Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([O:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([O:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[CH2:23][CH2:24][CH2:25][N:26]3[C:30](=[O:31])[C:29]4[C:28](=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:27]3=[O:36])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Clc1ccc(Oc2ccc(OC[C@@H]3CCCN3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCN1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Yield: 61246.2 %

Procedure:
(S)-2-[4-(4-Chloro-phenoxy)-phenoxymethyl]-pyrrolidine (200 mg, 0.658 mmol) was taken into anhydrous DMF (2 mL) in a nitrogen flushed 20 mL vial. N-(3-Bromopropyl)phthalimide (194 mg, 0.724 mmol) was added to the mixture followed by potassium carbonate (364 mg, 2.43 mmol). The reaction was sealed and heated at 60° C. for 24 h. The mixture was then cooled to room temperature and partitioned between ethyl acetate and water. The water layer was washed with ethyl acetate (3×). The combined ethyl acetate layers were then washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was then purified by silica gel flash chromatography (20:1 silica ratio, eluted with 40% methanol in dichloromethane). The overlap from the purification was repurified by silica gel flash chromatography (20:1 silica ratio, eluted with 1% methanol in dichloromethane followed by 5% methanol in dichloromethane) to obtain the title product (198 mg, 403 mmol, 61%); MS; m/z 491 (M); 1H NMR (400 MHz, DMSO-d6) δ 1.5-1.67 (m, 3H), 1.75-1.82 (m, 2H), 1.86-1.91 (m, 1H), 2.13-2.14 (m, 1H), 2.34-2.37 (m, 1H), 2.72-2.73 (m, 1H), 2.89-2.94 (m, 1H), 3.02-3.06 (m, 1H), 3.60-3.70 (m, 3H), 3.88-3.91 (m, 1H), 6.89-6.98 (m, 6H), 7.38 (d, J=9.2, 2H), 7.82-7.85 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][P:26]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=2)=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:34]([N:38]=[C:39]=[O:40])([CH3:37])([CH3:36])[CH3:35]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:39]([NH:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[S:3][C:4]=2[CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][P:26]([O:28][CH2:29][CH3:30])([O:31][CH2:32][CH3:33])=[O:27])=[CH:21][CH:20]=2)=[O:17])=[CH:12][CH:11]=1
Reactant: CCOP(=O)(Cc1ccc(NC(=O)CCc2sc(N)nc2-c2ccc(Cl)cc2)cc1)OCC
Reactant: CC(C)(C)N=C=O
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2sc(NC(=O)NC(C)(C)C)nc2-c2ccc(Cl)cc2)cc1)OCC
Reaction time: 20 h

Procedure:
A mixture of 3-[2-amino-4-(4-chlorophenyl)-5-thiazolyl)-N-[4-(diethylphosphonomethyl)phenyl]propionamide (400 mg), tert-butyl isocyanate (780 mg) and toluene (10 ml) was stirred at 70–80° C. for 20 hrs. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography and 3-(4-(4-chlorophenyl)-2-([(tert-butylamino)carbonyl]amino}-5-thiazolyl)-N-[4-(diethylphosphonomethyl)phenyl]propionamide was obtained as crystals (395 mg, yield: 83%) from a fraction eluted with 3% methanol-ethyl acetate. Recrystallization from ethyl acetate gave colorless prism crystals. melting point: 180–181° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[N:2][OH:3]
Reactant: NO
Reactant: COc1cccc(C=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(C=NO)c1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 103.1 %

