Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[N:8]=[C:9]([C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:6]=2[S:5][C:4]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[CH3:32][S:33]([CH2:36][C:37](O)=[O:38])(=[O:35])=[O:34]>>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:9]2[N:10]=[C:11]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[C:6]3[S:5][C:4]([CH2:25][N:26]4[CH2:31][CH2:30][N:29]([C:37](=[O:38])[CH2:36][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:28][CH2:27]4)=[C:3]([CH3:2])[C:7]=3[N:8]=2)=[CH:23][N:22]=1
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Reactant: CS(=O)(=O)CC(=O)O
Agent: Cl
Product: Cc1c(CN2CCN(C(=O)CS(C)(=O)=O)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 57.6 %

Procedure:
Crude HCl salt of 5-(7-methyl-4-morpholino-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (74 mg) was reacted with 50 mg 2-(methylsulfonyl)acetic acid via General Procedure B to give 54.6 mg of 350 after reverse phase HPLC purification. MS (Q1) 547.2 (M)+.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[S:13][CH2:12][CH:11]([NH:20][CH:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:22])[C:10]1=[O:28])=[O:7])(C)(C)C.[ClH:29]>O1CCOCC1>[ClH:29].[C:6]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[S:13][CH2:12][CH:11]([NH:20][CH:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:22])[C:10]1=[O:28])([OH:7])=[O:5]
Reactant: CCOC(=O)C(C)NC1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C(C)NC1CSc2ccccc2N(CC(=O)O)C1=O

Procedure:
0.9 g of the 5-t-butoxycarbonylmethyl-3-(1-ethoxycarbonylethylamino)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one obtained in Example 11 was dissolved in 10 ml of a 6N solution of hydrogen chloride in dioxane and then reacted at room temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, ether was added thereto so as to cause crystallization. The precipitated crystals were purified by silica gel column chromatography using a 50:3:5 mixture of chloroform, methanol and acetic acid as the eluent. Thus, there was obtained 400 mg of the desired compound.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[C:23]([F:31])[CH:22]=2)[C:11]2[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=2[CH:9]=1)=O)(C)(C)C.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=1>>[CH3:39][C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:6]([C:8]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[C:23]([F:31])[CH:22]=3)[C:11]3[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=3[CH:9]=2)=[O:5])=[N:34][CH:35]=1
Reactant: Cc1ccc(N)nc1
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(S(C)(=O)=O)c(F)c2)c2c(c1)OC(C)(CO)C2
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)c(F)c3)c3c(c2)OC(C)(CO)C3)nc1

