Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([N:5]([C@@H:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1)[C:6]([C:8]1[C:9]([C:28]([F:31])([F:30])[F:29])=[CH:10][C:11]2[O:16][C:15]([CH3:18])([CH3:17])[C:14](=[O:19])[N:13]([CH2:20][CH2:21][NH:22][C:23](=[O:26])[CH2:24][CH3:25])[C:12]=2[CH:27]=1)=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.Cl[C:46]([O:48][CH:49]([Cl:51])[CH3:50])=[O:47]>C(Cl)(Cl)Cl>[CH3:18][C:15]1([CH3:17])[C:14](=[O:19])[N:13]([CH2:20][CH2:21][NH:22][C:23](=[O:26])[CH2:24][CH3:25])[C:12]2[CH:27]=[C:8]([C:6]([N:5]([CH:2]([CH3:3])[CH3:4])[C@@H:32]3[CH2:37][CH2:36][CH2:35][N:34]([C:46]([O:48][CH:49]([Cl:51])[CH3:50])=[O:47])[CH2:33]3)=[O:7])[C:9]([C:28]([F:30])([F:29])[F:31])=[CH:10][C:11]=2[O:16]1
Reactant: CCC(=O)NCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCNC3)cc21
Reactant: CC(Cl)OC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(=O)NCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)Cl)C3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-isopropyl-2,2-dimethyl-3-oxo-N-[(3R)-piperidin-3-yl]-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide hydrochloride (3.0 g) in chloroform (25 ml) were added successively triethylamine (0.98 ml) and 1-chloroethyl chloroformate (0.63 ml) under ice-cooling, and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was concentrated to give the title compound (3.55 g) as white amorphous. The obtained title compound was used in the next reaction without further purification.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([CH2:27][N:28]([CH:37]=[O:38])[O:29]CC2C=CC=CC=2)[C:8]([N:10]2[CH2:26][CH2:25][CH2:24][C@H:11]2[C:12]([NH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:16])=[O:13])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO>[CH:1]1([CH2:6][C@H:7]([CH2:27][N:28]([CH:37]=[O:38])[OH:29])[C:8]([N:10]2[CH2:26][CH2:25][CH2:24][C@H:11]2[C:12]([NH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[O:16])=[O:13])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CN(CC(CC1CCCC1)C(=O)N1CCC[C@H]1C(=O)NC(=O)c1ccc(F)cc1)OCc1ccccc1
Solvent: CO
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)N1CCC[C@H]1C(=O)NC(=O)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
1-[3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-N-[(4-fluorophenyl)carbonyl]-L-prolinamide (0.34 mmol, 180 mg) was dissolved in MeOH (3 mL) and the solution was degassed. 10% Pd/C or Pd/BaSO4 (36 mg) was added and the suspension was charged with H2 via balloon. The reaction was stirred under H2 atmosphere for 1 hour, then filtered and concentrated to provide 1-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-N-[(4-fluorophenyl)carbonyl]-L-prolinamide (Example 1) in quantitative yield.
