Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.[O:25]=[CH:26][C@@H:27]([C@H:29]([C@H:31]([CH2:33][OH:34])[OH:32])[OH:30])[OH:28].CC(S[C@@H]1[O:44][C@H:43]([CH2:45][OH:46])[C@H:42]([OH:47])[C@H:41]([OH:48])[C@H:40]1[OH:49])C>>[CH2:26]([OH:25])[C@@H:27]([C@H:29]([C@@H:31]([CH2:33][OH:34])[OH:32])[OH:30])[OH:28].[O:46]=[CH:45][C@@H:43]([C@H:42]([C@H:41]([CH2:40][OH:49])[OH:48])[OH:47])[OH:44]
Reactant: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 24 h

Procedure:
To test the activity of the XR/Lad1/Alx1 operon, plasmid pATX112 was inserted into strain ZUC99 by electroporation (ZUC99/pATX112). The strain was inoculated from a single colony into 3 mL LB media supplemented with ampicillin (200 mg/L) and incubated overnight at 30° C. with shaking (250 RPM). After incubation, an aliquot of the culture was diluted 100-fold into 20 mL of fresh LB media contain L-arabinose (1% w/v) and ampicillin (200 mg/L) and incubated (30° C., 250 RPM) for 2 hrs. The culture was induced with isopropyl-β-D-thiogalactopyranoside (IPTG, 1 mM). The culture was incubated at 30° C. with shaking (250 RPM) and aliquots were removed at various time points after the IPTG induction. The samples were monitored for xylitol formation from L-arabinose by HPLC analysis using an Aminex HPX-87P column (BioRad, USA). After 24 hrs post induction, the XR/Lad1/Alx1operon strain (ZUC99/pATX112) displayed a 2% conversion of L-arabinose to xylitol, showing that the recombinant bacterium acquires the ability to produce xylitol from L-arabinose (Table 6).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[Cl:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=1/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[Cl:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=1/[CH:26]=[CH:27]/[C:28]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][C:8]2[O:9][C:5]([C:2]([F:1])([F:4])[CH3:3])=[CH:6][CH:7]=2)[N:12]=1)=[O:29]
Reactant: O=C(O)/C=C/c1c(F)ccc(F)c1Cl
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Product: CC(F)(F)c1ccc(Cn2ccc(NC(=O)/C=C/c3c(F)ccc(F)c3Cl)n2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-3,6-difluoro-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.14 min; [M+H]+=427.98.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:16])([CH2:14][NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[F:20][C:21]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([NH2:16])([CH2:14][NH:15][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:21]=2[F:20])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)(CN)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(N)(CNC(=O)c2ccc(F)cc2F)CC1

Procedure:
To a solution of 4-Amino-4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (250 mg; 1.1 mmol; 1.0 eq.) in pyridine (12 ml) at room temperature, a 0.1 M DCM solution of 2,4-difluoro-benzoyl chloride (182.8 mg; 1.04 mmol; 0.95 eq.) was added slowly. The reaction mixture was quenched by adding 0.5 mL of methanol when LC-MS showing no starting material remaining. The reaction mixture and concentrated to dryness to afford 4-Amino-4-[(2,4-difluoro-benzoylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:11]2[CH:16]=[C:15]([CH3:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:11]3[CH:16]=[C:15]([CH3:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C@@H:30]1[CH2:32][C@@H:31]1[C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)=[O:29])[CH3:26]>CCO>[CH2:25]([O:27][C:28]([C@@H:30]1[CH2:32][C@@H:31]1[C:33]1[CH:38]=[CH:37][C:36]([C:20]2[CH:21]=[CH:22][C:17]([C:16]3[O:15][N:14]=[C:13]([CH3:24])[C:12]=3[C@@H:10]([OH:11])[CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:18][CH:19]=2)=[CH:35][CH:34]=1)=[O:29])[CH3:26]
Reactant: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCc1ccccc1
Solvent: CCO
Product: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(-c2ccc(-c3onc(C)c3[C@@H](O)COCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 2-benzyloxy-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]ethanol and (cis)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. After the reaction the crude material was dissolved in EtOH (3 mL) and purified via preparatory chiral HPLC (Chiralcel-AD column, 8% EtOH in hexanes, 70 minutes) to afford three separate compounds. The first compound off of the column, containing a mixture of cis-cyclopropyl diastereomers, was the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([C@:15]([C@@H:23]2[O:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]2)([OH:22])[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>C(#N)C>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([C@:15]([C@@H:23]2[O:28][CH2:27][CH2:26][NH:25][CH2:24]2)([OH:22])[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][CH:3]=1
Reactant: COCCCC[C@@](O)(c1cccc(F)c1-c1cccc(C)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COCCCC[C@@](O)(c1cccc(F)c1-c1cccc(C)c1)[C@H]1CNCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-tert-butyl 2-((R)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholine-4-carboxylate (0.46 g, 0.96 mmol) in acetonitrile (50 mL) was added 2 N aq HCl (50 mL). The resulting solution was stirred at rt overnight and basified with 10 N aq NaOH to pH 10. Acetonitrile was removed under vacuum, and the aqueous residue was extracted with CH2Cl2 (4×5 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, and concentrated to give (R)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-5-methoxy-1-((R)-morpholin-2-yl)pentan-1-ol (0.38, quant.). MS m/z 388 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:29]\[OH:30])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccc(F)cc2F)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(/C(CC(c2ccc(Br)cc2)c2ccc(F)cc2F)=N/O)ccc1=O
Temperature: 100 °C

