Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.[CH3:5][NH:6]C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl.[C-]#N.[K+]>CO.O>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]([C:5]#[N:6])([N:2]([CH3:3])[CH3:1])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(C)C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
500 ml (10 eq.) dimethylamine solution and 109.9 g (5 eq.) dimethylamine hydrochloride were added to a solution of 50 g (1 eq.) tert-butyloxycarbonyl-4-oxopiperidine in 100 ml methanol and the mixture was cooled to 5° C. 5 ml (0.1 eq.) hydrochloric acid were then added dropwise to the reaction mixture over a period of 10 min and the mixture was stirred for 60 min at room temperature. 48.9 g (3 eq.) potassium cyanide were added in portions to this reaction mixture and the mixture was stirred for 24 h at room temperature. Once the conversion was complete, 150 ml water were added to the reaction mixture and it was extracted 3 times with 100 ml ethyl acetate. The combined organic phases were dried with Na2SO4. Following removal of the solvent under reduced pressure, crude product was obtained which was recrystallized out of hexane. 57 g (90%) of product were obtained in the form of a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12]C)=[O:11])=[C:5]([CH3:17])[N:4]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:27]([NH:29][S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])=[O:28])=[CH:20][CH:19]=2)[N:3]=1.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([OH:12])=[O:11])=[C:5]([CH3:17])[N:4]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][NH:26][C:27]([NH:29][S:30]([C:33]3[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=3)(=[O:32])=[O:31])=[O:28])=[CH:22][CH:23]=2)[N:3]=1
Reactant: COC(=O)c1cccc(-c2c(C)nn(-c3ccc(CCNC(=O)NS(=O)(=O)c4ccc(C)cc4)cc3)c2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4cccc(C(=O)O)c4)c3C)cc2)cc1
Yield: 85.3 %

Procedure:
To a stirred solution of methyl 3-[3,5-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-pyrazol-4-yl]benzoate (step 5, 1.1 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was added 2 M NaOH aq. (10 mL), and then the resulting mixture was refluxed for 3 h. After removal of the solvent, the crude product was partitioned between saturated citric acid aq. (40 mL) and dichloromethane (50 mL). The organic layer was dried (Na2SO4). After removal of the solvent, the crude product was purified by TLC with dichloromethane/methanol (10:1) to afford 500 mg (87%) of the title compound as white solids: MS (ESI) m/z 533 [M+H]+, 531 [M−H]−, 1H-NMR (CDCl3) δ 8.05 (2H, s), 7.71-7.29 (6H, m), 3.55 (2H, t, J=6.1 Hz), 2.88 (2H, t, J=6.1 Hz), 2.42 (3H, s), 2.34 (3H, s), 2.27 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19](O)=[O:20])[CH:11]=[N:12][C:13]=2[O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[NH2:22][N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19]([NH:22][N:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[O:20])[CH:11]=[N:12][C:13]=2[O:14][CH:15]2[CH2:16][CH2:17][CH2:18]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1
Reactant: NN1CCC(O)CC1
Product: O=C(NN1CCC(O)CC1)c1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(cyclobutoxy)-3-pyridinecarboxylic acid and 1-amino-4-piperidinol (CAN 79414-82-7) as starting materials; MS (EI) 402.4 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]([CH2:39][CH2:40][CH2:41][CH3:42])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=2)=[C:8]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:43]([C:45]1[C:46](=[C:56]([C:59]#[N:60])[C:57]#[N:58])[O:47][C:48]([CH3:55])([C:51]([F:54])([F:53])[F:52])[C:49]=1[CH3:50])#[N:44]>C(O)C.O1CCCC1>[CH2:39]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[CH:50][C:49]3[C:48]([CH3:55])([C:51]([F:54])([F:52])[F:53])[O:47][C:46](=[C:56]([C:57]#[N:58])[C:59]#[N:60])[C:45]=3[C:43]#[N:44])=[CH:16][CH:15]=2)=[C:8]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:7]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)s2)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: 60 °C
Yield: 82.5 %

