Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]([N:16]([CH3:18])[CH3:17])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:19][C:20]([F:36])([F:35])[C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29]([OH:31])=[O:30])[N:22]=1.[ClH:37]>O1CCOCC1>[CH3:17][N:16]([CH3:18])[CH:13]([C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:9][CH:10]=1)[CH2:14][NH:15][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([C:23]2[N:22]=[C:21]([C:20]([F:36])([F:35])[F:19])[O:25][N:24]=2)[CH:27]=1.[ClH:37].[CH3:17][N:16]([CH3:18])[CH:13]([C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:9][CH:10]=1)[CH2:14][NH:15][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([C:23]2[N:22]=[C:21]([C:20]([F:19])([F:36])[F:35])[O:25][N:24]=2)[CH:27]=1
Reactant: CN(C)C(CN)c1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccc(F)cc2)n1

Procedure:
N-(2-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide was synthesized from 1-(2-(4-fluorophenyl)oxazol-4-yl)-N1,N1-dimethylethane-1,2-diamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6. The free base was then stirred with HCl in dioxane solution (4 mL) for 0.5 h at 0° C. to room temperature. The reaction mixture was concentrated and triturated with diethyl ether to afford N-(2-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide hydrochloride (130 mg, yield 16%) as light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (br s, 1H), 9.18-9.15 (t, J=5.6 Hz, 1H), 8.55-8.54 (m, 2H), 8.27-8.25 (m, 1H), 8.21-8.19 (m, 1H), 8.11-8.07 (m, 2H), 7.79-7.75 (t, J=7.8 Hz, 1H), 7.45-7.41 (t, J=8.9 Hz, 2H), 4.84-4.81 (t, J=6.1 Hz, 1H), 4.20-4.13 (m, 1H), 3.87-3.82 (m, 1H), 2.87-2.84 (dd, J=6.9 Hz, 5.0 Hz, 6H). MS (ESI) m/z: Calculated for C23H19F4N5O3: 489.14. found: 490.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.CN(C1CCCCC1)C.[Cl:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([NH2:30])[C:26]=1[C:27]([OH:29])=[O:28]>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:30][C:25]2[C:26](=[C:21]([Cl:20])[CH:22]=[CH:23][CH:24]=2)[C:27]([OH:29])=[O:28])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1cccc(Cl)c1C(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C1CCCCC1
Product: O=C(Nc1cccc(Cl)c1C(=O)O)c1ccc(F)cc1
Temperature: 30 °C
Reaction time: 0.33 h

Procedure:
17.5 parts of 4-fluorobenzoyl chloride and 14 parts of N,N-dimethylcyclohexylamine are introduced simultaneously, from 2 feeds, into a solution of 17.1 parts of 6-chloroanthranilic acid in 230 parts of ethyl acetate at from 10° to 20° C., and the mixture is then stirred for 20 minutes at 30° C. Thereafter, the reaction mixture is washed once with 1 N hydrochloric acid and then with water, a colorless precipitate being formed. The latter is dissolved in ethyl acetate, and the organic phase is again washed with 1 N hydrochloric acid and then with water, dried over magnesium sulfate and evaporated down; 29 parts of N-(4'-fluorobenzoyl)-6-chloroanthranilic acid, of melting point 228°-233° C., are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][S:15][S:16][CH3:17])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:19][C:20]#[N:21].C(NC(C)C)(C)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][S:15][S:16][CH3:17])[C:10]([O:12][CH2:19][C:20]#[N:21])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCCl
Reactant: CSSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSSCC[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N
Reaction time: 8 h
Yield: 63 %