Procedure:
To a solution of 5-(3-(4-bromophenyl)-3-(2,4-difluorophenyl)propanoyl)-1-methyl-pyridin-2(1H)-one (0.2 g, 463 μmol) in ethanol (5 mL) and water (0.2 mL) was added hydroxylamine hydrochloride (80.4 mg, 1.16 mmol) and sodium hydrogencarbonate (77.7 mg, 925 μmol) and the resulting colourless suspension was heated at reflux (100° C. oil bath temperature) for 4.5 hours. After cooling down the reaction mixture was poured on water and ethyl acetate and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100). Colourless foam (0.205 g, 99%). MS (ESI+): m/z=449.1 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][NH:21]1>O1CCOCC1.CCOC(C)=O>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][C@@H:20]2[CH3:19])[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: C[C@H]1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H]1COCCN1c1nc(Cl)cc(Cl)n1
Temperature: 130 °C
Yield: 34.2 %

Procedure:
The 2,4,6-trichloropyrimidine (100 mg, 053 mmol) was dissolved in dioxane (2 mL) with DIPEA (280 μL, 1.6 mmol) and (S)-3-methylmorpholine (54 mg, 0.53 mmol). The reaction mixture was heated at 130° C. under microwave irradiations for 15 min. It was then diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Waters Sun Fire C18, 30×100 mm, 5 um; 0.1% TFA-water/acetonitrile; gradient acetonitrile 5-100% in 20 min) to afford the title compound (45 mg, 34%). tR: 3.70 min (HPLC 1); ESI-MS: 248.2/250.2 [M+H]+ (LC-MS 1).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.C(O[CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])C>>[N:2]1([NH:1][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3]1
Reactant: Nn1cccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNn1cccc1)C(=O)OCC

Procedure:
A mixture of N-aminopyrrole (575 mg, 7.0 mmol, commercially available) and diethyl ethoxymethylenemalonate (1.82 g, 8.4 mmol) was heated at 125° C. for 2 hours to give crude diethyl 2-((1H-pyrrol-1-ylamino)methylene)malonate. To this intermediate was added diphenyl ether (2 mL). The reaction was put under nitrogen and heated at 220° C. for 2 hours, while allowing the ethanol formed in the reaction to be distilled off. The reaction was cooled to room temperature and purified by silica gel flash chromatography (eluted with 100% CH2Cl2) to give the title compound (1.03 g, 71%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][CH2:17][N:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:21][S:20][C:19]1=[N:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[O:38][CH3:39])[CH2:9][C:10]([O:12]CC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][CH2:17][N:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:21][S:20][C:19]1=[N:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[O:38][CH3:39])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)CN(CCCn1c(-c2ccc(F)cc2)csc1=Nc1ccc(Cl)cc1OC)C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(Cl)ccc1N=c1scc(-c2ccc(F)cc2)n1CCCN(CC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.3 %

