Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([Cl:10])=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].O>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([Cl:10])=[C:4]([NH:11][CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1nc(Cl)c(NCCO)nc1N
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCCNc1nc(N)c(C#N)nc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Example 2, 2-amino-5 chloro-3-cyano-6-[(2-hydroxyethyl)amino]pyrazine (68 mg), was dissolved in pyridine (0.5 ml) and there was then added acetic anhydride (0.5 ml). The reaction mixture was stirred at room temperature for 2 hours, at which point thin layer chromatography showed no starting material remaining. Ice and then water were added to the reaction mixture, after which it was stirred for an additional 15 minutes. The product precipitated, was filtered, washed once with water, and dried (62.7 mg). Elemental Analysis for C9H10N5O2Cl:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18].Br[CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18]
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Reactant: N#Cc1ccc(CBr)cc1
Agent: Cl
Product: Cc1c(-c2cccnc2)n(Cc2ccc(C#N)cc2)c2ccc(Cl)cc12

Procedure:
5-Chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 2) and 4-bromomethyl-benzonitrile are processed according to the method described in Example 11 to give 4-(5-chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile. 1H NMR (400 MHz, MeOD) δ ppm 2.28 (s, 3H), 5.42 (s, 2H), 6.98 (d, J=8.3 Hz, 1H), 7.20 (dd, J=8.6, 2.0 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.55 (dd, J=7.8, 5.1 Hz, 1H), 7.57-7.62 (m, 2H), 7.66 (d, J=2.0 Hz, 1H), 7.84 (dt, J=7.8, 1.9 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.60 (dd, J=4.9, 1.6 Hz, 1H). HRMS (ESI) m/z 358.1120 [(M+H)+ Calcd for C22H17ClN3: 358.1111].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:18]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2ccc(Cl)cc2Cl)cc1
Yield: 6.6 %

Procedure:
In a manner similar to that described in Example 3, 2,4-dichloro-benzoyl chloride (0.070 g, 0.00033 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.006 g of 4-[4-(2,4-dichloro-benzoylamino)-phenyl]-4-oxo-butyric acid as a yellow solid; MS-(AP+) MH+366.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][CH2:26][NH:27][C:28](=[O:42])[C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][N:38]=[C:37](Cl)[N:36]=4)=[CH:31][CH:30]=3)[CH:23]=2)[NH:18][CH:17]=1)#[N:15]>>[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][CH2:26][NH:27][C:28](=[O:42])[C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][N:38]=[C:37]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[N:36]=4)=[CH:31][CH:30]=3)[CH:23]=2)[NH:18][CH:17]=1)#[N:15]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: NCCCCCCN1CCCCC1
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCCCCCN5CCCCC5)n4)cc3)cc12

Procedure:
Using 6-piperidin-1-ylhexylamine (reference example 93f) and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 550 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH:11](=[O:15])/[CH:12]=[CH:13]/[CH3:14].FC(F)(F)C(O)=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C@H:13]([CH3:14])[CH2:12][CH:11]=[O:15])=[CH:3]1
Reactant: C/C=C/C=O
Reactant: Cn1ccc2ccccc21
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CC=O)c1cn(C)c2ccccc12

