Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([O+](CC)CC)[CH3:7].[N:13]1([C:18]2([C:21](N)=[O:22])[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1.P([O-])([O-])(O)=[O:25].[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[N:13]1([C:18]2([C:21]([O:22][CH2:6][CH3:7])=[O:25])[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC(=O)C1(N2CCCC2)CC1
Reactant: CC[O+](CC)CC
Reactant: O=P([O-])([O-])O
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1(N2CCCC2)CC1
Reaction time: 20 h

Procedure:
A solution containing 11.4 g of triethyloxonium tetrafluoroborate and 40 ml of dichloromethane is added dropwise, at 0° C., to a suspension containing 1.54 g of the product obtained in Step 2, 10 g of disodium hydrogen phosphate and 120 ml of dichloromethane. After 20 hours at 20° C., 40 ml of 10% aqueous sodium carbonate solution are added. The mixture is separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and then concentrated to dryness. The residue is taken up in 1N aqueous hydrochloric acid and the resulting solution is left at 20° C. for 3 hours. The mixture is made alkaline with sodium carbonate and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated to dryness. Chromatography over silica gel (dichloromethane/tetrahydrofuran: 95/5) allows the desired product to be isolated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([C:43]([F:46])([F:45])[F:44])[CH:36]=1.C(N(C(C)C)CC)(C)C>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([C:43]([F:44])([F:45])[F:46])[CH:36]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: COc1ccc(CBr)cc1C(F)(F)F
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc(OC)c(C(F)(F)F)c3)C2)c1
Yield: 77.4 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (58.8 mg, 0.13 mmol) in CH3CN (5 ml) was added 4-Bromomethyl-1-methoxy-2-trifluoromethyl-benzene (53.0 mg, 0.20 mmol), and diisopropylethylamine (46 μl, 0.26 mmol). The reaction was microwaved at 130° C. for 10 minutes. The reaction was diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (64 mg, 77%). Calcd for C35H39F6NO3 (M+H) 635.68, Found 636.5.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C:3]([O:5][C:6]1[C:7]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2)=[O:4].[Se](=O)=[O:27]>O1CCOCC1>[CH3:1][C:2]([CH3:24])([CH3:25])[C:3]([O:5][C:6]1[C:7]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH:16]=[O:27])[CH:12]=[CH:11]2)=[O:4]
Reactant: CCCCOC(=O)c1ccc2ccc(C)nc2c1OC(=O)C(C)(C)C
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: CCCCOC(=O)c1ccc2ccc(C=O)nc2c1OC(=O)C(C)(C)C
Temperature: 20 °C
Yield: 70.8 %

Procedure:
A mixture of the preceding diester 3 (step 2) (11.5 g, 34 mmol) and selenium dioxide (6.7 g, 60 mmol) in 50 ml of 1,4-dioxane is heated under reflux for 12 hours. After cooling to 20° C., the reaction mixture is filtered on Celite® and concentrated under reduced pressure. The residue is chromatographed on a silica column, eluting a 4/1 cyclohexane/ethyl acetate mixture so as to give 8.6 g (71%) of n-butyl 8-(2,2-dimethylpropionyloxy)-2-formylquinoline-7-carboxylate 4. White solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:19]2[CH:20]=[N:21][CH:22]=[CH:14][C:15]=2[C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCc1ccc(C(F)(F)F)cc1
Yield: 28 %

Procedure:
The title compound was prepared in 28% yield from 4-(trifluoromethyl)-benzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 8.10 (br s, 1H), 8.04 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.81 (d, 2H, J=8.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 7.54 (d, 2H, J=8.0 Hz), 4.69 (s, 2H). [M+H] calc'd for C14H11F3N2O2, 297. found 297.
