Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:8]2[CH:9]=[C:10]([O:14]C)[C:11](Br)=[CH:12][C:7]=2[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:22][CH3:23])[CH2:3]1.CN(C=O)C.[CH3:34][S-:35].[Na+].Cl[O-].[Na+]>CCOC(C)=O.O.C(O)(=O)C>[O:1]=[S:2]1(=[O:28])[C:8]2[CH:9]=[C:10]([OH:14])[C:11]([S:35][CH3:34])=[CH:12][C:7]=2[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:22][CH3:23])[CH2:3]1
Reactant: C[S-]
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OC)cc2S(=O)(=O)C1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(SC)c(O)cc2S(=O)(=O)C1
Temperature: 60 °C
Yield: 92.4 %

Procedure:
To 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (WO9616051; 600 mg, 1.29 mmol) were added DMF (5 ml) and sodium methanethiolate (450 mg, 6.42 mmol). The reaction was then heated to 60° C. for 1 hour. The oil bath was then heated to 120° C. for 4 hours. To quench the reaction, the temperature was lowered to room temperature and excess acetic acid was added quickly. The reaction was kept under a flow of nitrogen through sodium hypochlorite for 2 hours. Water and EtOAc were added and the aqueous phase was extracted three times with EtOAc. The combined organic phases were washed with water, dried and concentrated under reduced pressure. The residue was then purified by flash chromatography [DCM:EtOAc, 9:1] to give the title compound 0.5 g (92%). NMR 0.65–0.8 (m, 6H), 0.95–1.6 (m, 8h), 3.1 (q, 2H), 3.6 (brq, 2H), 6.75 (s, 1H), 6.8 (t, 1H), 6.9 (d, 2H), 7.15 (t, 2H), 7.55 (s, 1H).
Reaction SMILES: C([NH:8][C:9]1([CH2:12][O:13][CH:14]2[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]2([CH3:22])[CH3:21])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.O.[OH-].[K+]>FC(F)(F)C(O)=O>[CH3:21][C:15]1([CH3:22])[CH2:16][CH2:17][C:18]([CH3:19])([CH3:20])[CH:14]1[O:13][CH2:12][C:9]1([NH2:8])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1(COC2C(C)(C)CCC2(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC1(C)CCC(C)(C)C1OCC1(N)CC1
Reaction time: 8 h

Procedure:
N-Boc-O-(2,2,5,5-tetramethyl-1-cyclopentyl)-1-amino-1-hydroxymethylcyclopropane is dissolved in trifluoroacetic acid and stirred overnight. The solution is poured into water and neutralized with 20% aqueous KOH. The mixture is extracted with ethyl acetate, dried over MgSO4, filtered and evaporated to give O-(2,2,5,5-tetramethyl-1-cyclopentyl)-1-amino-1-hydroxymethylcyclopropane.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.Cl.[CH3:19][NH:20][OH:21].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O.CCOCC>[CH3:19][N:20]([OH:21])[C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[Cl:1]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: CNO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CN(O)C(=O)c1cccc([N+](=O)[O-])c1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
To a stirred solution of 2-chloro-3-nitrobenzoic acid (6.0 grams, 0.031 mole) in toluene (100 mL) was added thionyl chloride (6.8 mL, 0.092 mole). Upon completion of addition, the reaction mixture was heated to reflux where it stirred for four hours. After this time, the reaction mixture was filtered and concentrated. The concentrate was taken up in ether and added dropwise to an ice-cold solution of N-methylhydroxylamine hydrochloride (2.6 g, 0.031 mole), sodium bicarbonate (5.5 g, 0.065 mole), water (20 mL), and ether (160 mL). Upon completion of addition, the reaction mixture was stirred for one hour. After this time, the reaction mixture was diluted with water and the ether layer was separated. The aqueous layer was extracted twice with ether. The combined ether layer and extracts were dried over magnesium sulfate and concentrated to provide 6.4 grams of N-methyl-N-hydroxy-2-chloro-3-nitrobenzamide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Oc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Oc1ccc(F)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
To a stirred solution of 25 g of 4fluorophenol in 40 cc of pyridine and 30 cc of toluene was added dropwise 40.9 g of 2-chlorobenzoylchloride at room temperature. And the resulting mixture was stirred at room temperature for 16 hours. Ice water was added to the reaction mixture and extracted with ethyl acetate. The ethylacetate layer was washed 4 times with 1N HCl , dried over magnesium sulfate. The solvent was distilled off and the crude product thus obtained was recrystallized from hexane to obtain 49.1 g of compound A. Yield: 87.8%.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Cl:26][C:27]1[N:32]=[CH:31][C:30]([NH:33][CH:34]=[C:35]([C:40]([CH:42]2[CH2:44][CH2:43]2)=[O:41])[C:36]([O:38]C)=O)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[N:32]=[C:31]2[C:30](=[CH:29][CH:28]=1)[N:33]=[CH:34][C:35]([C:40]([CH:42]1[CH2:44][CH2:43]1)=[O:41])=[C:36]2[OH:38]
Reactant: COC(=O)C(=CNc1ccc(Cl)nc1)C(=O)C1CC1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=C(c1cnc2ccc(Cl)nc2c1O)C1CC1
Temperature: 25 °C
Reaction time: 0.62 h