Procedure:
This example describes the alkylation of 1-methyl-1H-indole with (E)-crotonaldehyde, catalyzed by the trifluoroacetic acid salt of (1), to provide (R)-3-(1-methyl-1H-indol-3-yl)-butanal.
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.ClC(Cl)(O[C:17](=[O:23])[O:18][C:19](Cl)(Cl)Cl)Cl.[N-]=C=O.OC1[C:38]2[NH:37][C:36](=[O:39])[CH2:35][O:34][C:33]=2[CH:32]=[CH:31][CH:30]=1>CCOC(C)=O.CN(C=O)C>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:17](=[O:23])[O:18][C:19]2[C:38]3[NH:37][C:36](=[O:39])[CH2:35][O:34][C:33]=3[CH:32]=[CH:31][CH:30]=2)=[CH:5][CH:4]=1
Reactant: O=C1COc2cccc(O)c2N1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [N-]=C=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1COc2cccc(OC(=O)NCc3ccc(C(F)(F)F)cc3)c2N1
Temperature: 80 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
4-trifluoromethylbenzylamine (0.52 ml, 3.6 mmol) was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (1 g, 3.6 mmol) was added to the solution. The mixture was warmed at 80° C. for 4 hours then evaporated and the residue was dissolved in 5 ml of DMF. The solution of the isocyanate was added dropwise to a solution in DMF (10 ml) of compound 25 (400 mg, 2.42 mmol) and TEA (0.34 ml, 1 equiv.) and the mixture was stirred at rt for 8 hours. (TLC AcOEt 1/petroleum ether 1). The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column gave 400 mg of a white solid. Yield=45% 1HNMR (DMSO, 200 MHz) δ 4.38 (2H, d, J=6.4 Hz), 4.57 (2H, s), 6.85 (3H, m), 7.59 (2H, d, J=8.2 Hz), 7.72 (2H, d, J=8.4 Hz), 8.15 (1H, bt), 10.61 (1H, bs); [M+1] 367.1 (C17H13F3N2O4 requires 366.3).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7](S)=[CH:6][CH:5]=1.Cl[CH2:12][C:13](=[O:15])[CH3:14].O[O:17][S:18]([O-:20])=O.[K+]>CO>[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:18]([CH2:12][C:13](=[O:15])[CH3:14])(=[O:20])=[O:17])=[CH:6][CH:5]=1
Reactant: CC(=O)CCl
Reactant: Fc1ccc(S)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)CS(=O)(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
NaOH (1.0M, 40.5 mL, 40.5 mmol) was added at 0° C. to a solution of 4-fluorothiophenol (5.20 g, 40.5 mmol) in methanol (100 mL) followed by addition of chloroacetone (3.87 mL, 48.6 mmol). The reaction was stirred at 0° C. for 5 minutes. Oxone (50 g, 81 mmol) was added all at once. The suspension was stirred at 0° C. and monitored by LC-MS until there was no sulfoxide (reaction intermediate) observed. The reaction was filtered and solid washed with diethyl ether. Most organic solvents were removed from the filtrate. The solution was extracted with diethyl ether three times. Combined organic phases were extracted with 5% NaOH aq. solution three times. Combined aqueous phases were acidified with 1.0N hydrochloric acid to precipitate product. Pure Step A product, 1-(4-fluorophenylsulfonyl)propan-2-one, was obtained after flash chromatography (silica gel, 3:7 ethyl acetate:hexanes) as a white solid. LC-MS found: (M+1)+=217.2.
Reaction SMILES: N#N.[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:8]=[CH:7][C:6]([CH:9]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:10](OC)=[O:11])=[CH:5][CH:4]=1.C(=O)=O.CC(C)=O.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[C:3]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:8]=[CH:7][C:6]([C@@H:9]([O:14][Si:15]([C:18]([CH3:20])([CH3:21])[CH3:19])([CH3:17])[CH3:16])[CH:10]=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)C(O[Si](C)(C)C(C)(C)C)c1ccc(-c2ccccc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)O[C@@H](C=O)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Yield: 95.2 %

Procedure:
A 100 mL 2-necked round bottom flask was equipped with a septum, N2 inlet and 2.6 g (7.4 mmol) of the (R)-(-)-methyl acetate of Example O dissolved in 45 mL of dry toluene. The solution was cooled to -78° C. (CO2 /acetone), and 9 mL (9 mmol) of a 1.0M solution of DIBAL-H in toluene was added slowly (5 min.) with stirring. The reaction mixture was stirred for 1 h at -78° C. and poured into a mixture of 100 g of ice and 100 mL of CHCl3. The reaction flask was rinsed with 100 mL of CHCl3 and the mixture was stirred vigorously for 30 min. After separation of the CHCl3 layer, the aqueous phase was washed with 100 mL of CHCl3 (emulsion!) and the combined CHCl3 extracts were washed once with brine 80 mL, dried (Na2SO4) and concentrated leaving 2.3 g (95%) of the title aldehyde as a colorless oil which was not further purified: 1H-NMR (CDCl3)δ9.54 (d, J=2.1 Hz, 1H), 7.63-7.35 (m, 9H), 5.05 (d, J=2.1 Hz, 1H), 0.97 (s, 9H), 0.14 (s, 3H), 0.07 (s, 3H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH2:5])[CH3:2].[C:10]1(=[O:15])[O:14][CH2:13][CH2:12][CH2:11]1>>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH:5][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][OH:15])[CH3:2]
Reactant: CCCCC(CC)CN
Reactant: O=C1CCCO1
Product: CCCCC(CC)CNC(=O)CCCO
Temperature: 100 °C
Reaction time: 1 h

