Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16](=[O:22])[CH2:15][CH2:14]3)[CH2:6]1)=O.[CH3:23][NH2:24]>CO>[CH3:23][NH:24][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16](=[O:22])[CH2:15][CH2:14]3)[CH2:6]1)=[O:2]
Reactant: CN
Reactant: COC(=O)C1CN(c2ccc3c(c2)CCC(=O)N3C)C(=O)O1
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2ccc3c(c2)CCC(=O)N3C)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a stirred solution of 3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester (EXAMPLE 67, Step 4, 150 mg, 0.49 mmol) in MeOH (2 mL) is added MeNH2 (2 mL, 4.0 mmol, 2.0 M solution in MeOH). The reaction mixture is then stirred for 30 minutes at room temperature. Solvent is removed and the residue is washed with ether to give the title compound as a white solid (120 mg, 80%), 1H NMR (300 MHz, DMSO) a 8.37 (d, 1H), 7.44–7.07 (m, 3H), 5.04 (dd, 1H), 4.25 (t, 1H), 3.99 (dd, 1H), 3.23 (s, 3H), 2.86 (t, 2H), 2.65 (d, 3H), 2.50 (m, 2H); MS for C15H17N3O4 m/z 304.5 (M+H)+.
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[Cl:28].Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1ccc(Cl)c(Cl)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.90 g, 5.0 mmole), triethylamine (0.50 g, 5.0 mmole) and 4-(dimethylamino)pyridine (0.61 g, 5.0 mmole) in dry dichloromethane (100 mL) was added a solution of 3,4-dichlorophenyl isocyanate (0.94 g, 10.0 mmole) in dry dichloromethane (25 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 24 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a beige solid (1.07 g, 58% yield), mp=89–91° C.; MS (−) ESI m/z=366 (M−H)−; [α]D25=+25.9° (c=1, EtOH).
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=O)[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[CH2:13]([NH2:17])[CH2:14][CH:15]=[CH2:16]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:13]([N:17]1[C:1](=[O:12])[CH2:2][C:3]2[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:7])[CH2:14][CH:15]=[CH2:16]
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: C=CCCN
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=CCCN1C(=O)Cc2ccccc2C1=O
Temperature: 160 °C
Yield: 37.7 %

Procedure:
Homophthalic anhydride (1.5 g, 9.25 mmol), 3-buten-1-amine (1.129 ml, 11.10 mmol), and 4 A molecular sieves (300 mg) were combined in toluene (15 ml) and heated to 160° C. in a microwave for 40 minutes. The reaction mixture was diluted with CH2Cl2 and the slurry was filtered over CELITE. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (gradient elution, 10-20% EtOAc/Hexane) to afford the title compound (0.75 g, 36%) as an oil. LCMS (ES+) m/z 216.03 (M+H)+.
Reaction SMILES: [CH2:1]([C:11]1[O:12][CH2:13][CH2:14][N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[CH3:16][O:17][SiH:18]([O:21][CH3:22])[O:19][CH3:20]>>[CH3:16][O:17][Si:18]([O:21][CH3:22])([O:19][CH3:20])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][C:11]1[O:12][CH2:13][CH2:14][N:15]=1
Reactant: CO[SiH](OC)OC
Reactant: C=CCCCCCCCCC1=NCCO1
Product: CO[Si](CCCCCCCCCCC1=NCCO1)(OC)OC

