Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.O[CH2:53][CH2:54][C:55]([CH3:61])([CH3:60])[C:56]([O:58][CH3:59])=[O:57].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:53][CH2:54][C:55]([CH3:61])([CH3:60])[C:56]([O:58][CH3:59])=[O:57])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Reactant: COC(=O)C(C)(C)CCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCC(C)(C)C(=O)OC)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.1 M) was added methyl 4-hydroxy-2,2-dimethylbutanoate (appendage 5) (2 eq.) and cesium carbonate (2 eq.). The reaction was heated to 80° C. and stirred for 18 h. After cooling to rt, the reaction was diluted with ether. The organic extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 20% EtOAc in toluene) to afford the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH3:11][S:12][CH2:13][CH2:14][CH2:15]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:15][CH2:14][CH2:13][S:12][CH3:11])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CSCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CSCCCOc1cc(C)c(Br)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (4.02 g, 20.0 mmol), 3-(methylthio)-1-propanol (2.12 g, 20.0 mmol) and tributylphosphine (7.97 mL, 32.0 mmol) in toluene (320 mL) was added 1,1′-(azodicarbonyl)dipiperidine (8.07 g, 32.0 mmol), and the mixture was stirred at room temperature for 18 hr under nitrogen atmosphere. Hexane (160 mL) was added to the reaction mixture, the insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-25:75) to give the title compound (5.03 g, yield 87%) as a pale-yellow oil.
Reaction SMILES: [S:1]([Cl:3])Cl.[CH3:4][NH:5][C:6](=[O:16])[O:7][CH2:8][CH:9]([CH2:14][CH3:15])[CH2:10][CH2:11][CH2:12][CH3:13].C(N(CC)CC)C>C(Cl)Cl>[Cl:3][S:1][N:5]([CH3:4])[C:6](=[O:16])[O:7][CH2:8][CH:9]([CH2:14][CH3:15])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(CC)COC(=O)NC
Reactant: ClSCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(CC)COC(=O)N(C)SCl
Temperature: 5 °C
Reaction time: 2 h
Yield: 103.8 %

Procedure:
To a solution of 62 g (0.6 mole) of sulfur dichloride in 200 ml of methylene chloride cooled to 0° C. under a nitrogen atmosphere was added a solution of 75 g (0.4 mole) of 2-ethylhexyl N-methylcarbamate and 44.5 g (0.44 mole) of triethylamine in 100 ml of methylene chloride at -10° to 3° C. The addition took 2 hr. After stirring for 1 hr at 5° C., the mixture was filtered under a positive nitrogen atmosphere, and the filtrate was concentrated. The product was extracted into 200 ml of hexanes and the solid triethylamine hydrochloride was filtered. The filtrate was concentrated to give 105.4 g of 2-ethylhexyl N-chlorothio-N-methylcarbamate.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:44])[CH2:29][CH2:30][NH:31][C:32]([C:34]1[N:35]=[C:36]2[CH:41]=[CH:40][C:39](Cl)=[N:38][N:37]2[CH:43]=1)=[O:33])[CH3:26].C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH2:25]([O:27][C:28](=[O:44])[CH2:29][CH2:30][NH:31][C:32]([C:34]1[N:35]=[C:36]2[CH:41]=[CH:40][C:39]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)=[N:38][N:37]2[CH:43]=1)=[O:33])[CH3:26]
Reactant: CCOC(=O)CCNC(=O)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCNC(=O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 95 °C
Reaction time: 24 h
Yield: 29.7 %

