Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:12]([NH:23][C:24]([C:26]2[CH:27]=[N:28][CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:31]=2)=[O:25])[CH:11]=1)([O-])=O>C(Cl)(Cl)Cl.CO.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:12]([NH:23][C:24]([C:26]2[CH:27]=[N:28][CH:29]=[C:30]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:31]=2)=[O:25])[CH:11]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2[N+](=O)[O-])cc1NC(=O)c1cncc(-c2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2N)cc1NC(=O)c1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 83.6 %

Procedure:
To a solution mixture of tert-butyl 4-(2-nitrophenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate (0.28 g) in chloroform (3.0 mL) and methanol (2.0 mL), 10% palladium-carbon (0.13 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 5 hours and 40 minutes. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform/methanol] to obtain 0.22 g of tert-butyl 4-(2-aminophenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate as a light yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[C:9]([S:20][CH3:21])=[C:10]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:11]([O:13]CC)=[O:12]>O.C(O)C>[CH3:7][C:8]1[C:9]([S:20][CH3:21])=[C:10]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1ccc(C)c(C)c1SC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CSc1c(C(=O)O)ccc(C)c1C
Yield: 99.2 %

Procedure:
A solution of potassium carbonate (10.67 g) in water was added to a solution of ethyl 3,4-dimethyl-2-methylsulphenylbenzoate (21.19 g) in ethanol. The mixture was heated at reflux for 0.5 hours then partially evaporated. Water was added and the mixture was acidified to pH 1. The solid was filtered off and washed with water to give 3,4-dimethyl-2-methylsulphenylbenzoic acid (18.39 g) as a white solid, m.p. 117.8°-120.3° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:13]=C)[N:9]1[CH:15]=[CH:16][N:17]=[C:8]1[C:7]([NH:18][CH2:19][CH2:20][CH2:21][OH:22])=[N:6]2.C[N+]1([O-])CC[O:29]CC1.I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[OH:22][CH2:21][CH2:20][CH2:19][NH:18][C:7]1[C:8]2[N:9]([CH:15]=[CH:16][N:17]=2)[C:10]2[C:5]([N:6]=1)=[CH:4][C:3]([C:2]([F:1])([F:23])[F:24])=[C:12]([CH:13]=[O:29])[CH:11]=2
Reactant: C=Cc1cc2c(cc1C(F)(F)F)nc(NCCCO)c1nccn12
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1cc2c(cc1C(F)(F)F)nc(NCCCO)c1nccn12
Temperature: 30 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
A solution of 3-{[7-(trifluoromethyl)-8-vinylimidazo[1,2-a]quinoxalin-4-yl]amino}propan-1-ol (110 mg; 0.32 mmol; 1 eq), osmium tetroxide (2.5% in tert-butanol, 166 mg; 0.016 mmol; 0.05 eq), N-methylmorpholine oxide (76 mg; 0.654 mmol; 2 eq) in acetone (3 ml) and water (0.33 ml) is stirred at 30° C. during 3 days. A suspension of sodium periodate (280 mg; 1.31 mmol; 4 eq) in water (1.6 ml) is then added and the resulting reaction mixture is stirred at 30° C. during 16 h. Partition (aqueous sodium sulfite/ethyl acetate), extraction of the aqueous phase (ethyl acetate), reunion of the organic phases, drying (magnesium sulphate) and purification by prep CCM on silicagel (dichloromethane/methanol 95:5) affords the title product as an off-white powder (64 mg; 0.19 mmol; 59%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@H:12]([C:18](=[O:36])[N:19]1[C@H:24]([C:25](=[O:35])[NH:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:22][CH2:21][NH:20]1)[CH2:13][CH2:14][C:15](O)=[O:16].CN1CCOCC1.P(Cl)(Cl)(Cl)(Cl)Cl>C1COCC1>[CH2:27]([NH:26][C:25]([C@H:24]1[N:19]2[C:18](=[O:36])[C@@H:12]([N:3]3[C:4](=[O:11])[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:2]3=[O:1])[CH2:13][CH2:14][C:15](=[O:16])[N:20]2[CH2:21][CH2:22][CH2:23]1)=[O:35])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)CC[C@@H](C(=O)N1NCCC[C@H]1C(=O)NCCc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(NCCc1ccccc1)[C@@H]1CCCN2C(=O)CC[C@H](N3C(=O)c4ccccc4C3=O)C(=O)N12
Temperature: 0 °C
Reaction time: 3 h
Yield: 43.6 %