Reaction SMILES: [I:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.[C:22](Cl)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26]>ClCCl.N1C=CC=CC=1>[I:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH:15][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH3:2])=[N:10][C:11]([NH:14][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])=[N:12][CH:13]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Reactant: CCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC(=O)Nc1ncc(Oc2cc(I)c(OC)cc2C(C)C)c(NC(=O)CCCC)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 19.8 %

Procedure:
To a 0° C. solution of 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (1.0 g, 2.5 mmoles) in dichloromethane (80 ml) and pyridine (3 ml), was slowly added valeryl chloride (2.4 ml, 20.2 mmoles). The mixture was stirred at room temperature for 60 hours, and then solvent was removed under reduced pressure. The residue was washed twice with water and then dissolved in dichloromethane. This organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was passed through a silica gel plug (40% ethyl acetate in hexane). The crude mixture was dissolved in a mixture of concentrated ammonium hydroxide aqueous solution and methanol (3 ml/27 ml) and stirred at room temperature for 15 minutes. Solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (20%, 35% ethyl acetate in hexane), to give crude pentanoic acid [5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-2-pentanoylamino-pyrimidin-4-yl]-amide was obtained, which was crystallized from ether and hexane to give pure pentanoic acid [5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-2-pentanoylamino-pyrimidin-4-yl]-amide (141 mg) as white solid, MS (M+H)=569. The filtrate from the recrystallization was dried and re-dissolved in a mixture of concentrated ammonium hydroxide aqueous solution and methanol (10 ml/40 ml) and stirred at room temperature for 5 hours. This solution was concentrated under reduced pressure, and the residue was partitioned between dichloromethane and water. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate in hexanes), and recrystallized from ethyl acetate and hexane to give pure pentanoic acid [4-amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-amide (395 mg) as white solid, MS (M+H)=485.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][C:6](N)=[CH:5][CH:4]=1.N([O-])=O.[Na+].C([O-])(=O)C.[Na+].[CH3:19][C:20]1[C:26]2[CH:27]=[C:28]([OH:32])[C:29]([OH:31])=[CH:30][C:25]=2[O:24][C:22](=[O:23])[CH:21]=1>CC(C)=O>[Cl:2][C:3]1[CH:9]=[CH:8][C:6]([C:21]2[C:22](=[O:23])[O:24][C:25]3[C:26]([C:20]=2[CH3:19])=[CH:27][C:28]([OH:32])=[C:29]([OH:31])[CH:30]=3)=[CH:5][CH:4]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1cc(=O)oc2cc(O)c(O)cc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: CC(C)=O
Product: Cc1c(-c2ccc(Cl)cc2)c(=O)oc2cc(O)c(O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.9 %

Procedure:
To a mixed solution of 25 ml of concentrated hydrochloric acid and 15 g of ice were added 3.83 g (30,0 mmol) of p-chloroaniline (purchased from Tokyo Kasei), 7 ml of a 30% aqueous solution of sodium nitrite (purchased from Wako Junyaku Kogyo) in order, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium acetate (purchased from Wako Junyaku Kogyo) was added to the mixture to adjust its pH to 4, insoluble materials were filtrated, the filtrate was added to a suspension of 5.77 g (30.0 mmol) of 4-methylesculetin (purchased from Tokyo Kasei) in 90 ml of acetone, 0.8 g of cupric chloride dihydrate (purchased from Kanto Kagaku) was further added thereto, and the mixture was stirred for 1 hour. The resultant mixture was concentrated under reduced pressure, most of the solvent was removed, 300 ml of ethyl acetate was added to the residue and mixed, insoluble material (unreacted 4-methylesculetin) was filtrated, an organic layer was separated, the water layer was extracted with ethyl acetate twice, the combined organic layer was washed with brine and dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, the residue was purified according to column chromatography on silica gel (ethyl acetate:hexane=1:1 as an eluent), the effluent fraction containing an objective compound was allowed to stand, and the precipitate was collected and dried to give 533 mg (yield: 5.9%) of 3-(4-chlorophenyl)-4-methyl-6,7-dihydroxycoumarin (as a light yellow crystalline) represented by the following formula 35b: ##STR159##
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C.[CH2:50]([O:52][C:53](=[O:73])[C@H:54]([OH:72])[CH2:55][C@H:56]([NH2:71])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([Cl:70])[CH:65]=2)=[CH:60][CH:59]=1)[CH3:51]>C(Cl)Cl>[CH2:50]([O:52][C:53](=[O:73])[C@H:54]([OH:72])[CH2:55][C@H:56]([NH:71][C:9]([C:7]1[CH:8]=[C:4]([C:1](=[O:3])[CH3:2])[NH:5][N:6]=1)=[O:11])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([Cl:70])[CH:65]=2)=[CH:60][CH:59]=1)[CH3:51]
