Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:25]=[CH:24][CH:23]=[CH:22][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH:11]C(=O)OCC3C=CC=CC=3)[C:4]2=[N:3][CH:2]=1.C(O)C>[Pd]>[CH:1]1[N:5]2[C:6]3[CH:25]=[CH:24][CH:23]=[CH:22][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH2:11])[C:4]2=[N:3][CH:2]=1
Reactant: O=C(N[C@@H]1CCc2ccccc2-n2ccnc21)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: N[C@@H]1CCc2ccccc2-n2ccnc21
Yield: 100.4 %

Procedure:
Dissolve benzyl N-[(4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-yl]carbamate (6.95 g, 20.85 mmol) in absolute ethanol (375 mL, 6.44 moles) and add 10% palladium on carbon (Pd/C) (0.70 g, 6.57 mmol). Place the mixture on a Parr shaker under Hydrogen (H2) for 7 hours (60 psi, ambient temperature). Remove the catalyst by filtration and concentrate the filtrate under reduced pressure to give the title compound (4.17 g, 100%) as a yellow solid: MS (m/z): 200 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]Br.[C:7](#[N:11])[CH2:8][C:9]#[N:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:8]1([C:7]#[N:11])([C:9]#[N:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCC#N
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC1(C#N)CCCC1
Yield: 53.3 %

Procedure:
A mixture of 43.19 g of 1,4-dibromobutane, 13.2 g of malononitrile, 55.3 g of potassium carbonate and 1 liter of acetonitrile was refluxed for 42 hours, filtered while hot and evaporated to dryness giving a dark oil. This oil was vacuum distilled, giving 12.8 g 1,1-cyclopentanedicarbonitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:25]=[C:26]([CH:30]=[O:31])[CH:27]=[N:28][CH:29]=2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[BH4-].[Na+].O>C(O)C>[OH:31][CH2:30][C:26]1[CH:25]=[C:24]([C:4]2[CH:5]=[C:6]3[C:10](=[C:2]([CH3:1])[CH:3]=2)[C:9](=[O:11])[N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]([F:22])([F:23])[F:21])=[CH:17][CH:18]=2)[CH2:7]3)[CH:29]=[N:28][CH:27]=1
Reactant: Cc1cc(-c2cncc(C=O)c2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2cncc(CO)c2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.3 %

Procedure:
To a solution of 5-[7-Methyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindol-5-yl]-pyridine-3-carbaldehyde (91 mg, 0.212 mmol), in ethanol (10 mL) was added sodium borohydride (10 mg, 0.212 mmol). The mixture stirred for 4 hrs at room temperature and was poured into water and was extracted with ether. The organics were dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography eluting with 30-100% ethyl acetate in hexanes. The isolated product stirred in 1N HCl/MeOH overnight and was neutralized with 1N NaOH, extracted with ether, and concentrated to afford the title compound (62 mg, 68%) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 8.74 (s, 1H), 78.61 (s, 1H), 8.15 (s, 1H), 7.41-7.36 (m, 4H), 7.22 (d, 2H), 4.91 (s, 2H), 4.82 (s, 2H), 4.36 (s, 2H), 2.85 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH2:5][C:6]([CH3:8])=[CH2:7])[CH:3]=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[CH3:1][C:2]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([CH2:5][C:6]([CH3:8])=[CH2:7])[CH2:3][OH:4]
Reactant: C=C(C)CC(C)(C=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C=C(C)CC(C)(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A 376 g sample of 2,4-dimethyl-2-phenyl-4-pentenal (prepared via the method of U.S. Pat. No. 3,996,290) was added to 38 g of lithium aluminum hydride in 1200 ml of anhydrous ether over a 1 hr period with cooling to maintain 25° C. At the end of the addition, 76 g of water and 61 g of 10% aqueous sodium hydroxide were carefully added and the mixture was stirred for 2 hrs. The mixture was filtered, concentrated on a rotary evaporator and distilled, affording 370 g of 2,4-dimethyl-2-phenyl-4-penten-1-ol, (bp 125°-127°/0.5 mm Hg), in a 97% yield and a purity of 99%. Spectral data were in agreement with the assigned structure.
Reaction SMILES: [C:1]1([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[C:25]([CH3:27])([CH3:26])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:28]([O:30]C)=[O:29])[CH:22]=4)[NH:17]3)=[CH:12][CH:11]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]3[C:25]([CH3:27])([CH3:26])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:28]([OH:30])=[O:29])[CH:22]=4)[NH:17]3)=[CH:14][CH:15]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)C3=CCCCC3)cc1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(NC(=O)C2=CCCCC2)cc1
Yield: 47.5 %

