Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C=CC2C=CC(OC)=CC=2)=C(N)C=1.BrC1C=CC(OCCN2CCCCC2)=C(F)C=1.[F:37][C:38]1[CH:39]=[C:40]([NH:53][C:54]2[CH:59]=[C:58]([O:60]C)[CH:57]=[CH:56][C:55]=2[C:62]#[C:63][C:64]2[CH:69]=[CH:68][C:67]([O:70]C)=[CH:66][CH:65]=2)[CH:41]=[CH:42][C:43]=1[O:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[F:37][C:38]1[CH:39]=[C:40]([NH:53][C:54]2[CH:59]=[C:58]([OH:60])[CH:57]=[CH:56][C:55]=2[C:62]#[C:63][C:64]2[CH:69]=[CH:68][C:67]([OH:70])=[CH:66][CH:65]=2)[CH:41]=[CH:42][C:43]=1[O:44][CH2:45][CH2:46][N:47]1[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]1
Reactant: COc1ccc(C#Cc2ccc(OC)cc2Nc2ccc(OCCN3CCCCC3)c(F)c2)cc1
Agent: COc1ccc(C=Cc2ccc(OC)cc2N)cc1
Agent: Fc1cc(Br)ccc1OCCN1CCCCC1
Product: Oc1ccc(C#Cc2ccc(O)cc2Nc2ccc(OCCN3CCCCC3)c(F)c2)cc1
Yield: 56.6 %

Procedure:
Synthesized from 5-methoxy-2-[2-(4-methoxyphenyl)vinyl]phenylamine and 1-[2-(4-bromo-2-fluorophenoxy)ethyl]piperidine according to an analogous synthetic method to Example 116, [3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl][5-methoxy-2-(4-methoxyphenylethynyl)phenyl]amine (124 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (66 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([CH:10]2[CH:15]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH2:14][CH2:13][CH2:12][NH:11]2)=O)[CH2:4][CH2:3]1.FC(F)(F)S(O)(=O)=O>>[F:24][C:20]1[CH:21]=[CH:22][C:23]2[C:8](=[C:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[CH2:16][CH2:17][C:18]=2[CH:19]=1
Reactant: CN1CCC(C(=O)C2NCCCC2CCc2cccc(F)c2)CC1
Agent: O=S(=O)(O)C(F)(F)F
Product: CN1CCC(=C2c3ccc(F)cc3CCc3cccnc32)CC1
Yield: 38 %

Procedure:
A solution of (1-methyl-4-piperidinyl)[3-[2-(3-fluorophenyl)ethyl]-2-piperidinyl]methanone (15.0 g, 0.046 mole) in 74 mL (125.5 g, 0.837 mole) of trifluoromethanesulfonic acid is stirred at ambient temperature for 18 hours. The reaction is quenched with ice-water and the solution made basic with potassium hydroxide. The product is extracted into ethyl acetate. The ethyl acetate solution is filtered to remove insolubles and the filtrate is concentrated to a residue. Following purification by silica gel chromatography, 5.4 g (0.0175 mole) of product is obtained in 38% yield.
Reaction SMILES: [CH2:1]([C@H:3]1[O:5][CH2:4]1)Cl.[CH3:6][C:7]1([CH3:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1>>[CH3:6][C:7]1([CH3:13])[CH2:12][CH2:11][N:10]([CH2:1][C@H:3]2[CH2:4][O:5]2)[CH2:9][CH2:8]1
Reactant: ClC[C@@H]1CO1
Reactant: CC1(C)CCNCC1
Product: CC1(C)CCN(C[C@H]2CO2)CC1

Procedure:
The compound is prepared analogously to J. Amer. Chem. Soc. 80; 1958, 1257 by reacting (S)-epichlorohydrin with 4,4-dimethylpiperidine, while the reaction temperature should not exceed 35° C.: Boiling point: 101-104° C./15 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13]O)[S:11][CH:12]=2)=[CH:4][CH:3]=1.P(Br)(Br)[Br:16].O>C1(C)C=CC=CC=1>[Br:16][CH2:13][C:10]1[S:11][CH:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: BrP(Br)Br
Reactant: OCc1nc(-c2ccc(Cl)cc2)cs1
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(-c2csc(CBr)n2)cc1
Temperature: 120 °C
Yield: 16.6 %

Procedure:
To the solution of [4-(4-Chloro-phenyl)-thiazol-2-yl]-methanol (0.80 g, 3.55 mmol) in 10 ml of toluene was added PBr3 (0.51 ml, 5.33 mmol) and the reaction mixture was heated at 120° C. for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (0.17 g, 17%). The corresponding cyano derivative was also prepared by the same general method.