Procedure:
Boc-L-Hcm-OH (43 mg, 153 μmol) was dissolved in THF (1 mL). To the solution were added chloroacetonitrile (484 μL, 7.65 mmol) and diisopropylamine (53 μL, 306 μmol). The mixture was stirred overnight under N2 atmosphere. After 18 h, additional chloroacetonitrile (484 L, 7.65 mmol) was added. Concentration under reduced pressure followed by flash chromatography over silica gel with AcOEt-Hexane (3:1) gave the titled compound in (31.3 mg, 63% yield): 1H NMR (360 MHz, CDCl3) δ 5.02 (s, 1H), 4.73 (dd, J=31.3 Hz, 2H) 4.49 (s, 1H), 2.77-2.73 (m, 2H), 2.37 (m, 3H), 2.37-2.27 (m, 1H), 2.13-2.02 (m, 1H), 1.46 (s, 9H); LRMS (ESI) m/z calcd for C12H21N2O4S2 (M+H)+ 321.1. found 321.0.
Reaction SMILES: CI.[CH2:3]([C:6]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10]([CH3:19])([CH3:18])[C:11]2=[O:17])[CH:4]=[CH2:5].[C:20](=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.O>[CH2:3]([C:6]1[C:15]([O:16][CH3:20])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10]([CH3:19])([CH3:18])[C:11]2=[O:17])[CH:4]=[CH2:5]
Reactant: C=CCc1c(O)ccc2c1CCC(C)(C)C2=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: C=CCc1c(OC)ccc2c1CCC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
575 μl of methyl iodide was added to a mixture consisting of 1.06 g of 5-allyl-6-hydroxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one, 0.77 g of potassium carbonate, and 10 ml of N,N-dimethylformamide. The obtained mixture was stirred at room temperature under nitrogen atmosphere overnight. Water and ethyl acetate were added to the reaction solution, so as to obtain an organic layer. The obtained organic layer was washed with water (5 times) and a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 1.09 g of the subject compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.C([Li])(C)(C)C.B(OC)(OC)[O:16]C.C(OO)(=O)C.S(=O)(O)[O-].[K+]>CCOCC>[Cl:9][C:4]1[CH:3]=[C:2]([OH:16])[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: COB(OC)OC
Agent: CC(=O)OO
Agent: O=S([O-])O
Agent: [K+]
Solvent: CCOCC
Product: Oc1cc(F)cc(Cl)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-bromo-3-chloro-5-fluorobenzene (16 g, 76 mmol) in 250 mL of anhydrous ether at −78° C. was added tert-butyllithium (1.7 M, 100 mL, 170 mmol). After stirring at −78° C. for 1 h, trimethyl borate (20 mL, 176 mmol) was added, and the reaction was allowed to warm to room temperature overnight. The resulting mixture was cooled to −10° C., and was added peracetic acid (32% in acetic acid, 35 mL). After stirring at 0° C. for 30 min, potassium bisulfite (5 g) was added. After stirring at room temperature for 30 min, the aqueous layer was separated and the organic mixture was extracted with 3 M aqueous sodium hydroxide (3×100 mL). The aqueous extracts were acidified with concentrated hydrochloric acid (pH=2), and was extracted with ether (3×150 mL). The combined ether extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to afford the crude phenol, which was azeotroped with heptane (100 mL) to remove traces of acetic acid to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.51 (br s, 1H), 7.35 (br d, 1H), 7.21 (m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([N:24]3[CH2:29][CH2:28][CH:27]([N:30]4[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[CH2:33][O:32][C:31]4=[O:40])[CH2:26][CH2:25]3)=[O:23])=[C:17]([O:41][CH2:42][C:43]([F:46])([F:45])[F:44])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([N:24]3[CH2:29][CH2:28][CH:27]([N:30]4[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[CH2:33][O:32][C:31]4=[O:40])[CH2:26][CH2:25]3)=[O:23])=[C:17]([O:41][CH2:42][C:43]([F:46])([F:44])[F:45])[CH:16]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)OCc5ccccc54)CC3)c(OCC(F)(F)F)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(OC2CCNCC2)cc1OCC(F)(F)F)N1CCC(N2C(=O)OCc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Into a stirred solution of 1-(1-(4-(1-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)piperidin-4-yl)-4H 3,1-benzoxazin-2(1H)-one (3.5 g, 5.4 mmol) from Example 1 in EtOAc (125 mL) at 0° C. was bubbled HCl gas for 15 min. The resulting suspension was stirred at 0° C. for 45 min. Excess HCl was removed by bubbling argon though the mixture for 15 min. Ether (125 mL) was added and the cold suspension was filtered. The solids were washed with additional ether and then dried under reduced pressure for 18 h to give the hydrochloride salt of the title compound as an amorphous white powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:30])[CH:27]([NH2:29])[CH3:28]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:29][CH:27]([CH3:28])[CH2:26][NH2:30])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: CC(N)CN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(C)CN)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and propane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (dd, J=7.83, 1.01 Hz, 1 H), 7.82 (d, J=7.33 Hz, 1 H), 7.69-7.56 (m, 2 H), 7.46-7.38 (m, 2 H), 7.28 (dd, J=8.46, 1.64 Hz, 1 H), 6.11-5.96 (m, 1 H), 5.13 (s, 2 H), 3.66-3.49 (m, 2 H), 3.30-3.20 (m, 3 H), 2.47-2.39 (m, 3 H), 2.24-2.19 (m, 2 H), 1.32-1.22 (m, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[I:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27].FC1C=C(C[C@H](NC(=O)OCC2C=CC=CC=2)[C@H]2CO2)C=C(F)C=1>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]([OH:12])[CH2:13][NH:27][CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([I:22])[CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Reactant: NCc1cccc(I)c1
Agent: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1)OCc1ccccc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cccc(I)c1