Procedure:
In a glass reaction vessel 12.9 grams of 2-ethylhexylamine were admixed with 8.6 grams of butyrolactone and the mixture heated to 100° C. on a steam bath until reaction was completed in a period of one hour. A conversion of greater than 95%, based on butyrolactone, was achieved. The product upon cooling to room temperature was a colorless, clear, moderately viscous liquid. IR=6.09 mu.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[CH:8]2[C:9]([CH:11]([CH3:13])[CH3:12])=[CH:10][CH:5]([CH:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:7]2)[N:4]1CC1C=CC=CC=1.[H][H]>[Pd].C(O)C>[ClH:1].[CH3:2][CH:3]1[CH:8]2[C:9]([CH:11]([CH3:12])[CH3:13])=[CH:10][CH:5]([CH:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:7]2)[NH:4]1
Reactant: [H][H]
Reactant: CCOC(=O)C1CC2C(C(C)C)=CC1N(Cc1ccccc1)C2C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CC2C(C(C)C)=CC1NC2C
Yield: 100.8 %

Procedure:
A mixture of ethyl 3-methyl-8-isopropyl-2-(phenylmethyl)-2-azabicyclo[2.2.2]oct-7-ene-6-carboxylate hydrochloride (23.2 g, 63.8 mmol), ethanol (200 mL) and 10% palladium on carbon (2.3 g) was placed on a Parr hydrogenator at 44 psi of hydrogen pressure for 4 hours. The catalyst was removed by filtration and the solvent was concentrated in vacuo to afford 17.6 g (100%) of ethyl 3-methyl-8-isopropyl-2-azabicyclo[2.2.2]oct-7-ene-6-carboxylate hydrochloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[CH2:8][CH:9]([C:11]1[C:16]2[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=2[C:14]([O:22][CH3:23])=[CH:13][CH:12]=1)O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[CH2:8][CH2:9][C:11]1[C:16]2[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=2[C:14]([O:22][CH3:23])=[CH:13][CH:12]=1
Reactant: COc1ccc(C(O)Cc2c(Cl)cncc2Cl)c2c1OC(C)(C)C2
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CCc2c(Cl)cncc2Cl)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
Under an argon atmosphere, a solution (80 ml) of Compound 45a (3.0 g) obtained in Step A in methylene chloride was cooled to −78° C., and then boron trifluoride ether complex (2.0 ml) and triethylsilane (3.9 ml) were succcessively added thereto, followed by stirring at room temperature for 3 hours. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=20/1) to give Compound 45 (1.57 g, 54.7%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](Cl)=[N:10][OH:11].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[C:21][CH:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[OH:23].C(=O)(O)[O-].[Na+]>C(O)(C)C.CCOCC>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[O:11][N:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:21]=1[CH:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[OH:23]
Reactant: ON=C(Cl)c1ccc(Cl)cc1Cl
Reactant: OC(C#Cc1ccccc1Cl)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)O
Product: OC(c1cccnc1)c1c(-c2ccc(Cl)cc2Cl)noc1-c1ccccc1Cl
Temperature: 55 °C
Yield: 16.7 %