Procedure:
In 12 ml of ethanol and 4 ml of tetrahydrofuran were dissolved 500 mg (0.84 mmol) of 5-[2-[4-dibutylamino-2-(tert-butyldiphenylsiloxy)phenyl]vinyl]thiophene-2-carboaldehyde and 234 mg (0.92 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred with heating at 60° C. for 4.5 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography and washed with ethanol to give 576 mg of a dark reddish brown crystal (yield: 82.6%; mp: 186-187° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18](Br)[CH:19]=1>CS(C)=O>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:19]=1
Reactant: Brc1cncc(Br)c1
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(COc2cncc(Br)c2)cc1
Temperature: 90 °C
Reaction time: 1.25 h
Yield: 47.8 %

Procedure:
To a solution of 4-methoxybenzyl alcohol (1.73 g) in DMSO (10 mL) at room temperature was added sodium hydride (500 mg). The reaction mixture was stirred for 75 min and then a solution of 3,5-dibromopyridine (3.0 g) in DMSO (15 mL) was added. The reaction mixture was then heated at 90° C. for 2.5 h and then allowed to cool to room temperature, quenched with water (60 mL) and extracted into diethyl ether (3×60 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give 3-bromo-5-(4-methoxy-benzyloxy)-pyridine as a white solid (1.76 g).
Reaction SMILES: [F:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10](B4OC(C)(C)C(C)(C)O4)=[CH:11][CH:12]=3)[C@@:7]3([CH2:28][O:27][C:26]([NH2:29])=[N:25]3)[C:6]=2[CH:5]=[C:4]([O:30][CH3:31])[CH:3]=1.Cl[C:33]1[CH:38]=[N:37][CH:36]=[C:35]([C:39]#[C:40][CH3:41])[N:34]=1.C(=O)([O-])[O-].[K+].[K+]>O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([C:33]4[CH:38]=[N:37][CH:36]=[C:35]([C:39]#[C:40][CH3:41])[N:34]=4)=[CH:11][CH:12]=3)[C@@:7]3([CH2:28][O:27][C:26]([NH2:29])=[N:25]3)[C:6]=2[CH:5]=[C:4]([O:30][CH3:31])[CH:3]=1
Reactant: CC#Cc1cncc(Cl)n1
Reactant: COc1cc(F)c2c(c1)[C@]1(COC(N)=N1)c1cc(B3OC(C)(C)C(C)(C)O3)ccc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC#Cc1cncc(-c2ccc3c(c2)[C@@]2(COC(N)=N2)c2cc(OC)cc(F)c2O3)n1
Temperature: 110 °C
Yield: 30.6 %

Procedure:
Combined tetrakis(triphenylphosphine)palladium (54.2 mg, 0.047 mmol), (S)-4′-fluoro-2′-methoxy-7′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (200 mg, 0.47 mmol, prepared as described in Method BB40) and 2-chloro-6-(prop-1-ynyl)pyrazine (93 mg, 0.61 mmol) in a sealable tube and potassium carbonate (1.5 M) (1.6 mL, 2.35 mmol) was added. The tube was sealed and heated at 110° C. in a microwave for 8 min. The reaction solution was diluted with water and extractd by EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc again. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by chromatography through a gold Redi-Sep pre-packed silica gel column using a gradient of 25% to 50% to 80% DCM: MeOH: NH4OH (90:10:1) in 40% EtOAc in hexane to provide (S)-4′-fluoro-2′-methoxy-7′-(6-(prop-1-ynyl)pyrazin-2-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (60 mg, 0.144 mmol, 30.7% yield) as white solid.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]4[CH2:33][C:32](=O)[C:29]5([CH2:31][CH2:30]5)[CH2:28]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:35])[NH:6]2.Br[Zn][CH2:38][Zn]C[Zn]Br.C1OCCC1>O1CCCC1>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]4[CH2:33][C:32](=[CH2:38])[C:29]5([CH2:30][CH2:31]5)[CH2:28]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:35])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCCN1CC(=O)C2(CC2)C1
Reactant: Br[Zn]C[Zn]C[Zn]Br
Solvent: C1CCOC1
Product: C=C1CN(CCOc2cc3nccc(Oc4ccc5[nH]c(C)cc5c4F)c3cc2OC)CC12CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The above product from Example 2 (50 mg) was dissolved into anhydrous tetrahydrofuran (5 ml) and Nysted reagent (1.5 eq, 20% solution) was added to the reaction. The reaction was stirred at RT for two days and quenched with NH4Cl solution and extracted with EtOAc followed by washing with water, then brine and dried over Na2SO4 and purified with silica gel column to give the titled compound. Mass: (M+1), 474
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5]1.Cl[C:20]1[N:25]=[C:24]([C:26]2[C:27]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)=[N:28][N:29]([CH3:31])[CH:30]=2)[CH:23]=[CH:22][N:21]=1>C(O)CCC.O1CCOCC1>[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([NH:18][C:20]3[N:25]=[C:24]([C:26]4[C:27]([C:32]5[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=5)=[N:28][N:29]([CH3:31])[CH:30]=4)[CH:23]=[CH:22][N:21]=3)[CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5]1
Reactant: CN1CCC(COc2cccc(N)c2)CC1
Reactant: Cc1ccc(-c2nn(C)cc2-c2ccnc(Cl)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: Cc1ccc(-c2nn(C)cc2-c2ccnc(Nc3cccc(OCC4CCN(C)CC4)c3)n2)cc1

