Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C2C(=CC=CC=2)C=C(B(O)[OH:12])C=1.Br[C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][N:19]=[C:20]2[C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2.[C:35]([C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][C:38]=1[NH:52][CH:53]1[CH2:58][CH2:57][CH:56]([OH:59])[CH2:55][CH2:54]1)#[N:36]>>[OH:59][CH:56]1[CH2:57][CH2:58][CH:53]([NH:52][C:38]2[CH:39]=[C:40]([C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][N:19]=[C:20]4[C:25]3[CH:26]=[N:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:41]=[CH:42][C:37]=2[C:35]([NH2:36])=[O:12])[CH2:54][CH2:55]1
Reactant: CC1(C)OB(c2ccc(C#N)c(NC3CCC(O)CC3)c2)OC1(C)C
Reactant: Brc1cccc2c(-c3cnc4ccccc4c3)nccc12
Reactant: OB(O)c1cnc2ccccc2c1
Product: NC(=O)c1ccc(-c2cccc3c(-c4cnc5ccccc5c4)nccc23)cc1NC1CCC(O)CC1

Procedure:
3-(5-Bromoisoquinolin-1-yl)quinoline was obtained according to Example 2(1) using 3-quinolineboronic acid instead of 4-cyano-3-(4-hydroxycyclohexylamino)phenylboronic acid pinacol ester. A compound of Comparative Example 1 was obtained as a pale yellow solid (yield based on 3 steps: 24%) according to Example 2(3) using the obtained 3-(5-bromoisoquinolin-1-yl)quinoline instead of compound (2b) and 4-cyano-3-(4-hydroxycyclohexylamino)phenylboronic acid pinacol ester instead of 4-cyano-3-(ethylamino)phenylboronic acid pinacol ester.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:12][Si:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][OH:16].C(N(CC)CC)C.[I-:26].[Na+]>ClCCl.CC(C)=O>[CH3:12][Si:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][O:16][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][I:26])=[CH:4][CH:5]=1
Reactant: C[Si](C)(C)CCO
Reactant: [I-]
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C[Si](C)(C)CCOC(=O)c1ccc(CI)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-(chloromethyl)benzoyl chloride (2.5 g, 13.22 mmol) in dichloromethane (100 ml) was added 2-(trimethylsilyl)ethanol (1.72 ml, 12.0 mmol). Triethylamine (9.21 ml, 66 mmol) was added and the reaction mixture stirred overnight. The dichloromethane was evaporated and the crude material taken up in ether and washed with water. The ether layer was dried (sodium sulfate) and evaporated to give a slightly yellow mobile oil. The oil (2.7 g) was dissolved in acetone (30 ml) containing sodium iodide (1.5 g) and stirred for two hours. The solvent was removed, ether added and the reaction filtered. The filtrate was then evaporated to give the title compound as a brown temperature unstable oil, 3.58 g, 75%.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(=S)=S.[CH2:8]([N:10]([CH2:18][CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1)[CH3:9].[C:20](Cl)(=[O:24])[C:21](Cl)=[O:22]>C(Cl)(Cl)Cl.O>[CH2:18]([N:10]([CH2:8][CH3:9])[C:11]1[CH:16]=[CH:15][C:14]([C:20](=[O:24])[C:21]([C:14]2[CH:15]=[CH:16][C:11]([N:10]([CH2:18][CH3:19])[CH2:8][CH3:9])=[CH:12][C:13]=2[CH3:17])=[O:22])=[C:13]([CH3:17])[CH:12]=1)[CH3:19]
Reactant: CCN(CC)c1cccc(C)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: S=C=S
Product: CCN(CC)c1ccc(C(=O)C(=O)c2ccc(N(CC)CC)cc2C)c(C)c1
Yield: 23.3 %

Procedure:
To 8.3 g of anhydrous aluminum chloride, 30 ml of carbon disulfide was added, followed by dropwise addition of 16.3 g of N,N-diethyl-m-toluidine under ice-cooling. Then, 5 g of oxalyl chloride was added dropwise thereto at 5° C. or lower, and reacted for 1 hour with stirring. After the reaction, 50 ml of water and 100 ml of chloroform were added to the reaction solution. The chloroform layer obtained by separation was washed with 2N hydrochloric acid, dried and concentrated. The residue was recrystallized from ethyl acetate to yield 3.5 g of yellow 1,2-bis(4-diethylamino-2-methylphenyl)ethane-1,2-dione.
Reaction SMILES: [CH3:1][C:2]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:3][CH2:4][C:5]#N.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.O.S([O-])([O-])(=O)=[O:29].[Mg+2]>C(Cl)Cl>[CH3:1][C:2]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:3][CH2:4][CH:5]=[O:29]
Reactant: O=S(=O)([O-])[O-]
Reactant: CC(C)(CCC#N)[N+](=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O
Product: CC(C)(CCC=O)[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 369.2 %