Procedure:
0.649 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 0.594 g of N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl)-β-alanine ethyl ester were dissolved in 7 ml of 1-methyl-2-pyrrolidone; 0.345 ml of N-ethyldiisopropylamine was added, followed by stirring in an oil bath (90-100° C.) for 24 hours. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (370:30:4). The desired fraction was collected and recrystallized from ethyl ether to yield 0.347 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5](Cl)=[C:4]2[CH:9]=[N:10][CH:11]=[CH:12][C:3]=12.[CH3:13][C@H:14]1[CH2:19][NH:18][CH2:17][CH2:16][NH:15]1>CN1C(=O)CCC1.O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:18]2[CH2:17][CH2:16][NH:15][C@@H:14]([CH3:13])[CH2:19]2)=[C:4]2[CH:9]=[N:10][CH:11]=[CH:12][C:3]=12
Reactant: Clc1nnc(Cl)c2cnccc12
Reactant: C[C@H]1CNCCN1
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@H]1CN(c2nnc(Cl)c3ccncc23)CCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1,4-dichloropyrido[3,4-d]pyridazine 3 (0.500 g, 2.50 mmol) in NMP (2.5 ml) was added (S)-2-methylpiperazine (0.300 g, 3.00 mmol). The reaction was stirred at 25° C. for 2 h. After one hour reaction contents were diluted with water (20×) and extracted with 10% MeOH in CH2Cl2 (3×25 mL). The combined organics were dried with Na2SO4 and concentrated in vacuo. Silica gel chromatography (gradient elution 0 to 5% MeOH in CH2Cl2) afforded (S)-1-chloro-4-(3-methylpiperazin-1-yl)pyrido[3,4-d]pyridazine 4 plus 10-15% substitution at the 4-position. 1H NMR (CDCl3) δ 9.48 (s, 1H), 9.03 (d, J=5.5 Hz, 1H), 7.94 (d, J=5.5 Hz, 1H) 3.96 (m, 2H), 3.11-3.88 (m, 5H), 2.93 (dd, J=12.8, 10.4, 1H). MS (calc'd) 263.1 (M+H, found) 264.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[C:13]3[N:14]([C:17]4[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=4)[N:15]=[CH:16][C:12]=3[CH2:11][CH2:10][C:8]=2[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN(C=O)C>[N:33]1([C:21]([C:20]2[CH:19]=[CH:18][C:17]([N:14]3[C:13]4[C:7]5[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=5[CH2:10][CH2:11][C:12]=4[CH:16]=[N:15]3)=[CH:25][CH:24]=2)=[O:23])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: CC(=O)Nc1nc2c(s1)-c1c(cnn1-c1ccc(C(=O)O)cc1)CC2
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2c(s1)-c1c(cnn1-c1ccc(C(=O)N3CCOCC3)cc1)CC2
Reaction time: 0.25 h

Procedure:
A solution of 3.5 mg (0.01 mmol) 4-(7-acetylamino-4,5-dihydro-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-1-yl)-benzoic acid (prepared analogously to Example 1) in 0.5 ml DMF is combined with 4 μL (0.03 mmol) triethylamine and 4 mg (0.01 mmol) O-pentafluorophenyl-1,1,3,3-tetramethyluronium hexafluorophosphate (PFTU) and stirred for 15 minutes. A solution of 1 mg (0.01 mmol) morpholine in 0.5 ml DMF is added to this mixture and it is shaken for 12 hours at ambient temperature. Then 3 mg polyamine resin HL (0.01 mmol, 200-400 mesh) are added and the mixture is shaken for a further 8 hours. The resin is filtered off and the filtrate is evaporated to dryness in vacuo.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([C:14]2[N:15]=[C:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[S:17][CH:18]=2)[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10].O.[CH3:31]N(C)C=O>>[OH:3][C:4]1[CH:5]=[C:6]([C:14]2[N:15]=[C:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[S:17][CH:18]=2)[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[O:10][CH3:31]
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)Nc2nc(-c3cc(O)c(O)c([N+](=O)[O-])c3)cs2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1c(O)cc(-c2csc(NS(=O)(=O)c3ccc(C)cc3)n2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 mg of sodium hydride (60%) were added to a solution of 0.5 g of N-[4-(3,4-dihydroxy-5-nitro-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide in 5 ml of dimethylformamide. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The residue was chromatographed on 60 g of Kieselgel 60 with methylene chloride/acetone/formic acid (90:10:2.5) as the eluent. The product-containing fractions were concentrated and, after boiling with 20 ml of diethyl ether, yielded 0.17 g of N-[4-(3-hydroxy-4-methoxy-5-nitro-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide as orange colored crystals.
Reaction SMILES: BrC1N=C(C#C[Si](C)(C)C)C(N)=NC=1.[CH3:15][C:16]1[CH:17]=CC(S(O)(=O)=O)=C[CH:21]=1.[Br:26][C:27]1[N:28]=[C:29]([C:44]#[C:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:30]([N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:34](=[O:36])[O-:35])=[N:31][CH:32]=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C>CCOC(C)=O.CN(C1C=CN=CC=1)C>[C:40]([O:39][C:37]([N:33]([C:30]1[C:29]([C:44]#[C:45][Si:46]([CH3:47])([CH3:49])[CH3:48])=[N:28][C:27]([Br:26])=[CH:32][N:31]=1)[C:34](=[O:35])[O:36][C:16]([CH3:17])([CH3:21])[CH3:15])=[O:38])([CH3:42])([CH3:43])[CH3:41]
Reactant: CC(C)(C)OC(=O)N(C(=O)[O-])c1ncc(Br)nc1C#C[Si](C)(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1C#C[Si](C)(C)C

