and the reaction mixture was stirred for 45 minutes at −78° C. The reaction was quenched by addition of saturated aqueous ammonium chloride. The aqueous mixture was extracted with ethyl acetate, and the combined organic layers were washed with water, washed with brine, dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (5% to 40% EtOAc in hexanes) to yield 9.76 g of cyclopentyl-(4,6-dichloro-2-methylsulfanyl-pyrimidin-5-yl)-methanol. Mass Spec. M+H=294.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[O:21][CH3:20])[N:11]=1
Reactant: CSc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2-(3-chlorobenzyl)-4-(methyl-sulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 470 mg (3.43 mmol) of 2-methoxybenzylamine to give 37 mg (28% of theory) of the title compound.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[NH:29][CH:26]([CH3:28])[CH3:27])=[O:13])[CH2:8]2
Reactant: CC(C)N
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: CC(C)Nc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccccc1

Procedure:
5-Isopropylamino-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and isopropylamine. Mass spectrum (ES) MH+=379.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1.[C:31]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([C:35]1[CH:40]=[CH:39][C:38]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:9][CH:10]=3)=[CH:27][CH:26]=2)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(Oc2ccc(Br)cc2)C2CCCCC2)cc1
Product: CC(C)(C)c1ccc(-c2ccc(OC(c3ccc(C(=O)NCCC(=O)O)cc3)C3CCCCC3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 128 starting from 3-{4-[(4-bromo-phenoxy)-cyclohexyl-methyl]-benzoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. MS: 512.3 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C-]#N.[Na+].[C:13]1(/[CH:19]=[CH:20]/[C:21](=[O:23])[CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][C:21](=[O:23])[CH3:22])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)/C=C/c1ccccc1
Reactant: O=Cc1cccc(F)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CC(C(=O)c1cccc(F)c1)c1ccccc1
Reaction time: 1.5 h
Yield: 56.8 %

Procedure:
A solution of 3-fluorobenzaldehyde (2.005 ml, 18.33 mmol) in DMF (5 ml) was added dropwise over the course of 0.5 hours to a mixture of sodium cyanide (0.450 g, 9.18 mmol) in DMF (20 ml) at 35° C. Stirring was then continued for 1.5 hours at 35° C. A solution of (E)-4-phenylbut-3-en-2-one (2.0 g, 13.68 mmol) in DMF (5 ml) was then slowly added dropwise over the course of 0.5 hours at 35° C. Stirring was continued for 3.5 hours at the same temperature. The reaction mixture was treated with twice its volume of water and extracted with DCM. The combined extracts were washed with water and brine, dried with Na2SO4, filtered and concentrated to give a liquid, purified by chromatography on silica gel using an automated Biotage system (EtOAc/Hex, 0-50%) to give 1-(3-fluorophenyl)-2-phenylpentane-1,4-dione (2.1 g, 7.77 mmol, 56.8% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.75-7.73 (m, 1H), 7.64-7.61 (m, 1H), 7.37-7.12 (m, 7H), 5.03 (dd, 1H), 3.61 (dd, 1H), 2.76 (dd, 1H), 2.19 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[NH:30]1[C:38]2[C:33](=[CH:34][C:35]([CH2:39]O)=[CH:36][CH:37]=2)[CH:32]=[CH:31]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:39][C:35]5[CH:34]=[C:33]6[C:38](=[CH:37][CH:36]=5)[NH:30][CH:31]=[CH:32]6)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: OCc1ccc2[nH]ccc2c1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1ccc2[nH]ccc2c1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(1H-indol-5-ylmethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and (1H-indol-5-yl)methanol following General Procedure J.