Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].F[C:16](F)(F)[C:17](O)=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:59]=[CH:58][C:38]([C:39]([NH:41][CH2:42][C:43]3([N:52]4[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]4)[C:48](=[O:49])[NH:47][C:46](=[O:50])[NH:45][C:44]3=[O:51])=[O:40])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:17]([N:55]1[CH2:54][CH2:53][N:52]([C:43]2([CH2:42][NH:41][C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([O:34][CH2:33][C:31]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=[C:23]([CH3:22])[CH:32]=4)=[CH:59][CH:58]=3)[C:44](=[O:51])[NH:45][C:46](=[O:50])[NH:47][C:48]2=[O:49])[CH2:57][CH2:56]1)(=[O:18])[CH3:16]
Reactant: Cc1cc(COc2ccc(C(=O)NCC3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCN(C2(CNC(=O)c3ccc(OCc4cc(C)nc5ccccc45)cc3)C(=O)NC(=O)NC2=O)CC1
Yield: 31 %

Procedure:
Following a procedure analogous to that used in reaction (10), the material from example 8 was reacted with acetyl chloride to provide the title compound (7 mg, 31%). MS found: (M+H)+=559.5.
Reaction SMILES: [C:1]1([C:7]2O[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][C:11](=[O:18])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.C[NH2:30]>CO.O>[C:1]1([C:7]2[CH:12]([C:11](=[O:18])[CH:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:30]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)oc(-c2ccccc2)cc1=O
Reactant: CN
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C1C(=O)C=C(c2ccccc2)N=C1c1ccccc1

Procedure:
3.5 gms of 2,6-diphenyl-3-ethoxycarbonyl-4-pyrone was dissolved in 33 mls of methanol. 2 mls of glacial acetic acid was added. 13.3 mls of 40% aqueous methylamine was then added very slowly at room temperature. After 6 hours the reaction mixture was diluted with 200 mls of water and extracted with methylene chloride. Evaporation yielded 3.5 gms of ethyl 2,6-diphenyl-4-oxonicotinate which was recrystallized from methylene chloride/ether. mp=177°-179°
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([O:12]CC)=[O:11])[C:5]([CH3:15])=[C:4]([CH3:16])[C:3]=1[C:17](=[O:35])[CH:18]=[CH:19][C:20]1[CH:25]=[C:24](C(C)(C)C)[C:23](O)=[C:22](C(C)(C)C)[CH:21]=1.[Cl:36]C1C=CC(C=O)=CC=1>>[OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([OH:12])=[O:11])[C:5]([CH3:15])=[C:4]([CH3:16])[C:3]=1[C:17](=[O:35])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:36])=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1c(C)c(C)c(C(=O)C=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(O)c1OC
Product: COc1c(O)c(C(=O)C=Cc2ccc(Cl)cc2)c(C)c(C)c1C(=O)O

Procedure:
This compound was synthesized from 2′-hydroxy-4′-(ethoxycarbonyldimethylmethyloxy)acetophenone (starting material 1) and 4-chlorobenzaldehyde according to general method 2 described earlier.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=3[CH:26]=2)[C@H:10]([C:27]([F:30])([F:29])[F:28])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:30][C:27]([F:28])([F:29])[C@H:10]1[C@@H:11]([NH:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=3[CH:26]=2)[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccc3c(c2)NC(=O)CS3)[C@H](C(F)(F)F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CSc2ccc(CN[C@H]3CCNC[C@H]3C(F)(F)F)cc2N1
Reaction time: 2 h

Procedure:
(3R,4S)-4-[(3-oxo-3,4-dihydro-2H-benzo-[1,4]thiazin-6-ylmethyl)amino]-3-(trifluoromethyl)piperidine-1-carboxylic acid tert-butyl ester (2e) (1 equiv.) is dissolved in CH2Cl2 and TFA (1:1, v/v). After 2 hrs, the solution is concentrated to dryness under vacuum and the residue is dissolved in 4 M HCl in dioxane. After 30 min, the slurry is triturated with Et2O and filtered. The solid is dissolved in H2O and the solution is made basic with aqueous NaOH. The basic aqueous solution is concentrated under vacuum and the residue is dried under high vacuum. The resulting solid is extracted with CH2Cl2/MeOH (10:1, v/v) and the solution is concentrated. The residue is dried under high vacuum to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH:9]1([C:14]2[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:17]2[CH:16]=[CH:15][C:14]([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[CH:19][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(C2CCCC2)cc1
Reactant: Clc1cc(I)ccn1
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: COCCOC
Solvent: O
Product: Clc1cc(-c2ccc(C3CCCC3)cc2)ccn1
Yield: 67.9 %

