Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[CH:20]=2)=[CH:8][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]4[CH:20]=3)=[CH:8][CH:7]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNCC1
Reactant: ClCCCOc1ccc(-c2cn3ccccc3n2)cc1
Product: c1ccn2cc(-c3ccc(OCCCN4CCCCC4)cc3)nc2c1
Temperature: 25 °C

Procedure:
The product of Example 16 Step A (60 mg) and piperidine (1.0 mL) were heated at 100° C. for 1.5 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous portion was extracted with a fresh portion of ethyl acetate (10 mL) and the organic portions combined and washed with brine (10 mL). The organic portions were dried over magnesium sulfate, filtered and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (60 mg). 1H-NMR (CD3OD) δ8.30 (m, 1H), 8.00 (s, 1H), 7.74 (m, 2H), 7.43 (m, 1H), 7.20 (m, 1H), 6.90 (m, 2H), 6.80 (m, 1H), 3.98 (t, J=6.0 Hz, 2H), 2.47 (m, 6H), 1.93 (m, 2H), 1.55 (m, 4H), 1.41 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)N)=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH:21]1[CH3:27].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:10][CH2:11][C:12]3[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[C:23]3[CH2:22][CH:21]([CH3:27])[N:20]([CH3:19])[CH2:25][C:24]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc(CCN(N)c2ccc(Cl)cc2)cn1
Reactant: CC1CC(=O)CCN1C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)C(C)C3)cn1
Temperature: 90 °C

Procedure:
To a stirred solution of 1-(4-chlorophenyl)-1-(2-(6-methylpyridin-3-yl)ethyl)hydrazine (1 g, 3.83 mmol) in dioxane (10 mL) was added 1,2-dimethylpiperidin-4-one (0.538 g, 4.59 mmol) and 0.5 mL of conc. sulfuric acid at RT. The reaction was heated at 90° C. for 2 h. After completion of reaction, the mixture was basified by addition of a saturated solution of NaHCO3. The product was extracted with EtOAc, and the organic layer washed with water, dried over sodium sulfate and concentrated. The solid obtained was purified by HPLC. 1HNMR (CD3OD, TFA salt) d (ppm): 8.30 (s, 1H), 8.05 (d, 1H), 7.64 (d, 1H), 7.50 (s, 1H), 7.24 (d, 1H), 7.10 (d, 1H), 4.50 (t, 2H), 4.40 (m, 1H), 4.0 (m, 1H), 3.80 (m, 1H), 3.30 (m, 3H), 3.0 (m, 4H), 2.62 (s, 3H), 1.50 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:9]=[N:10]/[CH3:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](/[C:19](=[CH:22]/[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])/[C:20]#[N:21])=[C:15]([F:28])[CH:14]=1.[OH-].[K+]>CS(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:20]#[N:21])[CH:22]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:11][NH:10][CH:9]2[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[C:15]([F:28])[CH:14]=1
Reactant: CC(C)(C)C/C=C(\C#N)c1ccc(Cl)cc1F
Reactant: C/N=C/c1cccc(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1CNC(c2cccc(Cl)c2Cl)C1(C#N)c1ccc(Cl)cc1F
Yield: 21 %

Procedure:
In a manner similar to the method described in Example 3a, [1-(2,3-dichloro-phenyl)-meth-(E)-ylidene]-methyl-amine (3.76 g, 20.00 mmol) reacted with (Z)-2-(4-chloro-2-fluoro-phenyl)-5,5-dimethyl-hex-2-enenitrile (5.03 g, 20.00 mmol) in DMSO (30 mL) in the presence of KOH powder (5.72 g, 56.11 mmol) to give rac-(2S,3S,4S)-3-(4-chloro-2-fluoro-phenyl)-2-(2,3-dichloro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (1.85 g 21.0%). LC-MS (ES+) m/z Calcd for C22H22Cl3FN2+H [(M+H)+]: 441, found: 441.
Reaction SMILES: C([O:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:22][CH2:23]Cl)C1C=CC=CC=1.B(Br)(Br)Br.C([O-])([O-])=O.[K+].[K+]>ClCCl>[CH:19]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[C:21]1[N:9]3[O:8][CH2:23][CH2:22][C:10]3=[N:11][C:12]=1[CH:13]=[N:14]2
Reactant: ClCCc1nc2cnc3ccccc3c2n1OCc1ccccc1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: c1ccc2c(c1)ncc1nc3n(c12)OCC3
Reaction time: 2 h
Yield: 12.3 %

