Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[OH:2][CH:3]([CH2:26][OH:27])[CH2:4][NH:5][C:6](=[O:25])[C:7]1[C:15]([I:16])=[C:14]([NH:17][C:18](=[O:22])[CH2:19][O:20][CH3:21])[C:13]([I:23])=[C:9]([C:10]([OH:12])=[O:11])[C:8]=1[I:24].S(=O)(=O)(O)O.O.O.O.[C:36]([O-:39])(=O)[CH3:37].[Na+].O.[C:42](O)(=[O:44])[CH3:43]>>[Cl-:1].[C:42]([O:2][CH:3]([CH2:26][O:27][C:36](=[O:39])[CH3:37])[CH2:4][NH:5][C:6](=[O:25])[C:7]1[C:15]([I:16])=[C:14]([NH:17][C:18](=[O:22])[CH2:19][O:20][CH3:21])[C:13]([I:23])=[C:9]([C:10]([OH:12])=[O:11])[C:8]=1[I:24])(=[O:44])[CH3:43]
Reactant: CC(=O)O
Reactant: CC(=O)[O-]
Reactant: COCC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NCC(O)CO)c1I
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COCC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Temperature: 5 °C
Reaction time: 1 h

Procedure:
5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-dihydroxypropyl)amide chloride (9.97 kg, 13.8 mol) was dispersed in acetic acid, and then anhydrous acetic acid (7.45 kg) was added thereto and the mixture was cooled to 5° C. Sulfuric acid (135 g) was slowly added thereto and the mixture was stirred for 1 hour. To the obtained clear solution, sodium acetate trihydrate (376 g) was added and dissolved at 0 to 5° C. And then water (96.6 kg) was added for 3 hours with maintaining 0 to 10° C. to produce solid. The produced solid was filtered and the title compound was obtained as a white solid (10.04 kg, yield 90.2%).
Reaction SMILES: ClC1C=CC(C2C=C(F)SC=2CO)=CC=1.OC1C=CC(CCC(OCC)=O)=C(C)C=1C.[F:32][C:33]1[S:37][C:36]([CH2:38][O:39][C:40]2[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][C:48]([O:50]CC)=[O:49])=[C:42]([CH3:53])[C:41]=2[CH3:54])=[C:35]([C:55]2[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=2)[CH:34]=1>>[Cl:61][C:58]1[CH:59]=[CH:60][C:55]([C:35]2[CH:34]=[C:33]([F:32])[S:37][C:36]=2[CH2:38][O:39][C:40]2[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][C:48]([OH:50])=[O:49])=[C:42]([CH3:53])[C:41]=2[CH3:54])=[CH:56][CH:57]=1
Reactant: CCOC(=O)CCc1ccc(OCc2sc(F)cc2-c2ccc(Cl)cc2)c(C)c1C
Agent: CCOC(=O)CCc1ccc(O)c(C)c1C
Agent: OCc1sc(F)cc1-c1ccc(Cl)cc1
Product: Cc1c(CCC(=O)O)ccc(OCc2sc(F)cc2-c2ccc(Cl)cc2)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 202 by coupling of [3-(4-chlorophenyl)-5-fluorothiophen-2-yl]methanol and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis of ethyl 3-(4-((5-fluoro-3-(4-chlorophenyl)thiophen-2-yl)methoxy)-2,3-dimethylphenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=8.0 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 6.95 (d, J=7.1 Hz, 1H), 6.62 (d, J=7.1 Hz, 1H), 6.51 (s, 1H), 4.98 (s, 2H), 2.97 (t, J=7.5 Hz, 2H), 2.68 (t, J=7.5 Hz, 2H), 2.28 (s, 3H), 2.21 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C22H20ClFO3S, 417.1 (M−H). found 417.1.
