Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[F:22][C:23]([F:37])([F:36])[C:24]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:25]=1[CH:26]=O>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:26][C:25]1[CH:28]=[CH:29][C:30]([C:32]([F:35])([F:34])[F:33])=[CH:31][C:24]=1[C:23]([F:22])([F:36])[F:37]
Reactant: O=Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: O=C(C=Cc1ccc(C(F)(F)F)cc1C(F)(F)F)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and 2,4-bis(trifluoromethyl)benzaldehyde (108 ul, 0.633 mmol) similar to Example 6 as a yellow solid (27 mg, 8%). 1H NMR (CDCl3): 8.03 (dd, J=2.0, 15.5 Hz, 1H), 7.97 (s, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.86 (d, J=7.2 Hz, 1H), 7.50 (d, J=15.6 Hz, 1H), 7.35 (d, J=3.3 Hz, 1H), 7.18 (dd, J=3.3, 9.0 Hz, 1H), 6.95 (d, J=9.3 Hz, 1H), 4.47-4.35 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)=[CH:6][C:5]([C:19]([N:21]=[S:22]([CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])([CH2:24][CH2:25][CH2:26][CH2:27][C:28](=[O:31])[O:29][CH3:30])=[O:23])=[O:20])=[CH:4][N:3]=1.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([NH2:48])[CH:43]=1>CN(C1C=CN=CC=1)C.ClCCCl.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:19]([N:21]=[S:22]([CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:29][CH3:30])=[O:31])=[O:23])=[O:20])=[CH:6][C:7]=1[C:8]#[C:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([NH:48][C:44]2[CH:45]=[CH:46][CH:47]=[C:42]([O:41][CH3:40])[CH:43]=2)=[O:15])[CH:11]=1
Reactant: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(C#Cc2cccc(C(=O)O)c2)c1
Reactant: COc1cccc(N)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(C#Cc2cccc(C(=O)Nc3cccc(OC)c3)c2)c1
Temperature: 60 °C

Procedure:
The reaction mixture of 3-{[2-amino-5-({[bis(5-methoxy-5-oxopentyl)(oxido)-sulfanylidene]amino}carbonyl)pyridin-3-yl]ethynyl}benzoic acid (56 mg, 0.1 mmol, 1.0 equiv.), m-anisidine (13.4 μL, 0.12 mmol, 1.2 equiv.), DMAP (2.5 mg, 0.02 mmol, 0.2 equiv.) and EDC (29 mg, 0.15 mmol, 1.5 equiv.) in DCE (1 mL) in a sealed vial was stirred and heated at 60° C. for 3 hours. The resulting brown solution was diluted with EtOAc, washed with sat. aq. NaHCO3, aq. NH4Cl, and brine, and finally dried with anhydrous Na2SO4. The solution was decanted, concentrated, and the oily residue was subject to a gradient column chromatography (from EtOAc-Hex 1:4 to 6:1) to yield Dimethyl 5,5′-[N-({6-amino-5-[(3-{[(3-methoxyphenyl)amino]carbonyl}phenyl)ethynyl]pyridin-3-yl}carbonyl)sulfonimidoyl]dipentanoate
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][N:8]([CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[C:7](=[O:20])[CH2:6]1)=O.O.[NH2:22][NH2:23].NC1CC(C)(C)NC(C)(C)C1.C(OC)(=O)C(CC(OC)=O)=C>CO>[NH:22]([C:3]([CH:5]1[CH2:9][N:8]([CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[C:7](=[O:20])[CH2:6]1)=[O:2])[NH2:23]
Reactant: NN
Reactant: COC(=O)C1CC(=O)N(C2CC(C)(C)NC(C)(C)C2)C1
Agent: C=C(CC(=O)OC)C(=O)OC
Agent: CC1(C)CC(N)CC(C)(C)N1
Solvent: O
Solvent: CO
Product: CC1(C)CC(N2CC(C(=O)NN)CC2=O)CC(C)(C)N1

Procedure:
4-Hydrazinocarbonyl-1-(2,2,6,6-tetramethyl-4-piperidinyl)-2-pyrrolidone was prepared by the hydrazinolysis of 4-(methoxycarbonyl)-1-(2,2,6,6-tetramethyl-4-piperidinyl)-2-pyrrolidone with excess hydrazine hydrate in methanol. The above intermediate half ester was prepared by the addition of 4-amino-2,2,6,6-tetramethylpiperidine to dimethyl itaconate according to the procedure described in U.S. Pat. No. 4,309,546.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[S:5][C:6](/[CH:18]=[CH:19]/[C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[N:8]=1.Cl>O.C(O)(C)C>[CH3:3][C:4]1[S:5][C:6](/[CH:18]=[CH:19]/[CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[N:8]=1
Reactant: CCCCCC(=O)/C=C/c1sc(C)nc1CCCCCCC(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCCCCC(O)/C=C/c1sc(C)nc1CCCCCCC(=O)O
Reaction time: 8 h
Yield: 69.4 %

