Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH2:25][O:26][CH2:27][CH2:28]O)[CH:3]=1.[NH:30]1[C:35](=[O:36])[CH2:34][O:33][CH2:32][C:31]1=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH:3]=1)[CH2:25][O:26][CH2:27][CH2:28][N:30]1[C:35](=[O:36])[CH2:34][O:33][CH2:32][C:31]1=[O:37]
Reactant: O=C1COCC(=O)N1
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCO)cc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCN2C(=O)COCC2=O)cc1Cl
Reaction time: 18 h

Procedure:
To a solution of Compound 158 (47 mg, 0.1 mmol), morpholine-3,5-dione (16 mg, 0.14 mmol) and triphenylphosphine (37 mg, 0.14 mmol) in THF (5 ml) was added diethyl azodicarboxylate solution (40% in toluene, 0.1 ml, 0.23 mmol) at RT. The reaction solution was stirred at the same temperature for 18 h and concentrated in vacuo. The residue was purified by chromatography (petroleum ether/ethyl acetate 1:1) to furnish the title compound, which was impure. The product was further purified by preparative TLC (petroleum ether/ethyl acetate 1:1) to give the pure title compound as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][NH:19][C:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:21]>CC(C)CC(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][NH:19][C:20]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[O:21])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCCCl)c1cccnc1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Solvent: CC(=O)CC(C)C
Product: O=C(NCCN1CCC(C(=O)c2ccc(F)cc2)CC1)c1cccnc1
Yield: 16.5 %

Procedure:
To a stirred solution of 11.2 parts of (4-fluorophenyl) (4-piperidinyl)methanone in 80 parts of 4-methyl-2-pentanone were added 5 parts of N-(2-chloroethyl)-3-pyridinecarboxamide and the whole was stirred and refluxed overnight. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 1.6 parts (16.5%) of N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-3-pyridinecarboxamide; mp. 118.3° C. (intermediate 114).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[C:5]([F:18])=[CH:4][N:3]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([CH2:27][S:28][CH3:29])[CH:26]=1)[NH2:23]>>[CH2:16]([O:15][C:9]1[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=1[C:6]1[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:23][C:22]2[CH:24]=[C:25]([CH2:27][S:28][CH3:29])[CH:26]=[C:20]([F:19])[CH:21]=2)[N:7]=1)[CH3:17]
Reactant: CCOc1cc(F)ccc1-c1nc(Cl)ncc1F
Reactant: CSCc1cc(N)cc(F)c1
Product: CCOc1cc(F)ccc1-c1nc(Nc2cc(F)cc(CSC)c2)ncc1F

Procedure:
Intermediate 36.2 was prepared under similar conditions as described in the preparation of Intermediate 20.1 using 2-chloro-4-(2-ethoxy-4-fluorophenyl)-5-fluoropyrimidine and 3-fluoro-5-[(methylsulfanyl)-methyl]aniline. The residue was purified by chromatography (hexane to hexane/ethyl acetate 7:3) to give the desired product.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH3:31][S:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=1>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:37]([C:36]2[CH:39]=[CH:40][C:33]([S:32][CH3:31])=[CH:34][CH:35]=2)[OH:38])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(F)cnc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ccc(C(O)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 45.1 %

Procedure:
To a solution of 1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine (3 g, 10.87 mmol) in dry tetrahydrofuran (40 mL) at −78° C. was added a solution of n-butyllithium in n-hexane (2.5 M, 6.8 mL 17 mmol). The mixture was stirred at −78° C. for 35 min and then treated with 4-methylsulfanyl-benzaldehyde (2.8 mL, 21.0 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 20% ethyl acetate/hexanes) afforded (1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-(4-methylsulfanyl-phenyl)-methanol as a white solid (2.1 g, 45.2%): LC/MS m/e calcd for C21H17FN2O3S2 [M+H]+ 429.51, observed 428.7.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]2[N:4]([C:5]3[C:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)=[CH:12][S:11][C:6]=3[C:7]2=[O:10])[CH:3]=1.[CH3:22][O-:23].[Na+]>>[CH3:22][O:23][C:2]1[CH:9]=[C:8]2[N:4]([C:5]3[C:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)=[CH:12][S:11][C:6]=3[C:7]2=[O:10])[CH:3]=1
Reactant: C[O-]
Reactant: COc1ccc(-c2csc3c2-n2cc(Br)cc2C3=O)cc1
Agent: [Na+]
Product: COc1ccc(-c2csc3c2-n2cc(OC)cc2C3=O)cc1