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 4-(3-fluoro-4-methanesulfonyl-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (232a) and 2-amino-5-picoline. 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1 H) 8.22 (d, J=8.59 Hz, 1 H) 8.12 (d, J=2.02 Hz, 1 H) 7.93 (t, J=8.46 Hz, 1 H) 7.58 (dd, J=8.34, 2.02 Hz, 1 H) 7.19 (d, J=1.26 Hz, 1 H) 7.13 (d, J=1.26 Hz, 1 H) 6.88 (dd, J=8.84, 2.27 Hz, 1 H) 6.82 (dd, J=10.86, 2.27 Hz, 1 H) 3.76 (d, J=5.56 Hz, 1 H) 3.64 (d, J=7.33 Hz, 1 H) 3.21 (s, 3 H) 2.81 (d, J=16.67 Hz, 1 H) 2.33 (s, 3 H) 1.97 (d, J=1.52 Hz, 1 H) 1.47 (s, 3 H); LCMS for C24H23FN2O6S m/z 487.00 (M+H+).
Reaction SMILES: C[O:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O.ClCCl>ClCCl>[C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:20]=[CH:21][C:3]([OH:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To a solution of the product from step 1 (0.5 g, 1.81 mmol) in dichloromethane (10 mL) at −78° C. was added boron tribromide (1.0 M solution in dichloromethane, 5.43 mL, 5.43 mmol) dropwise over 5-10 min. The subsequent mixture was stirred at −78° C. for an hour followed by ambient temperature for 1 h. After cooling the reaction mixture to 0° C., it was slowly added to cold water/dichloromethane (50 mL/50 mL). The organic portion was washed with water, brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using hexane/EtOAc (gradient system) to give the title compound (0.24 g, 47%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15].[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:10]1=[O:15]
Reactant: BrBr
Reactant: COc1ccccc1C1CCCCC1=O
Solvent: ClC(Cl)Cl
Product: COc1ccccc1C1CCCC(Br)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
2-(2-Methoxy-phenyl)-cyclohexanone (51 mg, 0.27 mmol) was dissolved in chloroform (1 mL). To this solution bromine (45.4 mg, 0.28 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 3 hours at room temperature and the solvent was removed under reduced pressure to yield the crude title compound (49 mg) which was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH:3]([OH:27])[CH2:4][NH:5][C:6]([C:8]1[C:13]([N:14]2C(C)=CC=C2C)=[CH:12][C:11]([C:21]([F:24])([F:23])[F:22])=[C:10]([O:25][CH3:26])[N:9]=1)=[O:7].Cl.NO>CCO.O>[F:29][C:2]([F:1])([F:28])[CH:3]([OH:27])[CH2:4][NH:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:21]([F:22])([F:24])[F:23])=[C:10]([O:25][CH3:26])[N:9]=1)=[O:7]
Reactant: COc1nc(C(=O)NCC(O)C(F)(F)F)c(-n2c(C)ccc2C)cc1C(F)(F)F
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Product: COc1nc(C(=O)NCC(O)C(F)(F)F)c(N)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
3-(2,5-Dimethyl-pyrrol-1-yl)-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-propyl)-amide (350 mg, 0.823 mmol) was dissolved in EtOH (14 ml) and water (7 ml). Hyroxylamine hydrochloride (572 mg, 8.23 mmol) was added followed by TEA (167 mg, 1.646 mmol) and the mixture was heated at reflux overnight. After cooling the RT, the mixture was purified by reverse phase chromatography eluting with MeOH; water (0.1% TFA) to afford the title compound as a pale yellow solid; LC-MS Rt=4.20 min[M+H]+ 348.2 (Method 10minLC_v002)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([CH2:20][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:15]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:27][C:28]1[CH:29]=[C:30]([N:35]=[C:36]=[O:37])[CH:31]=[CH:32][C:33]=1[F:34]>C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:29]=[C:30]([NH:35][C:36]([N:24]2[CH2:25][CH2:26][N:21]([CH2:20][C@@H:16]3[CH2:17][CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=4)[CH2:15]3)[CH2:22][CH2:23]2)=[O:37])[CH:31]=[CH:32][C:33]=1[F:34]
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Reactant: CS(=O)(=O)c1ccc(CCCN2CCC[C@@H](CN3CCNCC3)C2)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(CCCN2CCC[C@@H](CN3CCN(C(=O)Nc4ccc(F)c(Cl)c4)CC3)C2)cc1
Reaction time: 18 h
Yield: 49.3 %