Reaction SMILES: [NH:1]([CH2:8][CH:9]([OH:19])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28](OCC)=[O:29].CN(C)C=O>O.C(OCC)(=O)C>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH:9]2[CH2:8][N:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:27][C:28](=[O:29])[O:19]2)=[CH:17][CH:16]=1
Reactant: OC(CNc1ccccc1)COc1ccc(Cl)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CN(c2ccccc2)CC(COc2ccc(Cl)cc2)O1
Yield: 56.8 %

Procedure:
Two grams (0.0072 moles) of 1-anilino-3-(p-chlorophenoxy)-2-propanol [prepared in part (1)], 1.2 g (0.0087 moles) of K2CO3 and 2.9 g (0.0174 moles) of ethyl bromoacetate were added to 20 ml of N,N-dimethylformamide. The resulting mixture was refluxed for 5 hr with stirring. Concentration of the reaction mixture and addition of ethyl acetate and water to the residue gave a solid. The solid was collected by filtration and washed with ethyl acetate and water and dried (0.5 g). The filtrate was acidified with 10% aqueous hydrochloric acid and the organic layer was washed with water and dried over anhydrous magnesium sulfate. After the evaporation of ethyl acetate, 20 ml of acetic acid was added to the residue and refluxed for 3 hr. The reaction mixture was concentrated under reduced pressure, and 1.3 g of the solid was obtained by crystallizing the residue from ether. Recrystallization of the combined solids (1.8 g) from benzene gave 1.3 g (57%) of crystals, m.p.142°-144°.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][O:7][CH2:8][C@@H:9]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]([NH2:25])=O)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>C(Cl)Cl>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[CH2:6][O:7][CH2:8][C@@H:9]([N:16]1[CH2:17][CH2:18][N:19]([CH2:22][C:23]#[N:25])[CH2:20][CH2:21]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NC(=O)CN1CCN([C@H](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: N#CCN1CCN([C@H](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
In a round-bottomed flask fitted with a reflux condenser and a thermometer were introduced 3 g (6.13 mmoles) of (S)-2-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-acetamide dissolved in 30 ml of CH2Cl2 (compound 144 prepared at example 1.4.1 above). The solution was cooled to −78° C. and DMSO (0.7 ml, 9.8 mmoles) and oxalyl chloride (0.6 ml, 7.4 mmoles) were added. After 15 minutes, triethylamine (2.5 ml, 18.4 mmoles) was added dropwise and the reaction mixture was stirred at −70° C. until complete disappearance of the starting material. The reaction was quenched with water and the pH was adjusted to 11 by addition of aqueous NaOH. The aqueous solution was extracted with CH2Cl2 and the combined organic layers were dried over MgSO4 and concentrated. The crude was purified by chromatography on silica gel (eluent: CH2Cl2/MeOH/NH3: 98/2/0.2 v/v/v) to yield (S)-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-acetonitrile (compound 291, 2.14 g, 73%) as a pale yellow powder which was converted into the dichydrochloride salt by reaction with HCl in diethylether.