Procedure:
To a solution of the compound (3 g) obtained in Example 321 (1) in ethanol (5 ml) was added dropwise a 4N aqueous sodium hydroxide solution (5 ml), and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added water, and the mixture was acidified with a 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (2.92 g) as foam. (2) N-{3-[2-[(4-Chloro-2-methoxyphenyl)imino]-4-(4-fluorophenyl)thiazol-3 (2H)-yl]propyl}glycine
Reaction SMILES: [CH2:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:13]N1C(=O)C2=CC=CC=C2C1=O.N(OC(C)(C)C)=O.S(=O)(=O)(O)O.[OH-].[Na+].C1(=NO)CCCCCCCCCCC1.[N+](C1CCCCCCCCCCC1)([O-])=O>C(O)(=O)C>[C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCCCCCCCCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)(C)ON=O
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])C1CCCCCCCCCCC1
Solvent: CC(=O)O
Product: O=C1CCCCCCCCCCC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Cyclododecane (3.32 g; 19.8 mmol), N-hydroxyphthalimide (0.8 mmol), and acetic acid (4 ml) were placed in a flask, t-butyl nitrite (4 mmol) was added to the mixture in two installments of 2 mmol each once every 1 hour with stirring at 70° C. in an atmosphere of argon gas for a total of 2 hours. The resulting mixture was further treated with sulfuric acid having a concentration of 98% by weight (200 mg) with stirring at 70° C. for 15 minutes. The reaction mixture was then neutralized with sodium hydroxide and was analyzed to find that cyclododecanone oxime, nitrocyclododecane, and cyclododecanone were formed in yields of 60%, 2%, and 5%, respectively.
Reaction SMILES: C([CH:7]1[CH2:12][CH:11]2[CH2:13][CH:8]1[CH:9]=[CH:10]2)CCCCC.[CH2:14]([CH:24]1[CH2:29][CH:28]2[CH2:30][CH:25]1[CH:26]=[CH:27]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CCCC.[CH:31](=[C:33]1[CH2:38][CH:37]2[CH2:39][CH:34]1[CH:35]=[CH:36]2)[CH3:32]>>[CH:8]12[CH2:13][CH:11]([CH2:10][CH2:9]1)[CH:12]=[CH:7]2.[CH2:14]([CH:24]1[CH2:29][CH:28]2[CH2:30][CH:25]1[CH:26]=[CH:27]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH:31](=[C:33]1[CH2:38][CH:37]2[CH2:39][CH:34]1[CH:35]=[CH:36]2)[CH3:32]
Reactant: CCCCCCCCCCC1CC2C=CC1C2
Agent: CC=C1CC2C=CC1C2
Agent: CCCCCCC1CC2C=CC1C2
Product: C1=CC2CCC1C2

Procedure:
Polymerization was conducted in the same manner as in Preparation Example 1 except that 18 parts of 5-hexyl-2-norbornene (HNB) was used in place of 26 parts of 5-decyl-2-norbornene, and 3 parts of 5-ethylidene-2-norbornene (ENB) were added, thereby obtaining 21 parts of a norbornene terpolymer [Mn=71,100, Mw=107,000; compositional ratio NB/HNB/ENB of monomers=74/23/3 (molar ratio); Tg=323° C.] was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:16])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][N:19]=1.C([O-])([O-])=O.[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>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].CCOC(C)=O>[F:17][C:18]1[N:19]=[CH:20][C:21]([C:2]2[CH:3]=[CH:4][C:5](=[O:16])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=2)=[CH:22][CH:23]=1
Reactant: CC1(C)OB(c2ccc(F)nc2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1cc(Br)ccc1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(-c2ccc(F)nc2)ccc1=O
Temperature: 120 °C
Yield: 52 %

