Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24](Br)[CH:23]=[CH:22][C:21]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=3[O:37][CH3:38])[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cu][C:43]#[N:44].N#N>CN(C)C=O>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:43]#[N:44])[CH:23]=[CH:22][C:21]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=3[O:37][CH3:38])[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: N#C[Cu]
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(Br)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: N#N
Solvent: CN(C)C=O
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C#N)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (100 mg, 0.15 mmol) in N,N-dimethylformamide (1.5 mL) was added copper(I) cyanide (17 mg, 0.19 mmol). The resulting reaction mixture was N2 purged and sealed in a microwave vessel. The vessel was subject to microwave irradiation at 150° C. for 30 min. LC-MS indicated only the starting bromide was present. Added tetrakis(triphenylphosphine)palladium(0) (10 mg, 6 mol %) into the reaction mixture. Repeated microwave irradiation at 150° C. for 30 min. An aliquot indicated the desired product was formed and all starting bromide was consumed. Reaction crude was partitioned between water and hexanes. The aqueous phase was back extracted with diethyl ether. The combined extracts were dried over Na2SO4. The titled compound was obtained as a glassy material after two preparative TLC plates developed respectively by 20% EtOAc in hexanes and 4% EtOAc in dichloromethane. LC-MS: 595.03 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 1:1 mixture of rotamers δ 7.86 (s, 1 H), 7.61 (S, 0.5 H), 7.67-7.71 (m, 2.5H), 7.64-7.68 (m, 1 H), 7.32-7.36 (m, 1 H), 6.98 (d, J=8.5 Hz, 0.5H), 6.95 (d, J=8.5 Hz, 0.5 H), 6.68 (d, J=12 Hz, 1H), 5.62 (d, J=8.0 Hz, 0.5H), 5.46 (d, J=8.0 Hz, 0.5H), 4.85 (d, J=16.0 Hz, 0.5H), 4.80 (d, J=16.0 Hz, 0.5 H), 4.06 (d, J=16 Hz, 0.5 H), 3.79-3.86 (m, 1 H), 3.70-3.78 (m, 3.5 H), 3.16-3.24 (m, 1H), 3.75 (s, 1.5 H), 3.16-3.25 (m, 1H), 3.14 (s, 1.5 H), 3.13 (s, 1.5 H), 1.15-1.27 (m, 6 H), 0.54 (d, J=7.0 Hz, 1.5 H), 0.37 (d, J=6.5 Hz, 1.5 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.C([Li])CCC.C([Cu])#N.C([Cu])#N.C1COCC1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=1[I:40].[NH4+].[Cl-]>C1COCC1>[CH3:1][O:2][C:3]1[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[C@H:7]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=2[I:40])[N:8]=1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Reactant: COc1ccc(CBr)c(I)c1
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1ccc(OC)cc1I
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 75.1 %

