Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH:16]1[CH:20]=[C:19](B(O)O)[CH:18]=[N:17]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(#N)C>Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:19]3[CH:20]=[N:16][NH:17][CH:18]=3)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: OB(O)c1cn[nH]c1
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCNc1ccc2ncc(-c3cn[nH]c3)n2n1
Temperature: 160 °C
Yield: 63.3 %

Procedure:
A mixture of 3-bromo-N-butylimidazo[1,2-b]pyridazin-6-amine (100 mg, 0.37 mmol), (1H-pyrazol-4-yl)boronic acid (90 mg, 0.45 mmol), dichloro-bis(triphenylphosphino) palladium (II) (15 mg, 0.021 mmol), potassium phosphate (80 mg, 0.56 mmol), acetonitrile (1.5 mL) and H2O (0.5 mL) was heated in a sealed conical vessel at 160° C. for 1000 s by microwave irradiation. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 mL). The combined organic layers were concentrated under reduced pressure to afford an oil that was purified by reverse phase HPLC to afford butyl-[3-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-amine (60 mg, 62%) as a white solid: 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.67 (s, 1H), 7.59 (d, J=9.6 Hz, 1H), 6.67 (d, J=9.6 Hz, 1H), 3.44 (t, J=7.1 Hz, 1H), 1.70-1.80 (m, 1H), 1.46-1.59 (m, 1H), 1.03 (t, J=7.3 Hz, 1H); LCMS (ESI) m/e 257.3 [(M+H)+, calcd for C13H17N6 257.1].
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:45][CH2:46][CH2:47][N:48]1[C:52](=[O:53])/[C:51](=[CH:54]/[C:55]2[CH:60]=[CH:59][C:58]([O:61][CH2:62][CH3:63])=[CH:57][CH:56]=2)/[S:50][C:49]1=[O:64]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:45][CH2:46][CH2:47][N:48]2[C:52](=[O:53])/[C:51](=[CH:54]/[C:55]3[CH:60]=[CH:59][C:58]([O:61][CH2:62][CH3:63])=[CH:57][CH:56]=3)/[S:50][C:49]2=[O:64])=[O:9])=[CH:10][CH:11]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(/C=C2\SC(=O)N(CCNC(=O)c3ccc(C#N)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a solution of 4-cyanobenzoic acid (46 mg, 0.31 mmol) in 3 mL of DMF was added DIPEA (131 μL, 0.75 mmol) followed by HBTU (114 mg, 0.30 mmol). After being stirred at room temperature for 1 h, compound 76 (101 mg, 0.25 mmol) was added and then the reaction mixture was stirred at room temperature overnight. The reaction solution was diluted with 50 mL of ethyl acetate and washed with water (30 mL×5), collected the organic layer, dried over Na2SO4, filtered, concentrated and purified by silica column chromatography (15% ethyl acetate in hexanes) to afford 97 mg (92.1%) of the title compound 25d as a light-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH2:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.Cl[CH2:22][C:23]([CH2:25]Cl)=O.C(=O)([O-])[OH:28].[Na+].[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:25]=[C:23]([CH2:22][OH:28])[N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Reactant: O=C([O-])O
Reactant: O=C(CCl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: OCc1cn2c(n1)CN=C(c1ccccc1F)c1cc(Cl)ccc1-2
Yield: 47.6 %