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(C(C)=O)[nH]n1
Temperature: 25 °C
Yield: 13.8 %

Procedure:
To a stirred solution of 3-acetyl-1H-pyrazole-5-carboxylic acid (50.9 mg, 330 μmol), HATU (125 mg, 330 μmol), and DIPEA (104 μL, 0.6 mmol) in DMF (0.6 mL, 7.7 mmol), was added (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (104 mg, 300 μmol). The resulting mixture was stirred at room temperature until the reaction was complete. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The organics were dried over Na2SO4, and the solvent removed. Half of material was then purified by preparative HPLC to yield the title compound (20 mg) as a TFA salt. MS m/z [M+H]+ calc'd for C25H26ClN3O5, 484.16. found 484.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][CH:11]([C:15]([OH:17])=[O:16])[CH2:10]1.[C:18](O)([CH3:21])([CH3:20])[CH3:19].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][CH:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1
Reactant: CC(C)(C)O
Reactant: Cc1cccc(C)c1N1CC(C(=O)O)CC1=O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: ClCCl
Product: Cc1cccc(C)c1N1CC(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a 2 L, 3-neck flask was added 1-(2,6-dimethylphenyl)-5-oxopyrrolidine-3-carboxylic acid (93 g, 0.40 mol), anhydrous tert-butanol (60 mL, 0.63 mol), TEA (110 mL, 0.79 mol), DMAP (5.0 g, 41 mmol), and CH2Cl2 (800 mL). After the mixture was cooled in an ice bath under nitrogen atmosphere with mechanical stirring, 2,4,6-trichlorobenzoyl chloride (108 g, 0.443 mol) was added in portions over the course of 15 minutes such that the temperature did not exceed 10° C. After the addition was complete, the ice bath was removed, the mixture was allowed to warm to room temperature and stirred for an additional 14 h. TLC and LCMS indicated complete consumption of starting material and formation of desired product. The mixture was filtered and the filter cake was washed with EtOAc (100 mL) and ether (150 mL). The filtrate was washed with two 200 mL portions of 1 M NaHSO4, four 200 mL portions of saturated aqueous NaHCO3, and brine (100 mL). After drying over MgSO4, the organic phase was treated with 24 g of silica gel, and filtered. The filtrate was concentrated to 250 mL and diluted with hexane. A crystalline precipitate began to form, and an initial crop of 66 g was recovered. The filtrate was recovered and recrystallized (ether/hexanes) to afford a second crop (27 g); overall yield, 93 g (81%). LC-MS Rt (retention time): 2.28 min, MS: (ES) m/z 290 (M+H+).
Reaction SMILES: [C:1]([NH:5][C@H:6]([C:26]([O:28][C:29](=[O:31])[CH3:30])=[O:27])[CH2:7][C:8]1[CH:15]=[C:13]([I:14])[C:12]([O:16][C:17]2[CH:24]=[C:22]([I:23])[C:21]([OH:25])=[C:19]([I:20])[CH:18]=2)=[C:10]([I:11])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:32]([O:34][C:35](=[O:38])[CH2:36]Br)[CH3:33]>>[C:1]([N:5]([CH2:36][C:35]([O:34][CH2:32][CH3:33])=[O:38])[C@H:6]([C:26]([O:28][C:29](=[O:31])[CH3:30])=[O:27])[CH2:7][C:8]1[CH:15]=[C:13]([I:14])[C:12]([O:16][C:17]2[CH:24]=[C:22]([I:23])[C:21]([OH:25])=[C:19]([I:20])[CH:18]=2)=[C:10]([I:11])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)OC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(C)(C)C
Product: CCOC(=O)CN([C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)OC(C)=O)C(C)(C)C

Procedure:
alkylating amino group of t-butyl O-acetyl-thyroxine with bromoacetic acid ethyl ester to give t-butyl O-acetyl-N-carboethoxymethyl-thyroxine; then
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2([C:27]#N)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:10][C@@H:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)=O.C(#N)C.C[Mg]Br.C(OCC)(=O)C>O1CCCC1.CO.O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2([CH3:27])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:10][C@@H:9]1[CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(C2(C#N)CCN(C(=O)OC(C)(C)C)CC2)CCN1Cc1ccccc1
Agent: C[Mg]Br
Agent: O=C=O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 185.9 %

Procedure:
A solution of tert-butyl 4-[(3S)-4-benzyl-3-methylpiperazin-1-yl]-4-cyanopiperidine-1-carboxylate (242 g, 0.605 mol) in tetrahydrofuran (1.5 L) in a 5 L flask was cooled down to −40° C. using dry ice/acetonitrile. Methylmagnesium bromide (3.0 M in tetrahydrofuran, 800 mL) was slowly added. After the addition, the reaction mixture was slowly warmed up to room temperature and stirred overnight. After cooling down to −40° C. using dry ice/acetonitrile, celite (200 g), and then ethyl acetate (500 mL) were carefully added. After the addition, the mixture was stirred for 4 hours while the temperature slowly rose to room temperature. The reaction mixture was cooled back down to −40° C. again, and water (200 mL), and then methanol (1.5 L) were added. After