Reaction SMILES: [CH2:1]([C@:4]1([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:8](=O)O[C@@H](C(C)(C)C)[N:5]1C(OCC=C)=O)[CH:2]=[CH2:3].N1C[CH2:31][O:30]CC1.[O:33]1CCCC1>>[NH2:5][C@:4]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([CH2:1][CH:2]=[CH2:3])[CH2:8][C:31]([OH:30])=[O:33]
Reactant: C1CCOC1
Reactant: C1COCCN1
Reactant: C=CCOC(=O)N1[C@H](C(C)(C)C)OC(=O)[C@]1(CC=C)Cc1ccccc1
Product: C=CC[C@@](N)(CC(=O)O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2 g of allyl (2S,4S)-4-allyl-4-benzyl-2-tert-butyl-5-oxooxazolidine-3-carboxylate, 60 ml of tetrahydrofuran, 4.88 ml of morpholine and 300 mg of tetrakis-triphenylphosphinepalladium is stirred at room temperature for 20 minutes and then concentrated in vacuo. The residue is stirred in a mixture of 6 ml of glacial acetic acid and 20 ml of water for 30 minutes. After the volatile constituents have been stripped off in vacuo at 40° C., the product is purified by column chromatography (silica gel, mobile phase: methylene chloride:methanol=9:1).
Reaction SMILES: C([Li])CCC.[C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)#[CH:7].CC(C)([O-])C.[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>O.O1CCCC1.CCCCCC>[C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])#[CH:7]
Reactant: CCCCCCBr
Reactant: C#Cc1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#Cc1c(CCCCCC)ccc2ccccc12
Temperature: -90 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
Under a nitrogen atmosphere at −50° C., 1.6 mol/l hexane solution of n-butyllithium was added to 30 ml of a tetrahydrofuran solution containing 3 g of ethynylnaphthalene. After cooling to −90° C., 15 ml of a tetrahydrofuran solution containing 2.5 g of potassium tertiary butoxide was added thereto, and the mixture was stirred at −80° C. for 1 hour and then allowed to warm to 5° C. 3.3 g of bromohexane was added dropwise at −70° C., and the mixture was stirred at 30° C. overnight. 100 ml of water was added dropwise at 0° C., and the compounds generated were extracted with added hexane. The hexane layer was washed thrice with 300 ml of distilled water and dried over anhydrous magnesium sulfate for 24 hours, and the mixture was then filtered and evaporated for removal of the solvent. After column purification and solvent removal, the product was purified by column chromatography while hexane was used as the developing solvent, to give 2.2 g of 1-ethynyl-2-n-hexylnaphthalene.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:14]O.N1C=CC=CC=1.S(Cl)([Cl:24])=O.O>O1CCCC1>[Cl:24][CH2:14][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH2:10][CH2:11][O:12][CH3:13])[C:3]=1[O:2][CH3:1]
Reactant: COCCOc1cccc(CO)c1OC
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: COCCOc1cccc(CCl)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a solution of (2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}phenyl)methanol (0.37 g, 1.7 mmol) and pyridine (0.23 mL 2.8 mmol) in tetrahydrofuran (8 mL) at 0° C. was added thionyl chloride (0.14 mL, 1.9 mmol) and the reaction mixture warmed to room temperature and stirred for one hour. Then it was poured into water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined extract was washed with water and brine (20 mL each), dried over sodium sulfate, filtered and concentrated to give 1-(chloromethyl)-2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}benzene (0.33 g, 1.4 mmol, 82% yield). 1H NMR (400 MHz, CDCl3): 7.01-6.89 (m, 3H), 4.63 (s, 2H), 4.16-4.13 (m, 2H), 3.95 (s, 3H), 3.79-3.77 (m, 2H), 3.44, m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[N:6][CH:7]=1.CCN([CH:28]([CH3:30])[CH3:29])C(C)C.[Cl-].[CH3:32][OH:33]>C(Cl)Cl>[CH3:29][C:28](=[CH2:30])[C:32]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[N:6][CH:7]=1)=[O:33]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cncc(N)c3)c12
Reactant: CO
Agent: [Cl-]
Solvent: ClCCl
