Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:31]=[CH:30][C:14]([O:15][C:16]2[C:21]([F:22])=[C:20](F)[C:19]([F:24])=[C:18]([F:25])[C:17]=2[C:26]([F:29])([F:28])[F:27])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:32]([C:35]1[CH:41]=[CH:40][C:38]([O-:39])=[CH:37][C:36]=1[O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([O-:34])=[O:33].[K+].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[K+]>CS(C)=O>[N+:32]([C:35]1[CH:41]=[CH:40][C:38]([O:39][C:20]2[C:19]([F:24])=[C:18]([F:25])[C:17]([C:26]([F:27])([F:28])[F:29])=[C:16]([O:15][C:14]3[CH:13]=[CH:12][C:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])=[CH:31][CH:30]=3)[C:21]=2[F:22])=[CH:37][C:36]=1[O:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)([O-:34])=[O:33]
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(F)c(F)c(F)c2C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccc([O-])cc1OCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(Oc3ccc([N+](=O)[O-])c(OCc4ccccc4)c3)c(F)c(F)c2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
40 g of the 2-(4-benzyloxycarbonylphenoxy)-1-trifluoromethyl-3,4,5,6-tetrafluorobenzene (0.09 mol) prepared as described in Example 9 and 25.5 g of potassium 4-nitro-3-benzyloxyphenoxide (0.09 mol) are dissolved in 400 ml of dimethyl sulfoxide. 30 g of potassium carbonate (0.22 mol) are added in portions to the solution. The mixture is then stirred at room temperature for 24 hours and then heated at 60° C. for 24 hours, and 15 g of potassium hydrogencarbonate (0.15 mol) are then added. The reaction solution is then allowed to cool to room temperature and is filtered through a fluted filter. The crude product is extracted by shaking with 300 ml of ethyl acetate and 700 ml of water, and the organic phase is washed three times with water and evaporated in a rotary evaporator until the reaction product precipitates out. The reaction product is then recrystallized from a mixture of ethyl acetate and n-hexane (volume ratio 1:1) and then dried for 48 hours,under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 94%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][NH:6][C:7]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14]1)=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH3:2].[Cl:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]([C:7]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14]1)=[C:8]([C:9]#[N:10])[C:11]#[N:12])[CH2:31][C:30]1[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=1[Cl:28])[CH3:2]
Reactant: CCOC(=O)CNC(=C(C#N)C#N)N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: Clc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)CN(Cc1ccccc1Cl)C(=C(C#N)C#N)N1CCC[C@@H](NC(=O)OC(C)(C)C)C1

Procedure:
A solution of N-(1-{(3R)-3-[(tertbutoxycarbonyl)amino]piperidin-1-yl}-2,2-dicyanovinyl)glycine ethyl ester (300 mg), 2-chlorobenzyl bromide (0.15 ml) and potassium carbonate (330 mg) in acetone (4 ml) was stirred at 25° C. for 24 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1) to obtain the title compound (340 mg) as a white amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:19]=[O:20])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[N:7]2.O1CCC[CH2:22]1.C[Mg]Br.C(OCC)C>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:19]([OH:20])[CH3:22])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[N:7]2
Reactant: O=Cc1cc2c(Cl)cccc2nc1-c1cccc(F)c1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1cc2c(Cl)cccc2nc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring hetereogeneous mixture of 5-chloro-2-(3-fluorophenyl)quinoline-3-carbaldehyde (1.0120 g, 3.542 mmol) in tetrahydrofuran (35.42 mL, 3.542 mmol) was added methylmagnesium bromide 3 M in diethyl ether (3.542 mL, 10.63 mmol) dropwise at 0° C. (started at 11:10 am), and the mixture was then stirred at room temperature. After 3 h, the reaction was quenched with saturated aq. NH4Cl (50 mL) and extracted with EtOAc (50 mL×2). The combined orgainc layers were washed with water (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 10 min as eluent to give 1-(5-chloro-2-(3-fluorophenyl)quinolin-3-yl)ethanol as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.79 (1 H, s), 8.00-8.05 (1 H, m), 7.73-7.85 (2 H, m), 7.54-7.63 (1 H, m), 7.41-7.47 (2 H, m), 7.33-7.40 (1 H, m), 5.56 (1 H, d, J=4.3 Hz), 4.98-5.06 (1 H, m), 1.27 (3 H, d, J=6.7 Hz); LC-MS (ESI) m/z 302.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.CN([CH:26]=[O:27])C>>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:26]=[O:27])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: c1ccc(CN2CCCc3ccccc32)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2c(c1)CCCN2Cc1ccccc1