Procedure:
A solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (Compound C-2) PTSA salt 3 (2350 g, 5.31 mol) in EtOAc (11.5 L) is stirred with a 20% w/w aq. solution of KHCO3 (4.5 kg, 1.5 eq.) for at least 30 min. The layers are separated and the organic layer is concentrated then dissolved in EtOAc (7 L) and added to a reactor. DMAP (19.5 g, 0.16 mol) is added followed a solution of Boc2O (2436 g, 11.16 mol) in EtOAc (3 L) is added lowly. The reaction is stirred for at least 30 min to ensure complete reaction then activated charcoal (Darco G-60, 720 g) and Celite (720 g) are added and stirred for at least 2 h. The mixture is filtered washing the solid pad with EtOAc (2×1.8 L). The filtrate is concentrated to afford tert-butyl N-tert-butoxycarbonyl-N-[5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-yl]carbamate (Compound C-3) that is used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.B(O)(O)[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:3][CH:4]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Clc1ccc(Br)nc1
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: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(Cl)cn2)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Bromine (18.0 ml, 353.7 mmol) is slowly added to a soln. of 2-amino-5-chloropyridine (15.0 g, 116.7 mmol) in 47% aq. HBr (75.0 ml) at −10° C. An aq. soln. of NaNO2 (28.1 g, 407.3 mmol) is slowly added. The mixture is stirred for 1 h at −10 to −5° C., then for 1 h at 5° C. The mixture is neutralised with 5M aq. NaOH soln. maintaining the temperature below 25° C. The precipitate is filtered and recrystallized from pentane to give 2-bromo-5-chloropyridine. 2-Bromo-5-chloropyridine (5.0 g, 26.0 mmol), p-tolylboronic acid (4.0 g, 29.4 mmol) and tetrakis(triphenylphosphine)palladium (1.44 g, 1.2 mmol) are dissolved in toluene:EtOH 9:1 (1375 ml). A 2M aq. Na2CO3 soln. (62.5 ml) is added to the reaction mixture. The mixture is stirred at 90° C. for 24 h, cooled to rt and filtered over celite. The toluene layer is separated and washed with brine. The aq. layers are extracted with AcOEt. The combined organic extracts are dried over MgSO4 and filtered. The filtrate is evaporated to give a brown solid which is purified by FC (silica gel, eluent toluene) to give 5-chloro-2-p-tolyl-pyridine. (R)-3-Quinuclidinol (2.97 g, 23.4 mmol) is added to a suspension of NaH (0.96 g of a 60% dispersion in mineral oil, 22.8 mmol) in DMF (90 ml). The mixture is stirred for 1 h at rt. 5-Chloro-2-p-tolyl-pyridine (4.00 g, 19.6 mmol) is added and the mixture is heated for 135 h at 135° C. The reaction mixture is diluted with toluene and washed with 1M aq. NaOH soln. and brine. The aq. layers are re-extracted with toluene (3×). The combined organic extracts are dried over MgSO4 and filtered. The filtrate is evaporated to give a brown oil which is purified by FC (silica gel, eluents: AcOEt, then AcOEt/MeOH/NEt3 87:10:3) and recrystallized from CH3CN to give (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane; mp° C.: 110-112; [α]Drt=+21.2° (0.50, MeOH), M+H+ 295.2.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:35])[CH2:5][C@@H:6]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[CH2:36](Br)[CH:37]=[CH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:3][CH:4]([CH3:35])[CH2:5][C@@H:6]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[C:7]([CH2:36][CH:37]=[CH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: BrCC=Cc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(CC=Cc1ccccc1)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.9 %