Procedure:
A solution of hydroxylamine hydrochloride (10 g, 0.144 mol) in distilled water (20 ml) was added to 20%(w/v) aqueous sodium hydroxide solution (28 ml). 3-Methoxybenzaldehyde (14 ml, 0.12 mol) was added in one portion and the mixture was stirred for 2 hours at 0-5° C. The mixture was adjusted to pH7 and extracted with dichloromethane. The extracts were combined, dried (MgSO4) and the solvent removed by evaporation to give the title compound (18.7 g, 100%) as a colourless oil. NMR (CDCl3): 3.8 (s, 3H), 6.9 (m, 1H), 7.1 (m, 2H), 7.15 (m, 1H), 8.1 (s, 1H), 8.6 (br s, 1H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[CH:21][N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1.CI>O1CCCC1>[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[C:21]([CH3:1])[N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2nc(Cl)ccc21
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2nc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To N,N-diisopropylamine (13 mL, 93 mmol, Aldrich) in tetrahydrofuran (200 mL) at −78° C. was added 1.6 M n-butyllithium in hexanes (55 mL, 88 mmol, Aldrich). The reaction mixture was warmed to 0° C., and the mixture was stirred for 30 minutes. The reaction mixture was cooled to −78° C., and 5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine (17.1 g, 58.4 mmol, from Step 1) in tetrahydrofuran (86 mL) was added dropwise over 30 minutes. The reaction mixture was then stirred for 1 hour at −78° C., and methyl iodide (7.3 mL, 120 mmol, Aldrich) was added dropwise over 5 minutes. The reaction was allowed to warm to 5° C. over 3 hours, then cooled to −20° C. and quenched by the addition of 1 N HCl. EtOAc was added, and the solution was stirred for 15 minutes and left at ambient temperature overnight. The layers were separated and the organic layer was washed sequentially with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a wet orange solid that was then triturated with MeOH (18 mL). The solid was isolated by filtration, washed and dried at 40° C. under high vacuum for 2.2 h to give 14.4 g of product. Additional amount of product was obtained by flash chromatography of the filtrate (eluting with a gradient from 0-40% EtOAc in hexanes) afforded 1.87 g. (Yield: 16.3 g, 91%).
Reaction SMILES: [C:1]([O:9]C)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH:11]1([C:14]([CH3:16])=[O:15])[CH2:13][CH2:12]1.C[O-].[Na+]>C1C=CC=CC=1>[CH:11]1([C:14](=[O:15])[CH2:16][C:1]([C:2]2[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=2)=[O:9])[CH2:13][CH2:12]1
Reactant: COC(=O)c1ccncc1
Reactant: CC(=O)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(CC(=O)C1CC1)c1ccncc1

Procedure:
A mixture of 13.7 g. of methyl isonicotinate, 16.8 g. of cyclopropylmethyl ketone and 6 g. of sodium methoxide in 150 ml. of benzene is heated under reflux for 8 hours. The mixture is filtered and the collected solid is dissolved in water. The aqueous mixture is made weakly acidic with dilute hydrochloric acid and extracted with ether. The ethereal solution is dried over magnesium sulfate and concentrated under reduced pressure to give 1-cyclopropyl-3-(4-pyridyl)-1,3-propanedione as a mobile, yellow liquid, infra-red sectrum 6.15μ (CHCl3, β-diketone).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:33][C:34]1([CH2:39][NH2:40])[CH2:38][CH2:37][NH:36][CH2:35]1>>[NH2:40][CH2:39][C:34]1([F:33])[CH2:38][CH2:37][N:36]([C:2]2[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH2:35]1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Reactant: NCC1(F)CCNC1
Product: NCC1(F)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccn[nH]2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and (3-fluoropyrrolidin-3-yl)methanamine to afford an off-white powder. HPLC (Condition 4) tR=4.3 min, UPLC-MS (Condition 3) tR=0.80 min, m/z=481 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.92-2.10 (m, 2H) 3.03 (d, J=19.94 Hz, 2H) 3.11-3.67 (m, 6H) 6.41 (br. s, 1H) 7.31 (d, J=8.60 Hz, 2H) 7.79-7.91 (m, 3H) 8.08 (d, J=1.56 Hz, 1H) 8.73 (br. s, 1H) 10.23 (s, 1H) 12.90-13.16 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:25]=[CH2:26])=[CH:5][C:6]2[C:18](=[O:19])[C:17]3[C:16]4[C:11](=[CH:12][C:13]([C:20]#[N:21])=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:8]([CH3:23])([CH3:22])[C:7]=2[CH:24]=1>[C].[Pd].C(OCC)(=O)C>[CH2:25]([C:4]1[C:3]([O:2][CH3:1])=[CH:24][C:7]2[C:8]([CH3:23])([CH3:22])[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[C:18](=[O:19])[C:6]=2[CH:5]=1)=[CH:15][CH:14]=[C:13]([C:20]#[N:21])[CH:12]=4)[CH3:26]
Reactant: C=Cc1cc2c(cc1OC)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc2c(cc1OC)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.3 %