Procedure:
tert-Butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, PREPARATION 3, 1.75 g, 5.8 mmole) is mixed with isopropanol (30 ml). The reaction flask is charged with 3-iodobenzylamine (VI). The reaction mixture is heated to reflux for 45 minutes, HPLC analysis indicates complete disappearance of the epoxide (V). The reaction mixture is concentrated under reduced pressure and the residue is partitioned between ethyl acetate (150 ml) and aqueous hydrochloric acid (3%, 35 ml). The organic phase is separated and washed with aqueous hydrochloric acid (3%, 20 ml), bicarbonate, saline and dried over sodium sulfate. Concentration under reduced pressure gives the title compound, M+H=535.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5](/[CH:6]=[CH:7]/[C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[N:9]=2)=[CH:4][CH:3]=1.[OH:17][C:18]([CH3:33])([CH3:32])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[O:30][CH3:31].CN(C)CCN(C)C.B(O)O.O.CO.FC(C(O)=O)(F)F>CO.O.C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]2[CH:13]=[CH:12][N:11]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:18]([OH:17])([CH3:33])[CH3:32])=[C:22]([O:30][CH3:31])[CH:23]=3)[C:10](=[O:14])[N:9]=2)=[CH:15][CH:16]=1
Reactant: O=c1nc(/C=C/c2ccc(Cl)cc2)cc[nH]1
Reactant: COc1cc(B(O)O)ccc1OCC(C)(C)O
Agent: [Cu+2]
Agent: [Cu]
Agent: CC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1cc(-n2ccc(/C=C/c3ccc(Cl)cc3)nc2=O)ccc1OCC(C)(C)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred mixture of (E)-4-(4-chlorostyryl)pyrimidin-2(1H)-one Part A (21 mg, 0.09 mmol), 4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenylboronic acid Part D of Procedure 4 (43 mg, 0.18 mmol) and copper (II) acetate (16.39 mg, 0.090 mmol) in MeOH (2 mL) and H2O (0.5 mL) was added N1,N1,N2,N2-tetramethylethane-1,2-diamine (21 mg, 0.18 mmol) at RT. After stirring at RT for 45 min under oxygen, the reaction diluted with CH2Cl2 and washed sequentially with 5% aq. sulfuric acid and sat. NaHCO3. The organic phase was dried (MgSO4) and concentrated. LC/MS showed incomplete reaction (starting pyrimidinone:desired product=ca. 4:1). The crude product mixture was resubjected to the above reaction conditions using another 2 equivalents of the boronic acid, copper salt and N1,N1,N2,N2-tetramethylethane-1,2-diamine After the above described workup, the crude product mixture was subjected to preparative HPLC (ODS column/water-MeOH-TFA 90:10:0.1 to 10:90:0.1 gradient) to afford a brown solid. Further purification was achieved by dissolution of this solid in a few drops of MeOH followed by addition of MTBE (ca. 1 mL) which upon standing at RT induced the formation of a yellow precipitate. The precipitated yellow solid was isolated to afford the title compound (E)-4-(4-chlorostyryl)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-2(1H)-one B-6 (8 mg, 0.018 mmol, 20% yield) as a yellow solid. LC/MS 427 (M+H)+, tR 0.84 min (method 5); 1H NMR (400 MHz, chloroform-D) δ 7.91 (1H, d, J=16.06 Hz), 7.69 (1H, d, J=6.78 Hz), 7.54 (2H, d, J=8.28 Hz), 7.39 (2H, d, J=8.53 Hz), 6.87-7.01 (4H, m), 6.49 (1H, d, J=6.78 Hz), 3.87 (3H, s), 3.85 (2H, s), 1.36 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:6][C:3]=1[C:4]#[N:5].C([OH:27])(CC)(C)C>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[CH:6][C:3]=1[C:4]([NH2:5])=[O:27]
Reactant: COc1cc(N)c(C#N)cc1OCCCN1CCOCC1
Reactant: CCC(C)(C)O
Solvent: ClCCl
Product: COc1cc(N)c(C(N)=O)cc1OCCCN1CCOCC1
Temperature: 79 °C