Procedure:
A mixture of methyl 2-(4-(cyclohex-1-enecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (217 mg, 0.52 mmol) in methanol (3 mL) and water (1.5 mL) was treated with a solution of sodium hydroxide (353 mg, 2.63 mmol) in water (1.5 mL) was heated to reflux until the completion of the reaction (monitored by Thin layer chromatography). The methanol was removed under vacuum. The residue was acidified with 2M hydrochloric acid to pH=1. The precipitates were collected by filtration to afford 100 mg of 2-(4-(cyclohex-1-enecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow solid Yield: 53%. MS (ESI+APCI) M+1=405.2.
Reaction SMILES: C(O[C:5]1[C:9](N=C=O)=[CH:8][S:7][C:6]=1/[C:13](=[CH:15]/[CH:16]([CH3:18])[CH3:17])/[CH3:14])(C)C.[CH:19]([O:22][C:23](NC1C=CSC=1/C(=C\C(C)C)/C)=[O:24])([CH3:21])[CH3:20].C(OC(NC1C=CSC=1C(CC(C)C)=C)=O)(C)C>[C].[Pd].CO>[CH:19]([O:22][C:23]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH:13]([CH3:14])[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:24])([CH3:21])[CH3:20]
Reactant: C/C(=C/C(C)C)c1sccc1NC(=O)OC(C)C
Reactant: C/C(=C\C(C)C)c1scc(N=C=O)c1OC(C)C
Agent: [Pd]
Agent: C=C(CC(C)C)c1sccc1NC(=O)OC(C)C
Solvent: CO
Product: CC(C)CC(C)c1sccc1C(=O)OC(C)C
Reaction time: 9 h
Yield: 70 %

Procedure:
b 2.06 g (7.72 mmol) of the mixture of 3-isopropoxy-carbonylamino-{2-(E)-(4-methyl-2-penten-2-yl)}thiophene, 3-isopropoxycarbonylamino-{2-(Z)-(4-methyl-2-penten-2-yl)}thiophene, and 3-isopropoxycarbonylamino-{2-(4-methyl-1-penten-2-yl)}thiophene obtained in Example 13 and 0.41 g of 5% palladium carbon (Degussa chemical catalyst E106R/W) were charged into 20 ml of methanol, and after nitrogen purge, a hydrogenation reaction was conducted at normal pressure under hydrogen atmosphere for 9 hours. After nitrogen purge, the catalyst was filtrated off, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to obtain 1.61 g of the intended compound as a colorless crystal (yield: 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH2:25][F:26])[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH2:25][F:26])[C:17]([OH:19])=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CCF)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cn(C(CCF)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
359 mg (853 μmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluorobutanoate (racemate) in 8.5 ml of dichloromethane and 2.5 ml (32 mmol) of TFA were reacted according to General Method 6A. Yield: 306 mg (96% of theory)
Reaction SMILES: C=O.[H-].[Na+].[F:5][C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14]3[N:18]=[C:19](/[CH:21]=[CH:22]/[C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]5)=[C:25]([O:35][CH3:36])[CH:24]=4)[N:20]=[C:13]23)[CH:9]=[CH:10][CH:11]=1.O.[C:38](=O)(O)[O-:39].[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:5][C:6]1[CH:7]=[C:8]([C:12]2([CH2:38][OH:39])[CH2:17][CH2:16][CH2:15][N:14]3[N:18]=[C:19](/[CH:21]=[CH:22]/[C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]5)=[C:25]([O:35][CH3:36])[CH:24]=4)[N:20]=[C:13]23)[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cc(/C=C/c2nc3n(n2)CCCC3c2cccc(F)c2)ccc1-n1cnc(C)c1
Reactant: O=C([O-])O
Agent: C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3(CO)c2cccc(F)c2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Paraformaldehyde (186 mg) and sodium hydride (containing 40% of mineral oil, 28.7 mg) were added to a solution of 8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine synthesized by the method in Examples 1 and 2 (154 mg) in DMF (3 mL), and the reaction solution was stirred at room temperature for 30 minutes. Thereafter, ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 204 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].N1CCC[C@H]1C(O)=O.C(O)(=O)C.Br[C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1>CS(C)=O.CCOC(C)=O.O.[I+].[Cu+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: Brc1ncccn1
Agent: [Cu+]
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc2c(ccn2-c2ncccn2)c1
Temperature: 90 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
A nitrogen stream was bubbled through a mixture of 5-bromoindole (2 g, 10.201 mmol) in DMSO (10 mL). Then, K2CO3 (4.23 g, 30.604 mmol), Copper (I) iodine (0.097 g, 0.51 mmol), L-proline.trifluoric acetic acid (0.234 g, 1.02 mmol) and 2-bromopyrimidine (1.622 g, 10.201 mmol) were added. The resulting reaction mixture was stirred in a sealed tube at 90° C. for 48 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and water and filtered through diatomaceous earth. The filtrate was evaporated in vacuo. The residue was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield D35 (2.6 g, 92%).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[C:10]([CH2:12][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)#[N:11]>O.C(O)C>[N:22]1[C:23]2[C:18](=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][CH2:12][C:10](=[N:2][OH:3])[NH2:11])[CH:19]=[CH:20][CH:21]=1
Reactant: NO
Reactant: N#CCOc1cccc2cccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(COc1cccc2cccnc12)=NO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6.4 g of hydroxylamine hydrochloride in 10 ml of water and 6.4 g of potassium carbonate in 10 ml of water is added dropwise at room temperature, within 15 minutes, to 15.8 g of 8-(cyanomethoxy)-quinoline in 100 ml of ethanol, in the course of which the reaction mixture warms up to 30° C. After 3 hours' stirring at room temperature, the reaction mixture is diluted with 250 ml of water; it is subsequently filtered, and the residue is washed with water and dried. There is thus obtained 2-(8-quinolinoxy)-acetamide oxime in the form of light-brown powder, m.p. 201°-204° C. (decomposition).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][CH2:5][CH:4]([NH:7]C(=O)OCC2C=CC=CC=2)[CH2:3]1.[ClH:19]>>[ClH:19].[F:1][C:2]1([F:18])[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3]1
Reactant: O=C(NC1CCC(F)(F)C1)OCc1ccccc1
Agent: Cl
Product: NC1CCC(F)(F)C1
Temperature: 25 °C
Yield: 85 %