Procedure:
The diastereomeric product 21 was obtained by a reaction of the lithium salt of the chiral auxiliary (2R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine with the bromo derivative 20 using a crucial modification of a procedure reported in the literature [U. Schollkopf, “Enantioselective Synthesis of Non-Proteinogenic Amino Acids via Metallated Bis-Lactim Ethers of 2,5-Diketopiperazines.” Tetrahedron, 39, pp 2085-2091 (1983)]. Briefly, (2R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (4.39 mL, 24.5 mmol) was dissolved in 4 mL of THF (freshly distilled from LiAlH4). The light yellow solution was cooled to −78° C. (dry ice/acetone bath) and stirred for 15 min under argon. A 2.5 M solution of n-butyl lithium (9.79 mL, 24.5 mmol) was added drop wise over a period of 10 min and the mixture was stirred for 20 min at −78° C. In a separate flask CuCN (1.096 g, 12.23 mmol) was stirred with 4 mL of freshly distilled THF at room temperature for 10 min. The white suspension was then cooled to 0° C. (ice bath) and stirred at that temperature for 20 min. The n-BuLi reaction mixture was then transferred to the white suspension of CuCN/THF under argon using a cannula. The resulting yellow suspension turned into a yellow solution within two minutes. The reaction mixture was then stirred at 0° C. for 15 min and cooled to −78° C. After 15 min of stirring at −78° C., a solution of bromomethyl anisole derivative 20 (4.00 g, 12.23 mmol) in 6 mL of freshly distilled THF was added drop wise. The color of the reaction mixture changed to greenish brown. After stirring for a further period of 2 hours at −78° C., the reaction mixture was warmed gradually to room temperature. The reaction mixture was then poured into a saturated solution of NH4Cl and extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to provide an oily compound which was purified by flash column chromatography to yield pure 2,5-Dihydro-3,6-dimethoxy-2-isopropyl-5-(2-iodo-4-methoxybenzyl)-(2R,5S)-pyrazine (21) as a yellow oil (3.95 g, 75%).
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:10][CH2:9][C@H:8](O)[CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1.[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[N:1]1([C@H:6]2[CH2:10][CH2:9][C@H:8]([N:16]3[C:15](=[O:17])[C:14]4=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]4[C:12]3=[O:22])[CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O[C@H]1CC[C@@H](n2cccn2)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](n2cccn2)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
A solution of cis-3-(1H-pyrazol-1-yl)cyclopentanol (5.01 g, 32.9 mmol) in THF (150 mL) was cooled to 0° C. and treated with phthalimide (5.33 g, 36.2 mmol), diisopropylazodicarboxylate (7.1 mL, 36.1 mmol) and triphenylphosphine (9.48 g, 36.1 mmol). The reaction mixture was stirred at 0° C. for 4 h. The reaction mixture was poured water and then extracted with EtOAc. The organic layer was dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (Chromatrex, Hexane/EtOAc=5/1) to yield trans-N-[3-(1H-pyrazol-1-yl)cyclopentyl]phthalimide (4.85 g, 52%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([CH2:16][CH:17]([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[CH2:18][NH2:19])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=1)[CH2:16][C:13]1([F:12])[CH2:15][CH2:14]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(CC1(F)CC1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(CC1(F)CC1)c1ccc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 3-(1-fluorocyclopropyl)-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine. LCMS (MH+): m/z=435.1, tR (minutes, Method G)=2.46
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[N:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[OH:32]>>[O:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[CH2:9][NH:8][C:6]1[N:7]=[C:2]([C:21]2[CH:20]=[CH:19][C:18]([OH:32])=[C:17]([O:16][CH3:15])[CH:22]=2)[CH:3]=[N:4][CH:5]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: Clc1cncc(NCc2ccco2)n1
Product: COc1cc(-c2cncc(NCc3ccco3)n2)ccc1O
Yield: 92 %