Procedure:
The ethyl acetate suspension of 8-methoxy-6,6-dimethyl-11-oxo-9-vinyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound E4-3, 25 mg, 0.07 mmol) and palladium carbon (25 mg) were stirred at room temperature for 1 hr under hydrogen atmosphere. The reaction solution was filtered through Celite. The filtrate was concentrated under reduced pressure and the resulting residues were purified by high performance liquid chromatography to obtain the title compound (white solid, 3.2 mg, 13%).
Reaction SMILES: [C:1]([OH:4])(=O)C.ClC1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:14][CH2:13]2)[N:9]=[CH:8][N:7]=1.C([O-])(=O)C.[Na+]>O>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH2:16][CH2:17][N:12]([C:10]3[N:9]=[CH:8][NH:7][C:1](=[O:4])[N:11]=3)[CH2:13][CH:14]=2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(C2=CCN(c3ncnc(Cl)n3)CC2)cc1
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=c1nc(N2CC=C(c3ccc(F)cc3)CC2)nc[nH]1
Temperature: 0 °C
Yield: 89 %

Procedure:
To an acetic acid (9.0 mL)-water (1.8 mL) solution of 2-chloro-4-[4-(4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl]-1,3,5-triazine (900 mg, 3.10 mmol) synthesized in Reference Synthesis Example 341, sodium acetate (900 mg, 11.0 mmol) was added and the resultant mixture was stirred at 90° C. for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure and water was added to the obtained residue, followed by stirring the resultant mixture at 0° C. The precipitated solid was collected by filtration and the solid was dried under reduced pressure to obtain the title compound (750 mg, yield 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][CH:10]([C:14]([F:17])([F:16])[F:15])[CH:11](O)[OH:12])[CH:7]=1.C(Cl)(=O)C(Cl)=[O:24].CS(C)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:24])([C:14]([F:17])([F:16])[F:15])[CH:11]=[O:12])[CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(Cl)cc1C(C)(C)CC(C(O)O)C(F)(F)F
Solvent: CS(C)=O
Product: COc1ccc(Cl)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Yield: 98.1 %

Procedure:
2 g (6.12 mmol) of 4-(5-chloro-2-methoxyphenyl)-hydroxy-4-methyl-2-trifluoromethyl-pentan-1-ol is oxidized with 854.6 mg (6.733 mmol) of oxalyl chloride and 1.05 ml (14.812 mmol) of DMSO as described in Example 2 according to Swern. After the working-up, 1.95 g (98.4%) of the desired aldehyde is obtained, which is incorporated in crude form into the next stage.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C([Li])CCC.CN(C)[CH:27]=[O:28]>C1COCC1.[Cl-].[NH4+]>[CH:14]1([CH2:13][O:12][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH:27]=[O:28])[CH:3]=3)[N:8]=[CH:7][CH:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Brc1ccc2nccc(OCC3CCCCC3)c2c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc2nccc(OCC3CCCCC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a solution of 6-bromo-4-cyclohexylmethoxy-quinoline (0.510 g, 1.59 mmol) in THF (10 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (0.765 mL, 1.92 mmol, 1.2 equiv.) at −70° C. During the addition, the color of the solution was turned into red and this solution was stirred for 1 h at this temperature. Then, a solution of dimethylformamide (0.246 mL, 3.19 mmol) in THF (1 mL) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 2 h. Then, the mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude residue which was purified by using a Biotage silica gel column chromatography to afford 0.205 g (48% yield) of 4-cyclohexylmethoxy-quinoline-6-carbaldehyde as a white solid: EI-HRMS m/e calcd for C17H19NO2 (M+) 269.3513, found 269.3511.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[CH:11]=2)[CH:5]=1.OO>C(O)(=O)C.C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][O:17][C:3](=[O:2])[CH3:4])[CH:11]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(-c2ccnc(C)c2)c1
Agent: OO
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cccc(-c2ccnc(COC(C)=O)c2)c1