Procedure:
1 equivalent of the compound obtained in Example 12 is stirred, at ambient temperature, into a solution of sodium methanolate. After 12 hours' reaction, the reaction mixture is concentrated under reduced pressure. The residue is taken up in dichloromethane; the organic phase is then washed with a saturated NaCl solution, dried over sodium sulphate and then concentrated under reduced pressure. Chromatography on silica gel (dichloromethane) allows the expected product to be isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C(=O)N([Br:24])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:4]=1[F:9]
Reactant: Cc1ccc(Cl)c(Oc2ccccc2)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1c(CBr)ccc(Cl)c1Oc1ccccc1
Temperature: 25 °C
Yield: 8.7 %

Procedure:
A mixture of 1-chloro-3-fluoro-4-methyl-2-(phenyloxy)benzene (0.500 g, 2.113 mmol), NBS (0.414 g, 2.324 mmol) and AIBN (0.017 g, 0.106 mmol) in carbon tetrachloride (8 mL) was heated at reflux overnight. The reaction mixture was cooled to RT and filtered through Celite. The solvent was evaporated. Chromatography of the residue gave the desired product (0.058 g, 9%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.27-7.35 (m, 3H), 7.18-7.27 (m, 2H), 7.05-7.11 (m, 1H), 6.89 (d, 2H), 4.30-4.59 (m, 2H).
Reaction SMILES: O(C(C)(C)C)[Na].[NH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].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.[Fe+2]>[CH3:19][C:13]1[CH:18]=[CH:17][C:16]([N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:15][CH:14]=1
Reactant: C1CCNCC1
Reactant: Cc1ccccc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Product: Cc1ccc(N2CCCCC2)cc1
Temperature: 100 °C
Yield: 77 %

Procedure:
This example is representative of procedure "B". Into a screw-capped test tube were weighed 29 mg (0.052 mmol) Pd(dba)2, 55 mg (0.10 mmol) DPPF, and 144 mg (1.5 mmol) NaO-t-Bu. The solid materials were suspended in 12 ml of toluene. 4-Methylphenyltriflate (240 mg, 1.0 mmol) was dissolved in 1 ml of toluene and added to the test tube. The test tube was sealed with a cap containing a PTFE septum and removed from the dry box. Piperidine (148 μl, 1.5 mmol) was added to the test tube by syringe. The reaction mixture was heated at 100° C. for 5 hours. TLC of the reaction mixture indicated complete consumption of the starting triflate. The reaction mixture was cooled to room temperature, and the mixture was absorbed onto silica gel. Chromatography on a silica gel column using 50:1 hexanes:diethyl ether afforded 1-(4-methylphenyl)piperidine as a clear oil. (135 mg, 77% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])=O)=O)[CH3:2].C(Cl)Cl.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>N1C=CC=CC=1>[O:11]1[C:9]2=[CH:8][N:7]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:18])[CH:17]=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C=CCCCCOC(=O)CNC(=O)C(=O)OCC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2c(cn1)OCCCC2