Procedure:
A suspension of 20.0 g of 7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-ylamine and 9.72 g of 1,3-dichloroacetone in 300 ml of dioxan was treated with 5.84 g of sodium hydrogen carbonate and heated at reflux for 6 h. Then, 160 ml of 1N aqueous sodium hydroxide solution were added dropwise and the mixture was boiled for a further hour. The reaction mixture was concentrated in a vacuum to a large extent, treated with water and extracted three times with equal volumes of dichloromethane. The combined organic phases were dried over magnesium sulphate, concentrated in a vacuum and chromatographed over 1 kg of silica gel. With dichloromethane containing 5% methanol there were obtained 11.3 g of the desired product which was recrystallized from ethyl acetate/diisopropyl ether. There were thus obtained 10.5 g (44%) of 8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 199-201° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:16][CH2:15][N:14]3[CH2:17][CH2:18][CH2:19][C@@H:13]3[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[Na+].[Na+].[F:26][C:27]([F:39])([F:38])[C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1.C(OCC)(=O)C>CN(C)C=O.ClCCl>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([N:11]2[CH2:16][CH2:15][N:14]3[CH2:17][CH2:18][CH2:19][C@@H:13]3[CH2:12]2)=[O:10])=[CH:3][C:2]=1[NH:1][S:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([F:26])([F:38])[F:39])[CH:29]=1)(=[O:36])=[O:35]
Reactant: Nc1cc(C(=O)N2CCN3CCC[C@@H]3C2)ccc1F
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)c(NS(=O)(=O)c2cccc(C(F)(F)F)c2)c1)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To (R)-(3-amino-4-fluorophenyl)(hexahydropyrrolo[1,2-α]pyrazin-2(1H)-yl)methanone (79 mg, 0.3 mmol) and sodium carbonate (64 mg, 0.6 mmol) in N,N-dimethylformamide (1 mL) was added 3-(trifluoromethyl)benzene-1-sulfonyl chloride (88 mg, 0.36 mmol) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 18 hours. Then ethyl acetate was added, and the mixture was washed with water (2×10 mL). The organic phase was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (methanol/dichloromethane=1:15) to give the titled compound: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.25 (m, 1H), 1.60-2.20 (m, 6H), 2.70-3.10 (m, 5H), 4.35-4.55 (m, 1H), 7.22 (m, 3H), 7.82 (m, 1H), 8.00 (m, 3H); MS (ESI) m/z 472 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].C(O[C:12](=[O:15])[NH:13][OH:14])(C)(C)C.Br[C:17]([CH3:23])([CH3:22])[C:18]([O:20][CH3:21])=[O:19]>CS(C)=O>[C:2]([N:13]([OH:14])[C:12]([C:17]([CH3:23])([CH3:22])[C:18]([O:20][CH3:21])=[O:19])=[O:15])([CH3:5])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)NO
Reactant: COC(=O)C(C)(C)Br
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C(C)(C)C(=O)N(O)C(C)(C)C
Temperature: 0 °C
Yield: 141.4 %

Procedure:
To a solution of potassium tert-butoxide (2.78 g) in dry DMSO (40 mL), tert-butyl-N-hydroxycarbamate (3.00 g) was added. After 5 minutes methyl 2-bromoisobutyrate (2.97 g) in DMSO (50 mL) was added dropwise, maintaining the temperature below 30° C. After 0.5 hrs at room temperature the reaction was poured into ice/water (120 mL) and extracted three times with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4 and the solvent evaporated to dryness to give methyl 2-(tert-butyl-N-hydroxycarbamoyl)isobutyrate (5.04 g, 96%) which was used without purification in the next step. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 9.53 (1H, s), 3.66 (3H, s), 1.40 (9H, s), 1.33 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[C:18]([C:21]1[CH:26]=[CH:25][N+:24]([O-:27])=[CH:23][CH:22]=1)([OH:20])=O.[OH:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[OH:28][CH:29]1[CH2:30][CH2:31][N:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:21]5[CH:26]=[CH:25][N+:24]([O-:27])=[CH:23][CH:22]=5)=[O:20])=[CH:13][CH:12]=3)[N:6]=[CH:5]4)=[O:40])=[CH:37][CH:36]=2)[CH2:33][CH2:34]1
Reactant: O=C(O)c1cc[n+]([O-])cc1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Product: O=C(Nc1ccc(-n2ncc3cc(NC(=O)c4ccc(N5CCC(O)CC5)cc4)ccc32)cc1)c1cc[n+]([O-])cc1

Procedure:
Compound 999 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole, 4-carboxypyridine 1-oxide, and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C31H28N6O4: 549.12; found: 549.08.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:8]([CH2:9][C:10](=O)[C:11]2=[CH:25]O)[CH2:7]1)=[O:5])[CH3:2].C(O)(=O)C.O.[NH2:33][NH2:34].C([O-])(O)=O.[Na+]>C(O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:8]([CH2:9][C:10]3[NH:33][N:34]=[CH:25][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC2CC(=O)C(=CO)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1CC2Cc3[nH]ncc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1