Procedure:
A mixture of 52 mg (0.23 mmol) of 2,4-dichloro-N-hydroxybenzenecarboximidoyl chloride, 50 mg (0.21 mmol) of 3-(2-chlorophenyl)-1-(3-pyridyl)-2-propyn-1-ol, and 30 mg (0.36 mmol) of sodium bicarbonate in 3 mL of isopropyl alcohol was heated at 55° C. overnight with shaking. The reaction mixture was cooled, diluted with ether, and then washed with saturated sodium bicarbonate. The ether fraction was dried over magnesium sulfate. The drying agent was filtered off, and the ether was removed by rotoevaporation. The crude product was purified by prep TLC to give 15 mg (0.035 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)hydroxymethyl]isoxazole. 1H NMR (CDCl3): δ 5.80 (br s, 1). MS m/z: 431.0 (M+H).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([CH2:27][C:28]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)Cc1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and phenylacetyl chloride, there is obtained ethyl N-(phenylacetyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e:M+ 384 (2), 355 (1), 293 (100), 265 (15), 194 (11), 179 (26), 167 (67), 91 (20);
Reaction SMILES: [Na].[N+:2]([CH3:5])([O-:4])=[O:3].[CH3:6][C:7]1([CH3:14])[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1.C(O)(=O)C>C(O)C.O>[CH3:6][C:7]1([CH3:14])[CH2:12][CH2:11][C:10]([CH2:5][N+:2]([O-:4])=[O:3])([OH:13])[CH2:9][CH2:8]1
Reactant: C[N+](=O)[O-]
Reactant: CC1(C)CCC(=O)CC1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC1(C)CCC(O)(C[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of sodium (0.2 g, 0.009 mol) and ethanol (5 mL, 0.08 mol) was added a solution of nitromethane (0.77 g, 0.013 mol) and 4,4-dimethyl-cyclohexanone (1 g, 0.008 mol) in ethanol (1 mL) dropwise. The mixture was stirred at room temperature for 4 hours. Acetic acid (2 mL) and water (10 mL) were added and the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), washed with brine (30 mL×3), dried over sodium sulfate, and purified by flash chromatography to afford the desired product as a clear oil. (1.5 g, 90%).
Reaction SMILES: C(Cl)(=O)C.[O:5]=[C:6]1[O:12][C@H:11]([C@H:13]([CH2:15][OH:16])[OH:14])[C:9]([OH:10])=[C:7]1[OH:8].[CH3:17][C:18]([CH3:20])=O>>[CH3:17][C:18]1([CH3:20])[O:14][CH:13]([CH:11]2[O:12][C:6](=[O:5])[C:7]([OH:8])=[C:9]2[OH:10])[CH2:15][O:16]1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: CC(C)=O
Solvent: CC(=O)Cl
Product: CC1(C)OCC(C2OC(=O)C(O)=C2O)O1
Temperature: 32.5 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
5,6-O-isopropylidene-L-ascorbic acid was synthesized by the addition of acetyl chloride (124.9 mL) to a slurry of L-ascorbic acid USP (1000 g) in acetone (4.5 L). The mixture was stirred vigorously at 35-30° C. After two hours, the crystalline product separated. The crystals were collected by filtration, washed with cold acetone, and dried in a vacuum desciccator over potassium hydroxide pellets. The product, produced in 77% yield, consisted of needle-shaped crystals with a melting point of 217-223° C.
Reaction SMILES: C([O-])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[Cl:11][C:12]1[CH:22]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]([OH:23])=[C:14]([C:24](=[O:27])[CH2:25][CH3:26])[CH:13]=1.[C:28](Cl)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:11][C:12]1[CH:13]=[C:14]2[C:15](=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:22]=1)[O:23][C:26]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:25]([CH3:28])[C:24]2=[O:27]
Reactant: O=C([O-])c1ccccc1
Reactant: CCOC(=O)c1cc(Cl)cc(C(=O)CC)c1O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1cc(Cl)cc2c(=O)c(C)c(-c3ccccc3)oc12
Yield: 89.5 %

Procedure:
A 23.8 g (0.165 mole) quantity of sodium benzoate was added with stirring to a mixture of 12.8 g (0.05 mole) of ethyl 5-chloro-3-propionylsalicylate and 21.1 g (0.15 mole) of benzoyl chloride. The resulting mixture was heated at 180° to 190° C. for 8 hours to undergo reaction. The reaction mixture was cooled and 100 ml of a 5% aqueous solution of sodium carbonate was added. The mixture was stirred to precipitate solids. The solids were recrystallized from alcohol, giving 15.3 g (89.5%) of white crystals, M.P. 127.0° to 128.2° C. Table 1 below shows the results of chemical analysis.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[NH2:19].FC1C=CC(NC2CCN(C(OC(C)(C)C)=O)CC2)=CC=1OC>>[F:15][C:16]1[CH:17]=[C:18]([NH:19][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(N)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: COc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1F
Product: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1F