Procedure:
To a solution of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)pyridin-2(1H)-one (568 mg, 1.868 mmol) in DME (6227 μL, Ratio: 2.000) was added PdCl2(dppf) (68.3 mg, 0.093 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (500 mg, 2.242 mmol), 2M Na2CO3 (3113 μl, Ratio: 1.000) at room temperature. The reaction mixture was heated at microwave synthesizer for 10 min at 120° C. To the reaction mixture, sodium sulfate and EtOAc were added. After filtered off, the volatile materials were removed in vacuo. The crude product was purified by flash chromatography (gradient EtOAc in heptane) yielding 6′-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-[3,3′-bipyridin]-6(1H)-one (52%). LCMS (m/z): 321.3 (MH+), 0.93 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9]Br)[CH3:2].[C:20]1([CH3:32])[CH:25]=[CH:24][C:23]([S:26]([CH2:29][N+:30]#[C-:31])(=[O:28])=[O:27])=[CH:22][CH:21]=1.[H-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][C:29]([N+:30]#[C-:31])([S:26]([C:23]1[CH:22]=[CH:21][C:20]([CH3:32])=[CH:25][CH:24]=1)(=[O:27])=[O:28])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:18])([C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:19])[CH3:2]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C(C)(CCCCBr)c1ccc(C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOCC
Solvent: CS(C)=O
Product: [C-]#[N+]C(CCCCC(C)(C(=O)OCC)c1ccc(C)cc1)(CCCCC(C)(C(=O)OCC)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 6-bromo-2-methyl-2-p-tolyl-hexanoic acid ethyl ester (21 g, 64.22 mmol), tetra-n-butylammonium iodide (2.37 g, 6.42 mmol), and p-toluene-sulphonylmethyl isocyanide (TosMIC, 6.26g, 32.11 mmol) in anhydrous DMSO (320 mL) and anhydrous diethyl ether (110 mL) was added sodium hydride (60% dispersion in mineral oil, 3.24 g, 80.92 mmol) at rt under N2 atmosphere. The reaction mixture was stirred for 24 h at rt, then carefully hydrolized with ice-water (600 mL) and extracted with diethyl ether (2×300 mL). The combined organic layers were washed with brine (2×300 mL), dried over MgSO4, and concentrated to furnish a crude 2,12-dimethyl-7-isocyano-2,12-di-p-tolyl-7-(toluene-4-sulfonyl)-tridecanedioic acid diethyl ester A solution of this crude intermediate in CH2Cl2 (500 mL) and concd HCl (140 mL) was stirred for 2 h at rt. The reaction mixture was diluted with water (500 mL) and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×200 mL). The combined organic layers were washed with saturated NaHCO3 solution (150 mL), and brine (150 mL), dried over MgSO4, and concentrated in vacuo. The resulting crude oil was purified by flash chromatography (silica gel, ethyl acetate/hexanes=1/20, 1/10) to furnish 2,12-dimethyl-7-oxo-2,12-di-p-tolyl-tridecanedioic acid diethyl ester (9.0 g, 67.12%) as a light yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm) 7.10 (d, 4H, J=7.9 Hz), 7.02 (d, 4H, J=7.9 Hz), 4.05 (q, 4H, J=7.0 Hz), 2.25 (t, J=9 Hz, 4H), 2.20 (s, 6H), 1.95-1.70 (m, 4H), 1.42 (s, 6H), 1.50-1.05 (m, 8H), 1.08 (t, 6H, J=7.0 Hz). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm) 211.10, 176.00, 141.00, 135.80, 128.50, 124.51, 60.50, 49.50, 42.01, 39.50, 24.05, 22.10, 20.50, 13.00. HRMS (LSIMS, nba): Calcd. for C33H47O5 (MH+): 523.3424, found: 523.3405.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=2[Cl:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=3[Cl:42])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Clc1ccc(Cl)c(Sc2ccc(Br)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3cc(Cl)ccc3Cl)cc2)c1C
Yield: 28.6 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-(4-bromo-phenylsulfanyl)-2,5-dichlorobenzene (0.334 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(2,5-dichloro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.076 g, 28%) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]1.[Cl:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([O:41][CH3:42])[C:27]=1[OH:43]>>[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][N:22]([CH3:23])[CH3:24])[CH2:17][CH2:16]2)[CH:29]=[C:28]([O:41][CH3:42])[C:27]=1[OH:43]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N1CCC(CN(C)C)CC1
Product: COc1cc(-c2ccc3ncc(C(C)=O)c(N4CCC(CN(C)C)CC4)c3c2)cc(Cl)c1O
Yield: 49.4 %

Procedure:
Following general procedure D, 1-(6-bromo-4-{4-[(dimethylamino)methyl]piperidin-1-yl}quinolin-3-yl)ethanone (17.7 mg, 0.045 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (28 mg, 0.100 mmol) to afford the desired product (10.4 mg, 49%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 8.76 (s, 1H), 8.32 (d, J=1.3 Hz, 1H), 8.07-7.97 (m, 2H), 7.31 (d, J=2.1 Hz, 1H), 7.25 (d, J=2.1 Hz, 1H), 4.00 (s, 3H), 3.48 (d, J=12.5 Hz, 2H), 3.16 (t, J=11.5 Hz, 2H), 2.68 (s, 3H), 2.43 (d, J=6.6 Hz, 2H), 2.36 (s, 6H), 2.01-1.85 (m, 3H), 1.67-1.54 (m, 2H); ESI MS m/z 468 [C26H30ClN3O3+H]+; HPLC>99% (AUC), tR=10.12 min.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[O:5][C:4]([CH3:16])([CH3:15])[CH2:3]1.S(=O)(=O)(O)O.[C:22](=O)([O-])[O-].[K+].[K+]>CO>[NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:22])=[O:13])[CH:10]=2)[O:5][C:4]([CH3:16])([CH3:15])[CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)CC(N)c2cc(C(=O)O)ccc2O1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)C(N)CC(C)(C)O2

Procedure:
0.05 mol of 4-amino-6-carboxy-2,2-dimethylchroman is treated with 9.5 ml of conc. sulfuric acid in 200 ml of methanol and the dark solution is heated to reflux for 6 hours. The reaction mixture is adjusted to pH 9 with ice cooling by addition in portions of saturated aqueous potassium carbonate solution and the precipitated salt is filtered off. The solvent is distilled off on a rotary evaporator, the oily residue is treated with water and the mixture is extracted several times with diethyl ether. After removing the solvent by distillation, the oily amorphous residue is crystallized under n-heptane.