Procedure:
The solution of 76 mg of sodium borohydride in 6 ml of water was added to the solution of 351 mg of 2-methyl-4-(6-carboxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole (Ib, R1 = CH3) in 4 ml of isopropanol. The reaction mixture was allowed to stand overnight at room temperature, then diluted with 50 ml of water, acidified with 1 N hydrochloric acid and extracted with 3 × 25 ml of ethyl acetate. The ethyl acetate extract was dried over sodium sulphate and evaporated in vacuo. The obtained 317 mg of evaporation residue was purified by preparative thin layer chromatography in the way specified in Example 6. Thus, 245 mg of 2-methyl-4-(6-carboxyhexyl)-5-(3-hydroxy-1-trans-octenyl)-thiazole (Id, R1 = CH3) were obtained. IR spectrum (film): ν OH 3500-2300, ν CH 3000-2860, ν C=O 1710, ν C=C 1640 cm -1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl[CH:8]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:8]2[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9]2)[CH:6]=1
Reactant: COC(=O)C1CC(Cl)C1
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)C1CC(n2cc(Br)cn2)C1
Temperature: 70 °C

Procedure:
A mixture of 4-bromo-1H-pyrazole (500 mg, 3.40 mmol), methyl 3-chlorocyclobutanecarboxylate (607 mg, 4.08 mmol), and potassium carbonate (1.18 g, 8.50 mmol) in DMF (5 mL) was heated to 70° C. for 24 hours. The reaction mixture was cooled to ambient temperature and diluted with diethyl ether (200 mL). The mixture was washed with water (2×50 mL) and then brine (25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by column chromatography on silica (0-100% diethyl ether/hexanes) to afford methyl 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanecarboxylate (Isomer 1) and methyl 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanecarboxylate (Isomer 2). Methyl 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanecarboxylate (Isomer 1): MS ESI calc'd. for C9H12BrN2O2 [M+H]+ 259 and 261. found 259 and 261. 1H NMR (500 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.59 (s, 1H), 5.02-4.95 (m, 1H), 3.65 (s, 3H), 3.20-3.14 (m, 1H), 2.75-2.66 (m, 2H), 2.64-2.56 (m, 2H).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9]([CH:10]=[CH:11][CH3:12])=[CH:8][CH:7]=[CH:6][C:5]=1[C:13](=[O:16])[CH2:14][CH3:15].C(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(O)C.O>[OH:3][C:4]1[C:9]([CH:10]=[CH:11][CH3:12])=[CH:8][CH:7]=[CH:6][C:5]=1[C:13](=[O:16])[CH:14]=[CH:15][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: CC=Cc1cccc(C(=O)CC)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC=Cc1cccc(C(=O)C=Cc2ccccc2)c1O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
60 ml of 50% (w/v) sodium hydroxide was added dropwise during 30 minutes to a solution of 17.6 g of a 7:3 E-Z mixture of 2'-hydroxy-3'-(1-propenyl)propiophenone (prepared as described in R. E. Ford. et al., J. Med. Chem., 29,538, (1986)) and 10.82 g of benzaldehyde in 73 ml of ethanol stirred at 0° C. The temperature of the reaction mixture was raised to 25° C. and stirring was continued for 4 hours. After standing at room temperature overnight, 150 ml of water was added, followed by dropwise addition of 95 ml of 37% hydrochloric acid under stirring at O° C. The precipitated solid was filtered by suction, washed with water and desiccated, yielding 26.8 g of 1-[2-hydroxy-3-(1-propenyl)phenyl]-3-phenyl-2-propen-1-one. This material was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:18]([CH3:19])[C:17](=[O:20])[C:16](C(O)=O)=[CH:15][C:11]=2[CH:12]=[N:13][N:14]=1.C1COCC1.O.O.C([O-])(=O)C.[Li+].C1C(=O)N([Br:43])C(=O)C1>O>[Br:43][C:16]1[C:17](=[O:20])[N:18]([CH3:19])[C:10]2[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[N:14][N:13]=[CH:12][C:11]=2[CH:15]=1
Reactant: Cn1c(=O)c(C(=O)O)cc2cnnc(-c3ccc(F)cc3F)c21
Reactant: O=C1CCC(=O)N1Br
Agent: CC(=O)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)c(Br)cc2cnnc(-c3ccc(F)cc3F)c21
Temperature: 55 °C