Procedure:
To a solution of 9-(4-chloro-benzenesulfonyl)-6-hydroxymethylene-7-oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester (7) (2.48 g, 5.99 mmol) in ethanol (10 mL) was added glacial acetic acid (0.2 mL) followed by hydrazine monohydrate (2.9 mL, 59.9 mmol). The reaction mixture was stirred at room temperature for 1 h after which saturated NaHCO3 (10 mL) was added. The resulting solution was extracted with EtOAc (3×20 mL); the organic extracts were combined, dried (Na2SO4), filtered, concentrated and purified by silica gel column chromatography (eluant hexane/EtOAc, 9/1 to 1/1) and preparative HPLC to give 12-(4-chloro-benzenesulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene-10-carboxylic acid ethyl ester (8) as a white solid. Retention time (min)=1.739, method [1], MS (ESI) 410.1 (M+H); 1H NMR (CDCl3) δ 7.66 (d, J=8.2 Hz, 2H), 7.51 (s, 1H), 7.38 (d, J=8.2 Hz, 2H), 5.37 (bs, 1H), 4.61-4.55 (m, 1H), 4.09 (q, J=7.1 Hz, 2H), 3.04 (dd, J=17.6, 7.1 Hz, 1H), 2.67 (d, J=17.6 Hz, 1H), 2.48-2.31 (m, 1H), 2.11-1.91 (m, 4H), 1.20 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:13][C:12]([SH:14])=[N:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:18]1[C:19]([C:24]#[N:25])=[N:20][CH:21]=[CH:22][N:23]=1>CN(C=O)C.C1C=CC=CC=1>[CH2:1]([S:8][C:9]1[S:13][C:12]([S:14][C:18]2[C:19]([C:24]#[N:25])=[N:20][CH:21]=[CH:22][N:23]=2)=[N:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Sc1nnc(SCc2ccccc2)s1
Reactant: N#Cc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: N#Cc1nccnc1Sc1nnc(SCc2ccccc2)s1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(benzylthio)-1,3,4-thiadiazole-2-thiol (240 mg, 1.00 mmol) in DMF and benzene (4 ml, 1/1) was added NaH (60% dispersion in mineral oil, 44 mg, 1.10 mmol) slowly at 0° C. under a nitrogen atmosphere. The resulting suspension was stirred at 0° C. for 15 minutes and then to the mixture was added 3-chloropyrazine-2-carbonitrile (140 mg, 1.00 mmol). The reaction was stirred at room temperature for 2 hr. The reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water, brine and dried over MgSO4. Removal of the solvent gave the crude product which was purified by chromatography to give the title compound as off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.Cl.[Cl:13][C:14]1[CH:30]=[CH:29][C:17]([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][SH:28])[CH2:21][CH2:20]2)=[CH:16][CH:15]=1.CCl>C(N(CC)CC)C>[OH2:10].[ClH:1].[ClH:13].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[SH:28][CH2:27][CH2:26][CH2:25][N:22]2[CH2:23][CH2:24][N:19]([CH2:18][C:17]3[CH:16]=[CH:15][C:14]([Cl:13])=[CH:30][CH:29]=3)[CH2:20][CH2:21]2)[OH:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: CCl
Agent: Cl
Solvent: CCN(CC)CC
Product: O
Product: OC(Nc1ccc(Cl)cc1)=[SH]CCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 42.4 %

Procedure:
The procedure described in Example 2 was followed, using 1.5 g of 4-chlorophenyl isocyanate, 3.5 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 1.2 g of triethylamine and 50 ml of methyl chloride, to give 1.1 g (21% of theory) of N-(4-chlorophenyl)-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride monohydrate as an off-white crystalline solid, M.p. 243°-245° C.
Reaction SMILES: [C-]#[N:2].[Na+].[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH:12]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:14]S([O-])(=O)=O.O>CN(C)C=O>[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH:12]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][C:14]#[N:2]
Reactant: [C-]#N
Reactant: CCCCC(CCS(=O)(=O)[O-])c1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(CC#N)c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a suspension of 11.3 g (0.23 mole) of sodium cyanide in 100 ml of dry dimethyl formamide (DMF) is added dropwise a solution of 50 g (0.154 mole) of 2-(2,4-dichlorophenyl)-hexylmethane sulfonate in 50 ml of DMF. The reaction mixture is stirred at 70° overnight. It is then poured into 500 ml of water and extracted with ether. The combined ether extracts are washed with water, then saturated saline solution and finally dried over magnesium sulfate. Solvent is evaporated under reduced pressure to give 37 g of crude product which is further purified by vacuum distillation (107.5°-110°/0.05 mm) to give 33.9 g (86%) of expected product.
Reaction SMILES: C(O[C:9]1[CH:14]=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:12]([F:26])=[CH:11][C:10]=1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)C1C=CC=CC=1.[H][H].C(O)(=[O:38])C>[Pd]>[F:26][C:12]1[CH:11]=[C:10]([C:27]2[C:32]([OH:38])=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH:9]=[CH:14][C:13]=1[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:16])=[O:17]
Reactant: [H][H]
Reactant: CC(=O)O
Reactant: COc1ccc(S(=O)(=O)c2cc(OCc3ccccc3)c(-c3cccc(F)c3)cc2F)cc1
Agent: [Pd]
Product: COc1ccc(S(=O)(=O)c2ccc(-c3cc(F)ccc3O)cc2F)cc1