Procedure:
A mixture of 2-chloro-4-iodopyridine (6.43 g, 26.3 mmol), (4-cyclopentylphenyl)boronic acid (5.0 g, 26.3 mmol), Pd(Ph3P)4 (0.0.91 g 0.79 mmol), sodium carbonate (8.37 g, 79 mmol), DME (257 mL) and water (64 mL) was degassed with nitrogen and then refluxed overnight. The reaction mixture was concentrated and extracted with ethyl acetate. The the ethyl acetate layer was dried on Na2SO4 and then further purified by column chromatography using dichloromethane in hexanes and then vacuum distilled to give 2-Chloro-4-(4-cyclopentylphenyl)pyridine (4.6 g, 68% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=[O:9])[CH3:8])=[CH:3][CH:2]=1.[Br:10]Br>C(Cl)(Cl)(Cl)Cl>[BrH:10].[Br:10][CH2:8][C:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[O:9]
Reactant: CC(=O)c1ccncc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: Br
Product: O=C(CBr)c1ccncc1
Yield: 783.1 %

Procedure:
To a stirred solution of 1-(pyridin-4-yl)-ethanone (10 g, 0.08 mol) in CCl4 (150 mL) was added Br2 (3.99 mL, 0.02 mol) dropwise at 0° C. and the mixture was then refluxed for 1 h. The reaction mixture was filtered and dried in vacuo to afford 2-bromo-1-(pyridin-4-yl)-ethanone hydrobromide (22 g, 94%) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].I[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.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.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:12][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: Ic1cccnc1
Reactant: CCOC(=O)c1nc(C)cnc1N
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(C)cnc1Nc1cccnc1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
3-Amino-6-methyl-pyrazine-2-carboxylic acid ethyl ester (Example C) (800 mg, 4.4 mmol) and 3-iodopyridine (1.63 g, 8.0 mmol) were dissolved in 17 ml dry dioxane. 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (510 mg, 0.88 mmol), cesium carbonate (2.30 g, 7.0 mmol) and tri(dibenzylideneacetone)dipalladium chloroform complex (460 mg, 0.44 mmol) were added and the reaction mixture was stirred for 16 hours at 130° C. The reaction mixture was then evaporated and purified by flash chromatography on silica gel (heptane/ethyl acetate 9:1->heptane/ethyl acetate 1:2). The desired product was obtained as a yellow oil (455 mg, 40%), MS: m/e=259.2 (M+H+).
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:28]1CCN2C(=NCCC2)CC1.CI>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10]([O:12][CH3:28])=[CH:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Solvent: CI
Product: COC1=CC(=O)OC(CCc2ccc(C(C)(C)C#N)c(F)c2)(C2CCCC2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
A magnetically stirring solution of 2-{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile (− rotation, 0.15 g, 0.40 mmol) was cooled to 0° C. DBU (0.18 mL, 1.21 mmol) was added followed by MeI (0.076 mL, 1.21 mmol) and reaction was stirred at 0° C. for 1 hour. The reaction mixture was partitioned between 1N HCl and EtOAc. The layers of the resulting reaction mixture were separated and the organic layer was washed with brine (1×10 mL), then dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (20% EtOAc in Hexanes) to give the desired product as a yellow oil (0.062 g, 41%). 1H NMR (400 MHz, CDCl3): δ 1.18 (d, J=6.5 Hz, 3H), 1.40 (d, J=6.5 Hz, 3H), 1.50-1.78 (m, 8H), 1.94-2.05 (m, 2H), 2.18 (s, 3H), 2.64-2.73 (m, 3H), 3.75 (s, 2H), 5.17 (s, 1H), 6.89-6.97 (m, 2H), 7.35-7.40 (m, 1H). MS (ESI): 386 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:19][C:20]([O:22]C)=[O:21])[C:9](=[O:18])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[Li+].Cl>C1COCC1.CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:19][C:20]([OH:22])=[O:21])[C:9](=[O:18])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)CN(C(=O)/C=C/c1ccccc1)c1ccc(Br)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CN(C(=O)/C=C/c1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 9.8 %