Procedure:
A stirred solution of 1-(benzyloxy)-2-(2-chloroethyl)-1H-imidazo[4,5-c]quinoline (0.6058 g, 1.793 mmol) in 10 mL of dichloromethane was treated with a 1 M solution of BBr3 in dichloromethane (5.4 mL, 5.379 mmol). After 2 hours, 10 mL of saturated, aqueous K2CO3 solution were added and the reaction mixture stirred under ambient conditions for 3 hrs. The organic portion was separated and washed successively with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Chromatography (SiO2, 0-15% CMA/CHCl3) gave 0.0465 g of 8,9-dihydroisoxazolo[2′,3′:1,2]imidazo[4,5-c]quinoline as a tan solid.
Reaction SMILES: C([C:4]1[O:12][C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(O)=O>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:5]2[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:11]3[O:12][CH:4]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)c1oc2cccnc2c1-c1ccc(F)cc1
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: Fc1ccc(-c2coc3cccnc23)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 57 %

Procedure:
A mixture of 2-carboxy-3-(4-fluorophenyl)-furo[3,2-b]pyridine (1.8 g, 7 mmol), copper metal (0.56 g, 8.81 mmol) in quinoline (10 ml) was heated at reflux. After 45 min., the reaction was cooled to room temperature and the product was extracted into water. The aqueous layer was acidified with hydrochloric acid and acetic acid. The product was filtered and dissolved in ether. The ether layer was dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography using ethyl acetate-hexanes (1:9) as the eluant gave 3-(4-fluorophenyl)-furo[3,2-b]pyridine as a solid (0.85 g).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([O:6][CH3:7])=[O:5].[CH2:17]([N:24]([CH2:28][CH2:29]Cl)[CH2:25][CH2:26]Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(N(CC)C(C)C)(C)C>[CH2:17]([N:24]1[CH2:28][CH2:29][N:2]([C@@H:3]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([O:6][CH3:7])=[O:5])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(Cc2ccccc2)CC1
Yield: 102.5 %

Procedure:
A solution of 5.9 g (23 mmol) of commercial methyl (S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and of 9.6 g (23 mmol) of benzylbis(2-chloroethyl)amine in 50 ml of N,N-diisopropylethylamine is heated at 127° C. for 3 h 30. After evaporation of the N,N-diisopropylethylamine, the reaction medium is hydrolyzed and then extracted with ethyl acetate. The organic phase is washed with an aqueous solution of sodium hydroxide having a concentration of 1N, and with water, and then dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product obtained is purified by chromatography on silica gel, elution being carried out with a 50/50 heptane/ethyl acetate mixture. 8.9 g (64%) of methyl (S)-2-(4-benzylpiperazin-1-yl)-3-tert-butoxycarbonylaminopropanoate are obtained in the form of a yellow oil.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:23][C:12]=1[C:13]([O:15]CC1C=CC=CC=1)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCOCC1.CO>[CH2:3]([O:10][C:11]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=2)=[CH:23][C:12]=1[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OCc1ccccc1)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
An 2 mol/L aqueous solution of sodium hydroxide (1.1 mL) was added to a solution mixture of the obtained benzyl 2-(benzyloxy)-5-(pyridin-4-yl)benzoate (0.29 g) in dioxane (2.9 mL) and methanol (2.9 mL), followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and water was added to the residue. After adjusting the pH to 4 with 6 mol/L hydrochloric acid, ethyl acetate was added thereto. The reaction mixture was filtrated to collect the solid substance to obtain 0.19 g of 2-(benzyloxy)-5-(pyridin-4-yl)benzoic acid as a white solid.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH2:23].P>C1(C)C=CC=CC=1.C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH:23][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: Nc1ccc(F)cc1F
Reactant: COc1ccc2c(c1)CCc1cc(Cl)ccc1C2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: P
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)CCc1cc(Nc3ccc(F)cc3F)ccc1C2=O
Yield: 66 %