Procedure:
A suspension of the product of step (ii) (838 mg) in acetic acid (30 ml) and 10% Pd/C (200 mg) was stirred under 2 bar pressure of hydrogen for 30 min. The catalyst was removed by filtration and the filtrate was evaporated to give the subtitle compound, yield 630 mg.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:5]2[CH2:11][NH:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[ClH:19].[CH2:20]([N:22]([CH2:25][CH2:26][Cl:27])[CH2:23][CH3:24])[CH3:21]>>[ClH:27].[ClH:19].[ClH:27].[NH2:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:5]2[CH2:11][N:10]([CH2:21][CH2:20][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:9][CH2:8][C:6]=2[N:7]=1.[ClH:27].[ClH:27].[ClH:27].[NH2:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:5]2[CH:11]([CH2:21][CH2:20][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[NH:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CCN(CC)CCCl
Reactant: Nc1nc2c(c(-c3ccc(F)cc3)n1)CNCC2
Agent: Cl
Product: CCN(CC)CCC1NCCc2nc(N)nc(-c3ccc(F)cc3)c21
Product: CCN(CC)CCN1CCc2nc(N)nc(-c3ccc(F)cc3)c2C1
Yield: 74.1 %

Procedure:
The title compound was prepared as described in Example 17 starting with 2-amino-4-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (2.0 g, 8.2 mmol) and diethylaminoethylchloride hydrochloride (2.8 g, 16.4 mmol) to give 1.1 g (39%) of 2-amino-5-(2- diethylaminoethyl)-4-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine trihydrochloride. m.p. 234°-236° C. MS: 343(MH+).
Reaction SMILES: Cl.[OH:2][CH:3]([C:6]([CH3:20])([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[CH3:19])=[CH:10][CH:9]=1)Cl)[C:4]#[N:5].N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>>[C:27]([O:2][C:3](=[C:6]([CH3:20])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[CH3:19])=[CH:10][CH:9]=1)[C:4]#[N:5])(=[O:29])[CH3:28]
Reactant: Cc1ccsc1-c1ccc(C(C)(Cl)C(O)C#N)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(=O)OC(C#N)=C(C)c1ccc(-c2sccc2C)cc1
Yield: 92 %

Procedure:
A 30-ml portion of the toluene solution containing 3.7 g (0.0145 mole) of 3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]glycidonitrile obtained in (1) was saturated with dried hydrogen chloride and stirred for a further one hour so that 2-hydroxy-3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]-3-chloropropionitrile may be formed. To the reaction mixture, which had been freed from the remaining hydrogen chloride by introducing dried nitrogen, was added 1.43 g (0.0181 mole) of pyridine and 1.70 g (0.0167 mole) of acetic anhydride, followed by adding 2.1 g (0.0207 mole) of triethylamine. After refluxing for 15 hours, the reaction mixture was washed with diluted hydrochloric acid, dried over anhydrous sodium sulfate, and freed from the solvent by distillation under reduced pressure to obtain 4.2 g (92% yield) of oily 2-acetoxy-3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]acrylonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:28]=[N:27][NH:26][C:5]2=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=[C:15]([Cl:17])[CH:16]=1)[O:8][C:7]2=[O:25].[CH:29]([NH2:32])([CH3:31])[CH3:30]>O1CCCC1>[CH:29]([NH:32][C:7]([C:6]1[C:11]([NH:10][C:9]([C:12]2[N:13]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=[C:15]([Cl:17])[CH:16]=2)=[O:8])=[C:2]([Cl:1])[CH:3]=[C:4]2[C:5]=1[NH:26][N:27]=[CH:28]2)=[O:25])([CH3:31])[CH3:30]
Reactant: O=c1oc(-c2cc(Cl)nn2-c2ncccc2Cl)nc2c(Cl)cc3cn[nH]c3c12
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1c(NC(=O)c2cc(Cl)nn2-c2ncccc2Cl)c(Cl)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.3 %

Procedure:
To a suspension of 210 mg (0.40 mmol) of the above 5-chloro-7-[5-chloro-2-(3-chloro-pyridin-2-yl)-2H-pyrazol-3-yl]-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 4.2 mL of tetrahydrofuran is added 110 μl (1.3 mmol) of isopropylamine. The reaction mixture is stirred for 4 hours at ambient temperature and then concentrated in vacuo. The residue is Purification of the residue by reverse-phase chromatography affords 111 mg (52%) of the product as a white solid; LC/MS:514/516 (M+Na)+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:16][C:17]([CH3:22])([CH3:21])[C:18](O)=[O:19].[C:23]1([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1C=CC=CC=1>[CH3:21][C:17]1([CH3:22])[S:16][CH:11]([C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=2)[N:33]([CH2:32][CH2:31][CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]1=[O:19]
Reactant: NCCCCc1ccccc1
Reactant: CC(C)(S)C(=O)O
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Solvent: c1ccccc1
Product: CC1(C)SC(c2cccc(Oc3ccccc3)c2)N(CCCCc2ccccc2)C1=O