Procedure:
To a solution of 1-[((3R)-1-{3-[4-(methylsulfonyl)phenyl]propyl}piperidin-3-yl)methyl]piperazine (215 mg, 0.57 mmol) in toluene (15 ml) was added 3-chloro-4-fluorophenyl isocyanate (107 mg, 0.62 mmol) and the solution stirred for 18 hours. A further portion of 3-chloro-4-fluorophenyl isocyanate (54.0 mg, 0.31 mmol) was added and stirred for 30 minutes. The reaction was evaporated to an oil and flash column chromatography (silica, CH2Cl2 to 10% MeOH/CH2Cl2) gave N-(3-chloro-4-fluorophenyl)-4-[((3R)-1-{3-[4-(methylsulfonyl)phenyl]propyl}piperidin-3-yl)methyl]piperazine-1-carboxamide as a white foam (155 mg, 50%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.N1C=CC=CC=1>C1COCC1.[Ti](Cl)(Cl)(Cl)Cl>[C:11]1(=[C:5]2[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C1CCCCC1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(=C2CCCCC2)C(=O)O1
Temperature: 0 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
A titanium tetrachloride solution (36.0 mL, 36.0 mmol) (1M solution in DCM) was added slowly to a cooled (0° C.) round bottom flask containing dry THF (75 mL). To the resulting yellow slurry was slowly added the 2,2-dimethyl-1,3-dioxane-4,6-dione (2.50 g, 17.0 mmol) (commercially available from Aldrich) and cyclohexanone (1.80 mL, 17.0 mmol) (commercially available from Aldrich) dissolved in THF (25 mL). Pyridine (7.0 mL, 87.0 mmol) was then added and the resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction was then quenched with water (200 mL) and the mixture was extracted with ether (2×300 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (2×150 mL) and brine (1×100 mL) and dried over magnesium sulfate. The filtrate was concentrated, and the residue was recrystallized using ether and hexanes to give 5-cyclohexylidene-2,2-dimethyl-1,3-dioxane-4,6-dione (1.86 g, 48% yield). MS ESI (neg.) m/e: 223.1 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:20][S:21][C:22]2[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14](C(=O)C)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>Cl>[CH3:1][C:2]1[C:3]([CH2:20][S:21][C:22]2[NH:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CC(=O)N1CCN(CCSc2ccnc(CSc3nc4ccccc4[nH]3)c2C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1c(SCCN2CCNCC2)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
2-((3-Methyl-4-(2-(4-acetylpiperazin-l-yl)ethylthio)-2-pyridyl)methylthio)-1H-benzimidazole (38 g) was dissolved in 6N hydrochloric acid and the mixture was stirred at 50° C. for 2 hours. After the completion of the reaction, the mixture was made alkaline with potassium carbonate and extracted with a mixed solvent of chloroform-methanol. The chloroform-methanol layer was dried over anhydrous magnesium sulfate, the solvent was distilled away and the residue was recrystallized from ethanol to give 2-((3-methyl-4-(2-(piperazin-l-yl)ethylthio)-2-pyridyl)methylthio)-1H-benzimidazole as crystals, melting point 166°-168° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CCO.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)c1ccc(N)cc1O
Temperature: 25 °C
Yield: 87.2 %

Procedure:
To a refluxing solution of 2-tert-butyl-5-nitrophenol (C-1-a) (196 mg, 1.0 mmol) in EtOH (10 mL) was added ammonium formate (200 mg, 3.1 mmol), followed by 140 mg of 10% Pd-C. The reaction mixture was refluxed for additional 30 min, cooled to room temperature and filtered through a plug of Celite. The filtrate was concentrated to dryness and purified by column chromatography (20-30% EtOAc-Hexane) to give 2-tert-butyl-5-aminophenol (C-1) (144 mg, 87%). 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 6.74 (d, J=8.3 Hz, 1H), 6.04 (d, J=2.3 Hz, 1H), 5.93 (dd, J=8.2, 2.3 Hz, 1H), 4.67 (s, 2H), 1.26 (s, 9H); HPLC ret. time 2.26 min, 10-99% CH3CN, 5 min run; ESI-MS 166.1 m/z (MH+).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][OH:20].N1C=CC=CC=1>C(O)C>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[N:19][OH:20])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C=O)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C=NO)cc1
Yield: 90 %