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[NH:34][C:35](=[O:38])[CH2:36][OH:37])[NH:30][C:29](=[O:39])[CH2:28]2.N1CCCCC1>C(O)C>[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[NH:34][C:35](=[O:38])[CH2:36][OH:37])[NH:30][C:29](=[O:39])/[C:28]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Reactant: O=C(CO)Nc1cc2c(cc1F)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(/C=C2\C(=O)Nc3cc(NC(=O)CO)c(F)cc32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 86.3 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1 H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f (40 mg, 0.125 mmol) was dissolved in 2 mL of ethanol under stirring at room temperature, and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-acetamide 9f (25.1 mg, 0.112 mmol) was then added to the solution. Upon completion of the addition, the mixture was stirred until all dissolved, and piperidine (50 μL, 0.5 mmol) was then added to the reaction solution. Upon completion of the addition, the reaction system was stirred at 80° C. in an oil bath in dark for 2 hours. The reaction was completed until TLC showed the disappearance of starting materials, and the oil bath was removed. The reaction system was naturally cooled down to room temperature to precipitate solids. The resulting solids were filtered to give the title compound (S,Z)-N-{5-fluoro-3-[5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-acetamide 9 (51 mg, yield 80%) as a yellow solid.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[F:6][C:7]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].O.C(OCC)(=O)C>C1COCC1.C(OCC)C>[CH:1]1([CH:9]([C:8]2[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:7]=2[F:6])[OH:10])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Reactant: Br[Mg]C1CC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccc(C(F)(F)F)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
31 ml (15.6 mmol) of 0.5N cyclopropylmagnesium bromide solution in THF were added to 2.00 g (10.4 mmol) of 2-fluoro-4-(trifluoromethyl)benzaldehyde in 40 ml of diethyl ether at 0° C., and the mixture was warmed to RT and stirred at RT overnight. The reaction mixture was added to water and ethyl acetate, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 95/5) to result in 1.68 g (69% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C:6]2[CH:8]=[C:9]([CH:12]=O)[CH:10]=[CH:11][C:5]=2[C:4](=[O:14])[O:3]1.[CH2:16]([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[BH4-].[Na+]>O>[CH2:16]([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2[CH:36]=[CH:35][C:33]([NH:34][CH2:12][C:9]3[CH:10]=[CH:11][C:5]4[C:4](=[O:14])[O:3][C:2]([CH3:15])([CH3:1])[O:7][C:6]=4[CH:8]=3)=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCc1ccc(C#Cc2ccc(N)cc2)cc1
Reactant: CC1(C)OC(=O)c2ccc(C=O)cc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCCCCCc1ccc(C#Cc2ccc(NCc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
A solution of 2,2-dimethyl-4-oxo-4H-1,3-benzodioxine-7-carbaldehyde (700 mg; 3.38 mmol) and 4-[(4-hexylphenyl)ethynyl]aniline (940 mg; 3.38 mmol) in toluerene (40 mL) was refluxed for 48 hours with azeotropic removal of water. The solvent was removed under reduced pressure and the residue was taken up in a mixture of MeOH (20 mL) and THF (20 mL). NaBH4 (130 mg, 3.38 mmol) was added and the resulting mixture was stirred at rt for 8 hours. The solvents were removed under reduced pressure. The residue was taken up in EtOAc and washed with a saturated aqueous solution of NaACO3 and brine. The organic layer was dried (Na2SO4) and the solvent was removed under reduced pressure to give a brown oil. Purification by flash chromatography on silica (EtOAc:c-Hex 1:9 then 1:4) gave 466 mg (30%) of the title compound as a pale yellow oil. HPLC, Rt: 6.1 min (purity: 95.6%). LC/MS, M+(ESI: 468.0, M−(ESI): 466.1.