Product: C=C(C)C(=O)Nc1cncc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To ethyl 4-(5-aminopyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (59 mg, 0.14 mmol) in DCM (1.0 mL) was added Hunig's base (0.060 mL, 0.34 mmol) at 0° C. Methacyloyl chloride (0.015 mL, 0.15 mmol) was then added dropwise and the reaction was allowed to warm to room temperature. After being stirred for 17 hours at room temperature, MeOH was added to quench the reaction and the solution was concentrated in vacuo. The crude reaction was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. The products were collected and lyophilized to afford a colorless solid. LRMS (ESI) calc'd for C18H18N5O3 [M+H]+: 352, found 352. 1H NMR (600 MHz, DMSO-D6) δ 13.17 (s, 1H), 10.22 (s, 1H), 9.04 (s, 1H), 9.02 (d, 1H, J=1.7 Hz), 8.55 (s, 1H), 8.50 (m, 1H), 8.45 (m, 1H), 5.93 (s, 1H), 5.65 (s, 1H), 3.99 (q, 2H, J=7.2 Hz), 2.01 (s, 3H), 1.00 (t, 3H, J=7.2 Hz).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][CH3:3].[I-].[NH2:9][N+:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[N:9]1[N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=[C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH:3]=1
Reactant: N[n+]1ccccc1
Reactant: CCOC(=O)CC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cnn2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
Ethyl propionate (50.2 mL, 49.54 mmol) and 1-aminopyridinium iodide (10.0 g, 45 mmol) were added to a suspension of potassium carbonate (8.71 g, 63.02 mmol) in N,N′-dimethylformamide (100 mL) and the resulting mixture was stirred at room temperature for 2 h before being poured into 100 mL of water. Ethyl acetate was then added and the aqueous layer was separated and washed with ethyl acetate (×2). The combined organic layers were dried over magnesium sulphate, filtered and evaporated. The crude product was purified by flash chromatography (hexanes to 4:1 hexanes/ethyl acetate) to give the title compound (4.30 g, 50%) as an orange solid.
Reaction SMILES: [N+:1]([C:4]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[C:5]1[N:6]=[N:7][NH:8][N:9]=1)([O-:3])=[O:2].[BH4-:16].[Na+:17].[H][H]>>[N+:13]([C:4]([N+:1]([O-:3])=[O:2])([N+:10]([O-:12])=[O:11])[C:5]1[N:6]=[N:7][N:8]([B-:16]([N:7]2[N:8]=[N:9][C:5]([C:4]([N+:1]([O-:3])=[O:2])([N+:10]([O-:12])=[O:11])[N+:13]([O-:15])=[O:14])=[N:6]2)([N:7]2[N:8]=[N:9][C:5]([C:4]([N+:1]([O-:3])=[O:2])([N+:10]([O-:12])=[O:11])[N+:13]([O-:15])=[O:14])=[N:6]2)[N:7]2[N:8]=[N:9][C:5]([C:4]([N+:1]([O-:3])=[O:2])([N+:10]([O-:12])=[O:11])[N+:13]([O-:15])=[O:14])=[N:6]2)[N:9]=1)([O-:15])=[O:14].[Na+:17]
Reactant: [H][H]
Reactant: O=[N+]([O-])C(c1nn[nH]n1)([N+](=O)[O-])[N+](=O)[O-]
Reactant: [BH4-]
Agent: [Na+]
Product: O=[N+]([O-])C(c1nnn([B-](n2nnc(C([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])n2)(n2nnc(C([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])n2)n2nnc(C([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])n2)n1)([N+](=O)[O-])[N+](=O)[O-]
Temperature: -196 °C
Reaction time: 0.5 h

Procedure:
A 150 mL glass ampule equipped with a grease free high-vacuum PTFE valve and a TEFLON™ coated stir bar was flamed-out under vacuum. Inside the dry-box, the ampule was loaded with 876 mg (4.00 mmol) 5-(trinitromethyl)-2H-tetrazole and 37.8 mg (1.00 mmol) sodium borohydride. The ampule was connected to a vacuum line, evacuated and cooled to −196° C. About 5 mL of dry dimethoxyethane was slowly condensed into the ampule. The ampule was closed and allowed to warm to ambient temperature. As soon as the solvent melted and contacted the solid mixture at the bottom of the ampule gas evolution started. The mixture was then stirred for about 30 minutes at ambient temperature. The clear, light yellow solution was cooled to −196° C., and the evolved hydrogen pumped off. The ampule was closed off and heated to 60° C. while stirring. After 3 hours, an orange solution was obtained and the temperature was raised to 80° C. After 24 hours, the solution was allowed to cool to ambient temperature and then cooled to −196° C., the evolved hydrogen pumped off and the reaction mixture allowed to warm to ambient temperature. Subsequent evacuation to a constant weight over 24 hours resulted in a yellow solid of sodium tetrakis(5-(trinitromethyl)-2H-tetrazolyl)borate, 1.0 mmol.