Procedure:
The procedure was carried out as described previously in step (a) of Example 5 with Compound 5 (0.42 g, 1.88 mmol), POCl3 (355 μL, 3.76 mmol), and DMF (3.5 mL). Compound 6 was obtained (0.36 g) as a viscous liquid and used without any further purification. The structure of Compound 6 is given below:
Reaction SMILES: [NH2:1][C:2]1[N:31]=[C:5]2[N:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C@@H:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.N1C=CC=CC=1.Cl[C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40]>C1COCC1>[CH3:43][CH:42]([O:41][C:39](=[O:40])[NH:1][C:2]1[N:31]=[C:5]2[N:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=3)[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C@@H:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1)[CH3:44]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: CC(C)OC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OC(C)C)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (25 mg, 59 μmol) was dissolved in a mixture of abs. THF (2.5 ml) and abs. pyridine (48 μl, 593 μmol, 10 eq.). At room temperature, isopropyl chloroformate (36 mg, 297 μmol, 5 eq.) was added and the mixture was heated at 80° C. for 12 h. Once HPLC analysis showed substantial conversion, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (23.2 mg, 77% of theory).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][C:9]1([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](Cl)[N:21]=1>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[N:21]=2)[CH2:10][C:9]1([CH3:16])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(O)CCN1Cc1ccccc1
Reactant: Clc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(Oc2cccc(Cl)n2)CCN1Cc1ccccc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
Combine 1-benzyl-2,2-dimethyl-piperidin-4-ol (preparation 9) 1.08 g, 4.92 mmol), N,N-dimethylformamide (20 mL) and 95% sodium hydride (0.12 g, 4.92 mmol) and stir. After 30 min., add 2,6-dichloropyridine (0.67 g, 4.52 mmol), stir and heat at 120° C. After 18 hr., cool to ambient temperature and partition between water (100 mL) and ethyl acetate (100 mL). Separate the organic layer and wash the aqueous layer with ethyl acetate (2×100 mL). Combine the organic layers, wash with water (5×100 mL), wash with aqueous NaCl solution, dry over sodium sulfate, filter and concentrate. Purify the residue by silica gel flash chromatography eluting with 9:1 hexane:ethyl acetate to obtain of the title compound (0.57 g, 38%). Mass spectrum (electrospray): m/z=331.1 (M+1); 1H NMR (CDCl3): 7.5 (dd, 1H), 7.3 (m, 5H), 6.8 (d, 1H), 6.6 (d, 1H), 5.2 (m, 1H), 3.9 (d, 1H), 3.2 (d, 1H), 2.65 (m, 1H), 2.4 (m, 1H), 2.0 (m, 2H), 1.7 (m, 1H), 1.6 (m, 1H), 1.3 (s, 3H), 1.2 (s, 3H).
Reaction SMILES: [F:1][C:2]1([F:7])[CH2:4][CH:3]1[CH2:5][OH:6].F[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1>>[F:1][C:2]1([F:7])[CH2:4][CH:3]1[CH2:5][O:6][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=[N+]([O-])c1cccnc1F
Reactant: OCC1CC1(F)F
Product: O=[N+]([O-])c1cccnc1OCC1CC1(F)F

Procedure:
Prepared analogously to example XII.1 using (2,2-difluorocyclopropyl)methanol and 2-fluoro-3-nitro-pyridine
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19](C(O)=O)=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].[CH3:34][S:35](C1C=CC(N)=NC=1)(=[O:37])=[O:36]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([S:35]([CH3:34])(=[O:37])=[O:36])=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33]
Reactant: CS(=O)(=O)c1ccc(N)nc1
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Product: CS(=O)(=O)c1ccc(NC(=O)CCC2c3c(F)cccc3C(=O)N2Cc2ccc(F)cc2)nc1