Reaction SMILES: [CH3:1][CH2:2][CH:3]1[NH:46][C:44](=[O:45])[CH:43]([CH:47]([OH:54])[CH:48]([CH2:50]/[CH:51]=[CH:52]/[CH3:53])[CH3:49])[N:42]([CH3:55])[C:40](=[O:41])[CH:39]([CH:56]([CH3:58])[CH3:57])[N:38]([CH3:59])[C:36](=[O:37])[CH:35]([CH2:60][CH:61]([CH3:63])[CH3:62])[N:34]([CH3:64])[C:32](=[O:33])[CH:31]([CH2:65][CH:66]([CH3:68])[CH3:67])[N:30]([CH3:69])[C:28](=[O:29])[CH:27]([CH3:70])[NH:26][C:24](=[O:25])[CH:23]([CH3:71])[NH:22][C:20](=[O:21])[CH:19]([CH2:72][CH:73]([CH3:75])[CH3:74])[N:18]([CH3:76])[C:16](=[O:17])[CH:15]([CH:77]([CH3:79])[CH3:78])[NH:14][C:12](=[O:13])[CH:11]([CH2:80][CH:81]([CH3:83])[CH3:82])[N:10]([CH3:84])[C:8](=[O:9])[CH2:7][N:6]([CH3:85])[C:4]1=[O:5].O>C(O)C.C(O)C(O)C>[CH3:1][CH2:2][C@@H:3]1[NH:46][C:44](=[O:45])[C@H:43]([C@H:47]([OH:54])[C@@H:48]([CH2:50]/[CH:51]=[CH:52]/[CH3:53])[CH3:49])[N:42]([CH3:55])[C:40](=[O:41])[C@H:39]([CH:56]([CH3:57])[CH3:58])[N:38]([CH3:59])[C:36](=[O:37])[C@H:35]([CH2:60][CH:61]([CH3:62])[CH3:63])[N:34]([CH3:64])[C:32](=[O:33])[C@H:31]([CH2:65][CH:66]([CH3:68])[CH3:67])[N:30]([CH3:69])[C:28](=[O:29])[C@@H:27]([CH3:70])[NH:26][C:24](=[O:25])[C@H:23]([CH3:71])[NH:22][C:20](=[O:21])[C@H:19]([CH2:72][CH:73]([CH3:75])[CH3:74])[N:18]([CH3:76])[C:16](=[O:17])[C@H:15]([CH:77]([CH3:79])[CH3:78])[NH:14][C:12](=[O:13])[C@H:11]([CH2:80][CH:81]([CH3:83])[CH3:82])[N:10]([CH3:84])[C:8](=[O:9])[CH2:7][N:6]([CH3:85])[C:4]1=[O:5]
Reactant: C/C=C/CC(C)C(O)C1C(=O)NC(CC)C(=O)N(C)CC(=O)N(C)C(CC(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(CC(C)C)C(=O)NC(C)C(=O)NC(C)C(=O)N(C)C(CC(C)C)C(=O)N(C)C(CC(C)C)C(=O)N(C)C(C(C)C)C(=O)N1C
Solvent: CC(O)CO
Solvent: CCO
Solvent: O
Product: C/C=C/C[C@@H](C)[C@@H](O)[C@H]1C(=O)N[C@@H](CC)C(=O)N(C)CC(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](C(C)C)C(=O)N1C

Procedure:
100 g of ciclosporin A were dissolved in 770 g of polymer of Example 2, 100 ml of ethanol and 75 ml of propylene glycol, and the clear viscous solution was then dispensed into capsules. Infinite dilution of this solution with water was possible.
Reaction SMILES: [NH2:1][C:2](=[O:11])[CH2:3][C:4]([CH3:10])([CH3:9])[CH2:5][C:6]([OH:8])=[O:7].[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[NH2:1][C:2](=[O:11])[CH2:3][C:4]([CH3:9])([CH3:10])[CH2:5][C:6]([O:8][CH3:12])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(CC(N)=O)CC(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CC(C)(C)CC(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-3,3-dimethyl-5-oxopentanoic acid (10.9 g; 68.6 mmoles) was dissolved in DMF (50 mL). Potassium carbonate (14.2 g; 103 mmoles) and methyl iodide (8.5 mL; 137.2 mmoles) were added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered, washing the filter cake with DMF. The DMF was removed under vacuum and the residue was suspended in ethyl acetate. The solids were removed by filtration and the ethyl acetate was removed under vacuum to give the product, methyl 5-amino-3,3-dimethyl-5-oxopentanoate, as a yellow oil (11.5 g; 97%). 1H NMR (400 MHz) DMSO-d6 δ 7.22 (1H, s, br), 6.73 (1H, s, br), 3.58 (3H, s), 2.39 (2H, s), 2.09 (2H, s), 1.02 (6H, s).