Procedure:
3-(1-Methyl-piperidin-4-ylmethoxy)-phenylamine dihydrochloride (206 mg, 0.7 mmol) is suspended in 1.5 mL n-butanol and 1.5 mL dioxane. 2-Chloro-4-(1-methyl-3-p-tolyl-1H-pyrazol-4-yl)-pyrimidine (100 mg, 0.35 mmol) is added and the mixture heated under reflux for 15 h. The yellow suspension is evaporated to dryness and the residue portioned between 8 mL 20% potassium carbonate solution and 10 mL dichloromethane. The organic phase is dried with sodium sulfate and evaporated. The crude product is purified by flash-chromatography on Silica Gel using dichloromethane/methanol 100:1.25→100:5 and then dichloromethane/methanol/conc. ammonia 100:5:0.25→100:10:0.25. The title compound is obtained as a foam.
Reaction SMILES: C(OC([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[N:24][C:25]([NH2:29])=[C:26]([OH:28])[CH:27]=3)=[CH:18][CH:17]=2)[CH2:10][CH:9]1[CH3:31])=O)(C)(C)C.Br[CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([F:44])([F:43])[F:42])[CH3:34].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[NH2:29][C:25]1[N:24]=[CH:23][C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:15]([N:11]3[CH2:10][CH:9]([CH3:31])[NH:8][CH:13]([CH3:14])[CH2:12]3)=[O:30])=[CH:21][CH:20]=2)=[CH:27][C:26]=1[O:28][CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([F:42])([F:43])[F:44])[CH3:34]
Reactant: CC(Br)c1ccccc1C(F)(F)F
Reactant: CC1CN(C(=O)c2ccc(-c3cnc(N)c(O)c3)cc2)CC(C)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CN(C(=O)c2ccc(-c3cnc(N)c(OC(C)c4ccccc4C(F)(F)F)c3)cc2)CC(C)N1
Temperature: 70 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
To a mixture of 4-[4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.12 mmol) and 1-(1-bromo-ethyl)-2-trifluoromethyl-benzene (32 mg, 0.12 mmol) in DMF (2 ml) was added 2 M Cs2CO3 (0.18 mL, 0.35 mmol), followed by water (0.5 mL), the mixture was stirred overnight then heated at 70° C. for 8 hr, LCMS showed that the reaction was completed. The DMF and water were removed. TFA (2 mL was added to the residue and stirred at room temperature for 3 hr. The TFA was removed, followed by addition of methanol. The residue was purified by prep-HPLC to afford (4-{6-amino-5-[1-(2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone (20 mg, yield 34.2%).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH:20]=1)[C:17](Cl)=O.N>>[Br:11][C:12]1[CH:20]=[C:16]([C:17]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:15]=[N:14][CH:13]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(Cl)c1cncc(Br)c1
Agent: N
Product: Brc1cncc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 1 using N′-hydroxynicotinimidamide (Aldrich) and 5-bromonicotinoyl chloride (Alfa). 1H NMR (300 MHz, DMSO-d6) δ 8.65-8.69 (m, 1H), 8.45-8.49 (m, 1H), 8.79 (t, J=1.7 Hz, 1H), 8.84 (dd, J=1.7, 2.0 Hz, 1H), 9.07 (d, J=2 Hz, 1H), 9.28-9.29 (m, 1H), 9.34 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 303 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH2:20][CH:19]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:18]2)=[CH:13][CH:12]=1>>[Br:1][C:2]1[O:6][C:5]([C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH:19]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:18]3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2ccc(N)cc2)C1
Product: CC(C)(C)OC(=O)NCC1CCN(c2ccc(NC(=O)c3ccc(Br)o3)cc2)C1