Procedure:
0.048 g of 60% sodium hydride was added to a stirred solution of 0.45 g of 1,2-dibenzyl 1-tert-butyl 4-methyl-1,1,2-(R)-pentanetricarboxylate in 10 ml of dry dimethylformamide under a nitrogen atmosphere. The mixture was stirred for 0.75 hour at 0° and for a further 2.5 hours at room temperature. The mixture was again cooled to 0° before the addition of 0.236 g of cinnamyl bromide. After allowing the mixture to return slowly to room temperature, the solution was stirred at room temperature for 2 days. The mixture was poured into 5% aqueous citric acid solution and the product was extracted four times with diethyl ether. The combined ether extracts were washed with water and sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation and the residue was purified by flash chromatography on silica gel using hexane/ether (9:1) for the elution. There was obtained 0.542 g of 1,2-dibenzyl 1-tert.butyl 4-methyl-1-(3 -phenylprop-2-en-1-yl)-1,1,2-(R)-pentanetricarboxylate in the form of a colorless oil; MS: 571 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C@H:17]([OH:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[C:21]=1[NH2:27])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1.Cl>[OH:28][C@@H:17]([CH2:16][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:18][O:19][C:20]1[C:21]2[NH:27][C:30](=[O:32])[NH:26][C:22]=2[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cccc(OC[C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)c1N
Agent: Cl
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cccc(OC[C@@H](O)CN(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Reaction time: 14 h
Yield: 92.9 %

Procedure:
(S)-[3-(N,N-Dibenzylamino)-2-hydroxypropoxy]-2,3-diaminobenzene (4.4 g, 11.6 mmol) was suspended in a mixture of toluene (60 mL) and 2N HCl (100 mL) at ambient temperature with vigorous stirring. An excess of triphosgene (17.3 g, 58.3 mmol) was added, and the stirring continued for 14 hours. The biphasic mixture was cautiously quenched and neutralized with sodium bicarbonate, causing an off-white precipitate to form at the interface. The precipitate was filtered and dried in vacuo to yield 4.35 g (93%) of a pale solid that was used without further purification. TLC, NMR and MS all indicated high purity of the intermediate.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:8][OH:9].[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.[CH2:19](O)[CH3:20]>CN(C)C=O>[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:8]([CH2:10][C:11]2[CH:18]=[CH:17][C:19]([CH3:20])=[CH:13][CH:12]=2)[OH:9])=[CH:13][CH:12]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: CCO
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CN(O)Cc2ccc(C)cc2)cc1

Procedure:
The procedure of Example 1 is repeated using 10.6 g of sodium carbonate, 1.74 g of hydroxylamine hydrochloride and 9.25 g of p-methylbenzyl bromide in 50 ml of dimethylformamide. Trituration of the crude product with ethanol affords 3.3 g of the above-named hydroxylamine as a white solid, mp 107°-109° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(C=C2SC(=O)NC2=O)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(CC2SC(=O)NC2=O)cc(C(C)(C)C)c1O
Yield: 59.2 %