Procedure:
wherein 2-(9-decenyl)-1,3-oxazoline is reacted with trimethoxysilane to form 2-[10-(trimethoxysilyl)decyl]-1,3-oxazoline.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH2:9][CH2:10][CH3:11].[NH2:14][C:15]1[S:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][N:19]=1>ClCCl>[CH:20]([C:17]1[S:16][C:15]([NH:14][C:8](=[O:12])[CH2:9][CH2:10][CH3:11])=[N:19][CH:18]=1)([CH3:22])[CH3:21]
Reactant: CCCC(=O)Cl
Reactant: CC(C)c1cnc(N)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)Nc1ncc(C(C)C)s1
Temperature: -5 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
Triethylamine (0.97 ml; 6.34 mmol) and butanoyl chloride (0.52 ml; 5.07 mmol) were added in this order to a solution of 2-amino-5-isopropyl-1,3-thiazole (0.6 g; 4.23 mmol) in dichloromethane (8 ml), cooled to −5° C. The reaction mixture was stirred at −5° C. for 2 hours and then warmed to room temperature. After additional 4 hours, the organic layer was washed with water, saturated sodium bicarbonate, 1N hydrochloric acid, brine, dried over sodium sulfate and evaporated. The residue was recrystallized from cyclohexane to yield 0.45 g (50%) of the title compound as a colourless solid (m.p. 95–97° C.)
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]([OH:12])(=[O:11])[C:8]([OH:10])=[O:9].[N:13]1([CH2:18][C:19]#[C:20][C:21]2[CH:50]=[CH:49][C:24]([CH2:25][C:26]3[C:27]4[CH:48]=[CH:47][CH:46]=[CH:45][C:28]=4[S:29][C:30]=3[C:31]3[CH:44]=[CH:43][C:34]([O:35][CH2:36][CH2:37][N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[CH:33][CH:32]=3)=[CH:23][CH:22]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]([OH:12])(=[O:11])[C:8]([OH:10])=[O:9].[N:13]1([CH2:18]/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][C:24]([CH2:25][C:26]3[C:27]4[CH:48]=[CH:47][CH:46]=[CH:45][C:28]=4[S:29][C:30]=3[C:31]3[CH:44]=[CH:43][C:34]([O:35][CH2:36][CH2:37][N:38]4[CH2:39][CH2:40][CH2:41][CH2:42]4)=[CH:33][CH:32]=3)=[CH:49][CH:50]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C(#Cc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1)CN1CCCC1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Product: C(=C/c1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1)\CN1CCCC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 439.6 %

Procedure:
A solution of 1-[2-(4-[3-[4-[3-(1-pyrrolidinyl)-1-propynyl]benzyl]benzo[b]thiophen-2-yl]phenoxy]ethyl]pyrrolidine (Example 129, Part D; 95 mg, 0.182 mmol) in 1.5 mL of toluene was treated with DIBAL-H (455 mL, 0.455 mmol; 1 M in toluene). The resulting mixture was heated at 40° C. for 3 h. The reaction mixture was cooled to 0° C. and quenched with excess MeOH. Saturated K+Na+ tartrate solution and EtOAc (10 mL each) were added, and the biphasic mixture was vigorously stirred for 2 h. The layers were separated, and the aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification by radial chromatography (SiO2; 98:1.5:0.5 CHCl3—MeOH—NH4OH) afforded 42 mg (0.80 mmol, 44%) of a pale yellow oil which was converted to the dioxalate salt according to the methods detailed in Example 1, Part C.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[F:11][C:12]([F:21])([F:20])[C:13]#[C:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>ClCCl>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]1[C:13]([C:12]([F:11])([F:21])[F:20])=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:1][N:2]=1
Reactant: CCOC(=O)C#CC(F)(F)F
Reactant: ON=C(Cl)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1onc(-c2ccccn2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.7 %

Procedure:
To a yellow, homogeneous mixture of N-hydroxypicolinimidoyl chloride (4.67 g, 29.8 mmol) and ethyl 4,4,4-trifluorobut-2-ynoate (4.50 g, 27.1 mmol) in dichloromethane (90 mL) at room temperature was added triethylamine (7.93 mL, 56.9 mmol) slowly over 30 min. During the addition, the reaction mixture slowly became dark in color. The reaction was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was diluted with ether (100 mL) and washed with water (100 mL). The organic layer was collected, and the aqueous layer was extracted with ether (2×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. By HPLC, the product mixture contained a ˜15:85 mixture of the desired isomer and its regioisomer. The mixture was purified by preparative HPLC, and the desired fractions were concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), washed with a saturated aqueous solution of sodium bicarbonate (100 mL), washed with brine (50 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded ethyl 3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylate (0.518 g, 1.81 mmol, 6.7% yield) as a pale yellow, viscous oil. The compound had an HPLC ret. time=2.18 min.—Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=286.9. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (t, J=7.15 Hz, 3H), 4.54 (q, J=7.03 Hz, 2H), 7.46 (ddd, J=7.53, 4.77, 1.25 Hz, 1H), 7.76-7.81 (m, 1H), 7.83-7.89 (m, 1H), and 8.78 (d, J=4.77 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[C:13](OCC)(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[N+:10]([C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:1][C:13](=[O:20])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4]2)([O-:12])=[O:11]
Reactant: Nc1ccc([N+](=O)[O-])cc1C=O
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]c1=O