Procedure:
To a solution of (S)-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-5-oxo-5-((S)-6-phenethylcarbamoyl-tetrahydro-pyridazin-1-yl)-pentanoic acid (0.74 g, 1.5 mmol) and N-methylmorpholine (0.6 g, 6.0 mmol) in THF (20 mL) at 0° C., is added PCl5 (470 mg, 2.25 mmol) in one portion. After stirring at 0° C. for 3 hours, the reaction mixture is concentrated and purified by chromatography (CH2Cl2/MeOH:97/3) to yield (1S,9S)-9-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid phenethyl-amide (310 mg, 43.6%) as white solid. (NMR and MS data confirmed, U-3133-65).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].Br[CH2:39][C:40]([O:42]C(C)(C)C)=[O:41].[OH-].[Li+]>>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][CH2:39][C:40]([OH:42])=[O:41])[CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[O:4])(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Li+]
Agent: [OH-]
Product: CC(C)CN([C@H](CO)CCCNC(=O)[C@H](Cc1cccc2ccccc12)NCC(=O)O)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (product of example 8) using tert-butyl bromoacetate. The final product was hydrolysed using lithium hydroxide to obtain the acid in 74% yield.
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][CH2:26][S:27]([NH2:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=[C:6]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:9]2=[O:15])[CH:7]=1.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1B(O)O>>[O:15]=[C:9]1[NH:10][C:11](=[O:14])[CH:12]=[CH:13][N:8]1[C:6]1[CH:7]=[C:2]([C:34]2[S:33][CH:37]=[CH:36][CH:35]=2)[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][CH2:26][S:27]([NH2:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=1
Reactant: COc1c(Br)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CCS(N)(=O)=O
Reactant: OB(O)c1cccs1
Product: COc1c(-c2ccc3c(c2)CC=C3CCS(N)(=O)=O)cc(-n2ccc(=O)[nH]c2=O)cc1-c1cccs1
Yield: 32 %

Procedure:
The product from Example 63, Part A (26.5 mg, 0.051 mmol) was reacted with thiophen-2-yl boronic acid (8.3 mg, 0.065 mmol) as described in Example 63, Part B to give the title compound as an off-white solid (8.6 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ 11.47 (s, 1 H) 7.86 (d, J=7.72 Hz, 2 H) 7.55-7.78 (m, 5 H) 7.50 (t, J=6.25 Hz, 1 H) 7.38 (d, J=2.57 Hz, 1 H) 7.16-7.21 (m, 1 H) 6.58 (s, 1 H) 5.69 (d, J=7.72 Hz, 1 H) 4.19 (d, J=4.78 Hz, 2 H) 3.48 (s, 2 H) 3.30 (s, 3 H) 2.96 (s, 3 H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.C1C(=O)N([Cl:27])C(=O)C1>CC(O)=O>[Cl:27][C:10]1[C:11]2[C:2](=[O:1])[NH:3][CH2:4][CH2:5][C:6]=2[C:7]([C:16]([O:18][CH3:19])=[O:17])=[CH:8][C:9]=1[O:12][CH:13]([CH3:15])[CH3:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc(OC(C)C)cc2c1CCNC2=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC(C)C)c(Cl)c2c1CCNC2=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
To a solution of methyl 1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (Cpd E, 400 mg, 1.52 mmol) in AcOH (5 mL) was added NCS (416 mg, 3.04 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was concentrated under vacuum and the residue was diluted with H2O and NaHCO3 (sat., aq.). The aqueous layer was extracted with EtOAc and the organic layer purified by column chromatography (50% EtOAc/heptanes) to give the title compound (Cpd F, 180 mg, 40%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 1.40 (s, 3H) 1.42 (s, 3H) 3.27-3.36 (m, 2H) 3.37-3.47 (m, 2H) 3.88-3.95 (m, 3H) 4.62 (dt, J=12.07, 6.13 Hz, 1H) 6.06 (br. s., 1H) 7.61 (s, 1H); MS 298.0 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[O:9][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Oc1cc(F)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
To a solution of 3-bromo-5-fluorophenol (2.54 g, 0.013 mol) in DMF (12 mL) under a N2 atmosphere was added potassium carbonate (3.59 g, 0.026 mol) and the reaction was stirred for 20 min at RT. 2-Chloro-5-trifluoromethylpyridine (2.4 g, 0.013 mol) was added and the reaction mixture was refluxed at 110° C. overnight. Water was added and the mixture was extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by silica gel column chromatography (10% ethyl acetate in hexane) to give the title compound (4.28 g, 96%). 1H NMR (500 MHz, CDCl3): δ 8.45 (s, 1H), 7.96 (dd, J=2 Hz, J=8.5 Hz, 1H), 7.16-7.15 (m, 2H), 7.08 (d, J=8.5 Hz, 1H), 6.89-6.85 (m, 1H); m/z (337.9, M+ H+)
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][C:21](=[O:23])[CH3:22])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C:7]1=[CH:6][CH2:5][C:4]2=[O:24])[CH3:2].C>C1C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][C:21](=[O:23])[CH3:22])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:24])[CH3:2]
Reactant: CC[C@]12CCC3=C(CCc4cc(OC(C)=O)ccc43)C1=CCC2=O
Solvent: c1ccccc1
Product: CC[C@]12CCC3=C(CCc4cc(OC(C)=O)ccc43)[C@@H]1CCC2=O