Procedure:
A solution of {(4-bromophenyl)-[(E)-(3-phenylacryloyl)]amino}acetic acid, methyl ester 1 (14.61 g, 0.39 mol) in THF (150 mL) and methanol (50 mL) was treated with lithium hydroxide (2.80 g, 0.117 mol) in water (50 mL). The reaction mixture was stirred at room temperature for 45 min and then acidified with conc. hydrochloric acid and concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 10% hydrochloric acid, brine, dried (Na2SO4) and the organic solution evaporated to give the title compound as a viscous oil (13.82 g, 97%). 1HNMR (300 MHz) (CDCl3) δ 4.53 (2H, s), 6.36 (1H, d, J=16 Hz), 7.27 (2H, d), 7.3-7.4 (5H, m), 7.60 (2H, d) and 7.76 (1H, d, J=16 Hz).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH3:9]>>[NH2:9][C@H:2]([C:1]([O-:8])=[O:7])[CH2:3][C:4]([O-:6])=[O:5].[NH4+:9].[NH4+:9]
Reactant: N
Reactant: O=C(O)/C=C/C(=O)O
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]
Product: [NH4+]

Procedure:
fumaric acid is reacted with ammonia in an inert diluent in the presence of aspartase or aspartase-producing microorganisms to give ammonium L-aspartate then
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[CH3:12][N:13]1CCCC1=O>Cl>[OH:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[N:13])=[CH:3][CH:4]=1
Reactant: CN1CCCC1=O
Reactant: OCCCc1ccc(Br)cc1
Agent: Cl
Product: N#Cc1ccc(CCCO)cc1

Procedure:
A mixture of 4-bromobenzenepropanol (9.0 g), cuprous cyanide (4.5 g), cuprous iodide (20 mg), and N-methyl-2-pyrrolidone (20 ml) was heated at 180°-190° for 4 h and poured into a solution of ferric chloride hexahydrate (4.5 g) in hydrochloric acid (2 M; 30 ml). The mixture was heated at 70°-80° for 15 min and extracted with EA (3×100 ml). The extract was washed with hydrochloric acid (2 M; 50 ml), water (50 ml), and aqueous sodium hydroxide (2 M; 50 ml), dried and evaporated. The residue was purified by [C] eluting with cyclohexane-ER (1:1) to give the title compound (3.5 g). T.l.c. (cyclohexane-ER 1:1) Rf 0.15
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH:25]([C:27]1[C:28]([C:33](Cl)=[O:34])=[N:29][CH:30]=[CH:31][CH:32]=1)=[CH2:26].NC1C=CC(N2C(=O)CC(=O)NC3C(CC)=CC=CC2=3)=CC=1>>[CH:25]([C:27]1[C:28]([C:33]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:34])=[N:29][CH:30]=[CH:31][CH:32]=1)=[CH2:26]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: C=Cc1cccnc1C(=O)Cl
Agent: CCc1cccc2c1NC(=O)CC(=O)N2c1ccc(N)cc1
Product: C=Cc1cccnc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 35 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 3-vinylpicolinic acid chloride, the title compound (yield 35%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][C:25]=2[NH:32][C:33](=[O:54])[CH2:34][CH2:35][NH:36][C:37]([O:39][CH2:40][CH:41]2[C:53]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:47]3[C:42]2=[CH:43][CH:44]=[CH:45][CH:46]=3)=[O:38])[O:6]1)=[O:4].[O:55]=[C:56](Cl)OC(Cl)(Cl)Cl.[Si:63]([O:80][CH2:81][CH2:82][CH2:83][CH:84]1[NH:88][CH2:87][CH2:86][O:85]1)([C:76]([CH3:79])([CH3:78])[CH3:77])([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>>[Si:63]([O:80][CH2:81][CH2:82][CH2:83][CH:84]1[N:88]([C:56]([O:31][CH2:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][C@H:7]3[C@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[O:6]3)=[C:25]([NH:32][C:33](=[O:54])[CH2:34][CH2:35][NH:36][C:37]([O:39][CH2:40][CH:41]3[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:47]=4[C:48]4[C:53]3=[CH:52][CH:51]=[CH:50][CH:49]=4)=[O:38])[CH:26]=2)=[O:55])[CH2:87][CH2:86][O:85]1)([C:76]([CH3:79])([CH3:77])[CH3:78])([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: CC(C)(C)[Si](OCCCC1NCCO1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)[C@H]1O[C@@H](Oc2ccc(CO)cc2NC(=O)CCNC(=O)OCC2c3ccccc3-c3ccccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: COC(=O)[C@H]1O[C@@H](Oc2ccc(COC(=O)N3CCOC3CCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2NC(=O)CCNC(=O)OCC2c3ccccc3-c3ccccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The construction of the glucuronide-based linker unit with DPO (2) involved a different strategy (Scheme 4). Intermediate 11 was activated with diphosgene and then reacted with oxazoline 12 (prepared in 3 steps from 1,4-butane diol) to afford the desired oxazoline carbamate 13. Removal of the silyl protecting group with fluoride was followed by oxidation to give aldehyde 14. This compound was used in a reductive alkylation reaction with doxorubicin-HCl (15) to give the doxorubicin derivative 16. Lastly, the β-glucuronide protecting groups and Fmoc group were removed in a 2-step sequence with lithium hydroxide and piperidine, and the resulting primary amine was capped with 10 to give the desired β-glucuronide DPO linker 17.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:10].[CH3:11][N:12]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[N:13]1>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:15]2[CH:14]=[N:13][N:12]([CH3:11])[CH:16]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(I)cc(C)c1Br
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cc1cc(-c2cnn(C)c2)cc(C)c1Br