Procedure:
In accordance with general method O, 0.52 g (1.9 mmol) of 2-chloro-8-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.30 g (2.3 mmol) of 2,4-difluoroaniline, 0.04 g of Pd(OAc)2, 0.16 g of phosphine ligand and 0.86 g (8.9 mmol) of Na—O-tert-butylate are reacted in 10 ml of toluene and 2 ml of tert-BuOH. Purification is carried out by column chromatography (flash; SiO2; hexane 90%/ethyl acetate 10%). Yield: 66%; m.p.: 157° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4]1.C(N(CC)C(C)C)(C)C.C(Cl)(Cl)(Cl)Cl.[P:44]([O-:61])([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C(#N)C>[O:8]=[C:6]1[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:28])([F:27])[F:29])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4][C@H:3]([CH2:2][O:1][P:44]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:61])[O:7]1
Reactant: O=C1O[C@@H](CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1O[C@@H](COP(=O)(OCc2ccccc2)OCc2ccccc2)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 34.6 %

Procedure:
The 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (150 mg, 0.37 mmol) obtained in step B of Example 1-14 was dissolved in acetonitrile (5 ml). Thereafter, N,N-diisopropylethylamine ml, 2.96 mmol), carbon tetrachloride (0.706 ml, 7.4 mmol), N,N-dimethylaminopyridine (14 mg, 0.22 mmol), and dibenzyl phosphite (0.410 ml, 1.86 mmol) were added to the solution. The obtained mixture was stirred at 50° C. for 15 hours. Thereafter, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=1:5), so as to obtain phosphate dibenzyl ester (R)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]-oxazolidin-5-ylmethyl ester (85 mg, 34%) in the form of a colorless foaming substance.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][N:12]1[C:16]([CH3:17])=[C:15]([OH:18])[C:14]([CH3:19])=[N:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[I:10][C:7]1[CH:8]=[CH:9][C:2]([O:18][C:15]2[C:14]([CH3:19])=[N:13][N:12]([CH3:11])[C:16]=2[CH3:17])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: Cc1nn(C)c(C)c1O
Reactant: O=Cc1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1nn(C)c(C)c1Oc1ccc(I)cc1C=O
Yield: 97.2 %

Procedure:
In a manner similar to the method described in Example 50a, 2-fluoro-5-iodobenzaldehyde (5.84 g, 23.4 mmol) (Aldrich) was reacted with 1,3,5-trimethyl-1H-pyrazol-4-ol (3.24 g, 25.7 mmol) and K2CO3 in N,N-dimethylacetamide to give 5-iodo-2-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)-benzaldehyde as a yellow solid (Yield 8.1 g, 97%).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:32])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:50])[C@@H:15]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si](C(C)(C)C)(C)C)[CH2:36]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:32])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:50])[C@@H:15]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([OH:42])[CH2:36]2)=[CH:10]1
Reactant: CCC(Oc1ccccc1Cl)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1ccccc1Cl)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 61.2 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.27 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2-chlorophenoxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described inExample 85, above] and 40.8 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 0.54 g of the title compound as white crystals, melting at between 145° and 147° C.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[C:17]3[N:25]=[C:24](S(C)=O)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:12]=[CH:13][CH:14]=1.CC1C=C(NC2C3N=C(S(C)(=O)=O)N=CC=3N=CN=2)C=CC=1>O1CCOCC1>[CH3:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[C:17]3[N:25]=[C:24]([NH:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cccc(Nc2ncnc3cnc(S(C)=O)nc23)c1
Reactant: NC1CCCCC1
Agent: Cc1cccc(Nc2ncnc3cnc(S(C)(=O)=O)nc23)c1
Solvent: C1COCCO1
Product: Cc1cccc(Nc2ncnc3cnc(NC4CCCCC4)nc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.3 ml of cyclohexylamine are added to 0.4 g of a mixture of 4-[(3-methylphenyl)amino]-6-methylsulphinyl-pyrimido[5,4-d]pyrimidine and 4-[(3-methylphenyl)amino]-6-methylsulphonylpyrimido[5,4-d]pyrimidine in 10 ml of dioxane and the mixture is stirred at room temperature overnight. The reaction mixture is evaporated, water is added to the residue and the solid is filtered off with suction. The crude product is purified by chromatography over a silica gel column with petroleum ether/ethyl acetate (2:1).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[CH2:18]([O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)[CH:17]=[CH2:16]
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: C=CCOc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 100.8 %