Procedure:
Hydrogenate 13β-ethyl-3-acetoxygona-1,3,5(10),8,14-pentaen-17-one (1.8 g.) dissolved in benzene (25 ml.) at atmospheric pressure in the presence of 10% palladized charcoal (100 mg.). After 1.1 molar equivalents of hydrogen has been absorbed (ca. 12 hr.) filter off the catalyst, evaporate the filtrate under reduced pressure and recrystallize the residue from ethanol. Filter the red product through `Florisil` (60 g.) with benzene-petroleum (3:1), remove the solvent and recrystallize the product from ethanol to obtain the title product, m.p. 132.5°-134.5°; ultra-violet absorption peak at 277 mμ (ε 12,800).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][CH2:8][CH:9]([O:12][CH3:13])[O:10][CH3:11])=[CH:4][CH:3]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>ClCCl.N1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][CH:9]([O:10][CH3:11])[O:12][CH3:13])[S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])=[CH:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(CNCc1ccc(Br)cc1)OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(CN(Cc1ccc(Br)cc1)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.4 %

Procedure:
60.5 g (4-Bromo-benzyl)-(2,2-dimethoxy-ethyl)-amine (1, crude product) were dissolved in 270 ml of dichloromethane/pyridine (8:1). At 0° C. a solution of 76.0 g (386.4 mmol) p-toluenesulfonylchloride in 100 ml of dichloromethane was added and the solution was stirred at room temperature. After 3 h, the reaction mixture was washed twice with 2 N HCl and saturated sodium hydrogen carbonate-solution. The organic layer was dried over magnesium sulfate and evaporated. Final silica gel chromatography (heptane/ethylacetate 4:1) gave 59.9 g of the title compound. Rt=1.82 min (Method C). Detected mass: 396.1/398.1 (M−OMe−).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([N:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1)=[O:35]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: O=C(NCC1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: C[C@H](O)C(=O)N1CCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (pyrrolidin-3-ylmethyl)-amide (example A146) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].C(O[CH:17]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([F:21])([F:20])[F:19])C.Cl>O1CCCC1>[F:19][C:18]([F:20])([F:21])[CH:17]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(Nc1ccccc1)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(Nc1ccccc1)C(F)(F)F
Yield: 54.5 %