Procedure:
4-Methyl-4-nitrovaleronitrile (10.4 g, 13 mmol) was dissolved in methylene chloride (100 ml) and 1M diisobutyl aluminum hydride-hexane solution (100 ml) was added dropwise at −50° C. The mixture was stirred for 0.5 h, and water (8 ml) was added gradually, after which magnesium sulfate (5.0 g) was added. The mixture was filtrated and 1N hydrochloric acid (50 ml) was added. The mixture was stirred for 0.5 h and the layers were separated. The organic layer was washed with saturated brine and the solvent was evaporated. The residue was dried to give oily 4-methyl-4-nitropentanal (6.9 g, 48 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14](I)=[CH:13][C:12]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCO[CH2:28][CH2:27]1>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14]([CH:27]=[CH2:28])=[CH:13][C:12]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(I)cc(Cl)c1-c1nc2ccnc(Cl)c2s1
Reactant: C1COCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=Cc1cc(Cl)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Temperature: 100 °C
Yield: 72 %

Procedure:
A mixture of 4-chloro-2-(2,6-dichloro-4-iodo-phenyl)-thiazolo[5,4-c]pyridine (0.30 g, 0.68 mmol), vinyl borane pinacol ester (0.105 g, 0.68 mmol), PdCl2(PPh3)2 (0.029 g, 0.04 mmol) and sodium carbonate (0.288 g, 2.70 mmol) in water (0.4 mL) and dioxane (4 mL) was degassed with nitrogen and heated at 100° C. for 2 hours. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and water. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0-8% EtOAc in pentane to give the desired compound as an off-white solid (0.168 g, 72% yield). 1H NMR (300 MHz, CDCl3): δ 8.51 (d, J=5.6 Hz, 1H), 7.98 (d, J=5.6 Hz, 1H), 7.53-7.45 (m, 2H), 6.69-6.62 (m, 1H), 5.91 (d, J=17.5 Hz, 1H), 5.52 (d, J=10.9 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=1>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:17][C:18]2[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: Cn1cncc1CBr
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2cncn2C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.2 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (846 mg, 5.9 mmol) was dissolved in anhydrous DMF (40 mL), then potassium carbonate (2.46 g, 17.8 mmol) and 5-(bromomethyl)-1-methyl-1H-imidazole (1.56 g, 8.9 mmol) were added. The mixture was stirred for 4 hours at room temperature. The solid was removed by filtration, washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 10% DCM in MeOH to afford 6-methyl-2-{[(1-methyl-1H-imidazol-5-yl)methyl]sulfanyl}pyrimidin-4-ol (589 mg, 42% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 2.22 (s, 3H), 3.61 (s, 3H), 4.44 (s, 2H), 6.02 (s, 1H), 6.88 (s, 1H), 7.56 (s, 1H); LRMS (ES+) m/z 237 (100%, M+1).
Reaction SMILES: Cl[C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=O.C(O)C.[ClH:15].[C:16]([CH2:19][O:20][NH2:21])([OH:18])=[O:17].C(CON)(O)=O.C([O-])(=O)C.[Na+]>O>[Cl:15][CH:19]([O:20][N:21]=[CH:4][C:3]1[C:6]([Cl:11])=[CH:7][CH:8]=[C:9]([Cl:10])[CH:2]=1)[C:16]([OH:18])=[O:17]
Reactant: NOCC(=O)O
Reactant: O=Cc1c(Cl)ccc(Cl)c1Cl
Reactant: Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)C(Cl)ON=Cc1cc(Cl)ccc1Cl