Procedure:
Ethyl-2-((2-(hex-5-en-1-yloxy)-2-oxoethyl)amino)-2-oxoacetate (0.35 g) and DCM (4 mL) were added to a vessel with stirring followed by the addition of pyridine (0.13 g). Tf2O (0.58 g) was then added to the mixture slowly at ambient temperature. The mixture was stirred at ambient temperature for 4 days after which time the mixture was extracted with 6N HCl (3×10 mL). The combined acid layers were washed with DCM (10 mL) and the pH was adjusted to ˜10 with solid K2CO3. The basic aqueous layer was extracted with DCM (20 mL). The organic layer was concentrated under reduced pressure to provide the title compound (A) and ethyl 2,3,4,5-tetrahydrooxepino[2,3-c]pyridine-7-carboxylate (B) as a 3:1 mixture as based on NMR analysis. 1H NMR (300 MHz, CDCl3) δ ppm 8.38 (s, 0.3H, cmpd B), 8.11 (s, 1H, cmpd A), 7.95 (s, 0.3H, cmpd B), 4.36-4.51 (m, 2.6H, cmpd A/B CH3CH2), 4.17-4.25 (m, 2H, cmpd A OCH2), 4.06-4.13 (m, 0.6H, cmpd B OCH2), 2.85-2.93 (m, 0.6H, cmpd B CH2), 2.71 (t, J=6.53 Hz, 2H, cmpd A CH2), 2.45 (s, 3H, cmpd A CH3), 1.99-2.15 (m, 2.6H, cmpd A/B CH2), 1.54-1.88 (m, 0.6H, cmpd B CH2), 1.44 (t, J=7.12 Hz, 0.9H, cmpd B CH3), 1.44 (t, J=7.12 Hz, 3H, cmpd A CH3); 13C NMR (75 MHz, CDCl3) δ ppm 166.53, 165.01, 162.88, 159.21, 153.21, 143.48, 143.11, 142.72, 139.52, 136.74, 134.94, 130.12, 127.21, 73.82, 65.85, 61.61, 61.21, 33.74, 31.53, 24.97, 22.11, 21.48, 14.56, 14.28; Cmpd A: HRMS (M+Na) m/z, calcd for C12H15NO3Na, 244.0950; found 244.0961; Cmpd B: HRMS (M+H) m/z, calcd for C12H16NO3, 222.1130; found 222.1130.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:28]5[C@H:27]([CH3:26])[CH2:31][O:30][C:29]5=[O:32])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)nc2)CC1
Yield: 71.5 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (525 mg) described in Preparation Example 106 and (R)-4-methyloxazolidin-2-one (212 mg) described in Preparation Example 25, the title compound (394 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>ClCCl>[Br:18][CH2:19][CH2:20][C:21]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)=[O:22]
Reactant: O=C(Cl)CCBr
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(CCBr)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-(Trifluoromethyl)aniline (Aldrich, 16.11 g, 100 mmol) was added to a suspension of potassium carbonate (27.64 g, 200 mmol) in dichloromethane (225 mL) followed by the addition of 3-bromopropionyl chloride (10.08 mL, 100 mmol) in dichloromethane (40 mL). The mixture was stirred for 4 hours at ambient temperature, quenched with water (200 mL), the organic layer was washed twice with water (200 mL), dried over sodium sulfate, filtered through a silica gel plug, and rinsed with 1:1 ethyl acetate:hexane (400 mL), and concentrated under reduced pressure to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.99 (t, J=6.27 Hz, 2H), 3.74 (t, J=6.44 Hz, 2H), 7.41 (d, J=7.80 Hz, 1H), 7.56 (t, J=7.97 Hz, 1H), 7.77 (d, J=8.48 Hz, 1H), 8.11 (s, 1H), 10.39 (s, 1H). MS (DCI) m/z 312.99 (M+NH4)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].O.[NH2:11][NH2:12]>C(O)CCC.C1COCC1>[NH:11]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6])[NH2:12]
Reactant: NN
Reactant: N#Cc1ccnc(Cl)c1
Solvent: CCCCO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccnc(NN)c1
Temperature: 110 °C

Procedure:
20.0 g (144 mmol) of 2-chloroisonicotinonitrile are initially charged in 150 ml of 1-butanol, 303 ml (303 mmol) of a 1 M solution of hydrazine hydrate in THF are added and the mixture is heated for 16 h (bath temperature 110° C.). The mixture is concentrated and the residue is purified by flash chromatography on silica gel (mobile phase: dichloromethane/methanol 10:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:24]=[CH:23][C:8]([O:9][CH2:10][CH2:11][N:12]2C(=O)C3=CC=CC=C3C2=O)=[CH:7][CH:6]=1)=[O:4].O.NN>CO>[NH2:12][CH2:11][CH2:10][O:9][C:8]1[CH:23]=[CH:24][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(OCCN)cc1
Yield: 89.9 %