Procedure:
A solution of 10.0 g (46 mmol) of 1,2-dihydro-2-oxo-3-quinolinecarboxylic acid, ethyl ester [J. Chem. Soc., 2518 (1962)] and 50 ml of sulfuric acid is stirred in an ice bath and a cold mixture of 9.75 ml of 70% nitric acid and 9.75 ml of sulfuric acid is added dropwise over 10 minutes. The reaction solution is stirred with ice bath cooling for 1 hour and then is poured into ice and water with stirring. The resulting solid is collected by filtration and washed with water and ethanol. After drying, 10.7 g of the requisite ester is obtained, mp>310°. The structure is assigned by an unequivocal synthesis from the condensation of 2-amino-5-nitrobenzaldehyde and diethyl malonate to give the same 1,2-dihydro-6-nitro-2-oxo-3-quinolinecarboxylic acid, ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:8])[NH2:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)[O:22][C:20](=O)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15]C1=2)=O>C(Cl)Cl>[O:22]=[CH:20][CH2:19][CH:18]1[CH2:15][CH:16]([NH:7][C:6](=[O:8])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:17]1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(N)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC(CC=O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.5 %

Procedure:
To a solution of 3-(2-hydroxy-ethyl)-cyclobutyl]-carbamic acid tert-butyl ester (5.2 g, 24.1 mmol) in anhydrous DCM (100 mL) was added Dess-Martin periodinane (20.5 g, 48.3 mmol) and stirred at room temperature for 5 hrs. The mixture was quenched with Na2S2O3 solution, extracted with DCM. The organic phase was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (eluted with PE:EA=5:1) to give the title compound (2.7 g, yield 52%) as an oily liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([OH:15])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.Cl[Si:24]([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>O1CCCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([Si:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([O:15][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:17][CH:18]=1
Reactant: O[Si](Cn1ccnc1)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)O[Si](Cn1ccnc1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.5 g (0.0047 mol) of bis(4-fluorophenyl)hydroxy(1H-imidazol-1-ylmethyl)silane in 20 ml of tetrahydrofuran was added 0.8 ml (0.0063 mol) of chlorotrimethylsilane. A solution of 0.8 ml (0.0057 mol) of triethylamine in 5 ml of tetrahydrofuran is added dropwise, giving a thick white precipitate. The mixture is stirred overnight at room temperature, then filtered and concentrated to an oil. The residue is taken up in ether, filtered, and the filtrate is evaporated to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH:4]=[C:5]1[CH:10]2[C:11]([CH3:13])([CH3:12])[C:7]([CH3:14])([CH2:8][CH2:9]2)[C:6]1=[O:15].[OH:20][S:21](O)(=[O:23])=[O:22].O=S(=O)=O>>[CH3:1][C:2]1[C:3]([CH:4]=[C:5]2[CH:10]3[C:11]([CH3:12])([CH3:13])[C:7]([CH3:14])([CH2:8][CH2:9]3)[C:6]2=[O:15])=[CH:16][C:17]([S:21]([OH:23])(=[O:22])=[O:20])=[CH:18][CH:19]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccccc1C=C1C(=O)C2(C)CCC1C2(C)C
Agent: O=S(=O)=O
Product: Cc1ccc(S(=O)(=O)O)cc1C=C1C(=O)C2(C)CCC1C2(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
25.4 g of 3-o-methylbenzylidene camphor are dissolved with stirring in 84 ml of oleum containing 20% by weight SO3 with cooling so as to maintain the temperature below 25° C. Stirring of the resulting reaction mixture is continued for an additional 30 minutes at ambient temperature at which time it is poured into 200 ml of crushed ice. The precipitate which forms is filtered and crystallized in 100 ml of acetone to produce white crystals melting at 130° C. and corresponding to the dihydrate.
Reaction SMILES: C(OC(N1CCC2C3C=CC(S(C4C=CC=C(O)C=4)(=O)=O)=CC=3OC2C1)=O)(C)(C)C.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]2[C:44]3[CH:50]=[CH:49][C:48]([S:51]([C:54]4[CH:59]=[C:58]([O:60][CH:61]([CH3:63])[CH3:62])[CH:57]=[C:56]([O:64]CC5C=CC=CC=5)[CH:55]=4)(=[O:53])=[O:52])=[CH:47][C:45]=3[O:46][CH:40]2[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]2[C:44]3[CH:50]=[CH:49][C:48]([S:51]([C:54]4[CH:59]=[C:58]([O:60][CH:61]([CH3:62])[CH3:63])[CH:57]=[C:56]([OH:64])[CH:55]=4)(=[O:53])=[O:52])=[CH:47][C:45]=3[O:46][CH:40]2[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)Oc1cc(OCc2ccccc2)cc(S(=O)(=O)c2ccc3c(c2)OC2CN(C(=O)OC(C)(C)C)CCC32)c1
Agent: CC(C)(C)OC(=O)N1CCC2c3ccc(S(=O)(=O)c4cccc(O)c4)cc3OC2C1
Product: CC(C)Oc1cc(O)cc(S(=O)(=O)c2ccc3c(c2)OC2CN(C(=O)OC(C)(C)C)CCC32)c1