Procedure:
A warm solution of 3.0 gm. (0.014 mole) of 2,3,6-trichlorobenzaldehyde in 50 ml. of ethanol was stirred into a warm solution of 1.6 gm. (0.015 equiv.) of carboxymethoxylamine hemihydrochloride and 0.7 gm. (0.008 mole) of anhyd. sodium acetate in 50 ml. water. Heating on the steam bath was maintained for one-half hour: then the reaction mixture was evaporated by 3/4 volume and was cooled. The solid present was removed by filtration, washed with water and dried in vacuum dessicator over phosphorus pentoxide to obtain 3.9 gm. (96.5%) of crude product melting at 159°-160° C. This material, twice recrystallized from aqueous-isopropyl alcohol, melted at 160°-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][O:7][C:8]([C:18]([F:21])([F:20])[F:19])([C:14]([F:17])([F:16])[F:15])[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][O:7][C:8]([C:14]([F:15])([F:16])[F:17])([C:18]([F:19])([F:20])[F:21])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(OCc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(OCc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl 2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionate (3.65 g.), N-aqueous sodium hydroxide (100 ml.) and ethanol (50 ml.) is stirred at ambient temperature for 2 days, and then evaporated in vacuo. Water is added, and the mixture is washed with ether. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with ether. The extract is dried with sodium sulphate, evaporated, and the residue is crystallised from light petroleum (b.p. 40°-60° C.) to give 2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionic acid, m.p. 98°-99° C. (1.42 g.).
Reaction SMILES: [CH:1]1([O:32]P([O-])([O-])=O)[CH:6]([O:7]P([O-])([O-])=O)[CH:5]([O:12]P([O-])([O-])=O)[CH:4]([O:17]P([O-])([O-])=O)[CH:3]([O:22]P([O-])([O-])=O)[CH:2]1[O:27]P([O-])([O-])=O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].N1C=CC=CC=1>O>[CH:6]1([OH:7])[CH:5]([OH:12])[CH:4]([OH:17])[CH:3]([OH:22])[CH:2]([OH:27])[CH:1]1[OH:32]
Reactant: O=P([O-])([O-])OC1C(OP(=O)([O-])[O-])C(OP(=O)([O-])[O-])C(OP(=O)([O-])[O-])C(OP(=O)([O-])[O-])C1OP(=O)([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: OC1C(O)C(O)C(O)C(O)C1O
Temperature: 65 °C

Procedure:
Crystalline sodium phytate C (4 g) was dissolved with sonication in water (20 ml) and converted to the free acid by passage through a column of Dowex 50×8-200 ion-exchange resign. The column eluate was adjusted to pH 8 with pyridine and evaporated to dryness. The residue was dissolved in water (30 ml) and pyridine (130 ml) containing N,N-dicyclohexylcarbodiimide (8 g) was added. The reaction mixture was heated to 65° C. for 18 h and evaporated to dryness. The residue was extracted with water (4×10 ml) filtered and the filtrate was evaporated to dryness to give the pentapyridinium Salt of Myo-inositol 1,6:2,3:4,5-Tripyrophosphate (3.355 g, 77% yield). 31P-NMR (D2O) δ: −8.83 & −13.53 (AB, J=22.3 Hz, 2P, ax-eq), −9.82 & −10.00 (AB, J=17.8 Hz, 2P, eq-eq), −10.18 (AB as a singlet, 2P, eq-eq); 1H-NMR (D2O) δ: 8.65 (d, J=5.6 Hz, 10H), 8.48 (dd, J=7.9, 7.9 Hz, 5H), 7.94 (dd, J=7.0, 7.0 Hz, 10H), 5.00 (bd, J=10.5 Hz, 1H), 4.57 (ddd, J=9.6, 9.6, 5.5 Hz, 1H), 4.43-4.36 (m, 2H), 4.30-4.18 (m, 2H); 13C-NMR (D2O) δ: 147.0, 140.9, 127.3, 77.9 (t, J=6.8 Hz), 76.4-76.0 (m), 75.4-75.0 (m), 73.8 (t, J=6.8 Hz), 73.3 (bs), 72.8 (bs). The compound was then dissolved in water (30 ml) and passed through a column Dowex 50Wx8 Na+ form. The column eluate was concentrated to dryness to give Hexasodium Salt of Myo-inositol 1,6:2,3:4,5-Tripyrophosphate (2.25 g, 97%) and used for biological experiments in 98.5% purity without any further purification. The impurity is unreacted starting material (or tripyrophosphate hydrolyzed back to starting material). 31P-NMR (D2O) δ: −8.34 & −13.14 (AB, J=21.7 Hz, 2P, ax-eq), −9.53 & −9.70 (AB, J=17.8 Hz, 2P, eq-eq), −9.92 (AB as a singlet, 2P, eq-eq); 1H-NMR (D2O) δ: 5.04 (bd, J=10.5 Hz, 1H), 4.65-4.59 (m, 1H), 4.51-4.36 (m, 2H), 4.32-4.18 (m, 2H); 13C-NMR (D2O) δ: 77.1-76.8 (m), 76.5-76.0 (m), 75.4-75.0 (m), 74.1-73.9 (m), 73.7-73.2 (m), 73.2-72.5 (m).
Reaction SMILES: [I:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:15])[C:4]=2[CH:3]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.CC(OC(C)=O)=O.CC(O)=O.[Br:42]Br>S(=O)(=O)(O)O.C(O)(=O)C>[Br:42][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[C:4](=[CH:3][C:2]([I:1])=[CH:14][CH:13]=3)[C:5](=[O:15])[C:6]=2[CH:7]=1
Reactant: O=C1c2ccccc2-c2ccc(I)cc21
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: O=C1c2cc(Br)ccc2-c2ccc(I)cc21
Reaction time: 2 h
Yield: 79.8 %