Procedure:
To a flask containing Dowtherm™ A (500 mL) at 250° C. was added methyl 3-(6-chloropyridin-3-ylamino)-2-(cyclopropanecarbonyl)acrylate (4.2 g, 15 mmol) portion wise over 3 to 5 min and the reaction mixture was stirred for an additional 30 to 45 min. The reaction mixture was removed from the heat source, cooled to room temperature and diluted with hexanes to facilitate precipitation. The solids were filtered, washed with hexanes and dried under vacuum to afford the intermediate (6-chloro-4-hydroxy-1,5-naphthyridin-3-yl)(cyclopropyl)methanone which was stirred with heat at 70° C. in neat phosphorus oxychloride (10 mL) with catalytic N,N-dimethylformamide for 4 h. The reaction was cooled and poured slowly into a vigorously stirring mixture of ice-cold satd. aq. sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica, methylene chloride/ethyl acetate) to provide the desired product (0.78 g, 20% over two steps) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 8.93 (s, 1H), 8.39 (d, J=8.7 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 2.65 (t, J=7.7, 4.5 Hz, 1H), 1.52-1.42 (m, 2H), 1.32-1.22 (m, 2H); ESI MS m/z 268 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:10]Cl.[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>C(#N)C>[CH2:14]([O:13][P:12]([CH2:10][C:3]1[CH:4]=[C:5]([CH:6]=[O:7])[CH:8]=[CH:9][C:2]=1[OH:1])(=[O:19])[O:16][CH2:17][CH3:18])[CH3:15]
Reactant: CCOP(OCC)OCC
Reactant: O=Cc1ccc(O)c(CCl)c1
Solvent: CC#N
Product: CCOP(=O)(Cc1cc(C=O)ccc1O)OCC
Temperature: 25 °C

Procedure:
0.1 mole 4-Hydroxy-3-chloromethylbenzaldehyde was stirred in 75ml acetonitrile and 0.1 mole triethyl phosphite was added dropwise into the stirring suspension. After all the triethyl phosphite had been added, the reaction was refluxed for 4 hours. The reaction was then cooled to room temperature. The reaction solution was then filtered and the acetonitrile was removed on a rotary evaporator leaving behind a solid. This was recrystallized from THF:hexanes in a -20° C. freezer. The product was isolated on a buchner funnel and washed with -20° C. THF. mp 88°-88.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1.C(N(CC)CC)C.Cl>[Cl-].[Cl-].[Zn+2].C(Cl)Cl>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]1[CH:15]([C:16]([OH:18])=[O:17])[CH2:14][C:13](=[O:19])[O:6]1
Reactant: COc1cccc(C=O)c1OC
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C2OC(=O)CC2C(=O)O)c1OC
Temperature: 25 °C
Yield: 73.9 %