Procedure:
Synthesized as described for 7-(3-Hydroxy-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester D01 starting from 7-(3-benzyloxy-5-isopropoxy-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=1[F:23].Cl>[Cu]Br.O1CCOCC1>[F:21][C:20]1[CH:15]=[C:16]([F:23])[CH:17]=[C:18]([F:22])[C:19]=1[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Fc1cc(F)c(Br)c(F)c1
Agent: [Cu]Br
Agent: Cl
Agent: [H-]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1F
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
Diethyl malonate (0.49 mol) was added to a mixture of sodium hydride (0.51 mol) and 1,4-dioxane (140 ml) at 55 to 60° C. within 2 hours. A mixture of 1,4-dioxane (50 ml) and diethyl malonate (0.13 mol) was added. The mixture was stirred for 10 minutes at 55° C. and copper(I) bromide (0.05 mol) was added. After 15 min. a mixture of 2-bromo-1,3,5-trifluorobenzene (0.25 mol) and 1,4-dioxane (10 ml) was added. The reaction mixture was heated at 100° C. for 15 hours and cooled to 15° C. Hydrochloric acid (12N, 35 ml) was added slowly at 15 to 20° C. The precipitate was filtered off. The filtrate was extracted with diethylether. The organic Phase was separated, dried with anhydrous sodium sulphate and filtered. The filtrate was evaporated under reduced Pressure to yield the product.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([NH2:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH:12](=O)[CH:13]([CH3:15])[CH3:14]>>[CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([N:8]=[CH:12][CH:13]([CH3:15])[CH3:14])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1
Reactant: CC(C)C=O
Reactant: CC1(C)CC(N)CC(C)(C)N1
Product: CC(C)C=NC1CC(C)(C)NC(C)(C)C1