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([N:7]2[CH:11]=[C:10]([NH:12][C:13]3[N:18]=[C:17]([N:19]4[CH2:23][CH2:22][C@:21]([CH2:26][CH3:27])([C:24]#[N:25])[C:20]4=[O:28])[CH:16]=[CH:15][N:14]=3)[CH:9]=[N:8]2)[CH2:4]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>O1CCCC1>[CH2:26]([C@:21]1([C:24]#[N:25])[CH2:22][CH2:23][N:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:10]3[CH:9]=[N:8][N:7]([CH:5]4[CH2:6][N:3]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:4]4)[CH:11]=3)[N:18]=2)[C:20]1=[O:28])[CH3:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@]1(C#N)CCN(c2ccnc(Nc3cnn(C4CNC4)c3)n2)C1=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@]1(C#N)CCN(c2ccnc(Nc3cnn(C4CN(S(C)(=O)=O)C4)c3)n2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of (3R)-1-(2-((1-(azetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-ethyl-2-oxopyrrolidine-3-carbonitrile dihydrochloride (83 mg) obtained in Example 185 in tetrahydrofuran (5 mL) were added triethylamine (30 μL) and methanesulfonyl chloride (33 μL) at room temperature, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized (ethyl acetate/hexane) to give the title compound (16 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25]2>>[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[C:25]2=[CH:16][C:13]1[NH:12][C:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][N:3]([CH2:19][CH3:20])[CH2:1][CH3:2])[C:7](=[O:18])[C:8]=2[C:14]=1[CH3:15].[CH3:15][C:14]1[C:8]2[C:7](=[O:18])[NH:6][CH2:11][CH2:10][C:9]=2[NH:12][CH:13]=1
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(Br)cc43)c(C)c2C1=O
Product: Cc1c[nH]c2c1C(=O)NCC2
Yield: 98.7 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-bromo-1,3-dihydro-indole-2-one (commercially available from Aldrich) as starting materials to give 2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-2-diethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (56 mg, 98.7%) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C@:8]2([CH3:40])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH:16][C:17]([C:32]3[CH:37]=[CH:36][C:35](OC)=[CH:34][CH:33]=3)([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:9]2)[C:5]([F:41])=[CH:4][CH:3]=1.[Cl:42][C:43]1[C:44]([C:53]([OH:55])=O)=[N:45][CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1.C1C=NC2N(O)N=NC=2C=1.Cl.CN([CH:70]=[O:71])C>C(OCC)(=O)C.C(Cl)CCl>[F:15][C:13]1([F:14])[CH2:12][O:11][C:10]([NH:16][C:17]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:71][CH3:70])[CH:33]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:9][C@@:8]1([C:6]1[N:7]=[C:2]([NH:1][C:53]([C:44]2[C:43]([Cl:42])=[CH:48][C:47]([C:49]([F:50])([F:51])[F:52])=[CH:46][N:45]=2)=[O:55])[CH:3]=[CH:4][C:5]=1[F:41])[CH3:40]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1Cl
Reactant: COc1ccc(C(NC2=N[C@](C)(c3nc(N)ccc3F)C(F)(F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(NC2=N[C@](C)(c3nc(NC(=O)c4ncc(C(F)(F)F)cc4Cl)ccc3F)C(F)(F)CO2)(c2ccccc2)c2cccc(OC)c2)cc1
Reaction time: 18 h
Yield: 29.2 %

Procedure:
[(R)-4-(6-amino-3-fluoro-pyridin-2-yl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine (250 mg, 0.444 mmol), 3-chloro-5-(trifluoromethyl)-picolinic acid (120 mg, 0.533 mmol) and HOAt (109 mg, 0.800 mmol) were dissolved in DMF (4.44 ml) under argon. EDC×HCl (128 mg, 0.667 mmol) was added and the reaction mixture was stirred at it for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude product was chromatographed over silica gel (Redisep column 12 g, cyclohexane/ethyl acetate) to give the title compound: 100 mg (29.2% yield).