Procedure:
The title compound was prepared from 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate and 3-fluoro-4-methoxyaniline using a method similar to that described for D9 in Description 9.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])=[C:4]([C:9]2[C:10]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:11]=3[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH:37]([O-])([O-])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.C(OCC)(=O)C.O>[F:36][C:30]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=1[O:28][C:3]1[C:2]2[N:1]=[CH:37][NH:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[C:11]=2[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=1
Reactant: CCOC([O-])[O-]
Reactant: Cn1cc(-c2ccc(N)c(N)c2Oc2ccc(F)cc2F)c2ccn(COCC[Si](C)(C)C)c2c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1cc(-c2ccc3[nH]cnc3c2Oc2ccc(F)cc2F)c2ccn(COCC[Si](C)(C)C)c2c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
A solution of 4-[3,4-diamino-2-(2,4-difluorophenoxyl)phenyl]-6-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (460 mg, 0.897 mmol) in tetrahydrofuran (7.76 mL) was treated with ethyl orthoformate (448 μL, 2.69 mmol) followed by addition of p-toluenesulfonic acid monohydrate (17.1 mg, 0.0897 mmol). The resultant reaction mixture was stirred at 50° C. for 1 h, after which time the reaction mixture was diluted with ethyl acetate and water. Layers were separated and the organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo to give the crude product. Purification by gradient flash column chromatography (50% EtOAc/hexanes to 100% EtOAc) gave the desired product (0.378 g, 81%). LCMS calculated for C27H29F2N4O3Si (M+H)+: m/z=523.2. found: 523.2.
Reaction SMILES: [C:1]1([CH2:11][C:12](=[O:16])[C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:17](OCC)C>>[C:1]1([CH2:11][C:12](=[O:16])[C:13]([O:15][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOCC
Reactant: O=C(O)C(=O)Cc1cccc2ccccc12
Product: COC(=O)C(=O)Cc1cccc2ccccc12

Procedure:
Sodium (677 mg, 29.4 mmol) is dissolved in ethanol (48 ml). To the solution are added 1-naphthylacetonitrile (5.07 g, 30.3 mmol), then after 20 min. diethyl oxalate (4.1 ml, 30.3 mmol) at r.t. and the mixture is stirred at r.t. for 2 hrs. and refluxed for 1 hour. After cooling to r.t. acetic acid (2 ml) is added. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and evaporated in vacuo to give 3-cyano-3-(1-napththyl)pyruvate. A mixture of 3-cyano-3-(1-naphthyl)pyruvate (6.56 g, 24.6 mmol) and 30% sulfric acid (400 ml) is heated at 100° C. for 2 hrs. After cooling, the mixture is extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and evaporated on vacuo to give 3-(1-naphthyl)pyruvic acid. To a solution of 3-(1-naphthyl)pyruvic acid(1.86 g, 8.7 mmol) in diethyl ether (20 ml) is added diazomethane diethyl ether solution (25 ml). The mixture is concentrated in vacuo and the residue is chromatographed on silica gel with hexane and ethyl acetate (3:2) to give methyl 3-(1-naphthyl)pyruvate.
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[C:16]([F:18])[C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[C:14]([F:25])[CH:13]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[H-].[Na+].[Br-].[CH2:29]1[CH2:33]OC[CH2:30]1>>[CH2:33]([N:11]([C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[C:12]1[CH:13]=[C:14]([F:25])[C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[C:16]([F:18])[CH:17]=1)[CH:29]=[CH2:30]
Reactant: C1CCOC1
Reactant: O=C(Nc1cc(F)c(-c2cccnc2)c(F)c1)OCc1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Product: C=CCN(C(=O)OCc1ccccc1)c1cc(F)c(-c2cccnc2)c(F)c1
Reaction time: 0.5 h

Procedure:
A mixture of N-carbobenzyloxy-4-(3-pyridyl)-3,5-difluoroaniline (PREPARATION 3, 543 mg, 1.60 mmol) in anhydrous THF (40 ml) is treated with sodium hydride (60% dispersion in mineral oil, 128 mg, 3.19 mmol, 2 eq). The reaction is kept under an atmosphere of nitrogen at 20-25° for 0.5 hr. After this time, ally bromide (691 μl, 7.99 mmol, 5 eq) is added. Stirring is continued at 20-25° for 16 hr. After this time, the reaction is carefully quenched with water (20 ml). The layers are separated and the aqueous layer is extracted with ethyl acetate (3×25 ml). The combined organics phases are washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The concentrate is purified by silica gel chromatography (125 g of silica gel) eluting with acetonitrile/chloroform (3/97-1 l). The appropriate fractions are concentrated to give the title compound. An analytical sample is prepared by preparative TLC (SG, acetonitrile/chloroform -6/94), mp=92-93°; FTIR (mull) cm-1 3068, 3061, 1710, 1705, 1643, 1635, 1412, 1263, 1024, 733; MS (EI) m/z: 380, 336, 309, 245, 91, 65; NMR (CDCl3) 8.72, 8.62, 7.99, 7.42-7.36, 7.03, 5.94, 5.23-5.18 and 4.34 δ.