Procedure:
In a procedure analogous to Example 2, reaction of 6-chloro-N-(2-furylmethyl)pyrazin-2-amine and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol furnished the product (92%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f3) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:8][CH:9]=2)[N:4]([C:23]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])[C:3]1=[O:30]>CO.[Pd]>[CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][CH:14]=3)=[N:8][CH:9]=2)[N:4]([C:23]([N:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:24])[C:3]1=[O:30]
Reactant: Cn1c(=O)n(C(=O)N2CCCC2)c2nc(/C=C/c3ccc(C(F)(F)F)cc3)ncc21
Agent: [Pd]
Solvent: CO
Product: Cn1c(=O)n(C(=O)N2CCCC2)c2nc(CCc3ccc(C(F)(F)F)cc3)ncc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-methyl-9-(pyrrolidin-1-ylcarbonyl)-2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-7,9-dihydro-8H-purine-8-one <the compound of Example 243> (50 mg) in methanol (10 ml) was added 10% palladium on carbon (5 mg) and the mixture was stirred for 2 hours at room temperature under hydrogen atmosphere. After removing the catalyst from the reaction mixture, the solvent was evaporated under reduced pressure, and the residue was dried to give the title compound 38 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][N:4]=1.C1C(=O)N([Br:20])C(=O)C1>C(#N)C>[Br:20][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([C:9]([F:12])([F:10])[F:11])[CH:7]=1
Reactant: COc1ccc(C(F)(F)F)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ncc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
To a stirred solution of 2-methoxy 5-(trifluoromethyl) pyridine (4 g, 22.58 mmol) was dissolved in acetonitrile (50 ml) was added NBS (6 g, 33.87 mmol) portion wise at 0° C. The reaction mixture was stirred for overnight at RT. The solvent was removed under vacuum, quenched with water (100 mL) and extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over sodium sulfate, and concentrated at reduced pressure to yield 3-bromo-2-methoxy-5-(trifluoromethyl)pyridine (12) as a pale yellow liquid (2 g, 34.7%).
Reaction SMILES: C([N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]=[C:9]1[C:15]1[C:16]([CH:26]2[CH2:28][CH2:27]2)=[CH:17][C:18]([CH3:25])=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21])C1C=CC=CC=1.Cl.[H][H]>[Pd].CO>[CH:26]1([C:16]2[C:15]([C:9]3[NH:8][C:12]([O:13][CH3:14])=[N:11][N:10]=3)=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:25])[CH:17]=2)[CH2:28][CH2:27]1
Reactant: [H][H]
Reactant: COC(=O)c1cc(-c2nnc(OC)n2Cc2ccccc2)c(C2CC2)cc1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(-c2nnc(OC)[nH]2)c(C2CC2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
A flask containing methyl 5-(4-benzyl-5-methoxy-4H-1,2,4-triazol-3-yl)-4-cyclopropyl-2-methylbenzoate (compound 91.4, 0.55 g, 1.46 mmol) and Pd/C (10%, 0.25 g) was purged with nitrogen, then MeOH (10 mL) and HCl (4 M in dioxane, 37 μL, 0.15 mmol) were carefully added. The system was then charged with hydrogen and the mixture was stirred at room temperature for 3 hours. Upon completion, the system was purged with nitrogen, then the mixture was neutralized with a few drops of NH4OH and filtered through Celite®. The filtrate was concentrated under reduced pressure and the residue was purified using prep-TLC (hexanes:EtOAc 1:1) to yield 0.3 g (71%) of the title compound as a clear oil. m/z (ES+) 288 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:35][CH2:36][CH2:37][N:38]1[C:42](=[O:43])[C:41]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:40]2[C:39]1=[O:48]>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[O:31][CH2:35][CH2:36][CH2:37][N:38]2[C:42](=[O:43])[C:41]3[C:40](=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:39]2=[O:48])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Product: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(OCCCN4C(=O)c5ccccc5C4=O)c3)cc2)cccc1[N+](=O)[O-]

Procedure:
The product from Example 61F and N-(3-hydroxypropyl)phthalimide were processed as described in Example 61G to provide the title compound.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].I[CH2:30][CH3:31]>CN(C)C=O>[CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2]
Reactant: CCNCC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Temperature: 150 °C