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28]CC3C=CC=CC=3)[C:25]([C:36](=O)[CH3:37])=[CH:24][C:23]=2[CH2:39][CH3:40])[C:12]=1[CH2:41][CH2:42][CH3:43].COC(OC)[N:48](C)C.C[N:54]([CH3:57])C=O>C(OCC)(=O)C.Cl>[CH2:39]([C:23]1[CH:24]=[C:25]([C:36]2[NH:48][N:54]=[CH:57][CH:37]=2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:41][CH2:42][CH3:43])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:2])=[O:44])[CH3:40]
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(C(C)=O)cc2CC)cccc1Oc1ccccc1C(=O)OC
Reactant: CN(C)C=O
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCOc2cc(O)c(-c3ccn[nH]3)cc2CC)cccc1Oc1ccccc1C(=O)O
Temperature: 115 °C
Yield: 63 %

Procedure:
A mixture of 2-(3-{3-[4-acetyl-5-benzyloxy-2-ethylphenoxy]propoxy}-2-propylphenoxy)benzoic acid methyl ester (3.07 g, 5.04 mmol) and dimethylformamide dimethylacetal (0.9 mL, 7 mmol) in N,N-dimethylformamide (3 mL) was heated at 110-120° C. for 35 h. The mixture was cooled to room temperature and diluted with a mixture of ethyl acetate and 1 N hydrochloric acid. The organic layer was separated, washed twice with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 30% ethyl acetate/70% hexane to ethyl acetate) of the residue provided 2.1 g (63%) of the title compound as a yellow oil. TQF MS ES+ exact mass calculated for C40H46NO7 (p+1): m/z=652.3274. Found: 652.3270. IR (CHCl3, cm−1) 2965, 1720, 1605. Anal. Calcd for C40H45NO7: C, 73.71; H, 6.96; N, 2.15. Found: C, 73.72; H, 6.95; N, 2.18.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([O:13][CH2:14][O:15][CH3:16])=[CH:10][CH:9]=[CH:8]2)[CH3:2].CN(C)[CH:19]=[O:20].O>CCOCC.CCCCCC.C([Li])CCC>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([O:13][CH2:14][O:15][CH3:16])=[C:10]([CH:19]=[O:20])[CH:9]=[CH:8]2)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCc1cccc2cccc(OCOC)c12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: CCc1cccc2ccc(C=O)c(OCOC)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
300 g of 8-ethyl-1-methoxymethoxynaphthalene was dissolved in 2.2 liters of absolute ether, in which 1.3 liters of a hexane solution of 1.6M n-butyl lithium was gently dropped at -20° C. in a stream of nitrogen. After the dropping, the solution was raised to room temperature and agitated for 2 hours. It was again cooled down to -40° C., to which 215 ml of N,N-dimethylformamide was added. After agitation for 30 minutes, 100 ml of water was added and the resultant organic phase was washed with a saturated saline solution. After drying with anhydrous magnesium sulfate, the solvent was distilled off and the residue was purified by silica gel column chromatography (5% ethyl acetate/hexane) to obtain 253 g of the captioned compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[N:21]=[C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:23][C:24]=2[C:25]([F:28])([F:27])[F:26])=[O:19])=[CH:13][N:12]=1)[C:5](O)=[O:6].[CH3:35][O:36][C:37](=[O:43])[C@@H:38]([NH2:42])[CH:39]([CH3:41])[CH3:40].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:35][O:36][C:37](=[O:43])[CH:38]([NH:42][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[N:21]=[C:22]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:23][C:24]=3[C:25]([F:27])([F:26])[F:28])=[O:19])=[CH:13][N:12]=2)=[C:2]([Cl:1])[CH:3]=1)[CH:39]([CH3:41])[CH3:40]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(O)c1ccc(-c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1ccc(-c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)c(Cl)c1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