Procedure:
To a suspension of 8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylic acid (7) (1.00 g, 3.15 mmol) in 10:1 THF:H2O (11 mL), stirred at 55° C., was added lithium acetate dihydrate (67 mg, 0.66 mmol). The mixture was stirred at 55° C. and treated with NBS (1.51 g, 8.48 mmol) in three equal portions at 30 min intervals. After addition of NBS was complete, the reaction mixture was stirred an additional 1 h at 55° C. In a separate flask, a suspension of 8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylic acid (7) (0.92 g, 2.89 mmol) in 10:1 THF:H2O (10 mL) stirred at 55° C. was treated with lithium acetate dihydrate (62 mg, 0.61 mmol) followed by NBS (1.39 g, 7.80 mmol) under the same conditions. Upon complete reaction, the two reaction mixtures were combined, diluted with water, and extracted with CH2Cl2. The combined organic layers were washed with 20% THF in water, dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography [eluting with a gradient of 10-40% B in A where the eluents were: A=CH2Cl2; B=1:49.5:49.5 MeOH:EtOAc:CH2Cl2] to give 3-bromo-8-(2,4-difluorophenyl)-1-methylpyrido[3,2-d]pyridazin-2(1H)-one as a yellow solid. MS (ESI, pos. ion) m/z: 350, 352 (M+1, M+3).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].C(=O)(O)[O-].[Na+].O>C(OCC)(=O)C>[C:4]1([C:3]2[CH2:13][CH:12]([C:11]([O:15][CH3:16])=[O:14])[O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=CC(=O)OC
Reactant: ON=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C1CC(c2ccccc2)=NO1
Reaction time: 22 h
Yield: 73.2 %

Procedure:
A solution of N-hydroxybenzimidoyl chloride (0.500 g; 3.21 mmol) in ethyl acetate (4 mL) was added dropwise to the mixture of methyl acrylate (0.58 mL; 6.43 mmol), sodium bicarbonate (0.818 g; 9.64 mmol), water 0.1 mL and ethyl acetate (16 mL) at room temperature and the resulting mixture was stirred for 22 hours. The solid was eliminated by filtration and washed with ethyl acetate. The filtrate was evaporated and the residue purified by flash chromatography on silica gel (eluent: 15 to 100% dichloromethane in heptane) to afford 0.482 g (73%) of methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][NH:9][C:10](=[O:11])[C:5]2=[N:4][CH:3]=1.[H-].[Na+].I[CH2:15][CH3:16]>CN(C)C=O.O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]([CH2:15][CH3:16])[C:10](=[O:11])[C:5]2=[N:4][CH:3]=1
Reactant: O=c1[nH]ccn2c(Br)cnc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ccn2c(Br)cnc2c1=O
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 20.1 %

Procedure:
3-Bromo-7H-imidazo[1,2-a]pyrazin-8-one (prepared as described in Example 5, 1.6 g, 7 mmol) was suspended in N,N-dimethylformamide (15 ml) then treated with sodium hydride (420 mg of a 60% dispersion in mineral oil, 10.5 mmol). The resulting mixture was heated at 60° C. for 20 min then treated with iodoethane (840 μl, 10.6 mmol). After stirring for 40 min the reaction was cooled, diluted cautiously with water (150 ml) and then extracted with dichloromethane (2×100 ml). The organics were combined, washed with water, dried over anhydrous magnesium sulphate, filtered and concentrated under high vacuum. The residue was triturated with diethyl ether and the resulting solid collected by filtration and recrystallized from ethyl acetate/methanol to furnish 3-bromo-7-ethyl-7H-imidazo[1,2-a]pyrazin-8-one as a white solid (0.34 g): δH (400 MHz, DMSO) 1.23 (3H, t, J 7), 3.94 (2H, q, J 7), 7.31 (1H, d, J 6), 7.41 (1H, d, J 6), 7.62 (1H, s); m/z (ES+) 244 and 242 [M+H]+.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]12[O:14][CH:10]1[CH2:11][CH2:12][CH2:13]2>C1COCC1.[Cu](I)I>[C:1]1([C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: C1CC2OC2C1
Agent: I[Cu]I
Solvent: C1CCOC1
Product: O[C@@H]1CCC[C@H]1c1ccccc1
Temperature: 25 °C