Procedure:
After repetition of the reduction step, a methylene chloride solution (894.3 kg) containing 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile (81.6 kg) was added portionwise to tert-amyl alcohol (186 kg) and the resultant mixture was distilled until the temperature of the distillate reached 57° C. Additional tert-amyl alcohol (726 kg) was added portionwise and distillation was continued until the residual volume of the reaction mixture was approximately 770 liters. Potassium hydroxide (flaked form; 51 kg) was added and the mixture was heated to 79° C. for 4 hours. The resultant mixture was cooled to ambient temperature to provide a solution of 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzamide which was used without being isolated.
Reaction SMILES: [C:1]([O:5][C:6]1C=CC(C2C=CC=C(F)C=2F)=CC=1)(=O)C=C.[F:20][C:21]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:22]=1[OH:28].C1C(O)=CC=C(Br)C=1>>[Br:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH2:1][O:5][CH3:6])=[C:21]([F:20])[CH:26]=1
Reactant: C=CC(=O)Oc1ccc(-c2cccc(F)c2F)cc1
Reactant: Oc1ccc(Br)cc1F
Agent: Oc1ccc(Br)cc1
Product: COCOc1ccc(Br)cc1F
Yield: 86.4 %

Procedure:
The same procedure as in the synthesis (a) of Example 1 was repeated except that 43.9 g of 2-fluoro-4-bromophenol were used instead of 40 g of p-bromophenol to give 46.7 g (Y., 86.4%) of methoxymethy 4-bromo-2-fluorophenyl ether. GC; 97.2% b.p.; 118°-120° C./14 mmHg
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1(C)C=CC=CC=1.[CH3:39][O:40][C@@H:41]1[C@H:45]2[CH2:46][C@@H:47]3[C@@H:52]([C:53](=O)[C@H:44]2[C@H:43]([CH3:55])[O:42]1)[CH2:51][CH2:50][CH2:49][CH2:48]3.[Cl-].[NH4+]>CCOCC>[CH3:39][O:40][C@@H:41]1[C@H:45]2[CH2:46][C@@H:47]3[C@@H:52]([C:53](=[CH2:2])[C@H:44]2[C@H:43]([CH3:55])[O:42]1)[CH2:51][CH2:50][CH2:49][CH2:48]3
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CO[C@H]1O[C@@H](C)[C@@H]2C(=O)[C@H]3CCCC[C@@H]3C[C@H]12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=C1[C@@H]2[C@H](C[C@H]3CCCC[C@H]13)[C@@H](OC)O[C@H]2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To 9.96 g(5 equivalents) of methyltriphenylphosphonium iodide in 400 ml of dehydrated ether suspension were added dropwise 4.1 ml(5 equivalents) of sodium bis(trimethylsilyl)amide-toluene solution(0.60M) under cooling with ice and under an atmosphere of argon. After stirring for 1 hour at room temperature, 1.17 g of (1S,3S,3aR,4aS,8aR,9aS)-1-methoxy-3-methyl-4-oxo-dodecahydronaphtho[2,3-c]furan(4.93 mmol) in 30 ml of dehydrated ether solution were added dropwise again under cooling with ice. After stirring for 2 hours at room temperature, 50 ml of cold saturated aqueous solution of ammonium chloride were added to the reaction mixture and solvent was distilled off. To the residue were poured 100 ml of saturated brine, which was extracted with ether(50 ml×3). The organic layer was dried over anhydrous magnesium sulfate, filtered and solvent was distilled off. The residue was purified by means of silica gel column chromatography(hexane:ethyl acetate=10:1) to obtain 1.0 g of (1S,3S,3aS,4aS,8aR,9aS)-1-methoxy-3-methyl-4-methylene-dodecahydronaphtho[2,3-c]furan (yield 86%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([NH2:12])[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.CN([CH:25]=[O:26])C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:8][C:6]1[CH:7]=[C:2]2[C:3](=[CH:4][CH:5]=1)[C:9]1([CH2:11][CH2:10]1)[NH:12][C:25]2=[O:26]
Reactant: NC1(c2ccc(F)cc2Br)CC1
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NC2(CC2)c2ccc(F)cc21
Temperature: 130 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
A mixture of 1-(2-bromo-4-fluorophenyl)cyclopropanamine (3.0 g, 17.4 mmol), Pd(dppf)Cl2 (0.4 g), DIPEA (5.05 g, 39.1 mmol) in DMF (40 mL) was stirred in an autoclave under 2 MPa of CO (g) at 130° C. for 16 hours. After it was cooled down to room temperature, the reaction mixture was diluted with EtOAt (300 mL) and washed with brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated under reduced pressure to give a crude product which was purified by chromatography to afford title compound (600 mg, yield 26%) as a brown solid.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][CH3:16])=[C:12]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:11]=[C:10]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([O:32]C3C=CC=CC=3)=O)=[CH:25][CH:24]=2)[N:9]=1)=[O:7])[CH3:4]>O1CCOCC1>[CH2:3]([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][CH3:16])=[C:12]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:11]=[C:10]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:2][CH3:1])=[O:32])=[CH:25][CH:24]=2)[N:9]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc(N2CCOCC2)c1OCC
Reactant: CN
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccc(NC(=O)NC)cc2)nc(N2CCOCC2)c1OCC
Yield: 50 %