Procedure:
5-Bromofuran-2-carboxylic acid was reacted with tert-butyl [1-(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate by method E. This resulted in the product with the molecular weight of 464.36 (C21H26BrN3O4); MS (ESI): 464 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]([Cl:33])=[CH:30][CH2:31]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:21][CH2:31][CH:30]=[C:29]([Cl:33])[Cl:28])[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:17])[F:18])=[CH:11][N:10]=1
Reactant: ClCC=C(Cl)Cl
Reactant: Oc1cc(Cl)c(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cnc(Oc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)c(Cl)c1
Temperature: 0 °C
Yield: 79.2 %

Procedure:
To a mixture of 93 mg of 3,5-dichloro-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenol, 40 mg of potassium carbonate and 10 ml of N,N-dimethylformamide, a solution prepared by dissolving 42 mg of 1,1,3-trichloro-1-propene in 3 ml of N,N-dimethylformamide was added dropwise at room temperature with stirring. After stirring at room temperature for 5 hours, the reaction solution was poured into ice-water, and extracted twice with 40 ml of diethyl ether. Then, the ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 96 mg of 3,5-dichloro-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, yield 79%; m.p., 97.8° C.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([O:15][C@H:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C@@H:17]([NH2:19])[CH3:18])=[CH:12][CH:13]=3)[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:26]1([S:29](Cl)(=[O:31])=[O:30])[CH2:28][CH2:27]1>>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([O:15][C@H:16]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:17]([NH:19][S:29]([CH:26]4[CH2:28][CH2:27]4)(=[O:31])=[O:30])[CH3:18])=[CH:12][CH:13]=3)[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2C2CCCC2)c1)c1ccccc1
Reactant: O=S(=O)(Cl)C1CC1
Product: C[C@H](NS(=O)(=O)C1CC1)[C@H](Oc1ccc2c(cnn2C2CCCC2)c1)c1ccccc1

Procedure:
The title compound was prepared from (1R,2S)-1-[(1-cyclopentyl-1H-indazol-5-yl)oxy]-1-phenylpropan-2-amine (32b, 17 mg, 51 μmol) and cyclopropanesulfonyl chloride (34 mg, 153 μmol) as described in Example 2b. Yield 10 mg (45%).
Reaction SMILES: Br[CH:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[N-:23]=[N+]=[N-].[Na+]>CN(C)C=O.O>[NH2:23][C:18]1[C:17](=[O:20])[CH2:16][CH2:15][C@@:14]2([CH3:21])[C:19]=1[CH:2]=[CH:3][C@@H:4]1[C@@H:13]2[CH2:12][CH2:11][C@@:9]2([CH3:10])[C@H:5]1[CH2:6][CH2:7][C:8]2=[O:22]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@]12CCC(=O)C=C1C(Br)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]12CCC(=O)C(N)=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 100 °C
Yield: 36 %

Procedure:
To a stirred solution of 1.1 g of 6-bromoandrost-4-en-3,17-dione in 57.4 ml of dimethylformamide are added 0.250 g of sodium azide dissolved in 2 ml of water. The resulting mixture is heated at 100° C. for 90 minutes, cooled and worked up as described in the example 1. There are obtained 0.325 g of the title compound, m.p. 148°-150° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([N:12]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]([CH3:23])[N:14]([CH3:24])[C:13]1=[O:25])(=[O:11])[CH:9]=[CH2:10].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(C(C)C)C(C)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:24][N:14]1[CH:15]([CH3:23])[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]([C:8](=[O:11])/[CH:9]=[CH:10]/[C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[C:13]1=[O:25]
Reactant: C=CC(=O)N1C(=O)N(C)C(C)C1c1ccccc1
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1C(c2ccccc2)N(C(=O)/C=C/c2cccnc2)C(=O)N1C
Temperature: 110 °C