Procedure:
A solution of diethyl malonate (1.98 mL, 13.0 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise, over 20 min, into a dispersion of sodium hydride (60% in oil, 0.52 g, 13.0 mmol) in dry tetrahydrofuran (30 mL) at 0° C., after which compound 325 (2.6 g, 11.9 mmol) was added and the mixture was stirred vigorously at reflux for 16 h. The reaction mixture was cooled, acidified to pH 3 using a 1N HCl solution. The aqueous layer was extracted twice with EtOAc. The extracts were combined, dried over sodium sulfate and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent dichloromethane-hexane, 0:100 to 60:40) to afford title compound 326 (2.16 g, 6.48 mmol, 54% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm: 7.21-7.16 (m, 2H), 6.81-6.76 (m, 1H), 6.75-6.71 (m, 2H), 5.06 (d, J=10.4 Hz, 1H), 4.83-4.73 (m, 1H), 4.25 (q, J=7.2 Hz, 2H), 4.18-4.05 (m, 2H), 3.85 (d, J=4.4 Hz, 1H), 1.28 (t, J=7.2 Hz, 3H), 1.13 (t, J=7.2 Hz, 3H). LRMS (M+1) 334.1 (100%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]([CH3:27])[CH2:25][C:24](=[O:28])[NH:23][N:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:27][CH:26]1[C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:20][CH:19]=2)=[N:22][NH:23][C:24](=[O:28])[CH2:25]1
Reactant: CC1CC(=O)NN=C1c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CC(=O)NN=C1c1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.7 %

Procedure:
A solution of 4-[4-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (1 g, 2.5 mmol) in methylene chloride at RT was treated with trifluoroacetic acid (3 mL, 38.9 mmol) and stirred at RT for 3 h. TFA was evaporated at reduced pressure to obtain 5-methyl-6-[4-(piperidin-4-yloxy)-phenyl]-4,5-dihydro-2H-pyridazin-3-one (0.35 g, 47%), MS m/z 288 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=O.[OH-].[Na+].[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:2]=[CH:1][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(C=Cc1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
The photo-reactive group of the side chain was synthesized as follows. First, 10.2 g (0.075 mol) of 4-hydroxyacetophenone was dissolved into 0.7 w/v % aqueous solution of NaOH. Benzaldehyde (8 g (0.075 mol)) then was added and the resulting solution was stirred for 8 hours at a room temperature. Then, the solution was neutralized with 5N HCl to yield 4-hydroxychalcone at 50% yield as follows.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[N:15]=[CH:14][S:13][C:8]3=2)[N:3]=1.[Cl:16][S:17](O)(=[O:19])=[O:18]>>[Cl:16][S:17]([C:6]1[CH:5]=[C:4]2[C:9]([N:10]=[C:11]([OH:12])[C:2]([OH:1])=[N:3]2)=[C:8]2[S:13][CH:14]=[N:15][C:7]=12)(=[O:19])=[O:18]
Reactant: O=S(=O)(O)Cl
Reactant: Oc1nc2ccc3ncsc3c2nc1O
Product: O=S(=O)(Cl)c1cc2nc(O)c(O)nc2c2scnc12
Temperature: 25 °C
Yield: 47 %