A mixture of 3-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid (50 mg, 0.1 mmol), (S)-2-amino-3-methyl-butyric acid methyl ester (17 mg, 0.1 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (21 mg, 0.15 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (30 mg, 0.15 mmol) in anhydrous dichloromethane (3 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried and concentrated to give a solid. The solid was purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 0%-100% ethyl acetate in hexane) to give 2-(3-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoylamino)-3-methyl-butyric acid methyl ester (41 mg, 66%) as a white solid. LCMS calcd for C29H24ClF3N4O5 (m/e) 600, obsd 601 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=[O:10])[S:5][C:6]=1[CH2:7][CH3:8].C(Cl)(=O)C(Cl)=O.N1C=C[CH:21]=[CH:20][CH:19]=1.C(O)(C)C>ClCCl.CN(C)C=O>[CH2:7]([C:6]1[S:5][C:4]([C:9]([O:11][CH:20]([CH3:21])[CH3:19])=[O:10])=[CH:3][C:2]=1[Br:1])[CH3:8]
Reactant: c1ccncc1
Reactant: CCc1sc(C(=O)O)cc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1sc(C(=O)OC(C)C)cc1Br
Yield: 48.1 %

Procedure:
A solution of 7 g (30 mmol) of 4-bromo-5-ethylthiophene-2-carboxylic acid was dissolved in dry dichloromethane (200 mL) and treated with oxalyl chloride (3.2 mL, 36 mmol) and dimethylformamide (0.5 mL) for 18.5 h. The solvents were removed in vacuo and the residual brown oil was passed through silica gel (2 inches in a 350 mL scintered-glass Büchner funnel) and eluted with 700 mL of hexanes:ethyl acetate 9/1 (v:v). The elutate was concentrated in vacuo and the oil dissolved in dry dichloromethane (200 mL). This solution was treated with pyridine (12 mL, 150 mmol) and dry isopropanol (60 mL, 750 mmol) for 4 h at room temperature. The solvents were removed in vacuo and the residue partioned between dichloromethane (100 mL) and water (200 mL). The aqueous layers were extracted with dichloromethane (2×30 mL). The combined organic layers were extracted with sodium bicarbonate (2×30 mL), brine (30 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. Purification by column chromatography on silica gel (250 g) eluting with hexanes:ethyl acetate 95/5 (v:v) gave isopropyl 2-ethyl-3-bromo-thiophene-5-carboxylate (4 g, 48%) as a yellow oil. 1H-NMR (DMSO-d6; 300 MHz) δ7.66 (s, 1H), 5.89 (septet, 1H, J=6.2 Hz), 2.80 (q, 2H, J=7.5 Hz), 1.29 (d, 6H, J=6.0 Hz), 1.24 (t, 3H, J=7.5 Hz).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]([O:15][C:16]1[C:23]([O:24][CH3:25])=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[Br:26])[CH:13]=[CH2:14].[C:27](#[N:31])[CH2:28][C:29]#[N:30].N1CCCCC1>C(O)C.O>[NH2:31][C:27]1[O:11][C:1]2[C:2]([CH:20]([C:19]3[CH:22]=[C:23]([O:24][CH3:25])[C:16]([O:15][CH2:12][CH:13]=[CH2:14])=[C:17]([Br:26])[CH:18]=3)[C:28]=1[C:29]#[N:30])=[CH:3][CH:4]=[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=21
Reactant: Oc1cccc2ccccc12
Reactant: N#CCC#N
Reactant: C=CCOc1c(Br)cc(C=O)cc1OC
Solvent: C1CCNCC1
Solvent: O
Solvent: CCO
Product: C=CCOc1c(Br)cc(C2C(C#N)=C(N)Oc3c2ccc2ccccc32)cc1OC
Temperature: 80 °C
Yield: 80 %

Procedure:
1-Naphthol (170 mg, 1.2 mmol), 4-allyloxy-3-bromo-5-methoxy-benzaldehyde (271 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 μl) and then stirred at 80° C. under LC-MS control till the reaction was complete. The reaction mixture was then cooled down to room temperature, diluted with 10 ml water, stirred for 2 h at room temperature, solids were collected by filtration, washed well with 1:1 mixture of ethanol/water and dried under high vacuum yielding 370 mg (0.8 mmol, 80%) of the title compound.