Procedure:
The product of Example 11, Part D (0.175 g, 0.529 mmol) and 5-Methanesulfonyl-pyridin-2-ylamine (91 mg, 0.529 mmol) were converted to the title compound in a manner analogous to the method described in Example 27 (159 mg, 62%). 1H NMR (400 MHz, CDCl3) d 8.74 (s, 1H); 8.30 (d, J=8.8 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.09 (broad s, 1H), 7.69 (d, J=7 Hz, 1H); 7.49-7.44 (m, 1H), 7.33-7.30 (m, 2H), 7.23 (t, J=8.8 Hz, 1H); 7.04 (t, J=8.6 Hz, 2H); 5.25 (d, J=15 Hz, 1H), 4.73 (m, 1H), 4.28 (d, J=15 Hz, 1H), 3.18 (s, 3H); 2.61-2.59 (m, 1H); 2.53-2.50 (m, 1H); 2.04-1.97 (m, 2H). MS: m/z (MH+) 486.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[CH:1]1([NH:8][C:29]2[N:28]=[C:27]([C:20]3[C:21]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:18][CH:19]=3)[CH:32]=[CH:31][N:30]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: NC1CCCCCC1
Product: c1cnc2[nH]cc(-c3ccnc(NC4CCCCCC4)n3)c2c1
Yield: 41 %

Procedure:
Using the procedure of example 1, cycloheptylamine (92 mg) was reacted with compound 1f (100 mg) to provide compound 15 (34 mg, 41%). 1H NMR (400 MHz, CD3OD) δ 8.95 (d, J=8.0 Hz, 1H), 8.28 (d, J=4.8 Hz, 1H), 8.19 (s, 1H), 8.12 (d, J=5.6 Hz, 1H), 7.25 (dd, J=8.0 Hz, 4.8 Hz, 1H), 7.01 (d, J=5.6 Hz, 1H), 4.12 (m, 1H), 2.13 (m, 2H), 1.79-1.63 (m, 10H). MS (ESI) m/z: 308 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.CO>C1COCC1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: O=C(O)c1ccc(I)cc1C(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(I)cc1C(F)(F)F
Temperature: 80 °C

Procedure:
To a solution of 4-iodo-2-(trifluoromethyl)benzoic acid (for a preparation see Intermediate 31)(16.7 g, 52.8 mmol) in THF (150 ml) at ambient temperature under nitrogen was added 1.0 M borane-tetrahydrofuran complex (100 ml, 100 mmol, Aldrich) dropwise. The solution was heated to 80° C. for 1.5 h. To the solution at ambient temperature was added methanol (75 ml) and then heated to 80° C. for 1 h. The solvent was removed in vacuo to leave a mobile oil. The residue was partitioned between ethyl acetate (200 ml) and 2 N aqueous HCl (100 ml). The phases were separated and the organic phase washed with 2 N aqueous sodium hydroxide (100 ml), brine (50 ml), then dried (MgSO4), filtered and the solvent removed in vacuo to give [4-iodo-2-(trifluoromethyl)phenyl]methanol as a pale brown solid (14.8 g).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21]C)[C:18]([O:23]C)=[C:17]([O:25]C)[CH:16]=2)=[N:10][C:9]=1[C:28]1[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[C:19]([OH:21])[C:18]([OH:23])=[C:17]([OH:25])[CH:16]=2)=[N:10][C:9]=1[C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc(NC(=O)c3cc(OC)c(OC)c(OC)c3)sc2Cc2ccccc2)cc1
Agent: BrB(Br)Br
Product: O=C(Nc1nc(-c2ccc(O)cc2)c(Cc2ccccc2)s1)c1cc(O)c(O)c(O)c1
Yield: 61.3 %

Procedure:
A procedure similar to that in Example 7 was used. N-[5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-yl]-3,4,5-trimethoxy-benzamide prepared in Example 37 and boron tribromide were used as starting materials. The obtained crude product was recrystallized with acetone to give a product as a pale yellow solid in a yield of 61.3%, mp: 245-246 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 4.19 (2H, s, CH2), 6.83 (2H, d, J=8.68 Hz, ArH), 7.06 (2H, s, ArH), 7.22˜7.35 (5H, m, ArH), 7.46 (2H, d, J=8.68 Hz, ArH), 12.15 (1H, br, CONH); EI-MS m/e (%): 434.1 (M+, 6), 282.1 (100); HREI-MS Calcd. for C23H18N2O5S: 434.0936. found: 434.0936.
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16](OC3CCCCO3)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH2:34][CH2:35][CH3:36])[C:5]=1[OH:37])(=[O:3])[CH3:2].[CH:38]([Si](C(C)C)(C(C)C)OCC1C=CC(C(C2C=C(C=CC=2)C#N)=C)=CC=1)(C)C>>[C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH2:38])=[CH:14][CH:15]=2)=[C:6]([CH2:34][CH2:35][CH3:36])[C:5]=1[OH:37])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Reactant: C=C(c1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc1)c1cccc(C#N)c1
Product: C=C(c1ccc(COc2ccc(C(C)=O)c(O)c2CCC)cc1)c1cccc(C#N)c1