Procedure:
21.0 g (0.10 mol) of 2,2,6,6-tetramethyl-4-(isobutylideneamino)-piperidine (b.p. 42°-43°/0.05 mm Hg), obtained by condensation of an equimolecular mixture of 2,2,6,6-tetramethyl-4-aminopiperidine with isobutyraldehyde at 0°, and 13.8 g (0.10 mol) of diethyl phosphite and 0.02 g of sodium ethylate (dissolved in 0.3 ml of ethanol) are heated for 31/2 hours at 90°. The reaction product is dissolved in ether, washed with a saturated sodium chloride solution, dried over potassium carbonate and, after removal of the solvent by distillation, distilled (b.p. 133°/0.4 mm Hg). Diethyl-1-[(2,2,6,6-tetramethyl-4-piperidyl)-amino]-isobutyl-phosphonate is obtained in this manner.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:14]([O:16][C:17](=[O:27])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[CH3:15].CCO>C1COCC1>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:27])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(=O)C=Cc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cccc(F)c1)C(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (1.59 g, 63.1 mmol) in 200 mL THF was added diethyl malonate (10.0 g, 62.4 mmol) gradually. The reaction mixture was stirred for 1 hr at room temperature. 3-(3-Fluorophenyl)acrylic acid ethyl ester (2-1) (11.1 g, 57.2 mmol; prepared via standard procedures from 3-fluorocinnamic acid) and EtOH (5 mL) are added. The mixture was then stirred at 90° C. for 12 hr, concentrated under diminished pressure and treated with 50 mL 10% sodium hydrogencarbonate solution. The aqueous mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried (Na2SO4). After solvent removal, the residue was purified using silica gel flash chromatography (6:1 hexane/EtOAc) to give 2-2 as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:40]=[CH:39][C:18]([C:19]([NH:21][C:22]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:23]=3[C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=3)=[O:25])=[O:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C1(OC)C=CC=CC=1>[F:38][C:35]1[CH:36]=[CH:37][C:22]([NH:21][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([N:11]3[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]3)=[CH:40][CH:39]=2)=[C:23]([CH:34]=1)[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(C(=O)Nc3ccc(F)cc3C(=O)Nc3ccc(Cl)cn3)cc2)CC1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1)c1ccc(N2CCCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-[4-(4-t-butoxycarbonylhexahydro-1,4-diazepin-1-yl)benzoylamino]-5-fluoro-N-(5-chloropyridin-2-yl)benzamide (Example P1, 0.59 g) in methylene chloride (3 mL) and anisole (1 mL) was added trifluoroacetic acid (3 mL) dropwise. The mixture was stirred overnight at room temperature before the solvent was evaporated. The residue was purified by using an SCX column. Yield 0.337 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:25])=[O:24])[CH:18]=1.[OH-].[Na+]>CS(C)=O.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:25])=[O:24])[CH:18]=2)=[C:4]([F:9])[CH:3]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.3 %

Procedure:
4-Amino-2-fluorophenol (9.63 g) was dissolved in dimethyl sulfoxide (100 ml) under a nitrogen atmosphere. Potassium tert-butoxide (9.07 g) was added at room temperature, followed by stirring for 15 min. 4-Chloropyridine-2-carboxamide (7.9 g) was added thereto, followed by stirring at 80° C. under a nitrogen atmosphere for 1 hr. The reaction mixture was allowed to cool down to room temperature. To the reaction mixture was added a 1N aqueous solution of sodium hydroxide (100 ml), then water (100 ml), followed by stirring for 5 hr. The precipitated solid was collected by filtration with suction, and washed with water (50 ml, 4 times). The resultant solid was hot air-dried at 60° C. for 2 days to provide the titled compound as pale brown powder (10.39 g, 83%).
Reaction SMILES: [F:1]/[C:2](=[C:8](/[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][CH3:23])[O:16][C:15]([CH3:25])([CH3:24])[CH:14]=[C:13]2[CH:26]([CH3:28])[CH3:27])\[CH3:9])/[C:3](OCC)=[O:4].[H-].C([Al+]CC(C)C)C(C)C>>[F:1]/[C:2](=[C:8](/[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][CH3:23])[O:16][C:15]([CH3:25])([CH3:24])[CH:14]=[C:13]2[CH:26]([CH3:27])[CH3:28])\[CH3:9])/[CH2:3][OH:4]
Reactant: CCCOc1cc2c(cc1/C(C)=C(/F)C(=O)OCC)C(C(C)C)=CC(C)(C)O2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CCCOc1cc2c(cc1/C(C)=C(/F)CO)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure L, ethyl (2E)-2-fluoro-3-(4-isopropyl-2,2-dimethyl-7-propoxy-2H-chromen-6-yl)-but-2-enoate (Compound 73, 130 mg, 0.33 mmol) and diisobutylaluminum hydride (1M in hexanes, 1.34 mL, 1.34 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).