Procedure:
N-[2-(4-Methoxycarbonylphenoxy)ethyl]phthalimide (158.86 g) prepared in accordance with (1) and 73.33 g of hydrazine hydrate were dissolved in 1.5 liters of methanol and the solution was refluxed for 1 hour. The precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was extracted with chloroform and washed with saturated sodium chloride solution twice. The organic solvent layer was dried with anhydrous magnesium sulphate and concentrated in vacuo. n-Hexane was added to the residue to make it crystallised followed by filtration to give 85.74 g of crystals (yield: 90%). M.p. 53°-55.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][NH2:10].[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O>>[CH2:17]([O:16][C:11](=[O:15])[C:12](=[N:10][NH:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[F:1])[CH3:14])[CH3:18]
Reactant: Cc1ccc(F)c(NN)c1
Reactant: CCOC(=O)C(C)=O
Product: CCOC(=O)C(C)=NNc1cc(C)ccc1F

Procedure:
The title compound was prepared in accordance with the general method of example 25b) from (2-fluoro-5-methyl-phenyl)-hydrazine and ethyl pyruvate.
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9](Cl)[C:8]=2[N:7]=[C:6]1[CH2:19][OH:20])[CH2:2][CH2:3][CH3:4].[NH3:21]>CO>[NH2:21][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][OH:20])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: N
Reactant: CCCCn1c(CO)nc2c(Cl)nc3ccccc3c21
Solvent: CO
Product: CCCCn1c(CO)nc2c(N)nc3ccccc3c21
Temperature: 160 °C

Procedure:
1-Butyl-4-chloro-1H-imidazo[4,5-c]quinoline-2-methanol (2 g, 6.9 mmole, Example 127) was combined with 12 mL of 12% ammonia in methanol and heated in a Parr bomb at 160° C. for about 20 hours. The resulting solid was collected, rinsed with methanol then purified by silica gel chromatography using ethyl acetate/methanol as the eluent. The resulting solid was slurried with ethyl acetate, collected by filtration and dried to provide the desired product, m.p. 223°-225° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([CH3:11])[CH:3]=1.CN(C)P(N(C)C)(N(C)C)=O.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Br.Br[CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>C1COCC1.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[C:9]#[N:10])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CC#N
Reactant: BrCc1cccnc1
Agent: Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1cc(Br)ccc1C(C#N)Cc1cccnc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution (4-bromo-2-methylphenyl)acetonitrile (III.1; 1 eq.) in THF (0.18M) and hexamethylphosphoramide (HMPA; 3.3 eq.) at −78° C. was added lithium hexamethyldisilazide (LiHMDS; 1.9 eq.). The reaction mixture was stirred 30 min at −78° C. To the resulting solution was cannulated a suspension of 3-(bromomethyl)pyridine hydrobromide salt (0.8 eq.) in THF (0.1M). The final mixture was allowed to warm slowly to 0° C., stirred 2 h, warm to room temperature then stirred for an extra 2 h. The resulting mixture was poured in saturated aqueous NaHCO3 and finally extracted with EtOAc. The organic extract was washed with water, brine, dried over Na2SO4 filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 60% in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: C[O-].[Na+].[CH2:4]1[O:14][C:13]2[C:6](=[CH:7][C:8]([NH2:15])=[C:9]([CH:12]=2)[CH:10]=O)[O:5]1.[C:16]([CH2:18][C:19]([NH2:21])=[O:20])#[N:17]>CO>[CH2:4]1[O:5][C:6]2[CH:7]=[C:8]3[C:9]([CH:10]=[C:18]([C:19]([NH2:21])=[O:20])[C:16]([NH2:17])=[N:15]3)=[CH:12][C:13]=2[O:14]1
Reactant: N#CCC(N)=O
Reactant: Nc1cc2c(cc1C=O)OCO2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cc2cc3c(cc2nc1N)OCO3
Yield: 89.3 %

Procedure:
To sodium methoxide (1.90 g., 0.03 mole) in methanol (50 ml.) is added 4,5-methylenedioxy-2-aminobenzaldehyde (5.0 g., 0.03 mole) and 2-cyanoacetamide (2.50 g., 0.03 mole). The mixture is heated to reflux for fifteen minutes and then cooled in an ice bath. The bright yellow solid is filtered off and recrystallized from acetic acid to give 6.18 g. (89.3%) of the desired product. M.P. 308° C. (dec.). (m/e = 231)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH:7]1[CH3:16])[CH3:2].[H][H]>[Pd].C(O)C>[CH3:15][O:14][C:12]([N:9]1[CH2:10][CH2:11][C@H:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])[C@H:7]([CH3:16])[CH2:8]1)=[O:13]
Reactant: CCOC(=O)C=C1CCN(C(=O)OC)CC1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C[C@H]1CCN(C(=O)OC)C[C@H]1C
Yield: 99 %