Procedure:
Into a flame-dried 3-neck flask, fitted with a condenser and addition funnel were placed 25.0 g (0.184 mol) of anhydrous, powdered ZnCl2. Then 100 mL of CH2Cl2 were added, followed by 15.3 g (0.092 mol) of 2,3-dimethoxybenzaldehyde and 13.8 g (0.138 mol) succinic anhydride. Triethylamine (25.6 mL, 0.184 mol) was added dropwise to the flask with rapid stirring and the reaction was heated at reflux for 4 days. The reaction was cooled to room temperature and poured over a mixture of ice and conc HCl. The mixture was extracted with EtOAc (3×250 mL), then washed with 2 N HCl (1×250 mL), and brine (1×250 mL). The product was extracted with saturated NaHCO3 (4×200 mL) until TLC indicated no product remaining in the organic layer. The aqueous layer was washed with CH2Cl2 (1×200 mL) and acidified with conc HCl. The white, milky solution was extracted with CH2Cl2 (3×250 mL), the organic extracts were dried over Na2SO4, and evaporated under vacuum to produce 18.0 g (0.068 mol, 73.6%) of pale yellow solid that was recrystallized from EtOAc/hexanes; mp 129-130° C. (lit.34 mp 132° C.). 1H NMR: (300 MHz, CDCl3): δ 7.01 (t, 1H, J=7.5 Hz, ArH); 6.89 (dd, 1H, J=8.1 Hz, J=2.5 Hz, ArH); 6.82 (dd, 1H, J=8.1 Hz, J=2.5 Hz, ArH); 5.73 (d, 1H, J=6.6 Hz, ArCH); 3.81 (s, 3H, ArOCH3); 3.80 (s, 3H, ArOCH3); 3.44 (dt, 1H, J=8.5 Hz, J=6.6 Hz, CHCOOH); 2.90 (d, 2H, J=8.5 Hz, COCH2). EIMS (M+)=266. Additional details are described in Stevens et al., “A New Synthetic Route to Furofuranoid Lignans Via the Intramolecular Mukaiyama Reaction,” J. Chem. Soc., Perkin Trans. 1, 185-190 (1992), the disclosure of which is incorporated herein by reference.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[N:2]1.[CH3:14]O>S(=O)(=O)(O)O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]1
Reactant: CO
Reactant: O=C(O)Cc1n[nH]c2ccccc12
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1n[nH]c2ccccc12

Procedure:
A solution of 1H-indazole-3-acetic acid (1.0 g) prepared according to J. Am. Chem. Soc., 79, 5245 (1957), in methanol (30 ml) containing five drops of concentrated sulfuric acid was refluxed for 8 hours. The reaction mixture was then concentrated to a low volume and diluted with ethyl acetate (20 ml). The organic layer was washed with water (2×10 ml) and then with sodium bicarbonate solution (10 ml, 10%). The ethyl acetate layer was collected and then dried to obtain the title compound (yield: 0.8 g; m.p. 146° C.).
Reaction SMILES: C(Br)Br.[CH2:4](N(CC)CC)C.[Cl:11][C:12]1[CH:23]=[CH:22][C:15]([O:16][CH2:17][NH:18][C:19](=[S:21])[S-:20])=[CH:14][CH:13]=1.[K+].S1CCS1>O.CN(C)C=O>[Cl:11][C:12]1[CH:23]=[CH:22][C:15]([O:16][CH2:17][N:18]=[C:19]2[S:20][CH2:4][S:21]2)=[CH:14][CH:13]=1
Reactant: CCN(CC)CC
Reactant: S=C([S-])NCOc1ccc(Cl)cc1
Agent: C1CSS1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: BrCBr
Product: Clc1ccc(OCN=C2SCS2)cc1