Procedure:
The title compound is prepared in a similar manner as 3-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile, employing 3-[1-(4-triisopropylsilanyloxymethyl-phenyl)-vinyl]-benzonitrile to give 0.46 g, 47%, of the title compound as a white solid. LCMS M+1 412.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([C:17]2([C:32]([F:35])([F:34])[F:33])[O:21][N:20]=[C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[C:24]([CH3:31])[CH:23]=3)[CH2:18]2)[CH:13]=[C:14]([Cl:16])[CH:15]=1>N1C=CC=CC=1.O>[Cl:8][C:5]1[CH:4]=[N:3][C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([C:19]3[CH2:18][C:17]([C:12]4[CH:13]=[C:14]([Cl:16])[CH:15]=[C:10]([Cl:9])[CH:11]=4)([C:32]([F:35])([F:34])[F:33])[O:21][N:20]=3)=[CH:23][C:24]=2[CH3:31])=[N:7][CH:6]=1
Reactant: Nc1ncc(Cl)cn1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ncc(Cl)cn1
Yield: 65.5 %

Procedure:
In a solution of 3.86 g of 2-amino-5-chloropyrimidine in 100 mL of pyridine, 10.0 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 was added at room temperature with stirring, and stirred at the same temperature for 23 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in 30 mL of 1,4-dioxane, a solution of 3.02 g of potassium hydroxide in 20 mL of water was added and stirred at room temperature for 1.5 hour. After the completion of the reaction, the reaction mixture was diluted with 380 mL of water, precipitated crystal was filtered off, and washed with 150 mL of water. The resulting crude product was dissolved in 50 mL of ethyl acetate with heating, and 50 mL of 2N hydrochloric acid was added and stirred for 1 hour, and then 50 mL of toluene was added, and precipitated crystal was filtered off. Thereafter, the reaction mixture was washed with 50 mL of water, and then with 50 mL of toluene to obtain 7.95 g of the aimed product as white crystal. Melting point 137.0 to 141.0° C.
Reaction SMILES: [CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[O:3][CH2:2]1.C(N(CC)CC)C.[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>C(OCC)(=O)C>[CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][N:7]([C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:19]([CH3:18])=[CH:20][CH:21]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)N2CCC3(CC2)OCCO3)cc1
Reaction time: 2 h

Procedure:
To a solution of 4-piperidone ethylene ketal (1.43 g, 10 mimol) and triethylamine (10 mmol, 1.4 ml) was added dropwise a solution of 4-methylbenzoyl chloride (1.55 g, 10 mmol) in ethyl acetate (20 ml) and the mixture stirred for 2 h. The mixture was washed twice with water followed by brine, dried over sodium sulphate and evaporated to give an off-white solid, m.p. 59°-61° C.
Reaction SMILES: C([O:4][CH:5]([O:12][C:13](=[O:15])C)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.[CH3:16]C1C=C(O)C(=CC=1)C(O)=O>S(=O)(=O)(O)O.C(O)(=O)C>[CH3:16][C:9]1[CH:10]=[CH:11][C:6]2[C:5](=[O:4])[O:12][CH2:13][O:15][C:7]=2[CH:8]=1
Reactant: CC(=O)OC(OC(C)=O)c1ccccc1
Reactant: Cc1ccc(C(=O)O)c(O)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)OCOC2=O

Procedure:
61 g of benzal diacetate, 44.6 g of 4-methylsalicylic acid and 45 ml of acetic acid are combined and 5 drops of concentrated sulfuric acid are added and the mixture is heated under reduced pressure, allowing acetic acid to distill off. When the theoretical amount of acetic acid is collected (about 2.5 hours) the mixture is allowed to cool, diluted with ether and the ether solution washed with potassium carbonate solution, sodium bisulfite solution and dried over sodium sulfate. The ether is removed in vacuo and the resulting solid crystallized from ethyl acetate/hexane to give 7-methyl-1,3-benzodioxane-4-one.
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]4[N:31]([CH3:41])[C:32]5[C:37]([CH:38]=4)=[C:36]([O:39][CH3:40])[CH:35]=[CH:34][CH:33]=5)=[O:29])=[C:23]([O:42][CH3:43])[CH:22]=3)[N:12]=2)[CH2:7][CH2:6]1)(=O)C.[OH-].[K+].Cl>C(#N)C.O>[OH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]4[N:31]([CH3:41])[C:32]5[C:37]([CH:38]=4)=[C:36]([O:39][CH3:40])[CH:35]=[CH:34][CH:33]=5)=[O:29])=[C:23]([O:42][CH3:43])[CH:22]=3)[N:12]=2)[CH2:7][CH2:6]1
Reactant: COc1cc(-c2nc([C@H]3CC[C@H](OC(C)=O)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COc1cc(-c2nc([C@H]3CC[C@H](O)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Temperature: 110 °C