Procedure:
Scheme IB, step A: A one liter three necked round bottom flask equipped with a mechanical stirrer, addition funnel, thermometer is charged with 1M THF solution of phenylmagnesium bromide (300 mL, 300.0 mmol) and copper iodide (3.8 g, 20.0 mmol). To this reaction mixture was then added cyclopentene oxide (25.23 g, 300.0 mmol) dissolved in THF (50.0 mL) dropwise over a period of 60 minutes (reaction was quite exothermic, reaching THF reflux by the end of addition). The reaction mixture was then stirred to room temperature and quenched with 25% solution of ammonium chloride (200.0 mL). Added ether (80.0 mL) and separated upper organic layer. Washed organic layer with 25% ammonium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated filtrate to provide (+,−) trans-2-phenyl-cyclopentanol as a brown oil (mass =47.7 g);
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:17][N:18](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[Si:10]([O:9][CH2:8][C:7]1[C:2]([C:17]#[N:18])=[N:3][CH:4]=[CH:5][CH:6]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccnc1Br
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1C#N
Temperature: 120 °C
Yield: 82 %

Procedure:
A mixture of 2-bromo-3-((tert-butyldimethylsilyloxy)methyl)pyridine (30.1 g, 100.0 mmol, 1 eq.) and Zn(CN)2 (23.5 g, 200.0 mmol, 2.0 eq.) in DMF (100.0 mL) was purged with N2 for 5 min and added Pd(PPh3)4 (5.78 g, 5.0 mmol, 0.05 eq.). The mixture was heated at 120° C. for 2 h under N2, cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((tert-butyldimethylsilyloxy)methyl)picolinonitrile (20.4 g, 82%) as a colorless oil. LRMS (M+H+) m/z 249.1.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.C([O-])([O-])=O.[Na+].[Na+].B(O)(O)[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:7]1[C:2]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: O=C(O)c1ccc(B(O)O)cc1
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: O
Solvent: COCCOC
Product: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a solution of 5.3 g (36.1 mmol) 2,3-dichloropyridine in 200 mL 1,2-dimethoxyethane and 200 mL distilled water were added 22.3 g (0.21 mol) Na2CO3, 5.0 g (30.1 mmol) 4-carboxylphenylboronic acid and 0.5 g Pd(PPh3)4, followed by mixing for 18 hours under a heat flux condition by stirring. After being cooled to room temperature, the solution was 50% concentrated in a vacuum. The aqueous layer was washed with ethyl acetate and adjusted into pH 1 with conc. HCl. Thereafter, extraction with ethyl acetate was conducted three times and the organic layer was dried over magnesium sulfate and concentrated in a vacuum. The concentrate was separated using column chromatography (developing solvent: chloroform/methanol=10/1) to afford 5.3 g of 4-(3-chloropyridin-2-yl)benzoic acid as a white precipitate (yield: 75%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[O:16][C:17]([CH2:20]I)=[CH:18][N:19]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.C(N[C:29]([C:31]1N=CN2[C:40]3[CH:41]=CC(F)=C[C:39]=3[C:38](=O)[N:37](C)[CH2:36][C:35]=12)=O)C#C.IN1C(=O)CCC1=O.C(NCCCC)CCC>C1COCC1>[CH2:36]([N:37]([CH2:20][C:17]1[O:16][C:15]([C:14]2[N:13]=[CH:12][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:24][C:6]=4[C:7](=[O:23])[N:8]([CH3:22])[CH2:9][C:10]=23)=[N:19][CH:18]=1)[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:35][CH2:31][CH3:29]
Reactant: CN1Cc2c(-c3ncc(CI)o3)ncn2-c2ccc(F)cc2C1=O
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Agent: O=C1CCC(=O)N1I
Solvent: CCCCNCCCC
Solvent: C1CCOC1
Product: CCCCN(CCCC)Cc1cnc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)o1
Temperature: 25 °C
Reaction time: 42 h
Yield: 15 %