Procedure:
A suspension of 2-iodofluoren-9-one (1.046 g, 3.42 mmol; Maybridge) and iodobenzene diacetate (1.21 g, 3.76 mmol; Aldrich) in 1:1 Ac2O—HOAc (10 mL) was treated with bromine (180 μL, 3.48 mmol; Aldrich) followed by 3 drops concentrated sulfuric acid. The mixture solidified, so it was diluted with acetic acid until it could be stirred. After 2 h, the reaction was quenched with aq. Na2S2O3, neutralized with K2CO3, and filtered. The solid filter cake was washed with water, dried, and recrystallized from hot EtOH to afford the title compound (1.05 g, 2.73 mmol; 80% yield): 1H NMR (300 MHz, CDCl3) δ ppm 7.97 (dd, J=2, 1 Hz, 1H), 7.84 (dd, J=8, 2 Hz, 1H), 7.75-7.79 (m, 1H), 7.63 (dd, J=8, 2 Hz, 1H), 7.39 (d, J=7 Hz, 1H), 7.24-7.31 (m, 1H); MS (DCI/NH3): m/z 384 (M+1)+, 386 (M+3)+.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.C[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20].[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH2:26]C(Cl)(Cl)Cl>>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[CH3:26])[C:1]([C:17]1[CH:16]=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:18]=1)=[O:10]
Reactant: COc1ccccc1C
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2ccc(C)c(OC)c2)cc1
Reaction time: 24 h

Procedure:
The procedures and equipment used in this monomer preparation are as described in Example I. A solution of 94.5 g m-anisoyl chloride (0.554 mole) in 113 ml of tetrachloroethane was added dropwise to a stirred, cooled mixture of 80.7 g o-methylanisole (0.661 mole), 94.5 g anhydrous aluminum chloride, and 113 ml tetrachloroethane, keeping the temperature of about 15° C. The mixture stood at room temperature for 24 hr. After adding ice and extracting with methylene chloride as in the preparation of 3,4'-methoxybenzophenone of Example I, an impure liquid was obtained from which the 3,4'-dimethoxy-4-methylbenzophenone was obtained by fractional distillation in a 25 cm Vigreux column at 198° C. and 2.0 torr (0.27 kPa) pressure. Yield was 114 g (0.445 mole).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[N:7]=[N:8][C:9]([Cl:15])=[CH:10][C:11]=1[C:12](O)=[O:13].[Cl-].[Cl-].[Cl-].[Al+3].[CH3:20][C:21]1[C:26]2[NH:27][C:28](=[O:30])[O:29][C:25]=2[CH:24]=[CH:23][CH:22]=1>ClCCCl>[Cl:5][C:6]1[N:7]=[N:8][C:9]([Cl:15])=[CH:10][C:11]=1[C:12]([C:23]1[CH:22]=[C:21]([CH3:20])[C:26]2[NH:27][C:28](=[O:30])[O:29][C:25]=2[CH:24]=1)=[O:13]
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Reactant: Cc1cccc2oc(=O)[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)c2cc(Cl)nnc2Cl)cc2oc(=O)[nH]c12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2.00 mL (27.4 mmol) thionyl chloride were added to 1.92 g (9.95 mmol) 3,6-dichloro-pyridazine-4-carboxylic acid in 10 mL 1,2-dichloroethane and the mixture was refluxed for 2 h. The reaction mixture was evaporated to dryness and coevaporated with 1,2-dichloroethane. Then 5.30 g (39.8 mmol) aluminium trichloride and 1.56 g (10.5 mmol) 4-methyl-3H-benzoxazol-2-one were added and the mixture was stirred for 1 h at 100° C. under a nitrogen atmosphere. Then it was stirred for a further 2 h at 120° C., 3 h at 130° C. and then cooled for 48 h at RT. The mixture was decomposed with ice water and extracted with DCM. The organic phases were combined, washed with water, dried on sodium sulphate, filtered and evaporated down i. vac. The residue was triturated with DIPE, suction filtered and dried.
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:19][C:18]([NH2:20])=[N:17][N:16]=3)=[CH:11][CH:10]=2)[CH:3]=1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>N1C=CC=CC=1.CO>[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:20][C:18]2[O:19][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][C:4]4[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=4)=[CH:14][CH:13]=3)=[N:16][N:17]=2)=[O:28])=[CH:25][C:24]=1[C:32]([F:33])([F:34])[F:35]
Reactant: Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Agent: Br
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2nnc(-c3ccc(Oc4cccnc4)cc3)o2)cc1C(F)(F)F
Reaction time: 3 h
Yield: 16.2 %