Procedure:
To a mixture of 19.3 g. of methylene bromide and 3.7 g. of triethylamine in 100 ml. of dimethylformamide was added 10.0 g. of potassium p-chlorophenoxymethyldithiocarbamate in portions. After one to two hours, the mixture was poured into water and partitioned into ethylene chloride. The dried ethylene chloride mixture was saturated with dry hydrogen chloride and the resulting salt collected by filtration. Hydrolysis of the salt in a chloroform-water mixture followed by separation, drying and concentration of the chloroform layer gave 3.5 g. of the dithietane as pale yellow crystals, m.p. 64.5°-66.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]#N)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[H-].C([Al+]C(C)C)(C)C.CCCCCC.[OH2:25]>ClCCl>[CH3:1][O:2][C:3]1([CH:9]=[O:25])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COC1(C#N)CCOCC1
Reactant: O
Agent: CC(C)[Al+]C(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Product: COC1(C=O)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
4-Methoxytetrahydro-2H-pyran-4-carbonitrile (1.00 g, 7.08 mmol) was dissolved in dichloromethane (20 mL). To this, a 1 mol/L solution of diisopropylaluminum hydride in hexane (10.9 mL, 10.9 mmol) was added at −78° C. and the mixture was stirred at room temperature for 30 minutes. The reaction was stopped by addition of water (10.9 mL) at 0° C. The mixture was stirred at room temperature for 1 hour and then filtered through Celite. The solvent was evaporated off under reduced pressure and the residue was dissolved in tetrahydrofuran (10 mL). To this, a 1 mol/L aqueous hydrogen chloride solution was added and the mixture was stirred at room temperature for 30 minutes. The reaction was stopped by addition of a saturated aqueous sodium bicarbonate solution to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give 4-methoxytetrahydro-2H-pyran-4-carbaldehyde (195 mg, yield: 19%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:8][NH2:9])[S:5][C:6]=1[CH3:7].Br[C:11]1[C:12](=[O:31])[N:13]([CH3:30])[N:14]=[C:15]([O:17][CH2:18][C@H:19]2[CH2:21][C@@H:20]2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][N:23]=2)[CH:16]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(O[Na])(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]>[CH3:1][C:2]1[N:3]=[C:4]([CH2:8][NH:9][C:11]2[C:12](=[O:31])[N:13]([CH3:30])[N:14]=[C:15]([O:17][CH2:18][C@H:19]3[CH2:21][C@@H:20]3[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][N:23]=3)[CH:16]=2)[S:5][C:6]=1[CH3:7]
Reactant: COc1ccc([C@H]2C[C@@H]2COc2cc(Br)c(=O)n(C)n2)nc1
Reactant: Cc1nc(CN)sc1C
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc([C@H]2C[C@@H]2COc2cc(NCc3nc(C)c(C)s3)c(=O)n(C)n2)nc1
Temperature: 85 °C