Procedure:
A solution of 3-bromopyridine (8.6 mL, 88.5 mmole), (4 R, 5 S)-1-acryloyl-3,4-dimethyl-5-phenylimidazolidin-2-one (14.4 g. 59 mmole), Pd(OAc)2 (662 mg, 2.95 mmole), P(o-tolyl)3 (1.80 g, 5.9 mmole), and (i-Pr)2NEt (22 mL, 124 mmole) in dry DMF (300 mL) was degassed (3×vacuum/N2 purge) then heated to 110° C. After 2 hr the mixture was cooled and poured into EtOAc. The resulting mixture was washed with H2O (3×), and the combined aqueous layers were back-extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered through a plug of silica gel, and concentrated. The residue was taken up in 1: EtOAc/hexanes and the solid was collected, washed with 1:1 EtOAc/hexanes, and dried in vacuo to afford a first crop of the title compound. The filtrate was concentrated and the crystallization process was repeated to afford a second crop. The total yield of the title compound was 17.53 g (92%): 1H NMR (400 MHz, CDCl3) δ 8.48-8.85 (m, 2H), 8.25 (d, J=15.9 Hz, 1 H), 7.89-7.97 (m, 1 H), 7.68 (d, J=15.9 Hz, 1 H), 7.15-7.38 (m, 6 H), 5.43 (d, J=8.5 Hz, 1 H), 3.90-4.02 (m, 1 H), 2.88 (s, 3H), 0.85 (d, J=6.6 Hz, 3 H); MS (ES) m/e 322 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.O1CCC[CH2:35]1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH3:35])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:27])([F:28])[F:29])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOCC
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
Dissolve 4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (860 mg, 2.08 mmoles) in diethyl ether (100 mL) under N2. Cool the solution to 0° C. in an ice bath, and add sodium hydride (1.1 equiv; 2.29 mmoles; 91.52 mg), followed by injecting methyl iodide (2.00 equiv; 4.16 mmoles; 259.12 μL). Stir the mixture for 1 hour at 0° C., and then warm to room temperature. Inject tetrahydrofuran (40 mL) into the above mixture, and then stir at room temperature overnight. Concentrate the mixture under reduced pressure, and then dissolve the residue in EtOAc. Wash with saturated aqueous sodium chloride. Purify the residue via silica gel chromatography, eluting with EtOAc:hexane (7:3) to offer 270 mg (30% yield) of a title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Cl:21])[C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[C:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1)#[N:23].C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:16])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30](=[O:31])[C:27]3[CH:26]=[CH:25][C:24]([C:22]#[N:23])=[CH:29][N:28]=3)[CH:3]=[C:4]([Cl:21])[C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: C[C@@]1(c2cc(N)cc(Cl)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(C#N)cn3)cc(Cl)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reaction time: 1.5 h
Yield: 68.5 %

Procedure:
To a cooled (ice bath) solution of (4S,6S)-4-(5-amino-3-chloro-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.090 g, 0.276 mmol) and 5-cyano-2-pyridinecarboxylic acid (0.060 g, 0.405 mmol) in n,n-Dimethylformamide (1.5 mL) was added dropwise 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.352 mL, 0.553 mmol). After stirred for 1.5 h, reaction went to completion. The reaction mixture was quenched with saturated NaHCO3 and diluted with water. The resulted suspension was stirred for 30 min, and filtered. The filter caked was washed with water and purified by Shimadzu HPLC to afford the title compound (0.086 g, 0.189 mmol, 68.3% yield) as off-white solid. MS m/z=456.0 [M+H]+. Calculated for C19H14ClF4N5O2: 455.79
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[C:8]([C:9](O)=[O:10])=[CH:7][N:6]=[C:5]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[N:4]=1.C(Cl)(=O)C([Cl:23])=O>ClCCl.CN(C)C=O>[F:1][CH:2]([F:19])[C:3]1[C:8]([C:9]([Cl:23])=[O:10])=[CH:7][N:6]=[C:5]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[N:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cnc(C(F)(F)C(F)(F)F)nc1C(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cnc(C(F)(F)C(F)(F)F)nc1C(F)F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In 10 ml of dichloromethane, 467 mg of 4-(difluoromethyl)-2-(pentafluoroethyl)pyrimidine-5-carboxylic acid are admixed with two drops of N,N-dimethylformamide and cooled to 0° C. Following the dropwise addition of 167 μl of oxalyl chloride, the reaction mixture is stirred at room temperature for three hours and then concentrated by evaporation. This gives the crude product 4-(difluoromethyl)-2-(pentafluoroethyl)pyrimidine-5-carbonyl chloride.