Procedure:
A mixture of 10-(1-ethylamino-2-propyl)-2-phenothiazinecarbonitrile acid fumarate, D series (4 g), sodium carbonate (1.32 g) and iodoethane (1 cc) in dimethylformamide (50 cc) is heated to a temperature in the region of 150° C. for 6 hours. After being cooled, the reaction mixture is concentrated to dryness (30 mm Hg; 4 kPa) at 50° C. and the residue is taken up with ethyl acetate (100 cc) and washed successively with distilled water (50 cc) and with saturated aqueous sodium chloride solution (50 cc). The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-(1-Diethylamino-2-propyl)-2-phenothiazinecarbonitrile, D series (3.4 g) is thereby obtained in the form of a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)([C:14]#N)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.[CH3:32][OH:33]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)([CH2:14][CH:32]=[O:33])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Br)cc2)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CC=O)(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-(4-bromo-phenyl)-4-cyano-piperidine-1-carboxylic acid tert-butyl ester from Step 2 (5.67 g, 15.57 mmol, 1 eq) in 60 mL of dichloromethane was add a solution of DIBAL-H (1M in toluene, 23.36 mL, 23.36 mmol, 1.5 eq) in a drop-wise fashion. The resulting mixture was stirred at room temperature for 20 h and then 15 mL of methanol was added carefully. The mixture was stirred for 0.25 h and a precipitate formed. The resulting mixture was filtered through Celite and the salts were washed several times with ethyl acetate. The filtrate was adsorbed onto silica gel and purified by flash column chromatography eluting with a gradient of 5-20% ethyl acetate in hexane to give 1.78 g of 4-(4-bromo-phenyl)-4-(2-oxo-ethyl)-piperidine-1-carboxylic acid tert-butyl ester and 1.54 g of recovered starting material. 1H NMR (300 MHz, CDCl3): δ 9.35 (s, 1H), 7.50-7.46 (d, 2H), 7.15-7.10 (d, 2H), 3.82 (br. s, 2H), 3.11-3.04 (t, 2H), 2.35-2.28 (dt, 2H), 1.90 (br. s, 2H), 1.42 (s, 9H).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:20][CH2:19][C:8]2=[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:10][C:11]([S:12][CH3:13])=[C:7]2[C:6]1=[O:21])(=O)[CH3:2].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:2][C:1]1[O:21][C:6]2[C:7]3=[C:11]([S:12][CH3:13])[S:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]3[CH2:19][CH2:20][C:5]=2[N:4]=1
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(NC(C)=O)C2=O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(SC)c2c1CCc1nc(C)oc1-2
Yield: 93.8 %

Procedure:
A mixture of ethyl 5-acetylamino-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (2.46 g), phosphorus oxychloride (3.46 g) and toluene (80 ml) was refluxed under heating for 1.5 hours; the solution obtained was concentrated under reduced pressure, diluted with a saturated aqueous solution of sodium hydrogen carbonate (200 ml) and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield ethyl 4,5-dihydro-2-methyl-8-methylthiothieno[3,4-g]benzoxazole-6-carboxylate (2.18 g, 94.0%), which was then recrystallized from ethyl acetate-hexane. Light-yellow needles. Melting point 131-132° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([C:14]([OH:16])=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.[CH3:17]O>ClCCl>[CH:5]1([C:14]([O:16][CH3:17])=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1
Reactant: O=C(O)C1CCc2ccccc21
Reactant: CO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 100 %

Procedure:
Thionyl Chloride (0.95 mL, 13.0 mmol) was added to a room temperature solution of indane-1-carboxylic acid dissolved in 20 mL of dichloromethane. The reaction mixture was stirred at room temperature for 35 minutes after which time the volume was reduced by approximately 50% via a rotovap. Then 20 mL of methanol was added and the reaction was stirred at room temperature for 3 hours. Evaporation of the solvent and column chromatography (9/1 hexanes/EtOAc) afforded of methyl indane-1-carboxylate (2.2 g, 100%) as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.Cl.C([O:24][C:25](=[O:29])[CH2:26][NH:27][CH3:28])C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>[OH-].[Na+]>[CH3:28][N:27]([CH2:26][C:25]([OH:29])=[O:24])[C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)CNC
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: CN(CC(=O)O)C(=O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Yield: 54.6 %