Procedure:
2M Methyl amine (1.1 ml, 10 eq.) was added to a stirred solution of 5-ethoxy-6-morpholin-4-yl-2-(4-phenoxycarbonylamino-phenyl)-pyrimidine-4-carboxylic acid ethyl ester (110 mg, 1 eq.) in dioxane (3 ml), and the mixture was reacted at 80° C. overnight. The reaction mixture was concentrated and purified by flash chromatography to give a product (47.5 mg, 50%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:4]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:29][CH2:28][C@:27]([CH:33]([CH3:35])[CH3:34])([C:30](O)=[O:31])[CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[CH:33]([C@:27]1([C:30]([N:12]2[CH2:11][CH2:10][N:9]([C:5]3[CH:4]=[C:3]([C:2]([F:15])([F:1])[F:16])[CH:8]=[CH:7][N:6]=3)[CH2:14][CH2:13]2)=[O:31])[CH2:28][CH2:29][C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:26]1)([CH3:35])[CH3:34]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a solution of 1-[4-(trifluoromethyl)pyridin-2-yl]piperazine (145 mg, 0.627 mmol), (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (140 mg, 0.52 mmol) in methylene chloride (10 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (253 mg, 0.572 mmol) followed by triethylamine (0.156 mL, 1.12 mmol). After being stirred overnight, the reaction mixture was diluted with EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried (MgSO4), concentrated and purified by flash chromatography on silica gel (20% EtOAc/hexanes to 40% EtOAc/hexanes) to give 0.15 g of desired product. MS calculated for C24H35F3N4O3: (M+H) 485; found 385.2 (M-Boc+H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:25](OC)[O:26]C)=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:25]=[O:26])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C(OC)OC)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(C)=O
Product: COC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 34 %

Procedure:
To a solution of dimethyl 2-methyl-4-(3-nitrophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (7.5 g) in acetone (75 ml) was added 6 N hydrochloric acid (7.5 ml) and the mixture was stirred at room temperature for 6 hours. The pricipitates which were separated out during the reaction course were collected by filtration to give yellowish crystals of dimethyl 2-methyl-4-(3-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.26 g), and the filtrate was adjusted to pH 7.5 to 8 with an aqueous sodium bicarbonate solution, and the acetone was distilled off under reduced pressure to give additional crops of orange-yellow crystals (3.84 g) of the same product (total yield, 6.1 g). A small portion of the first crop was recrystallized from methanol to give pure crystals,
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][O:10][CH3:11])=[CH:4][CH:3]=1.[CH:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH3:11][O:10][CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]([OH:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:3][CH:4]=1
Reactant: CCCCCCCC=O
Reactant: COC=Cc1ccc(Br)cc1
Product: CCCCCCCC(O)c1ccc(C=COC)cc1

Procedure:
By the method of example 28, 1-bromo-4-(2-methoxyethenyl)benzene is prepared, lithiated, and reacted with octanal to provide 1-(4-(2-methoxyethenyl)phenyl)-1-octanol as a yellow oil after chromatography. The hydroxyl group is protected as the t-butyldimethylsilyl ether in the usual fashion, and the enol ether is then cleaved with chlorotrimethylsilane and sodium iodide as described in example 33. The resulting aryl acetaldehyde is obtained as an oil, and is immediately condensed with glyoxylic acid, by the method described in example 1(C). Under the reaction conditions, the silyl ether is simultaneously eliminated, and chromatography provides the title compound as a tan solid, mp 98°-99° after trituration with hot hexane.