Procedure:
The title compound is prepared from 2-bromo-5-iodo-1,3-dimethylbenzene and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following a procedure analogous to that described in Step 1 of Intermediate 17. LC (method 9): tR=1.09 min; Mass spectrum (ESI+): m/z=265 [M+H]+.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:29]=[C:28]([CH3:30])[C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:6]([CH3:31])[C:5]=1[CH2:32][CH3:33].[CH2:34]([O:36][C:37](=[O:48])[CH:38]=[C:39]([CH3:47])[CH:40]=[CH:41][CH:42]=[C:43]([CH:45]=O)[CH3:44])[CH3:35]>>[CH2:34]([O:36][C:37](=[O:48])[CH:38]=[C:39]([CH3:47])[CH:40]=[CH:41][CH:42]=[C:43]([CH3:45])[CH:44]=[CH:8][C:7]1[C:28]([CH3:30])=[CH:29][C:4]([O:3][CH3:2])=[C:5]([CH2:32][CH3:33])[C:6]=1[CH3:31])[CH3:35]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Reactant: CCc1c(OC)cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Agent: [Cl-]
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)c(CC)c1C

Procedure:
4-methoxy-2,6-dimethyl-3-ethyl-benzyl-triphenyl-phosphonium chloride is condensed with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester to produce 9-(4-methoxy-2,6-dimethyl-3-ethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester which is converted by the procedure of Example 7 to form 9-(4-methoxy-2,6-dimethyl-3-ethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid, m.p.: 197°-198° C.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8](=[O:24])[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([N+:17]([O-:19])=[O:18])=[CH:11][C:10]=1[NH:20]C(=O)C.CO.C(=O)(O)[O-].[K+]>C(OCC)(=O)C.O>[CH3:6][O:7][C:8](=[O:24])[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([N+:17]([O-:19])=[O:18])=[CH:11][C:10]=1[NH2:20]
Reactant: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1NC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1N
Temperature: 70 °C
Yield: 79.1 %

Procedure:
0.12 ml of sulfuric acid 98% are added dropwise at 0° C. (exothermic) to a suspension of 69 mg (0.257 mmol) of 2-acetylamino-5-methoxy-4-nitro-benzoic acid methyl ester, 0.69 ml of methanol and 0.12 ml of water. The mixture is then heated to 70° C. for 30 minutes, cooled to room temperature, poured onto a mixture of ice, water and ethyl acetate and the pH adjusted to 6 with concentrated potassium bicarbonate solution. The organic phase is separated, washed with brine, dried over sodium sulfate, filtered and evaporated, giving 46 mg (79%) of 2-amino-5-methoxy-4-nitro-benzoic acid methyl ester as red-brown crystals, m.p. 127-129° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2cccs2)c1C#N
Reactant: NCc1ccccc1
Solvent: C1COCCO1
Product: N#Cc1c(NCc2ccccc2)nc(N)nc1-c1cccs1
Temperature: 100 °C
Yield: 67.4 %