Procedure:
42 g of 4(4-chlorophenoxy)-phenol and 48 g of allyl bromide were heated at the boil at a reflux condenser, while stirring and adding 50 g of potassium carbonate, in 500 ml of butanol for 4 hours. Inorganic salts were then separated from the reaction solution by suction-filtration, the solvent was vaporized and the residue was distilled under greatly reduced pressure. 50 g of 4(4-chlorophenoxy)-phenyl allyl ether were obtained, boiling point: 173°-175° C. under a pressure of 2-3 mm mercury.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)=[O:11])=[O:9])=[CH:4][CH:3]=1.[CH2:19]([O:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[CH2:39])=[CH:34][C:33]=1[O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>[Pd]>[CH2:19]([O:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[CH2:39])=[CH:34][C:33]=1[O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[CH2:41]([O:40][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:9])[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH:39]=[CH:38][C:35]4[CH:36]=[CH:37][C:32]([O:31][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:33]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH:34]=4)=[CH:14][CH:13]=3)=[O:11])=[CH:4][CH:3]=2)[CH:36]=[CH:37][C:32]=1[O:31][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: [Pd]
Agent: C=Cc1ccc(OCCCCCCCCCCCC)c(OCCCCCCCCCCCC)c1
Product: CCCCCCCCCCCCOc1ccc(C=Cc2ccc(C(=O)C(=O)c3ccc(C=Cc4ccc(OCCCCCCCCCCCC)c(OCCCCCCCCCCCC)c4)cc3)cc2)cc1OCCCCCCCCCCCC