Procedure:
To a solution of 4-(tert-butyl-dimethyl-silanyloxymethyl)-benzonitrile (which may be prepared as described in Preparation of Intermediate 16; 15.21 g, 61.5 mmol) in toluene (100 mL) at 0° C. under argon was added dropwise di-isobutylaluminum hydride (1.0 M in toluene, 15 mL, 15 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h, after which it was cooled to 0° C. and charged with 100 mL of saturated aqueous Rochelle salt solution. The mixture was allowed to stir for 14 hours after which the mixture was extracted three times with EtOAc. The combined organic phases were washed with brine and dried over MgSO4. Filtration followed by removal of volatiles under reduced pressure gave 4-(tert-butyl-dimethyl-silanyloxymethyl)-benzaldehyde which was used without further purification. To a solution of the aldehyde in ethanol was added hydroxylamine hydrochloride (4.66 g, 67 mmol) and pyridine (5.4 mL, 67 mmol). The reaction mixture was stirred until no starting material was observed by TLC and then all volatiles were removed under reduced pressure. The resulting product was suspended in water and the aqueous phase was extracted three times with diethyl ether. The combined organic phases were washed with brine and dried over MgSO4. Filtration followed by removal of volatiles under reduced pressure gave 4-(tert-butyl-dimethyl-silanyloxymethyl)-benzaldehyde oxime (14.60 g, 90%) as a white solid. LRMS (ESI+): m/z [M+H]+ 266.1; 1H NMR (300 MHz, CDCl3) δ ppm 11.12 (s, 1H), 8.05 (s, 1H), 7.50 (d, 2H), 7.24 (d, 1H), 4.64 (s, 2H), 0.82 (s, 9H), 0.03 (s, 6H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[Cl:24][C:25]1[CH:30]=[C:29]([C:6]2[N:7]=[C:8]([N:10]3[C:14]4[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=4[N:12]=[CH:11]3)[S:9][C:5]=2[C:3]([OH:2])=[O:4])[CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)O)s3)c2cc1OC
Yield: 20.7 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3-chlorophenylboronic acid (23.5 mg, 0.15 mmol) gave 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (8.6 mg, 21%) as a white solid. MS m/z 416 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:23][C:24]1([F:28])[CH2:27][NH:26][CH2:25]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:23][C:24]1([F:28])[CH2:27][N:26]([C:19](=[O:21])[CH2:18][O:17][CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15]2)[CH2:25]1
Reactant: O=C(O)COC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(COC1CCN(C(=O)OCc2ccccc2)CC1)N1CC(F)(F)C1
Reaction time: 8 h
Yield: 65 %

Procedure:
2-(1-(Benzyloxycarbonyl)piperidin-4-yloxy)acetic acid (4.12 g, 14.05 mmol), 3,3-difluoroazetidine hydrochloride (1.4 g, 10.81 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (3.47 g, 10.81 mmol) were dissolved in DMF (50 mL), to this was added DIPEA (4.91 mL, 28.10 mmol) and the reaction was stirred overnight. The solvent was evaporated and the reaction mixture was quenched with 2M NaOH (50 mL), extracted with Et2O (3×50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford the desired material as a yellow gum (2.59 g, 65.1% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.67-1.49 (2H, m), 1.90-1.81 (2H, m), 3.26-3.19 (2H, m), 3.58-3.51 (1H, m), 3.84-3.78 (2H, m), 4.13 (2H, s), 4.36 (2H, t), 4.60 (2H, t), 5.12 (2H, s), 7.40-7.29 (5H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12.[ClH:25].FC1C=C(N[C:51]([NH:53][C:54](=[O:62])[CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[O:52])C=CC=1OC1C=CN=C2C=C(C(N3CCCC3)=O)SC=12>>[ClH:25].[ClH:25].[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:51]([NH:53][C:54](=[O:62])[CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)=[O:52])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1
Agent: Cl
Product: Cn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5)cc4F)c3s2)c1
Yield: 54 %

Procedure:
Starting from the compound 177 (scheme 35) and following the procedure described above for the synthesis of compound 305a, title compound 305c was obtained in 54% yield as a white solid. 1H NMR (d-DMSO) δ (ppm): 11.08 (s, 1H), 10.67 (s, 1H), 8.66 (d, 1H, J=6.2 Hz), 8.26 (s, 1H), 8.21 (s, 1H), 7.93 (s, 1H), 7.85(dd, 1H, J1=12.9 Hz, J2=2.5 Hz), 7.53(t, 1H, J=8.8 Hz), 7.65 (s, 1H), 7.48-7.45 (m, 1H), 7.35-7.30 (m, 4H), 7.28-7.24 (m, 1H), 6.94(d, 1H, J=6.1 Hz), 3.79 (s, 3H), 3.75 (s, 2H). MS (m/z): 502.1 (M+H) (found).
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH:10]=[CH:9]3)[CH2:6][CH2:5]1)[CH3:3].[OH-:24].[Na+].OO.O>CO>[O:24]1[C@H:14]2[C:13](=[O:23])[CH:12]=[C:11]3[C@:16]([CH3:17])([C@@H:15]12)[C@@H:18]1[C@H:8]([C@H:7]2[C@:21]([CH3:22])([CH2:20][CH2:19]1)[C@@H:4]([C@H:2]([OH:1])[CH3:3])[CH2:5][CH2:6]2)[CH:9]=[CH:10]3
Reactant: C[C@@H](O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@@H](O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 3 h
Yield: 60.4 %