Procedure:
Oxidation of 3-(2-methyl-pyridin-4-yl)-benzoic acid methyl ester (26.2 g, 0.11 mol; K4) with H2O2 (30%, 31.5 ml, 0.31 mol) in acetic acid (117 ml) at 70° C. for 27 h and subsequent reaction of the N-oxide in acetic acid anhydride (22 ml) at 135° C. for 30 min yielded after aqueous work-up 3-(2-acetoxymethyl-pyridin-4-yl)-benzoic acid methyl ester.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[Cl:13][C:14]1[CH:22]=[C:21]([F:23])[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:15]=1[C:16](Cl)=[O:17].OS([O-])(=O)=O.[K+]>C1COCC1>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:16](=[O:17])[C:15]2[CH:19]=[C:20]([N+:24]([O-:26])=[O:25])[C:21]([F:23])=[CH:22][C:14]=2[Cl:13])=[CH:6][CH:5]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 4-trifluoromethoxy-aniline (0.82 mL, 5.9 mmol), TEA (2.07 mL, 15 mmol) and THF (20 mL) is slowly dropped to the crude 2-chloro-4-fluoro-5-nitro-benzoic acid chloride (1.40 g, 5.9 mmoll) in 30 mL THF. The mixture is stirred for 1 h, poured into ice water and acidified to pH3 with KHSO4. The mixture is concentrated and the resulting precipitate is collected by filtration, washed with water and dried.
Reaction SMILES: Cl[CH2:2][CH2:3][C@@H:4]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Br:18])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:19][NH2:20]>C(O)C>[CH3:19][NH:20][CH2:2][CH2:3][C@@H:4]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Br:18])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClCC[C@@H](Oc1ccccc1Br)c1ccccc1
Reactant: CN
Solvent: CCO
Product: CNCC[C@@H](Oc1ccccc1Br)c1ccccc1
Yield: 99.2 %

Procedure:
Compound 1-B (1.31 g, 4.02 mmole) was dissolved in an aqueous solution of ethanol (40 ml) and methylamine (80 ml), and heated to reflux for 30 h. After cooling, the solution was extracted with chloroform (100 ml, twice), and an organic layer was decanted. The organic layer was dried over anhydrous sodium sulfate, and dried by evaporation under vacuum, to obtain the product as oil (1.28 g, 99.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10](COCC[Si](C)(C)C)[C:11]1[C:20]2[CH:19]=[CH:18][N:17](COCC[Si](C)(C)C)[C:16](=[O:29])[C:15]=2[C:14]2[CH:30]=[C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:32]=[CH:33][C:13]=2[N:12]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[C:20]2[CH:19]=[CH:18][NH:17][C:16](=[O:29])[C:15]=2[C:14]2[CH:30]=[C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:32]=[CH:33][C:13]=2[N:12]=1
Reactant: C[Si](C)(C)CCOCN(c1c(Cl)cc(F)cc1Cl)c1nc2ccc(N3CCOCC3)cc2c2c(=O)n(COCC[Si](C)(C)C)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]ccc2c(Nc3c(Cl)cc(F)cc3Cl)nc3ccc(N4CCOCC4)cc3c12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-((2,6-dichloro-4-fluorophenyl){[2-(trimethylsilyl)ethoxy]methyl}amino)-9-morpholin-4-yl-2-{[2-(trimethylsilyl)ethoxy]methyl}benzo[c]-2,6-naphthyridin-1(2H)-one (58 mg, 0.08 mmol) in dichloromethane (3 mL) was added TFA (2 ml) and the mixture was stirred at room temperature for 2.5 h. The solvents were evaporated and the residue was dissolved in MeOH, filtered and purified by reverse phase HPLC to afford the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][C:10]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[C:17]1([C:10]2([CH3:9])[C:14](=[O:15])[CH:13]=[C:12]([CH:16]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[O:11]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC1=CC(=O)C(C)(c2ccccc2)O1
Reactant: O=Cc1cccnc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(c2ccccc2)OC(C=Cc2cccnc2)=CC1=O
Temperature: 60 °C
Yield: 54.3 %