Procedure:
Benzyl 3,3-difluorocyclopentylcarbamate (1.5 g, 5.88 mmol) in 6N HCl (6 mL) was heated at 100° C. for 20 h. After the reaction mixture was cooled to rt, the brown solution was extracted with Et2O (2×2 mL) to remove unreacted starting material and toluene. The aqueous phase was dried in the speed vac with heating to give 3,3-difluorocyclopentanamine hydrochloride as a light brown solid (0.79 g, 85% yield). 1H NMR (MeOD-d4, 400 MHz): 4.79 (m, 1H), 2.62 (m, 1H), 2.32 (m, 2H), 2.18 (m, 2H), 1.87 (m, 1H). 13C NMR (MeOD-d4, 400 MHz): 131.4 (t), 41.0 (t), 34.8 (t), 28.9. 19F NMR (MeOD-d4, with CFCl3 as standard, 400 MHz): −93.0 (m, 2F). LC/MS: [M+H]=121.9.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[NH2:7])\[CH:4]([CH3:6])[CH3:5].[Cl:8][CH2:9][CH2:10][C:11](O)=O.C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[Cl:8][CH2:9][CH2:10][C:11]1[O:1][N:2]=[C:3]([CH:4]([CH3:6])[CH3:5])[N:7]=1
Reactant: O=C(O)CCCl
Reactant: CC(C)/C(N)=N\O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: CC(C)c1noc(CCCl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of (E)-N′-hydroxyisobutyrimidamide (510 mg, 5 mmol), 3-chloropropanoic acid (542 mg, 5 mmol) and dicyclohexylcarbodiimide (1.24 g, 6 mmol) in anhydrous dioxane (20 mL) was stirred at 0° C. for 1 h and then at room temperature for an additional 1 h. The reaction was then heated at 80° C. for an additional 18 h. The reaction was filtered and the filtrate was evaporated. The resulting residue was purified by silica chromatography (0-100% EtOAc in hexanes gradient) to give 5-(2-chloroethyl)-3-isopropyl-1,2,4-oxadiazole; 1H NMR (400 MHz, CDCl3) δ 3.85 (t, J=7.2 Hz, 2H), 3.27 (t, J=7.2 Hz, 2H), 3.03 (septet, J=7.2 Hz, 1H), 1.13 (d, J=7.2 Hz, 6H); ESMS m/z 175.1 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:32])[C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[C:23]([OH:30])[C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[O:21][C:20](=[O:31])[CH:19]=1>>[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:32])[C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[C:23]([O:30][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[O:21][C:20](=[O:31])[CH:19]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: CCOC(=O)CCCBr
Product: CCOC(=O)CCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12