Procedure:
A solution of 2.79 g (8.92 mmol) of (20R)-20-hydroxy-pregna-1,4,6-trien-3-one in 27 ml of methanol is treated with 0.83 ml of 10% methanolic sodium hydroxide, cooled to 0° C., and 5.4 ml of 30% hydrogen peroxide solution are added dropwise during 10 minutes with stirring. The solution is stirred at 0° C. for 45 minutes and then at room temperature for 3 hours. The suspension formed is treated with a total of 60 ml of water in portions, cooled to 0° C. and excess peroxide is destroyed by the addition of sodium hydrogen sulphite solution. The mixture is freed from methanol in a water-jet vacuum and the residue is extracted with ethyl acetate. The extract is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. Chromatography of the residue on 80 g of silica gel with hexane/ether (1:1) gives 1.77 g (60.4%) of uniform (20R)-1α,2α -epoxy-20-hydroxy-pregna-4,6-dien-3-one in the form of colourless crystals. The analytical sample is obtained by recrystallisation from methylene chloride/ether; melting point 206°-207° C., [α]D25 =+231.6° (c=0.5 in chloroform); UV (ethanol): λmax 292 nm (ε=21050).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[C:20]2[Cl:23])=[N:15]1)[CH2:11][C:12]#[CH:13]>>[Cl:23][C:20]1[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=1)=[N:15][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1)[CH:22]=2
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1cc2c(Cl)cccc2n1
Product: FCc1cccc(C#CCCn2cc3c(Cl)cccc3n2)n1
Yield: 70.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (51 mg, 0.27 mmol) and 2-but-3-ynyl-4-chloro-2H-indazole (50 mg, 0.24 mmol, Example 150(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 54 mg (0.17 mmol, 70%) of 4-chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])[CH:8]=1)[CH3:2].CN(C)C.[F:24][C:25]([F:42])([F:41])[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:38](Cl)=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:27]=1>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:38]([C:33]2[C:32]([C:29]3[CH:30]=[CH:31][C:26]([C:25]([F:24])([F:41])[F:42])=[CH:27][CH:28]=3)=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:39])=[C:9]([C:14](=[O:18])[N:15]([CH3:16])[CH3:17])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(N)c(C(=O)N(C)C)c1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CN(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(C(=O)N(C)C)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-(4-Amino-3-dimethylcarbamoylphenyl)propionic acid ethyl ester (1.52 g) was dissolved in ethyl acetate (10 mL), and trimethylamine (533 mg) was added thereto. After cooling down to 0° C., 4′-trifluoromethylbiphenyl-2-carbonyl chloride (synthesized from the corresponding carboxylic acid 0.529 g) was added thereto, and the mixture was stirred at room temperature overnight. After filtration of the insoluble material, the filtrate was concentrated and purified by column chromatography on silica gel (ethyl acetate:hexane=3:2, v/v) to give the title compound (0.843 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2F)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][CH3:32])(=[O:30])[CH2:28][SH:29].CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[CH3:32][O:31][C:27]([C:28]1[S:29][C:17]2[CH:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=[CH:21][C:16]=2[C:14]=1[CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)=[O:30]
Reactant: COC(=O)CS
Reactant: O=C(c1ccc(C(F)(F)F)cc1F)C1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1sc2cc(C(F)(F)F)ccc2c1C1CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a room temperature solution of (1-benzyl-piperidin-4-yl)-(2-fluoro-4-trifluoromethyl-phenyl)-methanone (7.5 g, 20.5 mmol), methyl thioglycolate (2.0 mL, 22.5 mmol), and DMF (100 mL) was added K2CO3 (5.65 g, 41.0 mmol). The reaction was stirred at 60° C. for 24 hours, cooled to room temperature and diluted with ethyl acetate (500 mL). The mixture was washed with water (2×300 mL) and brine (300 mL) successively, dried over magnesium sulfate, filtered, and the solvent removed to afford an oil. The oil was purified via chromatography (30% EtOAc in heptane) yielding 5.91 g (67%) as a solid.