Procedure:
To a stirred suspension of 150 mg (0.57 mmol) 2-amino-4-methanesulfinyl-6-thiophen-2-yl-pyrimidine-5-carbonitrile in 3 ml dioxane was added 0.16 ml (1.42 mmol) benzylamine and the mixture heated at 100° C. for 30 minutes. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate/hexane 1/3) followed by trituration in ether/hexane afforded 118 mg (68%) 2-amino-4-benzylamino-6-thiophen-2-yl-pyrimidine-5-carbonitrile as a light yellow crystalline solid. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C@H:16]3[CH2:18][C@H:17]3[CH2:19][CH2:20][OH:21])[CH2:12][CH2:11]2)=[N:8][CH:9]=1.Cl[C:23]1[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([C:30]#[N:31])[CH:24]=1>CN(C=O)C.CCOC(C)=O.O>[CH3:29][C:27]1[N:26]=[C:25]([C:30]#[N:31])[CH:24]=[C:23]([O:21][CH2:20][CH2:19][C@@H:17]2[CH2:18][C@@H:16]2[CH:13]2[CH2:12][CH2:11][N:10]([C:7]3[N:8]=[CH:9][C:4]([CH3:3])=[CH:5][N:6]=3)[CH2:15][CH2:14]2)[N:28]=1
Reactant: Cc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Reactant: Cc1nc(Cl)cc(C#N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(C#N)nc(C)n3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
NaH (60%, 18 mg, 0.45 mmol, 1.2 eq) was placed in a 1 dram vial and DMF (1.2 mL) added. A solution of 2-{(1S,2R)-2-[1-(5-methylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (100 mg, 0.375 mmol) was added dropwise (0.5 mL) to the slurry, and the mixture stirred at RT for 10 min. The solution was cooled to −20° C., and a solution of 6-chloro-2-methylpyrimidine-4-carbonitrile (115 mg, 0.75 mmol) in DMF (0.5 mL) was added drop-wise. The red mixture was stirred for 40 minutes. A solution of ice-cold saturated NH4Cl (aq., 1 mL) was added, and the mixture diluted with EtOAc (100 mL) and water (50 mL). The mixture was transferred to a separatory funnel, the mixture shaken, and the layers separated. The organic fraction was washed with water (20 mL), dried over MgSO4, filtered, and concentrated in vac. The red oil was purified by chromatography on silica gel 1:7 EtOAc:Hexanes to give the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](#[N:13])[CH2:10][C:11]#[N:12].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:31]2[CH2:35][C:34](=[O:36])[N:33]([CH3:37])[N:32]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>C(O)C>[NH2:12][C:11]1[O:36][C:34]2[N:33]([CH3:37])[N:32]=[C:31]([C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=3)[C:35]=2[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[C:9]#[N:13]
Reactant: O=Cc1ccccc1
Reactant: N#CCC#N
Reactant: COc1ccc(C2=NN(C)C(=O)C2)cc1OC
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-c2nn(C)c3c2C(c2ccccc2)C(C#N)=C(N)O3)cc1OC
Reaction time: 0.02 h
Yield: 8.6 %

Procedure:
A mixture of benzaldehyde (145 μL, 1.44 mmol, 1.0 equ.), malononitrile (90.0 mg, 1.44 mmol, 1.0 equ.) and triethylamine (200 μL, 1.44 mmol, 1.0 equ.) in ethanol (5.0 mL) was stirred for 1 min, followed by the addition of 3-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrazol-5(4H)-one (336 mg, 1.44 mmol, 1 equ.). The reaction mixture was concentrated after 24 h. The crude material was purified by column chromatography. (25% ethyl acetate in hexanes to 100% ethyl acetate), then re-crystallized from ethanol and washed with hexanes and ethanol to give 6-amino-3-(3,4-dimethoxyphenyl)-1-methyl-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (48.5 mg, 9%, 0.124 mmol) as a yellow solid. 1H-NMR (400 MHz) CDCl3: 7.29-7.28 (d, 2H), 7.23-7.21 (d, 2H), 7.00-6.98 (d, 1H), 6.88 (s, 1H), 6.72-6.70 (d, 2H), 4.84 (s, 1H), 4.75 (s, 2H), 3.82 (s, 6H), 3.60 (s, 3H), 13C-NMR (100 MHz) CDCl3: 157.6, 148.7, 148.6, 146.1, 145.7, 143.1, 128.9, 127.5, 127.4, 125.6, 119.3, 119.3, 110.9, 109.7, 94.7, 64.4, 55.7, 55.6, 38.3, 34.1; LC/MS-MS: 389.1→323.0 m/z; GS1 and GS2 at 30, DP=66, CE=31, CXP=22, tR=3.82 min.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13]N(C)[CH2:11][CH2:10]2)=[O:7])=[C:4]([F:19])[CH:3]=1.NC1CC[CH:24]([N:27]([CH3:29])[CH3:28])CC1>>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH:9]2[CH2:10][CH2:11][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:13][CH2:14]2)=[O:7])=[C:4]([F:19])[CH:3]=1
Reactant: CN1CCC(NC(=O)c2cc(Cl)c(N)cc2F)CC1
Reactant: CN(C)C1CCC(N)CC1
Product: CN(C)C1CCC(NC(=O)c2cc(Cl)c(N)cc2F)CC1

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 173, on a 2.64 mol scale, utilising 1-amino-4-dimethylaminocyclohexane (ABChem. Inc.; 472 mg, 3.31 mmol) after purification on a silica column (gradient (3-4% ammonia in methanol/DCM), as a pale brown foam (716 mg, 86%).