Reaction SMILES: OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.Cl.[NH2:33][CH:34]1[C:40](=[O:41])[N:39]([CH3:42])[C:38]2[CH:43]=[CH:44][CH:45]=[CH:46][C:37]=2[C:36]2[CH:47]=[CH:48][CH:49]=[CH:50][C:35]1=2.[C:51](O)(=[O:55])[C@H:52]([CH3:54])[OH:53]>C1COCC1>[OH:53][C@@H:52]([CH3:54])[C:51]([NH:33][CH:34]1[C:40](=[O:41])[N:39]([CH3:42])[C:38]2[CH:43]=[CH:44][CH:45]=[CH:46][C:37]=2[C:36]2[CH:47]=[CH:48][CH:49]=[CH:50][C:35]1=2)=[O:55]
Reactant: C[C@H](O)C(=O)O
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydroxybenzotriazole (344 mg, 2.55 mmol), diisopropylethylamine (659 mg, 5.1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (488 mg, 2.55 mmol) were added to a cooled (0° C.) solution of 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one hydrochloride (700 mg, 2.55 mmol) and L-(+)-lactic acid (252 mg, 2.8 mmol) in THF (7 ml) and stirred overnight at r.t. The solvent was evaporated, the residue was taken up in dichloromethane and washed with water. The organic phase was dried over Na2SO4 and evaporated. Upon chromatographic purification (silica gel, dichloromethane/methanol=1:0−9:1) the title compound (820 mg, quant.) was obtained as a white solid.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)[CH2:19][CH2:20][CH3:21]>ClCCl.O>[CH2:18]([O:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[S:1][CH:2]=[CH:3][C:4]2=3)=[O:28])=[CH:30][CH:31]=1)[CH2:19][CH2:20][CH3:21]
Reactant: c1cc2c(s1)CCCCN2
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOc1ccc(C(=O)N2CCCCc3sccc32)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a chilled (0° C.) solution of 0.306 g of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine and 417 μl of triethylamine is added 474 μl of 4-(n-butoxy)benzoyl chloride. The mixture is stirred for 3 days at room temperature, diluted with 50 ml of dichloromethane and ml of water. The organic layer is separated and washed with 20 ml each of 2N citric acid, 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate, the pad washed with CH2Cl2 and the filtrate evaporated. The residue is crystallized from hexane containing a small amount of ethyl acetate. The crystals (0.585 g) are purified by chromatography on silica gel plates with hexane-ethyl acetate (2:1) as solvent to give 0.40 g of crystals (from ethyl acetate-hexane), m.p. 87° C. to 90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:17]([N:20]=CN(C)C)(=[O:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:17]([NH2:20])(=[O:19])=[O:18]
Reactant: BrCCCc1ccccc1
Reactant: CN(C)C=NS(=O)(=O)c1cc(C(=O)c2ccc(O)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cc(C(=O)c2ccc(OCCCc3ccccc3)cc2)ccc1Cl
Temperature: 65 °C
Yield: 3.4 %

Procedure:
2-Chloro-N-dimethylaminomethylene-5-(4-hydroxy-benzoyl)-benzenesulfonamide (250 mg, 0.68 mmol) is dissolved in N,N,-dimethylformamide (5 mL). Potassium carbonate (235 mg, 1.7 mmol) is then added followed by (3-bromo-propyl)-benzene (135 mg, 0.68 mmol). The reaction is heated to 65° C. for 18 hours. The reaction mixture is diluted with water and extracted with ethyl acetate, the organic layer is separated and concentrated in vacuo. The crude ether is purified by column chromatography (gradient of ethyl acetate in hexanes 25-75%). The residue is dissolved in ethanol (3 mL), treated with concentrated HCl (400 μl) and heated to reflux for 2.5 hours after which the reaction is allowed to cool to ambient temperature overnight. The volatiles were removed in vacuo and the crude sulfonamide is purified by column chromatography (gradient of ethyl acetate in hexanes 20-70%) affording 10 mg of the title compound. 