Procedure:
To (trans)-4-(1-(3-methoxy-4-(4-methoxy-1-methyl-1H-indole-2-carboxamido)phenyl)-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (0.034 mmol, 20 mg) in acetonitrile (0.5 ml) and water (0.5 ml) was added potassium hydroxide (0.172 mmol, 9.65 mg) and the mixture was stirred at 110° C. After one hour the reaction mixture was neutralized with 2N hydrochloric acid, extracted with dichloromethane three times, the combined organic layers were dried (sodium sulfate) and concentrated in vacuo. The crude product was purified using column chromatography (silica gel; gradient dichloromethane to dichloromethane/methanol 25/1) to yield the title compound (7 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([NH2:8])=[CH:4][N:3]=1.C(N(CC)CC)C.[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19](Cl)=[O:20]>ClCCl>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:19](=[O:20])[C:18]2[C:17]([F:16])=[CH:25][CH:24]=[CH:23][C:22]=2[F:26])=[N:6][CH:7]=1
Reactant: Nc1cnc(Br)cn1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cnc(Br)cn1)c1c(F)cccc1F
Temperature: 25 °C

Procedure:
To a stirred solution of 2-bromo-5-amino-pyrazine (24 mmol), triethyl amine (TEA) (5 mL) in dry dichloromethane (DCM) (50 mL) at 00° C. was added 2,6-difluoro-benzoyl chloride (3.0 mL, 24 mmol) dropwise. The mixture was allowed to warm to room temperature over 2 h before it was washed with water (2×100 mL) and dried. Removal of solvents gave N-(5-bromo-pyrazin-2-yl)-2,6-difluorobenzamide (b) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]=1[CH3:19].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N+:7]([O-:33])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]=1[CH3:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)n1c(C)c(Cc2ccc(Cl)cc2Cl)c2ncccc21
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[N+]1([O-])C(C)=C(Cc2ccc(Cl)cc2Cl)c2ncccc21
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of ethyl 3-(2,4-dichlorobenzyl)-2-methylpyrrolo[3,2-b]pyridine-1-carboxylate (400 mg) in chloroform (6 ml) was added m-chloroperbenzoic acid (462 mg) at room temperature, and the mixture was stirred overnight. The reaction mixture was subjected to flash silica gel chromatography (silica gel, 40 ml, eluted with ethyl acetate and then with ethyl acetate-methanol=10-1), and crystallized from ether to give the objective compound (417 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Br:8].[CH:10]1([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[C:14]=2[CH2:26]O)[CH2:12][CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][CH2:26][C:14]2[C:15]([C:18]3[C:19]([Cl:25])=[CH:20][CH:21]=[CH:22][C:23]=3[Cl:24])=[N:16][O:17][C:13]=2[CH:10]2[CH2:12][CH2:11]2)=[CH:3][C:2]=1[Cl:1]
Reactant: Oc1ccc(Br)c(Cl)c1
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Clc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)ccc1Br
Temperature: 25 °C
Reaction time: 21 h

Procedure:
3-Chloro-4-bromophenol (3.8 g, 18.3 mmol) was mixed with (5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methanol (3.47 g, 12.2 mmol) and triphenylphosphine (6.41 g, 24.4 mmol) in toluene (150 mL). The mixture was cooled in an ice-bath and DIAD (4.8 mL, 24.4 mmol) as a solution in toluene (10 mL) was added drop-wise. The reaction was stirred at rt for 21 h and the solvents were removed on a rotavap leaving a yellow oily residue. This was dissolved in DCM (200 mL), silica (˜20 g) was added and the mixture was evaporated to dryness. This material was loaded on the top of a silica column and purified eluting with hexanes/MTBE 9:1. The product containing fractions were pooled and the solvent removed under reduced pressure, leaving pure product 8e as a colourless oil that crystallized upon drying under vacuum overnight. Yield: 5.07 g (88%). 1H-NMR (CDCl3), δ (ppm): 7.45-7.30 (m, 4H), 6.90 (s, 1H), 6.60-6.55 (m, 1H), 2.15-2.07 (m, 1H), 1.32-1.25 (m, 2H), 1.20-1.11 (m, 2H).