Procedure:
Using the procedures of Example 5, the title compound was prepared as a light yellow viscous oil (8.4 g, 65%) from 5.9 g (0.030 mole) of 3-phenoxybenzaldehyde (Fluka), 3.6 g (0.030 mole) of 2-mercapto-2-methylpropionic acid, and 4.6 g (0.030 mole) of 4-phenylbutylamine after refluxing in 250 ml of benzene overnight.
Reaction SMILES: [K].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[C:13]([O:19][CH2:20]Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:20][O:19][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11])=[CH:7][CH:8]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOC(=O)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.2 %

Procedure:
The potassium salt of 4-hydroxyphenylacetic acid (9.5 g. 0.05 mL) was suspended in dimethylformamide (25 mL). Chloromethyl pivalate (7.53 g, 0.05 mol) was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate (100 mL) . The ethyl acetate layer was washed, first with aqueous 5% NaHCO3 (100 mL) and then twice with water, then was dried over anhydrous MgSO4, filtered and evaporated to yield pivalyloxymethyl 4-hydroxyphenylacetate, melting at 159°-161° C. (yield 70.2%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:12]([OH:16])(=[O:15])[CH:13]=O.[CH2:17]([NH:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:18][NH:19][CH2:20][C:21]([OH:23])=[O:22].[OH-].[Na+]>CO.O>[C:26]([CH2:25][N:24]([CH2:13][C:12]([OH:16])=[O:15])[CH2:17][CH2:18][NH:19][CH:20]([C:9]1[CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=[CH:7][C:8]=1[OH:11])[C:21]([OH:23])=[O:22])([OH:28])=[O:27]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=CC(=O)O
Reactant: O=C(O)CNCCNCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1ccc(O)c(C(NCCN(CC(=O)O)CC(=O)O)C(=O)O)c1
Reaction time: 2 h
Yield: 37 %

Procedure:
Deionized water (10.3 g), 98% 4-acetamidophenol (15.1 g 0.1 mole), 50% aqueous glyoxylic acid (14.8 g, 0.1 mole), and methanol (50.5 g) were added to a beaker and mixed using a magnetic stirrer bar. Unsymmetrical ethylenediaminediacetic acid (19.5 g), prepared by the procedure of Example A, was added and the mix cooled in an ice-water bath. The pH of the mix was adjusted, while stirring, to approximately 8.0 with 50% sodium hydroxide solution. The temperature of the mix was maintained at less than 20° C. during the caustic addition. The ice-water bath was removed and the mix adjusted to pH 8.7 and stirred at 25°-32° C. for approximately 2 hours. The mix was transferred to a round-bottom reaction flask equipped with a water-cooled reflux condenser, magnetic stirrer bar, thermometer, and a heating mantle. The mix was heated, with stirring, at 70° C. for 8 hours and then cooled and filtered using a medium glass frit funnel and vacuum. The solids were allowed to dry by exposure to air for 7 hours and then placed in a vacuum oven and dried at 55°-60° C. for several hours. Approximately 29.6 g of solids were collected. The material was then agitated with approximately 300 g of acetone and filtered using a medium glass frit funnel and house vacuum. The solids were washed once again with an additional 300 g of acetone, air dried and then placed in a vacuum oven for one hour at 55°-60° C. Approximately 26.7 g of 2-[(2-{[bis(carboxymethyl)]-amino}ethyl)amino]-2-(5-acetamido-2-hydroxyphenyl)ethanoic acid, sodium salt were collected. These solids and 180 g of deionized water were placed in a beaker and stirred with a magnetic stirrer bar. The pH was adjusted to 2.2 with concentrated hydrochloric acid at which point the acid form of the product began to precipitate from solution. The product was collected by filtration and washed with approximately 150 g of deionized water. The product, 2-[(2-{[bis(carboxymethyl)]amino}ethyl)amino]-2-(5-acetamido-2-hydroxyphenyl)ethanoic acid was dried in a vacuum oven at 55°-60° C. for several hours. Approximately 14.2 g of product were obtained. Proton NMR verified the structure of the product. (See Table I.)