being stirred at room temperature overnight, the mixture was filtered through a thin layer of sand. The cake was taken back into a 5 L flask and stirred with methanol (2 L) for 5 hours. Insoluble solid was filtered off. The combined filtrates were concentrated to dryness. Methylene chloride (3.5 L) was added. Insoluble solid was filtered off. The filtrate was dried with magnesium sulfate. After the solvent was removed, 436 g (92.6%) of product was obtained as a white sticky solid. The crude product was essentially pure and used directly for next step. MS (EI) 388.3 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:24]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[NH2:24][C:18]([C:17]1[CH:21]=[CH:22][C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
To a solution of 4-[1-(tert-butoxycarbonyl)-4-piperidyl]benzoic acid (3.64 g) and 1-hydroxybenzotriazole (2.73 g) in dichloromethane (40 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSCD-HCl) (4.56 g) and the mixture was stirred at ambient temperature for 3 hours. To the reaction mixture was added water (20 ml) and an organic layer was separated and washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. A solution of the resulting residue in THF (30 ml) was added to a solution of conc. ammonium hydroxide (10 ml) in THF (30 ml) at ambient temperature and the mixture was stirred at the same temperature for 1 hour. To a reaction mixture was added ethyl acetate (200 ml) and the organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The precipitate was chromatographed on silica gel (200 ml) eluting with a mixture of dichloromethane and methanol (9:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give tert-butyl 4-[4-(aminocarbonyl)phenyl]-1-piperidinecarboxylate (3.34 g).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB([C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][C:19]3=[O:24])O1.Cl[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[N+:35]([O-:37])=[O:36].CCCCCC.C(OCC)(=O)C>O1CCOCC1.O.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>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][C:19]3=[O:24])=[C:28]([N+:35]([O-:37])=[O:36])[CH:29]=1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC1(C)OB(c2cccc3c2CCC3=O)OC1(C)C
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: [K+]
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(-c2cccc3c2CCC3=O)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Potash (7.5 g, 54.3 mmol) and Pd(PPh3)4(1.6 g, 1.4 mmol) were added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-1-one 34 (7.0 g, 27.1 mmol) and 4-chloro-3-nitroanisole (5.1 g, 27.1 mmol) in a mixture of dioxane (80 mL) and water (20 mL). The mixture obtained was heated to 80° C. under argon, kept at this temperature for 16 h (TLC monitoring, eluent: hexane-ethyl acetate, 1:1), cooled, filtered through Celite, evaporated, and dissolved in CH2Cl2. Then the mixture was filtered off from the insoluble portion, evaporated with silica gel, and purified on a short thick column with silica gel (eluent: hexane—CH2Cl2 100:0→0:100, CH2Cl2-ethyl acetate 100:0→50:50). Yield of 35: 5.59 g. The product was used in the next step without additional purification.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([N+]([O-])=O)[CH:14]=[CH:13][N:12]=1>>[Cl:10][C:11]1[CH:16]=[C:15]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:13][N:12]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Oc2ccccc2)ccn1
Yield: 97.9 %

Procedure:
Using the method of Example 3, Step A, phenol (494 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to provide 2-chloro-4-phenoxypyridine (1.27 g, 98% yield) as an oil. 1H NMR (CDCl3) δ 8.22 (d, 1H), 7.45 (t, 2H), 7.29 (t, 1H), 7.09 (d, 2H), 6.77-6.82 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:17])[C:11]2[CH2:15][O:14][C:13](=[O:16])[CH:12]=2)[CH:5]=[N:6][C:7]=1[Cl:8].[C:18]([Li])(C)(C)C.CI>O1CCCC1.CCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:17])[C:11]2[CH:15]([CH3:18])[O:14][C:13](=[O:16])[CH:12]=2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CN(Cc1cnc(Cl)c(Cl)c1)C1=CC(=O)OC1
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CI
Product: CC1OC(=O)C=C1N(C)Cc1cnc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
150 mg (0.55 mmol) of 4-[[(5,6-dichloropyridin-3-yl)methyl](methyl)amino]furan-2(5H)-one (10) are dissolved in 5 ml of tetrahydrofuran and cooled to −78° C., and 339 μl (0.58 mmol) of a 1.7 M solution of tert.-butyllithium in pentane are added. After 30 min of stirring at −78° C., 36 μl (0.58 mmol) of methyl iodide are added, and the mixture is stirred at −78° C. for a further 30 min and then warmed to room temperature. Concentration under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (4:1) gives 48 mg (27% of theory) of 4-[[(5,6-dichloropyridin-3-yl)methyl](methyl)amino]-5-methylfuran-2(5H)-one.