Reaction SMILES: [NH:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[N:3]1[CH2:13][CH:14]=[CH2:15].[Br:16]N1C(=O)CCC1=O>O>[Br:16][CH2:15][CH:14]1[CH2:13][N:3]2[C:4](=[O:12])[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]2=[N:1]1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCn1c(=O)[nH]c2ccccc2c1=N
Solvent: O
Product: O=C1Nc2ccccc2C2=NC(CBr)CN12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a suspension of 3,4-dihydro-4-imino-3-allyl-2(1H)-quinazolinone (0.5 g, 2.5 mmol) in water (30 mL) was added N-bromosuccinimide (443 mg, 2.5 mmol). The mixture was allowed to stir at room temperature for 30 minutes. The solid was collected by filtration and washed with water (10 mL) to afford 2-bromomethyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one (680 mg, 97%).
Reaction SMILES: [CH3:1][O:2][C:3](=O)[CH:4]([CH2:15][OH:16])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O.C(N1C=CN=C1)(N1C=CN=C1)=[O:19].C1COCC1>C(N(CC)CC)C>[C:1]1(=[O:19])[N:5]2[C:6]3[C:7]([NH:12][C:15](=[O:16])[CH:4]2[CH2:3][O:2]1)=[CH:8][CH:9]=[CH:10][CH:11]=3
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)C(CO)Nc1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1Nc2ccccc2N2C(=O)OCC12
Reaction time: 6 h

Procedure:
To 3-hydroxymethyl-1,2,3,4-tetrahydroquinoxalin-2-one (IV, EXAMPLE 286, 1.35 g), 1.00 g of carbonyldiimidazole, and 30 ml of THF are added 1.64 ml of triethylamine. The reaction is stirred at 20°-25° for 6 hr, then at 80° for 18 hr, at which time an additional 0.11 g carbonyldiimidazole are added. Heating is continued for another 6 hr, at which time the reaction mixture is cooled and the solvent is removed under reduced pressure. The residue is partitioned between methylene chloride and water, the organic layers are dried over sodium sulfate and concentrated. The residue is crystallized from methanol/dichloromethane to give the title compound, mp 230°-231°; MS (m/z) at 204; NMR (CDCl3) 4.60, 4.78, 6.93, 7.19, 7.82 and 8.48 δ.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1(=[O:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1.Br[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>O1CCCC1.CCCCCC.C(OCC)C>[O:23]=[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH:14]1[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: O=C1CCCc2ccccc21
Reactant: CCOC(=O)CCBr
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CCC1CCc2ccccc2C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
To a solution of diisopropylamine (16 ml) in tetrahydrofuran (350 ml) was added dropwise a 1.6M solution of butyl lithium in hexane (71 ml) under cooling at -78° C., and the mixture was stirred for 30 minutes. To the reaction mixture was added dropwise a solution of 3,4-dihydro-1(2H)-naphthalenone (16.5 g) in tetrahydrofuran (60 ml) over a period of about 20 minutes under cooling at -78° C., and the mixture was stirred for 30 minutes. To the mixture was added dropwise a solution of ethyl 3-bromopropanoate (20.5 g) in tetrahydrofuran (60 ml) over a period of about 20 minutes, and then further stirred for 30 minutes. The reaction mixture was stirred overnight at 20° C., and diluted with diethyl ether. The mixture was washed successively with water,5% aqueous sodium hydrogen carbonate solution, and 5% hydrochloric acid, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure to remove the solvent to give ethyl 1,2,3,4-tetrahydro-1-oxo-2-naphthalene-propanoate (10.1 g) as an oily product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([NH:27][C@@H:28]([C:30]([NH:32][CH2:33][C:34]([OH:36])=O)=[O:31])[CH3:29])=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:37][C@H:38]([C:46]([O:48][CH3:49])=[O:47])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C1(NC2CCCCC2)CCCCC1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([NH:27][C@@H:28]([C:30]([NH:32][CH2:33][C:34]([NH:37][C@H:38]([C:46]([O:48][CH3:49])=[O:47])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:36])=[O:31])[CH3:29])=[O:26])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To 