Procedure:
The product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (1.50 g, 5.68 mmol), sarcosine ethyl ester hydrochloride (1.05 g, 6.81 mmol), 1-hydroxybenzotriazole monohydrate (1.31 g, 6.81 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.63 g, 8.52 mmol) and N-methylmorpholine (1.87 mL, 17.0 mmol) in a similar manner to Example 5, was neutralized by adding 2 mol/L aqueous sodium hydroxide solution (20 ml), and the mixture was filtered to obtain (E)-N-methyl-N-carboxymethyl-4-[2-(1H-indazol-3-yl)vinyl]benzamide (1.04 g, 55%).
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][CH2:5][N:6]([CH2:17][CH2:18]Cl)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH2:28][C:29]#[N:30].O1CCCC1>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O.CC1C=CC=CC=1>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[C:28]1([C:29]#[N:30])[CH2:4][CH2:5][N:6]([S:7]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)(=[O:8])=[O:9])[CH2:17][CH2:18]1
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC(C#N)(c3ccc(Cl)cc3Cl)CC2)cc1
Reaction time: 3 h
Yield: 29 %

Procedure:
To a stirred and hot solution of 8.5 parts of N,N,N-triethylbenzenemethanaminium chloride, 40 parts of sodium hydroxide and 360 parts of a sodium hydroxide solution 50%, is added dropwise a solution of 72.7 parts of N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide and 45.5 parts of 2,4-dichlorobenzeneacetonitrile in 90 parts of tetrahydrofuran. Upon completion, stirring is continued for 3 hours at 50° C. The reacton mixture is cooled, 216 parts of methylbenzene and 480 parts of water are added and the layers are separated. The organic phase is washed with water, dried, filtered and evaporated. The residue is crystallized from 2-propanol, yielding 28 parts (29%) of 4-(2,4-dichlorophenyl)-1-(4-methylphenylsulfonyl)-4-piperidinecarbonitrile; mp. 145° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[NH2:26]>ClCCl>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:26][C:13](=[O:15])[CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: COc1ccc(N)cc1OC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)CNC(=O)OCc2ccccc2)cc1OC
Temperature: 25 °C

Procedure:
To a suspension of 25.9 g (124 mmol) of N-(phenylmethoxycarbonyl)glycine in 370 ml of dichloromethane, were added at 0° C., 0.74 ml of dimethylformamide and 18.8 g (148 mmol) of oxyalylchloride. The mixture was allowed to warm to room temperature and was then added dropwise to a mixture of 19.0 g (124 mmol) of 3,4-dimethoxyaniline (sublimed) and washed with 10% hydrochloric acid solution and twice with water, and dried over sodium sulfate. After the evaporation of the solvent, the residue was triturated with ether and dried in vacuo; yield: 26.3 g.
Reaction SMILES: [Zn](CC)[CH2:2]C.C(I)I.[CH3:9][C:10]1([CH3:31])[O:14][C:13](=[O:15])[C:12]([O:16][CH2:17][C:18]([CH3:20])=[CH2:19])=[C:11]1[C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)CCl>[CH3:9][C:10]1([CH3:31])[O:14][C:13](=[O:15])[C:12]([O:16][CH2:17][C:18]2([CH3:2])[CH2:20][CH2:19]2)=[C:11]1[C:21]1[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1
Reactant: CC[Zn]CC
Reactant: C=C(C)COC1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Solvent: ICI
Solvent: ClCCCl
Product: CC1(COC2=C(c3ccc(S(C)(=O)=O)cc3)C(C)(C)OC2=O)CC1
Reaction time: 0.08 h

Procedure:
To a solution of Et2Zn (0.82 mL) in 50 mL of ClCH2CH2Cl cooled at 0∞C. was added 1.3 mL of CH2I2 slowly. The mixture was stirred for 5 min. and treated with 0.63 g of the olefin of example 18 at 0∞C. The mixture was stirred for 20 min. at 0∞C. and 3 h at room temperature. The reaction was quenched by addition of 50 mL of saturated NH4Cl solution and the product was extracted with EtOAc (200 mL) The extract was dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromotography eluted with 3:2 hexane/EtOAc to give 400 mg of the title product as a white solid.