Procedure:
The title compound was prepared from ethyl 4-bromobutanoate and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.81 (s, 2H), 7.95 (d, 1H), 7.20 (d, 1H), 4.64 (s, 1H), 4.10-3.95 (m, 4H), 3.91 (s, 3H), 2.54 (t, 2H), 1.90 (m, 2H), 1.16 (t, 3H); MS (ESI): 466.9.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]([C@H:8]([OH:27])/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:16]([CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:14](=[O:15])[CH2:13][C@H:12]1[OH:26])([CH3:7])[CH3:6].[CH:28](Cl)(Cl)Cl.C(Cl)(Cl)Cl>>[CH3:1][CH2:2][CH2:3][CH2:4][C:5]([C@@H:8]([OH:27])/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:16]([CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:28])=[O:24])[C:14](=[O:15])[CH2:13][C@H:12]1[OH:26])([CH3:7])[CH3:6]
Reactant: ClC(Cl)Cl
Reactant: CCCCC(C)(C)[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Product: CCCCC(C)(C)[C@@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC
Reaction time: 6 h

Procedure:
2 mg 3H labelled 16,16-dimethyl PGE2, methyl ester Ono 802 ex May and Baker is dissolved in 0.67 g ethanol C2H5OH, 0.67 g chloroform CHCl3 is added. A slice of the polymer 1 mm×11 mm×22 mm weighing 0.2678 g is added to the Ono solution in a polythene bag which is then sealed. After 6 hours swelling the bag is cut open and the swollen gel is weighed. Uptake 0.97 g solution i.e. 1.45 mg Ono. The sample is then dried and the in vitro release of Ono into phosphate buffer pH 7.4 at 37° is measured as in Ex. 12. The half life of Ono in this sample is 6.3 hours. The results for 3 different thicknesses of polymer sample are given to the Table.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:25])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[C:5]([O:7][CH3:8])=[O:6].[C:26](N1C=CN=C1)(N1C=CN=C1)=[S:27]>O1CCCC1.ClCCl.O>[CH3:25][N:16]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH2:15][CH2:14][CH2:13][N:12]1[C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[NH:1][C:26]1=[S:27]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1ccc(NCCCN(C)CCc2ccccn2)c(N)c1
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)[nH]c(=S)n2CCCN(C)CCc1ccccn1
Temperature: 20 °C
Reaction time: 15 h
Yield: 85 %

Procedure:
A mixture of methyl 3-amino-4-({3-[methyl(2-pyridin-2-ylethyl)amino]propyl}amino)benzoate (4.09 g, 1 eq) and thiocarbonyldiimidazole (2.77 g, 1.3 eq) in tetrahydrofuran (100 ml) is stirred at approximately 20° C. for 15 hours. After concentration under reduced pressure at 40° C., the residue obtained is taken up in dichloromethane (150 ml) and water (50 ml). After decanting and extracting, the combined organic phases are washed with salt water, dried over Na2SO4 then evaporated under reduced pressure at 40° C. Purification by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 9:1) produces the expected compound in the form of a foam (3.94 g; 85% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:18](=[O:25])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH2:19].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].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]>[N+:15]([C:12]1[N:11]=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:18](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:7]=2)=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: CC(C)(C)OC(N)=O
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccn1
Temperature: 100 °C
Yield: 75.7 %