Procedure:
5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. Neat 4-methoxy-3-trifluoromethylbenzoyl chloride (179.0 mg, 0.75 mmol) was added directly into the solution. The reaction mixture formed an orange-red solution with a small amount of white precipitate. It was left to stir for 3 hours. Then it was diluted with ca. 1 mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (37.0 mg). Yield 16.2%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.[C:10]1([CH2:16][SH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:16]([S:17][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: SCc1ccccc1
Reactant: COc1ccc(Br)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(SCc2ccccc2)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 105.7 %

Procedure:
To a solution of 2-bromo-5-methoxypyridine (1.13 g) in toluene (15 mL) were added phenylmethanethiol (820 mg), N,N-diisopropylethylamine (1.71 g), tris(dibenzylideneacetone)dipalladium(0) (220 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (278 mg), and the mixture was stirred under an argon atmosphere at 80° C. for 3 hr. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=49:1→19:1) to give the title compound as a yellow oil (yield 1.47 g, quantitative).
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[CH:3]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:48][O:49][C:50](=[O:57])[CH2:51][CH2:52][C:53]([CH2:55][NH2:56])=[O:54]>C(Cl)Cl.CN(C=O)C>[CH3:48][O:49][C:50](=[O:57])[CH2:51][CH2:52][C:53](=[O:54])[CH2:55][NH:56][C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[C:1]([O:12][CH3:13])=[O:11])=[O:7]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: COC(=O)CCC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CCC(=O)CNC(=O)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl hydrogen isophthalate (1.8 g, 10.2 mmol) is dissolved in methylene chloride (10 mL) and DMF (10 mL), and diisopropylethylamine (4.4 mL, 25.5 mmol), HATU (4.6 g, 12.2 mmol), and 5-aminolevulinic acid methyl ester hydrochloride (2 g, 11.2 mmol) are added. The reaction stirred at room temperature 1 h. The reaction is partitioned between ethyl acetate and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 4% methanol/chloroform) provides the title compound. ESI MS m/z 306.1 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12]Br.[C:14]([O-:17])(=[O:16])[CH3:15].[Na+]>CC(O)=O>[C:14]([O:17][CH2:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[Br:1])[C:6]([O:8][CH3:9])=[O:7])(=[O:16])[CH3:15]
Reactant: COC(=O)c1ccc(Br)c(CBr)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Br)c(COC(C)=O)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 79.3 %

Procedure:
To a solution of methyl 4-bromo-3-(bromomethyl)benzoate (6.5 g; 21 mmol; 1 eq.) in AcOH (32.5 mL) was added sodium acetate (3.46 g; 42 mmol; 2 eq.) and the reaction mixture was stirred at 100° C. for 12 hours. After concentration in vacuo, the residue was partitioned between Ethyl acetate and water. The organic layer was washed with 5% aq. NaHCO3 then brine, dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (c-hexane/ethyl acetate, 5/1) afforded the title compound (4.78 g, 79%) as a white solid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[N:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[Cl:5][C:6]1[N:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]=[C:1]=[O:2])=[CH:15][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(Oc2cccc(Cl)n2)cc1
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(Oc2cccc(Cl)n2)cc1
Reaction time: 0.33 h

Procedure:
A stream of phosgene was passed into 120 ml. of dry toluene maintained at a temperature of about 0° to about 5° C. until a weight of 13.4 grams (0.135 mole) had been absorbed. 4-((6-Chloro-2-pyridinyl)oxy)benzenamine (10.0 grams; 0.045 mole) in 100 ml. of dry toluene was then added to the stirred phosgene solution over a period of about 15 minutes while maintaining the reaction temperature within a range of about 2° to about 5° C. Following the completion of the addition, the reaction mixture was stirred for about 20 minutes and the reaction temperature then gradually raised as excess phosgene was purged with a stream of nitrogen. When a reaction temperature of about 85° C. was attained, the reaction mixture became clear. The toluene solvent was then substantially removed under reduced pressure and hexane added to the residue to give the desired 4-((6-chloro-2-pyridinyl)oxy)phenyl isocyanate product as a white crystalline product having a melting point of 96°-97° C.