30 ml. of DMF were added 2.5 gms. (0.005 moles) of Nα -t-butyloxycarbonyl-O-benzyl-L-tyrosyl-D-alanyl-glycine (prepared as in Example 1) and 1.08 gms. (0.005 moles) of the hydrochloride salt of L-phenylalanine, methyl ester. The mixture was stirred at 0° C., and 0.99 ml. (0.005 moles) of dicyclohexylamine was added. The mixture was stirred for 5 minutes at 0° C., and 670 mg. (0.005 mmoles) of HBT and 1.03 gms. (0.005 moles) of DCC were added. Stirring was continued at 0° C. for 2 hours and then at room temperature for 48 hours. The reaction mixture was cooled to 0° C., and the resulting precipitate was collected. The filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, and the ethyl acetate solution was extracted successively with 1 N sodium bicarbonate, water, 0.75 N citric acid, and water. The ethyl acetate solution was dried over magnesium sulfate and concentrated in vacuo. The resulting oil was crystallized from ether and recrystallized from ethyl acetate to give 2.7 grams (82%) of the title compound, m.p. 149°-152° C. [α]D25 +22° (C=0.5, MeOH).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3([CH3:17])[O:16][CH2:15][CH2:14][O:13]3)=[CH:9][CH:10]=2)[CH:5]([C:18]([O:20]CC)=O)[C:4]1=[O:23])[CH3:2].[F:24][C:25]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=1[NH2:27].Cl.C(Cl)Cl>C1C=CC=CC=1>[F:24][C:25]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=1[NH:27][C:18]([CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]3([CH3:17])[O:16][CH2:15][CH2:14][O:13]3)[CH:7]=2)[N:3]([CH2:1][CH3:2])[C:4]1=[O:23])=[O:20]
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC(=O)C1C(=O)N(CC)c2ccc(C3(C)OCCO3)cc21
Agent: Cl
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCN1C(=O)C(C(=O)Nc2ccc(F)cc2F)c2cc(C3(C)OCCO3)ccc21
Yield: 80 %

Procedure:
A mixture of 1.0 g. (3.1 mmoles) of ethyl 1-ethyl-5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylate and 809 mg. (6.3 mmoles) of 2,4-difluoroaniline in 40 ml of benzene was heated to reflux through a soxhlet filled with 4A sieves for 45 minutes. The reaction mixture was cooled and poured into a mixture of 400 ml. 2N hydrochloric acid and 100 ml. of methylene chloride. The organic layer was separated, dried over magnesium sulfate and concentrated to give 1.24 g. of a solid residue. Recrystallization from diisopropyl ether--methylene chloride gave 1.0 g. of product (80% yield), m.p. 166°-170° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].[CH3:25][N:26]1[C:31](=[O:32])[C:30]([NH:33][C:34]2[CH:46]=[C:37]3[CH2:38][N:39]([CH:42]4[CH2:45][O:44][CH2:43]4)[CH2:40][CH2:41][N:36]3[N:35]=2)=[CH:29][C:28](B(O)O)=[CH:27]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O.O.C([O-])(=O)C.[Na+]>O.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].C(#N)C>[CH3:20][C:14]1([CH3:21])[CH2:13][C:12]2[CH:11]=[C:10]3[N:17]([CH2:18][CH2:19][N:8]([C:4]4[C:3]([CH:23]=[O:24])=[C:2]([C:28]5[CH:29]=[C:30]([NH:33][C:34]6[CH:46]=[C:37]7[CH2:38][N:39]([CH:42]8[CH2:45][O:44][CH2:43]8)[CH2:40][CH2:41][N:36]7[N:35]=6)[C:31](=[O:32])[N:26]([CH3:25])[CH:27]=5)[CH:7]=[CH:6][N:5]=4)[C:9]3=[O:22])[C:16]=2[CH2:15]1
Reactant: Cn1cc(B(O)O)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2C=O)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a reflux condenser was charged with (4-chloro-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridine-3-carbaldehyde) 108a (280 mg, 0.81 mmol), 163a (440 mg, 0.96 mmol), Pd(dppf)Cl2 (40 mg, 0.049 mmol), K3PO4 (360 mg, 1.6 mmol), sodium acetate trihydrate (240 mg, 1.6 mmol), water (6 drops), and acetonitrile (20 mL). The system was evacuated and refilled with N2. The reaction mixture was stirred at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 163b (150 mg, 31%) as a yellow brown solid. MS-ESI: [M+H]+ 609.3