Procedure:
A mixture of (4,5-dimethylthiazol-2-yl)methanamine (28 mg, 0.2 mmol), 4-bromo-6-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyridazin-3(2H)-one (73 mg, 0.2 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), BINAP (18 mg, 0.03 mmol) and t-BuONa (38 mg, 0.4 mmol) in toluene (4 mL) under N2 was heated at 85° C. for 4 h. filtered and concentrated to give crude product which was purified by Pre-HPLC to give the title compound 6 as a oil. 1H NMR (400 MHz, CD3OD) δ 7.92 (d, 1H), 7.14 (dd, 1H), 7.02 (d, 1H), 5.66 (s, 1H), 4.45 (d, 2H), 4.05-4.01 (m, 1H), 3.92-3.88 (m, 1H), 3.71 (s, 3H), 3.51 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H), 1.95-1.90 (m, 1H), 1.63-1.58 (m, 1H), 1.06-1.01 (m, 1H), 0.91-0.86 (m, 1H), LCMS m/z (M+H) 428.1 found, 428.1 required.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.CON(C)[C:18](=[O:20])[CH3:19]>C1COCC1>[CH3:6][O:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:18](=[O:20])[CH3:19]
Reactant: COCCn1ccnc1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCn1ccnc1C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A solution of 30 ml (75 mmol) of 2.5 M n-butyllithium in hexanes was added slowly to a solution of 8.48 g (61.3 mmol) 1-(2-methoxyethyl)-1H-imidazole (WO 2003055876 A1) in 200 ml THF cooled in a dry ice-acetone bath. After stirring 1 h, 8 ml (75 mmol) of N-methoxy-N-methylacetamide was added quickly, and the solution was allowed to warm to room temperature over 30 min. After quenching with aqueous NH4Cl, the mixture was diluted with water and extracted twice with EtOAc. The combined EtOAc layers were which washed with brine, dried over anhydrous MgSO4, and concentrated to give an oil that was chromatographed on silica gel (100% DCM followed by gradient elution to 50% EtOAc in DCM). The title compound (8.5 g) was obtained as a mobile oil. MS (ES) (M+H)+: 169 for C8H12CN2O2; NMR: 2.69 (s, 3H), 3.34 (s, 3H), 3.71 (m, 2H), 4.61 (m, 2H), 7.12 (s, 1H), 7.26 (s, 1H).
Reaction SMILES: [N+]([O-])(O)=O.N([O-])=O.[Na+].[OH:9][CH2:10][C:11]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14](S)=[N:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>O>[OH:9][CH2:10][C:11]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:14]=[N:13][CH:12]=1
Reactant: CC(C)Cn1c(CO)cnc1S
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: O
Product: CC(C)Cn1cncc1CO
Reaction time: 2 h
Yield: 23.8 %

Procedure:
To 5.0M nitric acid (70 ml) was added sodium nitrite (215 mg), and 5-hydroxymethyl-1-isobutyl-2-mercaptoimidazole (14.5 g) was added by portions to the mixture at 0° C. The mixture was allowed to be at room temperature and the mixture was stirred for 2 hours, and water (100 ml) was added to the mixture. The mixture was neutralized with potassium carbonate at 0° C., and the solvent was distilled off under reduced pressure. Ethanol was added to the mixture, and the insolubles were filtered off, and the solvent was distilled off under reduced pressure. To the obtained residue was added methanol-ethyl acetate, and basic silica gel was added to the mixture. This mixture was purified by basic silica gel column chromatography to obtain solid, which was recrystallized from diisopropyl ether-ethyl acetate, to give 5-hydroxymethyl-1-isobutylimidazole (2.86 g) as brown crystals.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH2:4](Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClCCl>[CH2:4]([N:2]([CH3:1])[NH2:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CNN
Reactant: BrCc1ccccc1
Solvent: ClCCl
Product: CN(N)Cc1ccccc1
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
Methylhydrazine (0.1 ml, 2.0 mmol) in dichloromethane (5 ml) was treated dropwise with a solution of benzyl bromide (0.12 ml, 1.0 mmol) in dichloromethane (2 ml). After addition was complete the mixture was stirred for 10 min. and evaporated to dryness under reduced pressure. The residue was diluted with brine (5 ml) and ethyl acetate (5 ml). The organic phase was separated, dried over magnesium sulphate and evaporated to dryness under reduced pressure to give N-benzyl-N-methylhydrazine (0.082 g, 60%); υmax (CH2Cl2) 1650 cm-1 ; δH (CDCl3) 2.49 (3H, s), 3.41 (2H, s), 3.60 (2H, s), and 7.27 (5H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12])=[O:6].[OH:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(CC)CC.[OH-].[Na+].Cl>C(OCC)(=O)C>[OH:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:6])=[O:22]
Reactant: O=C(Cl)c1ccccc1O
Reactant: COC(=O)CCCNC(=O)c1cccc(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(O)CCCNC(=O)c1cccc(NC(=O)c2ccccc2O)c1