Procedure:
1,2-Bis-dodecyloxy-4-vinyl-benzene (JYC-II-004-A) was synthesized in 66% yield according to a simplified Wittig reaction procedure reported by Gaset and co-workers.3 The Pd-catalyzed Heck coupling reaction between 4,4′-dibromobenzil and 1,2-bis-dodecyloxy-4-vinyl-benzene gave 1,2-bis-{4-[2-(3,4-bis-dodecyloxy-phenyl)-vinyl]-phenyl}-ethane-1,2-dione (JYC-II-007-A) in 76% yield as a bright yellow solid. Bis{1,2-di-{4-[2-(3,4-bis-dodecyloxy-phenyl)-vinyl]-phenyl}-ethane-1,2-dithiolene}nickel (JYC-II-014-A) was prepared from the reaction between JYC-II-007-A and excess phosphorus pentasulfide in 1,4-dioxane at 110° C. for 5 h, followed by the reaction with NiCl2.6H2O. The product was isolated as a dark green solid. The synthesis of JYC-II-014-A is shown in FIG. 2.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[Cl:16].[F:17][C:18]1[CH:23]=[C:22](B(O)O)[C:21]([F:27])=[CH:20][N:19]=1.C(=O)([O-])[O-].[Na+].[Na+].B(O)O>COCCOC.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(Cl)Cl.O>[Cl:16][C:3]1[C:2]([C:22]2[C:21]([F:27])=[CH:20][N:19]=[C:18]([F:17])[CH:23]=2)=[N:7][C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1
Reactant: Clc1ccc(NCC2CCOCC2)nc1Br
Reactant: OB(O)c1cc(F)ncc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: Fc1cc(-c2nc(NCC3CCOCC3)ccc2Cl)c(F)cn1
Temperature: 105 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (0.500 g, 1.64 mmol), 2,5-difluoropyridin-4-ylboronic acid (0.260 g, 1.64 mmol), and sodium carbonate (2.45 ml, 4.91 mmol, 2 M in H2O) were dissolved in DME (7.36 ml). The solution was then degassed by sparging with argon for 5 min. It was then treated with PdCl2(dppf) CH2Cl2 adduct (0.267 g, 0.327 mmol). The reaction mixture was then heated in the microwave at 105° C. for 25 min. More boronic acid (0.260 g, 1.64 mmol) and PdCl2(dppf) CH2Cl2 adduct (0.267 g, 0.327 mmol), and H2O (˜2 ml) were added. Heating in the microwave was continued at 110° C. for 30 min. The reaction mixture was then filtered through a pad of Celite. The filtrate was then concentrated in vacuo to give 1.2090 g of crude product. The resulting residue was subjected to silica gel column chromatography. Elution using 10 EtOAc/90 heptane to 80 EtOAc/20 heptane gave 0.3584 g (65%) of 3-chloro-2′,5′-difluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine. LCMS (m/z): 340.0 (MH+), retention time=0.90 min. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.37 (qd, 3 H) 1.60 (br. s., 2 H) 1.68 (d, J=12.91 Hz, 3 H) 1.84 (ddd, J=11.15, 7.24, 4.30 Hz, 1 H) 3.21 (t, J=6.26 Hz, 2 H) 3.32-3.45 (m, 3 H) 4.00 (dd, J=11.15, 3.72 Hz, 2 H) 4.74 (br. s., 1 H) 6.45 (d, J=9.00 Hz, 1 H) 6.99-7.07 (m, 1 H) 7.51 (d, J=8.61 Hz, 1 H) 8.12 (s, 1 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C=O.[BH3-][C:12]#N.[Na+]>CC#N>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([CH3:12])[CH2:2][CH2:3]1
Reactant: OCC1CCNCC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN1CCC(CO)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-piperidylmethanol (1.0 g, 8.7 mmol) and HCHO (2 mL, 25 mmol, 37% in H2O) in CH3CN was added NaCNBH3 (0.5 g, 12.5 mmol). The resulting mixture was stirred for 1 h and filtered. The filtrate was concentrated and the residue was distilled (105° C., 40 torr) to give the title intermediate.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[C:29]([S:31][CH3:32])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:24]([O-:26])=[O:25])=[C:9]([CH:23]=1)[O:10][C:11]1[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=1[O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].ClC1C=C(C=CC=1)C(OO)=[O:38].C(OCC)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:30]=[C:29]([S:31]([CH3:32])=[O:38])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:24]([O-:26])=[O:25])=[C:9]([CH:23]=1)[O:10][C:11]1[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=1[O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)COc1ccccc1Oc1cc(Oc2ccc(SC)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)COc1ccccc1Oc1cc(Oc2ccc(S(C)=O)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
A solution of methyl {o-{5-[2-chloro-4-(methylthio)phenoxy]-2-nitrophenoxy}phenoxy}acetate (4.30 g, 0.009 mol) in methylene chloride is cooled to 0° C. and treated with 3-chloroperoxybenzoic acid (1.73 g, 0.010 mol). The reaction mixture is warmed to room temperature, stirred overnight, quenched with triethylamine (1.4 mL) and concentrated in vacuo. The residue is dissolved into ethyl acetate and the organic solution is washed sequentially with water and 2 N hydrochloric acid, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an amber oil. Column chromatography of the oil using silica gel and ethyl acetate gives the title product as an amber oil (2.6 g) which is identified by NMR spectral analyses.
Reaction SMILES: C([S:4][CH2:5][C:6]1[CH:7]=[C:8]([C:22]([O:24]C)=[O:23])[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20]C)=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)(=O)C.[OH-].[Na+].Cl>C1COCC1.O>[SH:4][CH2:5][C:6]1[CH:7]=[C:8]([C:22]([OH:24])=[O:23])[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1cccc(-c2ccc(CSC(C)=O)cc2C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2ccc(CS)cc2C(=O)O)c1
Reaction time: 24 h
Yield: 92.5 %

Procedure:
To a solution of 4-acetylthiomethyl-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (0.27 g, 0.75 mmol) in deoxygenated THF was added a degassed solution of sodium hydroxide (0.12 g, 3.0 mmol) in H2O (5 mL) at rt. After 24 h, additional solution of sodium hydroxide (0.09 g) in H2O (2 mL) was added to the reaction mixture and the mixture was stirred for 24 h. The mixture was acidified with 10% HCl and extracted with EtOAc. The extract was dried over MgSO4 and concentrated. The crude material was purified by column chromatography with (9:1 dichloromethane/EtOAc with 1% acetic acid) to afford 4-mercaptomethyl-[1,1′-biphenyl]-2,3′-dicarboxylic acid (0.20 g, 92%) as a white solid: 1H NMR (DMSO-d6) δ3.10 (t, J=8.03 Hz, 1H), 3.89 (d, J=8.03 Hz, 2H), 7.43 (d, J=7.53 Hz, 1H), 7.58-7.65 (m, 3H), 7.83 (d, J=2.01 Hz, 1H), 7.92 (s, 1H), 7.97-8.00 (m, 1H). Anal. Calcd. for C15H12O4S.0.5AcOH: C, 60.37; H, 4.43; O, 25.13; S, 10.07. Found: C, 60.28; H, 4.45; S, 10.15.