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[OH-].[K+]>CS(C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: Brc1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#CC(c1ccc(F)cc1)c1cccnc1
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
In a 1 liter 3 neck round bottomed flask was charged 20.0 g. of 4-fluorobenzyl cyanide (1.0 eq., 0.15 moles), in 300 ml. dimethylsulfoxide (DMSO) (dried over molecular sieves), and 46.8 g. of 3-bromopyridine (2.0 eq., 0.30 moles) while stirring under N2. The reaction mixture was heated to 60° C. at which time 12.4 g of KOH (1.5 eq., 0.22 moles) as powdered pellets was added neat. The reaction exotherms to 80° C. and was monitored by GLC. After 30 min., an additional 2.4 g. of potassium hydroxide (KOH) was added (0.3 eq., 0.043 moles) and 1 hr. later GLC showed 6% unreacted nitrile. The reaction was quenched by the addition of 500 ml. of water and then extracted with 1 liter of ether. The organic phase was washed 3 times 250 ml. H2O, dried over MgSO4 and concentrated to give 50 g. of oil. The crude product was distilled under vacuum to give 15.7 g. of oil (49.4% yield) bp 160°-170° C. @1-2 min. Hg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl[C:12]1[CH:22]=[C:16]2[N:17]([CH3:21])[CH2:18][CH2:19][CH2:20][N:15]2[C:14](=[O:23])[N:13]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][NH:10][C:12]1[CH:22]=[C:16]2[N:17]([CH3:21])[CH2:18][CH2:19][CH2:20][N:15]2[C:14](=[O:23])[N:13]=1
Reactant: NCc1cc(F)cc(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(NCc1cc(F)cc(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E59 starting from (3,5-difluorophenyl)methanamine and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][OH:17])=[N:13][CH:14]=1)[CH3:8].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.O>CN(C)C=O>[CH3:3][O:4][CH2:5][O:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[N:13][CH:14]=1)[CH3:8]
Reactant: COCOC(C)c1ccc(CCO)nc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOC(C)c1ccc(CCOc2ccc([N+](=O)[O-])cc2)nc1
Yield: 71.3 %

Procedure:
Sodium hydride in oil (60%, 1.6 g) was added in small portions with ice-cooling to a solution of 2-[5-(1-methoxymethoxyethyl)-2-pyridyl]ethanol (7.5 g) and 4-fluoronitrobenzene (5.0 g) in N,N-dimethylformamide (50 ml). The reaction mixture was stirred with ice-cooling for additional 1 hour, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily residue was subjected to silica gel column chromatography. A fraction eluted with chloroform-methanol (40:1, v/v) gave 5-(1-methoxymethoxyethyl)-2-[2-(4-nitrophenoxy)ethyl]pyridine (8.4 g, yield: 71%) as oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][C@@H:9]1[C:19](N(OC)C)=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].S(=O)(=O)(O)[O-].[K+].O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:10][C@@H:9]1[CH:19]=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CON(C)C(=O)[C@H]1CC[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](C=O)CC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cold (−78° C.) solution of 1-tert-butyloxycarbonyl-cis-2-{[methoxy(methyl)amino]carbonyl}-5-phenylpyrrolidine (1.36 g, 4.07 mmol) in THF (20 mL) under an atmosphere of nitrogen, a 1M solution of LAH in THF (4.07 mL, 4.07 mmol) was added dropwise and the mixture was stirred for 30 min. The mixture was warmed to 0° C. for 30 min and then quenched with potassium bisulfate solution in water (0.969 g, 7.12 mmol). EtOAc was added and the organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 50:50 mixture of ethyl acetate and hexane. Collection and concentration of appropriate fractions provided 1-tert-butyloxycarbonyl-cis-2-formyl-5-phenylpyrrolidine. HPLC RT=3.47 min, 99% at 215 nm (Method A); ES MS (M+H)=276.3.