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:5][CH:4]([CH2:6][O:7]CC2C=CC=CC=2)[CH2:3]1.I[Si](C)(C)C.C(=O)([O-])O.[Na+].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>CCCCCCC.C(OCC)(=O)C.C(OCC)(=O)C.O.ClCCl>[CH3:33][S:34]([O:7][CH2:6][CH2:4][CH2:3][C:2]([F:15])([F:1])[CH3:5])(=[O:36])=[O:35]
Reactant: FC1(F)CC(COCc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(F)(F)CCCOS(C)(=O)=O
Yield: 92.8 %

Procedure:
To a dichloromethane (16.6 mL) solution of {[(3,3-difluorocyclobutyl)methoxy]methyl}benzene (2.40 g, 11.3 mmol), was added dropwise iodotrimethylsilane (2.46 mL, 16.9 mmol) while stirring on ice, and stirred at room temperature for one hour. The reaction mixture was poured into ice-cooled aqueous sodium hydrogencarbonate, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. To the reaction mixture, were added ice and sodium thiosulfate, extracted with dichloromethane, and dried over anhydrous magnesium sulfate. The mixture was filtered, then the solvent in the filtrate was distilled off under reduced pressure, and the resultant crude product was dissolved in dichloromethane (100 mL), triethylamine (2.02 mL, 14.4 mmol) and methanesulfonyl chloride (1.31 mL, 14.5 mmol) were added while stirring on ice, and stirred at room temperature over one day and night. To the mixture, were added water and ethyl acetate. After thoroughly shaking the mixture, the organic layer was then separated, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate:n-heptane/ethyl acetate=11/4) to obtain the title compound (2.10 g, 10.49 mmol).
Reaction SMILES: Cl.C([O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH:15]=[C:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH:20]=[CH:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]2=3)[CH2:8]1)=[O:6])C.[OH-].[Na+:32].ClCCl.C(OCC)(=O)C>C(O)C>[Na+:32].[CH:26]1[C:21]2[CH:20]=[CH:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[C:16](=[CH:15][CH2:14][CH2:13][N:9]3[CH2:10][CH2:11][CH2:12][CH:7]([C:5]([O-:6])=[O:4])[CH2:8]3)[C:22]=2[CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C1CCCN(CCC=C2c3ccccc3C=Cc3ccccc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C([O-])C1CCCN(CCC=C2c3ccccc3C=Cc3ccccc32)C1

Procedure:
The above ester (4.5 g, 11 mmol) was dissolved in ethanol (80 ml), 32% sodium hydroxide (180 ml) was added and the mixture was heated at reflux for 1 h. To the cooled reaction mixture a mixture of dichloromethane and ethyl acetate was added. The phases were separated and the aqueous phase was treated with activated charcoal and filtered through millipore (0.22 μm). The solvent was evaporated from the filtrate in vacuo and the residue was dissolved in a mixture of water and dichloromethane (1:3). The phases were separated, the organic phase dried (MgSO4) and the solvent evaporated in vacuo. The residue was dissolved in water and freeze-dried to give 3.0 g of the title compound as an amorphous solid.