Procedure:
To a solution of 2.60 g (11.00 mmol) of methyl 4-(3-aminobenzoylamino)butanoate dissolved in 25 ml of ethyl acetate, very slowly add 1.40 g (10.00 mmol) of 2-hydroxybenzoyl chloride dissolved in 5 ml of ethyl acetate. Then add 1.00 g (10.00 mmol) of Et3N (triethylamine) and keep the reaction mixture at room temperature for 24 hours. Eliminate the solvent at low pressure, add 40 ml of 10% NaOH to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCl, filter the resulting solid and wash several times with water. Purify the reaction product by recrystallization (EtOH/H2O). This yields 1.60 g (48%) of 4-[3-(2-hydroxybenzoylamino) benzoylamino]butanoic acid as a white solid.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.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>[N:1]([CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([F:17])[CH:23]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(N=[N+]=[N-])c1ccc2ccccc2c1Br
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: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(N=[N+]=[N-])c1ccc2ccccc2c1-c1cccc(F)c1
Temperature: 100 °C
Yield: 41.4 %

Procedure:
To a mixture of 2-(1-azidoethyl)-1-bromonaphthalene (0.080 g, 0.29 mmol) and (3-fluorophenyl)boronic acid (48.6 mg, 0.348 mmol) in 1,4-dioxane (2 mL) was added a 1 M solution of sodium carbonate in water (0.34 mL, 19 mmol) and tetrakis(triphenylphosphine)palladium(0) (16.7 mg, 0.0145 mmol). The reaction mixture was heated at 100° C. overnight. After cool to room temperature, the mixture was diluted with ethyl acetate, washed with water, brine, dried over MgSO4, and then concentrated. The residue was purified on silica gel, eluting with 0 to 20% EtOAc in hexane, to give the desired product (35 mg, 41.5%). LCMS calculated for C18H14FN3Na(M+Na)+: m/z=314.1; found: 314.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[C:30]([C:34]([O:36]CC)=[O:35])=[CH:29][CH:28]=[CH:27]4)=[CH:20][CH:19]=2)=[C:14]([CH:39]([CH3:41])[CH3:40])[O:13][N:12]=1.C(O)C.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[C:30]([C:34]([OH:36])=[O:35])=[CH:29][CH:28]=[CH:27]4)=[CH:22][CH:23]=2)=[C:14]([CH:39]([CH3:41])[CH3:40])[O:13][N:12]=1
Reactant: CCOC(=O)c1cccc2cc(-c3ccc(OCc4c(CCc5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1onc(CCc2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(=O)O)cccc3c2)cc1
Temperature: 100 °C
Yield: 84 %

Procedure:
A solution of ethyl 6-[4-({[3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylate (0.110 g, 0.187 mmol) in tetrahydrofuran (2 mL) was placed in a microwave reaction tube. Ethanol (1 mL) was added followed by 1 N sodium hydroxide (0.36 mL, 0.36 mmol). The tube was sealed and heated in a microwave reactor to 100° C. for 500 seconds. Additional sodium hydroxide solution (0.2 mL, 0.2 mmol) was added and the solution was heated in a microwave reactor to 100° C. for another 500 seconds. The solution was neutralized and concentrated. The residue was partitioned between water and ethyl acetate. The organic layer was concentrated to yield the title compound as a white solid (0.088 g, 83.8%). 1H NMR (DMSO-d6): 13.14 (s, 1H), 8.91 (d, J=9 Hz, 1H), 8.27 (d, J=1 Hz, 1H), 8.20 (d, J=8 Hz, 1H), 7.96 (dd, J=2, 9 Hz, 2H), 7.80 (d, J=9 Hz, 2H), 7.58 (m, 1H), 7.43 (d, J=8 Hz, 2H), 7.26 (m, 1H), 7.15 (d, J=9 Hz, 2H), 4.98 (s, 2H), 3.35 (septet, J=7 Hz, overlapping H2O, 1H), 3.25-3.20 (m, 2H), 2.89-2.85 (m, 2H), 1.25 (d, J=7 Hz, 6H). HRMS C32H27NO4Cl2 m/z 560.1395 (M+H)+Cal; 560.1409 (M+H)+Obs.