Procedure:
A solution of Example A1 (1.5 g, 5.96 mmol) in dioxane (50 mL) was sparged with Ar, treated with tert-butyl carbamate (1.536 g, 13.11 mmol), Cs2CO3 (3.88 g, 11.92 mmol) and DPPF (0.420 g, 0.775 mmol), sparged with Ar, treated with Pd2(dba)3 (0.382 g, 0.417 mmol), sparged again with Ar and heated at 100° C. overnight. The mixture was cooled to RT, diluted with EtOAc, the solids removed via filtration through diatomaceous earth and washed with EtOAc. The filtrate was concentrated to dryness, treated with MeCN, sonicated and the solid collected via filtration. The filtrate was concentrated to dryness, treated again with MeCN and the solid collected. The filtrate was again concentrated to dryness, purified via silica gel chromatography (EtOAc/Hex) and combined with the two above-isolated solids to afford tert-butyl (4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)carbamate (1.5 g, 76%). MS (ESI) m/z: 333.1 (M+H+).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:5]2=[N:4][CH:3]=1)=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[CH:9][CH:8]=3.[C:24]([Si:26]([CH3:29])([CH3:28])[CH3:27])#[CH:25].C(Cl)Cl.[Cl-].[NH4+]>C(N(CC)CC)C.[Cu](I)I>[CH3:27][Si:26]([C:24]#[C:25][C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:5]2=[N:4][CH:3]=1)=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[CH:9][CH:8]=3)([CH3:29])[CH3:28]
Reactant: C#C[Si](C)(C)C
Reactant: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(Br)cnc12
Agent: I[Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)C#Cc1cnc2c(NCCCO)nc3cc(C(F)(F)F)ccc3n12
Temperature: 90 °C
Yield: 75 %

Procedure:
To a suspension of 3-{[1-bromo-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-4-yl]amino}propan-1-ol as prepared in example 2 (100 mg, 0.26 mmol), ethynyltrimethylsilane (81 μL, 0.57 mmol) and copper iodide (5 mg, 0.026 mmol) in anhydrous triethylamine (3.5 mL) degassed under argon for 10 minutes was added Pd(dppf)Cl2.DCM (11 mg, 0.013 mmol). The mixture was stirred at 90° C. for 1 h45 and then allowed to cool to room temperature, poured onto a saturated aqueous solution of ammonium chloride and extracted three times with ethyl acetate/tetrahydrofuran (1:1). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC (silica gel, dichloromethane/methanol 20/1) to afford the title compound (80 mg, 75%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][C:6]1[NH:7][C:8](=[O:24])[C:9]2[C:14]([CH3:15])=[C:13]([CH2:16][C:17]([O:19]CCCC)=[O:18])[S:12][C:10]=2[N:11]=1.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][C:6]1[NH:7][C:8](=[O:24])[C:9]2[C:14]([CH3:15])=[C:13]([CH2:16][C:17]([OH:19])=[O:18])[S:12][C:10]=2[N:11]=1
Reactant: CCCCOC(=O)Cc1sc2nc(Cc3ccc(Cl)c(Cl)c3)[nH]c(=O)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(CC(=O)O)sc2nc(Cc3ccc(Cl)c(Cl)c3)[nH]c(=O)c12
Temperature: 70 °C

Procedure:
92 Milligrams of butyl 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-acetate as synthesized in Production Example 25 was suspended in 1 mL of water and to which 0.63 mL of 1N aqueous sodium hydroxide solution was added, followed by an hour's stirring at about 70° C. Then the reaction mixture was neutralized with 0.63 mL of 1N hydrochloric acid, and the resulting precipitate was recovered by filtration and dried to provide 87 mg (quantitative) of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([C:7]1[CH:8]=[CH:9][C:10]([NH:15][C:16](=[O:18])[CH3:17])=[C:11]([CH:14]=1)[CH2:12]Br)(=[O:6])[CH3:5]>C(Cl)(Cl)Cl>[C:4]([C:7]1[CH:8]=[CH:9][C:10]([NH:15][C:16](=[O:18])[CH3:17])=[C:11]([CH:14]=1)[CH2:12][N:2]([CH3:3])[CH3:1])(=[O:6])[CH3:5]
Reactant: CNC
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1CBr
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(C(C)=O)cc1CN(C)C
Reaction time: 0.5 h

Procedure:
8.1 gm of dimethylamine were added to 21 gm of 5-acetyl-2-acetylamino-benzyl bromide in 500 ml of chloroform, and the mixture was stirred for 30 minutes. As soon as the exothermic reaction began, the undissolved substance dissolved. Subsequently, the reaction solution was extracted three times with water and twice with 2 N hydrochloric acid. The hydrochloric acid phase was extracted with chloroform, made alkaline with 2 N ammonia and again extracted twice with chloroform. The organic phase was evaporated, the residue was purified column-chromatographically on silicagel with ethyl acetate, and the corresponding fractions were combined and evaporated to dryness, whereby 5-acetyl-2-acetylamino-N,N-dimethyl benzylamine was obtained in crystalline form, having a melting point of 68°-72° C.