Procedure:
7,8-Dihydroxythiazolo[5,4-f]quinoxaline (0.44 g, 2 mmol) was added portionwise to 2 ml of chlorosulfonic acid with stirring at room temperature. Then the mixture was stirred at 150° C. for 5 h, and left over night at room temperature. The solution was added dropwise to 50 g of crushed ice with stirring. The resulting solid was collected by filtration after 1 h and washed with ice-water and a small amount of ethanol and ether, affording 0.30 g (47%) of crude 4-chlorosulfonyl-7,8-dihydroxythiazolo[5,4-f]quinoxaline. The crude product was stirred with 25 ml of aqueous ammonium hydroxide (25%) for 20 min at room temperature and at 100° C. for 10 min. Nitrogen was bubbled through the hot solution for 5-10 min and after cooling to 0° C. the solution was acidified to pH 1 with 4M hydrochloric acid. The resulting prcipitate was isolated by filtration and dissolved in 150 ml of hot N,N-dimethylformamide. A solid impurity was removed from the hot solution by filtration, and after treatment with charcoal the solution was cooled and evaporated to dryness. The residue was taken up with 15 ml of hot 2N sodium hydroxide, the resulting solution was treated with charcoal, cooled to 0° C. and acidified with 4M hydrochloric acid. The precipitated solid was isolated by centrifugation and washed with water and ethanol to give 60 mg (21%) of the title compound, m.p.>400° C.; IR (KBr): 1710, 1690 cm-1 ; 1H-NMR (DMSO-d6): 7.28 (broad s, 2H, NH2), 7.90 (s, 1H, ArH), 9.53 (s, 1H, ArH), 12.17 (broad s, 1H, OH), 12.60 (broad s, 1H, OH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[CH:11]=[C:10](N3CCCC3)[CH:9]2[C:26]([O:28][CH3:29])=[O:27])=[CH:4][CH:3]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[CH2:11][C:10]([OH:33])=[C:9]2[C:26]([O:28][CH3:29])=[O:27])=[CH:4][CH:3]=1
Reactant: COC(=O)C1C(N2CCCC2)=CC2=C(C(=O)CC(C)(C)C2)C1c1ccc(F)cc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: COC(=O)C1=C(O)CC2=C(C(=O)CC(C)(C)C2)C1c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A suspension of 13.0 g (32.7 mmol) of the compound of Example XII in 1100 ml of a sat. solution of citric acid is stirred at 60° C. for 16 h. The mixture is allowed to cool and extracted with ethyl acetate (3×600 ml). The combined organic phases are washed with sat. NaCl solution and dried over Na2SO4, giving a yellow residue which is purified by flash filtration over 450 g silica gel 60 using EtOAc/cyclohexane 1:20 to 20:1.
Reaction SMILES: [OH:1][C:2]1[C:7]2=[N:8][C:9]([CH3:16])=[C:10]([CH2:13][CH2:14]O)[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>CN(C)C=O>[OH:1][C:2]1[C:7]2=[N:8][C:9]([CH3:16])=[C:10]([CH2:13][CH2:14][Cl:19])[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc2c(O)cccn2c(=O)c1CCO
Solvent: CN(C)C=O
Product: Cc1nc2c(O)cccn2c(=O)c1CCCl

Procedure:
According to the U.S. Pat. No. 5,688,799 (hereinafter referred to as the '799 patent), the compound of formula I is prepared by the reaction of 2-amino-3-hydroxypyridine with 2-acetylbutyrolactone in the presence of p-toluenesulfonic acid in xylene solvent at reflux temperature for overnight using a water separator to yield 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. The 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one is converted into its hydrochloride salt, followed by reaction with thionyl chloride in dimethylformamide to produce 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.
Reaction SMILES: Cl.[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:4]=1[C:5]#[N:6].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23]Cl.C(N(CC)CC)C>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23][N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][O:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:3]([F:2])[C:4]=2[C:5]#[N:6])[CH2:14][CH2:15]1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: N#Cc1c(F)cccc1OCC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: N#Cc1c(F)cccc1OCC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Yield: 73 %

Procedure:
A mixture of 2-fluoro-6-(piperidin-4-ylmethoxy)-benzonitrile hydrochloride (240 mg; 0.89 mmol) (Example 126, Step 3) was heated with 3,4-dichlorobenzyl chloride (0.15 mL; 2.0 mmol) and triethylamine (0.3 mL; 2.0 mmol) to 50° C. for 16 hours. Reaction was cooled and quenched with dilute HCl and mixture extracted with ethyl acetate (2×20 mL). Combined organics washed with water, saturated sodium bicarbonate, brine and dried over Na2SO4. Crude material was purified by chromatography using 0.5-2% methanol/DCM gradient to afford 2-[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethoxy]-6-fluoro-benzonitrile as a yellow oil. (280 mg; 73% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[N:13]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl.O>[NH:1]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)[NH2:13]
Reactant: Nc1ccc2c(c1)C(=O)NCC2
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc2c(c1)C(=O)NCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a suspension of 7-amino-3,4-dihydro-2H-isoquinolin-1-one (8.1 g, 50 mmol) in conc. HCl (100 mL) in an ice-H2O bath was added a solution of NaNO2 (3.45 g, 50 mmol) in H2O dropwise at such a rate that the reaction mixture never rose above 5° C. A solution of SnCl2.2H2O(22.5 g, 0.1 mol) in conc. HCl (150 mL) was added dropwise after 30 min. The resulting mixture was stirred for another 2 h at 0° C. The precipitate was collected by suction, washed with ether to afford 7-hydrazino-3,4-dihydro-2H-isoquinolin-1-one (8.3 g), which was used for the next reaction without further purification.