Procedure:
To a solution of 3-pyridinecarboxaldehyde (1.03 g, 9.6 mM) and 2,5-dimethyl-2-phenyl-3(2H)-furanone (1.0 g, 8 mM) in ethanol (50 mL), was added 1N aqueous sodium hydroxide (2.4 mL, 2.4 mM). The reaction solution was heated at 60° C. for 8 hours. After the reaction solution cooled to room temperature, saturated aqueous sodium chloride (200 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a brown solid. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to afford a yellow crystalline solid (0.8 g, 36.3% yield), m.p. 106°-108° C.
Reaction SMILES: C[O:2][C:3](=[O:22])[C@H:4]([CH:19]([CH3:21])[CH3:20])[NH:5][C:6]([N:8]([CH3:18])[CH2:9][C:10]1[N:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[S:13][CH:14]=1)=[O:7].C1COCC1.Cl>O>[CH3:18][N:8]([C:6]([NH:5][C@H:4]([C:3]([OH:22])=[O:2])[CH:19]([CH3:20])[CH3:21])=[O:7])[CH2:9][C:10]1[N:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[S:13][CH:14]=1
Reactant: COC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Reaction time: 2 h

Procedure:
To a one liter three neck flask was charged the product of Example 73C (50 g, 0.153 mol), lithium hydroxide monohydrate,(13 g, 0.310 mol), 200 ml THF and 190 ml water. This hazy solution was stirred for 2 hours. The reaction was quenched with a solution of conc. HCl (32.4 g, 0.329 mol) in 65 mL water, the THF was removed under vacuum and the product extracted into methylene chloride (3×210 ml). (NOTE: If necessary, the pH of the aqueous layer should be adjusted to maintain pH 1-4 during the extractions.) The combined organics were then dried with 50 g sodium sulfate, filtered with a 150 ml methylene chloride rinse of the sodium sulfate, and the solvent was removed under vacuum. The product was dissolved in 450 ml THF and again the solvent was removed. Next the product was dissolved in 475 ml THF containing 0.12 g butylated hydroxytoluene (BHT) for storage. If desired, the solvent can be removed under vacuum and the residual syrup dried in a vacuum oven at 55° C. to provide a glassy solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([OH:27])=[CH:12][C:13]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[CH:14][CH:15]=1.O>C1(C)C=CC=CC=1>[C:3]([O:27][C:11]1[CH:12]=[C:13]([O:16][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:24]([CH3:26])[CH3:25])[CH:18]([CH3:20])[CH3:19])[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1])([CH3:10])([CH3:4])[CH3:2]
Reactant: COc1ccc(F)c(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2O)c1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 81.1 %

Procedure:
Under a nitrogen atmosphere, to a solution of 2′-fluoro-5′-methoxy-4-((triisopropylsilyl)oxy)-[1,1′-biphenyl]-2-ol (207 mg) in toluene (3.55 mL) was added N,N-dimethylformamidide-tert-butylacetal (636 μL) at room temperature, and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was cooled, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (96 mg) as a colorless oil.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[O:10].[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:8]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:12])[C:9]([CH3:11])=[O:10]
Reactant: CC(=O)C(=O)O
Reactant: CCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOC(=O)C(C)=O
Temperature: 25 °C
Yield: 76.1 %

Procedure:
A toluene solution (1 L) containing pyruvic acid (440 g, 5.0 mol), n-octanol (651 g, 5.0 mol) and p-toluenesulfonic acid monohydrate (2.5 g) was heated and refluxed for 16 hours under nitrogen flow. The reaction led to generation of water in the system. However, the water was removed using Dean-Stark trap. The resultant reaction solution was cooled down to room temperature, followed by removal of toluene using an evaporator under a reduced pressure. The residual was then purified using reduced pressure distillation (2 mmHg, 82 to 92° C.) to give octyl pyruvate (762 g, yield: 76%).