Procedure:
To 15.0 g (0.045 moles) of 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]} methylene-2,4-thiazolidinedione, in 375 ml of ethyl acetate, 3.0 g of 10% palladium on carbon was added. The mixture was heated at 80° C. in the presence of 50 psi (345 KPa) of hydrogen for 4.5 hours. An additional 3.0 g of 10% palladium on carbon was added and the mixture was again heated at 80° C. in the presence of 50 psi (345 KPa) of hydrogen for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated to afford a solid. The solid was recrystallized from toluene and dried at 60° C. to obtain 8.93 g (59% yield) of subtitled compound.
Reaction SMILES: [S:1]([NH2:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].N1C=CC=CC=1.[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>O1CCOCC1.O>[S:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:19]=2[Cl:18])=[CH:7][CH:8]=1)(=[O:10])(=[O:2])[NH2:11]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(NC(=O)c2ccc(Cl)cc2Cl)cc1
Reaction time: 2 h

Procedure:
10 g (60mmol) of sulfanilamide are suspended in 150 ml of dioxane and 4.6 g (60 mmol) of pyridine are added. 12.2 g (60 mmol) of 2,4-dichloro-benzoyl chloride are then added at 0° C., and stirring is continued for 2 hours at room temperature. The mixture is stirred in 200 ml of water, and the precipitate which separates out is filtered off with suction and dried;
Reaction SMILES: C([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]1[C:18]2=[N:19][NH:20][C:21](=[O:26])[C:22]3[CH:23]=[CH:24][CH:25]=[C:16]([C:17]=32)[NH:15][CH:14]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[NH:10]1[CH:11]=[CH:12][N:8]=[C:9]1[CH:13]1[C:18]2=[N:19][NH:20][C:21](=[O:26])[C:22]3[CH:23]=[CH:24][CH:25]=[C:16]([C:17]=32)[NH:15][CH:14]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1nccn1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1ncc[nH]1
Temperature: 40 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
A mixture of 9-(1-benzyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (200 mg, 0.48 mmol), 20% Pd(OH)2/C catalyst (100 mg) in methanol (15 mL) was purged with 1 atm hydrogen and stirred at 40° C. over overnight. Then the mixture solution was filtered and the filtrate was evaporated under reduced pressure. The residue was washed with methanol to obtain 9-(1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one as a light yellow solid (114 mg, yield 72%). 1H-NMR (400 MHz, DMSO-d6) δ: 4.41-4.43 (d, J=8.0 Hz, 1H), 4.98-5.00 (d, J=8.8 Hz, 1H), 6.68-6.73 (m, 1H), 6.86-6.97 (m, 1H), 7.12-7.14 (d, J=8.0 Hz, 1H), 7.20-7.37 (m, 7H), 7.54-7.58 (t, J=8.0 Hz, 1H), 11.77 (s, 1H), 12.19 (s, 1H); LC-MS (ESI) m/z: 330 (M+1)+.
Reaction SMILES: C(=O)([O-])O.[K+].Cl[CH2:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:9].[C-:19]#[N:20].[K+].Cl>O>[C:19]([CH2:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:9])#[N:20]
Reactant: [C-]#N
Reactant: O=C(O)CCCCCNC(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: N#CCC(=O)NCCCCCC(=O)O
Reaction time: 17 h

Procedure:
2.8 g (20 mMol) potassium hydrogen carbonate was added to 8.3 g (40 mMol) 6-(chloracetamido) hexanoic acid dissolved in 25 ml water. 3.2 g (48 mMol) potassium cyanide was then added to the clear solution which was cooled on ice. The reaction mixture was stirred for 17 hours and was then acidified with HCl (2 N). The residue after extraction was purified by chromatography (silica gel, solvent: ethyl acetate).