1H NMR (DMSO) δ 2.02-2.11 (m, 2H), 2.76 (t, 2H, J=7.16 Hz), 4.10 (t, 2H, J=6.41 Hz), 7.10 (d, 2H, J=8.67 Hz), 7.17-7.32 (m, 5H), 7.75-7.91 (m, 6H), 8.24 (d, 1H, J=1.88 Hz). MS (m/z): 430 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:58]1([CH2:63][C:64]2[O:68][N:67]=[C:66]([NH2:69])[CH:65]=2)[CH2:62][CH2:61][CH2:60][CH2:59]1>ClCCl.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:12])[NH:69][C:66]1[CH:65]=[C:64]([CH2:63][CH:58]2[CH2:59][CH2:60][CH2:61][CH2:62]2)[O:68][N:67]=1)[CH2:13][CH2:14][CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cc(CC2CCCC2)on1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(CC2CCCC2)on1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(S)-2-tert-Butoxycarbonylamino-pentanoic acid (21.7 mmol) was dissolved in 100 mL of dichloromethane at rt under N2. Diisopropylethylamine (43.3 mmol) was added, followed by PyBOP (32.5 mmol). The reaction was stirred for 10 minutes at rt. The isoxazole R (21.7 mmol) was separately dissolved in 25 mL of dichloromethane and then added to the reaction solution. The resultant mixture was stirred at rt for 36-48 hours. The crude material was then diluted in 200 mL EtOAc and washed with two 100 mL portions of water, followed by 100 mL of brine. The organics were then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude products were purified through flash chromatography on silica gel to give [1-(5-Cyclopentylmethyl-isoxazol-3-ylcarbamoyl)-butyl]-carbamic acid tert-butyl ester (14.0 mmol).
Reaction SMILES: [H-].[Na+].[CH3:3]I.[OH:5][C:6]([C:12]1[CH:25]=[CH:24][C:23]2[C:14](=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[CH:18][CH:17]=[N:16]3)[N:13]=1)([CH3:11])[C:7]([CH3:10])([CH3:9])[CH3:8]>>[CH3:3][O:5][C:6]([C:12]1[CH:25]=[CH:24][C:23]2[C:14](=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[CH:18][CH:17]=[N:16]3)[N:13]=1)([CH3:11])[C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)C(C)(O)c1ccc2ccc3cccnc3c2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COC(C)(c1ccc2ccc3cccnc3c2n1)C(C)(C)C
Yield: 55.2 %

Procedure:
By employing General Procedure II, NaH (0.008 g, 0.3 mmol), methyl iodide (0.020 mL, 0.3 mmol), and the corresponding 1-hydroxy-1,2,2-trimethylpropyl phenanthroline (0.023 g, 0.08 mmol), prepared as described by Example 5, were reacted to provide 0.013 g (55% yield) of the title methyl ether as a colorless oil: 1H NMR (300 MHz, CDCl3) δ9.23 (dd, J=4.50, 1.80 Hz, Hp9), 8.23 (dd, J=7.80, 1.80 Hz, Hp7), 8.17 (d, J=8.70 Hz, Hp4), 7.88 (d, J=8.40 Hz, Hp3), 7.81 and 7.74 (two d, J=8.70 Hz, Hp5 and Hp6), 7.60 (dd, J=8.00, 4.40 Hz, Hp8), 3.21 (s, OCH3), 1.94 (s, CH3), 0.98 (s, (CH3)3); 13C NMR (75 MHz) δ163.79, 150.37, 145.12, 143.90, 135.97, 134.34, 128.82, 127.18, 126.47, 125.99, 122.53, 121.43, 86.16, 51.36, 38.83, 26.10, 17.78; IR (CHCl3) 2957 (C—H Ar), 2928 (CH), 857 (C—H Ar) cm−1; HRMS m/e Calcd for C19H23N2O (MH+): 295.1810, found, 295.1818.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])[CH:6]=1)[CH3:3].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[CH:22][N:21]=1)([O-])=O>N1C=CC=CC=1>[NH3:2].[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:20]2[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[CH:22][N:21]=2)[CH:6]=1)[CH3:1]
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: CN(C)Cc1ccnc(CSCCN)c1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCSCc3cc(CN(C)C)ccn3)[nH]c2=O)cn1
Product: N
Yield: 123.1 %