Procedure:
A mixture of 56.9 parts of methyl 4-(2-ethoxy-2-oxoethylidene)-3-methyl-1-piperidinecarboxylate and 400 parts of ethanol was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 57 parts (99%) of ethyl cis-1-(methoxycarbonyl)-3-methyl-4-piperidineacetate (int. 19).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([O:19][CH3:20])[CH:11]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=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]>[Cl:8][C:4]1[CH:3]=[C:2]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][C:12]=2[O:19][CH3:20])[CH:7]=[CH:6][N:5]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: Clc1cc(Br)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1ccnc(Cl)c1
Temperature: 145 °C
Yield: 45 %

Procedure:
A mixture of 4-bromo-2-chloropyridine (1.92 g, 10 mmol), (4-fluoro-2-methoxyphenyl)boronic acid (1.70 g, 10 mmol) and K3PO4 (4.24 g, 20 mmol) in dioxane/water 10:1 (20 mL) was degassed with a stream of nitrogen for 10 min. After addition of Pd(dppf)Cl2 (816 mg, 1 mmol) the reaction mixture was heated at 145° C. for 90 minutes in a microwave oven. It was diluted with EtOAc and washed twice with sat. aq. NaHCO3 solution and once with brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (cHex/EtOAc 100:0 to 60:40) to yield the desired product A2 as a white solid (1.07 g, 45%). 1H NMR (400 MHz, d6-DMSO, 300K) δ 3.81 (s, 3H), 6.87 (dt, J=8.5 Hz, J=3.5 Hz, 1H), 7.05 (dd, J=11.4 Hz, J=2.5 Hz, 1H), 7.44 (dd, J=8.5 Hz, J=6.8 Hz, 1H), 7.48 (dd, J=5.3 Hz, J=1.5 Hz, 1H), 7.55 (m, 1H), 8.38 (d, J=5.3 Hz, 1H). MS (ES) C12H9ClFNO requires: 237. found: 238 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]#[N:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:18][CH2:19][CH2:20][CH2:21]I>C1COCC1>[Cl:18][CH2:19][CH2:20][CH2:21][C:1]1([C:6]#[N:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CC1CCCC1
Reactant: ClCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(CCCCl)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of cyclopentanecarbonitrile (1.04 mL, 10 mmol) in THF (20 mL) at −78° C. was added LiHMDS (1M in THF, 11 mL) via syringe. After 30 min, 1-chloro-3-iodopropane (1.6 mL, 15 mmol) was added at once and slowly warmed to room temperature. After 20 h, the reaction mixture was quenched with saturated ammonium chloride (1 mL), diluted with EtOAc (100 mL), dried (MgSO4), filtered and concentrated to give the title compound as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:6]2[O:7][C:8]([CH3:14])=[C:9]([C:11](O)=[O:12])[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O>>[CH:1]1([C:6]2[O:7][C:8]([CH3:14])=[C:9]([CH2:11][OH:12])[N:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1oc(C2CCCC2)nc1C(=O)O
Solvent: O=S(Cl)Cl
Product: Cc1oc(C2CCCC2)nc1CO
Reaction time: 0.67 h

Procedure:
A mixture of 2-cyclopentyl-5-methyl-4-oxazolecarboxylic acid (7.0 g) and thionyl chloride (14 ml) was refluxed with stirring for 40 minutes. The thionyl chloride was completely distilled off and the residue was dissolved in dimethoxyethane (70 ml). The solution was added dropwise to a mixture of sodium borohydride (2.7 g) and dimethoxyethane (50 ml) with ice-cooling and stirring. The mixture was stirred for 30 minutes, adjusted to pH 2 with 2N hydrochloric acid and refluxed for 30 minutes. The solvent was then distilled off and aqueous sodium hydrogen carbonate was added. The mixture was extracted with ethyl ether and the ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by chromatography using silica gel (75 g) [eluent: hexane-acetone (7:3)] to give 2-cyclopentyl-4-hydoxymethyl-5-methyloxazole as an oil; yield 4.0 g (61.5%).