Procedure:
A solution of 2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamine (0.5 g) and 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone (0.7 g) in pyridine (3 ml) was heated under reflux for 3.5 hours and evaporated to dryness. The residue was purified by elution from a column of silica gel with ethyl acetate:ethanol: 28% w/w aqueous ammonia (by volume 10:15:2) and recrytallisation from acetonitrile to give 2-[2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone (0.58 g) m.p. 128°-129.5°.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[NH2:12][NH2:13]>CO>[CH3:11][O:10][C:4]1[N:3]=[C:2]([NH:12][NH2:13])[C:7]([O:8][CH3:9])=[CH:6][N:5]=1
Reactant: NN
Reactant: COc1ncc(OC)c(Cl)n1
Solvent: CO
Product: COc1ncc(OC)c(NN)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
A slurry of 4-chloro-2,5-dimethoxypyrimidine (3.0 grams (g), 17.2 mmol) in methanol (15 milliliters (mL)) was treated with aqueous hydrazine (3.9 g of 35 wt. %, 42.5 mmol) in one portion causing a slow exotherm to 29° C. The reaction was then warmed to 50° C. and held at that temperature for 2 hours (h) at which time gas chromatography (GC) analysis indicated the reaction was complete. The clear solution was cooled to ambient temperature and allowed to stir overnight. The solvent was removed in vacuo and the resulting gummy solid was triturated with CH3CN (50 mL). The resulting mixture was filtered through a pad of silica gel (6 centimeter (cm)×6 cm). The pad was rinsed with CH3CN (550 mL). The filtrates were combined and the solvent removed in vacuo affording the title compound as a white solid (2.6 g, 89%): mp 115-117° C.; 1H NMR (300 MHz, DMSO-d6) 3.73 (s, 3H), 3.76 (s, 3H), 4.29 (bs, 2H), 7.51 (s, 1H), 8.23 (bs, 1H); MS(GC, 70eV) 170 (M+, 100%), 155(55%), 151 (40%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18](F)=[O:19].[O:23]=[CH:24][C@@H:25]([C@H:27]([C@@H:29]([C@@H:31]([C:33]([OH:35])=[O:34])[OH:32])[OH:30])[OH:28])[OH:26].C(=O)(O)[O-].[Na+].Cl>CC(C)=O.O>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([O:23][C@@H:24]1[O:32][C@H:31]([C:33]([OH:35])=[O:34])[C@@H:29]([OH:30])[C@H:27]([OH:28])[C@H:25]1[OH:26])=[O:19]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)F)C(C)(C)CCC1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O[C@@H]2O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]2O)C(C)(C)CCC1
Reaction time: 14 h
Yield: 55.5 %

Procedure:
Retinoyl fluoride (2.4 g) was dissolved in 300 ml of acetone. D-Glucuronic acid (6 g) dissolved in 75 ml of water and sodium bicarbonate (6 g) dissolved in 75 ml of water were added to the retinoyl fluoride solution. The mixture was stirred at room temp. for 12-16 hours. More water (100-150 ml) was added and the stirring was continued for 8-12 hours more until most of the retinoyl fluoride had reacted. The solution was diluted with water, acidified with 1N HCl, and the product was extracted with n-butanol. The extract was washed with water, dried over anhydrous sodium sulfate and then evaporated to dryness in a rotary evaporator. The residue was dissolved in 2-3 ml of diethyl ether and transferred to a silica gel (for dry column chromatography, wet packed with hexane) column. The column was developed with hexane containing diethyl ether (5-50%) to remove retinoic acid and other products. The major yellow band containing retinoyl glucuronide was next eluted with a mixture of CH2Cl2 /CH3OH (1:1). The solvent was evaporated to dryness to give solid retinoyl glucuronide (2.1 g, 60%).