Procedure:
125 ml of a crude THF solution of 8-fluoro-3-(5-iodomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one (prepared from 15.6 g (0.050 mol) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylic acid prop-2-ynylamide and 16.9 g (0.075 mol) of N-iodosuccinimide, subsequently completely freed from the solvents, dried azeotropically several times with toluene and dissolved in 500 ml of THF) were treated with 18.5 ml (0.109 mol) of dibutylamine and stirred at room temperature for 42 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated and the orange product was chromatographed over silica gel with dichloromethane/methanol 39:1 as the eluent. There was obtained 0.83 g (15%) of 3-(5-dibutylaminomethyl-oxazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as yellowish crystals; m.p. 100°-103° (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH2:17][O:18][C:19]([O:21]C1C=CC=CC=1)=O)=[C:12]2[N:28]1[CH:32]=[CH:31][N:30]=[CH:29]1)=[O:5].[CH3:38][NH2:39]>CO>[Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH2:17][O:18][C:19](=[O:21])[NH:39][CH3:38])=[C:12]2[N:28]1[CH:32]=[CH:31][N:30]=[CH:29]1)=[O:5]
Reactant: O=C(OCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1-n1ccnc1)Oc1ccccc1
Reactant: CN
Solvent: CO
Product: CNC(=O)OCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1-n1ccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-(2,6-dichlorobenzoylamino)-3-(phenoxycarbonyloxymethyl)-4-(imidazol-1-yl)quinoline (100 mg) in methanol (4 ml) was dropwise added a solution of 2M solution of methylamine in methanol (4 ml) under ice-cooling, and the mixture was stirred for 1 hour at ambient temperature. The mixture was concentrated in vacuo, and the residue was crystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-4-(imidazol-1-yl)-3-(methylcarbamoyloxymethyl)quinoline (50 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[C:9]2[C:5]([CH2:6][N:7]([CH3:13])[C:8]2=[O:12])=[CH:4][CH:3]=1.[CH2:14]([O:16][C:17]1[C:18](=O)[C:19](=[O:24])[C:20]=1[O:21]CC)[CH3:15]>C(O)C>[CH2:14]([O:16][C:17]1[C:20](=[O:21])[C:19](=[O:24])[C:18]=1[NH:1][C:2]1[C:10]([OH:11])=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][N:7]([CH3:13])[C:8]2=[O:12])[CH3:15]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CN1Cc2ccc(N)c(O)c2C1=O
Solvent: CCO
Product: CCOc1c(Nc2ccc3c(c2O)C(=O)N(C)C3)c(=O)c1=O
Temperature: 60 °C
Yield: 72.7 %

Procedure:
A mixture of 0.19 g (1.07 mmol) of 6-amino-7-hydroxy-2-methyl-2,3-dihydroisoindol-1-one and 0.80 g (4.70 mmol) of 3,4-diethoxycyclobut-3-ene-1,2-dione in 10 ml of ethanol was heated at 60° C. for 24 hours. The reaction medium was concentrated and was taken up with diethyl ether with stirring (formation of a precipitate). The solid obtained was filtered off, washed twice with diethyl ether and dried. 235 mg of product were obtained. Yield=73%.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.OO.NC(N)=[O:14].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:9])=[N+:4]([O-:14])[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)c(Cl)n1
Reactant: NC(N)=O
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(Br)c(Cl)[n+]1[O-]
Temperature: 25 °C
Yield: 102.2 %

Procedure:
To a solution of 3-bromo-2-chloro-6-methylpyridine (1 g, 4.84 mmol) and urea hydrogen peroxide (911 mg, 9.69 mmol) in DCM (24 mL) at 0° C. was added trifluoroacetic anhydride (1.4 mL, 9.69 mmol). After warming to 25° C. over 12 h, the solution was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 1% MeOH in DCM) yielding the title compound (1.1 g, quant.) as a white solid: LCMS (ES) m/z=223 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]2[N:19]([CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:18]3[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=3[N:12]2[C:13](=[O:16])[C:14]=1[OH:15])=[O:8].C(N(CC)CC)C.[S:43](Cl)([CH3:46])(=[O:45])=[O:44]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]2[N:19]([CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][N:25]([S:43]([CH3:46])(=[O:45])=[O:44])[CH2:26][CH2:27]3)[C:18]3[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=3[N:12]2[C:13](=[O:16])[C:14]=1[O:15][S:43]([CH3:46])(=[O:45])=[O:44])=[O:8]
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)c1nc2n(CCN3CCNCC3)c3ccccc3n2c(=O)c1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Oc1c(C(=O)NCc2ccc(Cl)c(Cl)c2)nc2n(CCN3CCN(S(C)(=O)=O)CC3)c3ccccc3n2c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.3 %

Procedure:
3-Hydroxy-4-oxo-10-(2-piperazin-1-yl-ethyl)-4,10-dihydro-benzo[4,5]imidazo[1,2-α]pyrimidine-2-carboxylic acid, 3,4-dichloro-benzylamide (Example 15.5) (75 mg, 0.146 mmol) and triethylamine (60 μL, 0.31 mmol) were dissolved in dichloromethane (1 mL) and to this was added mesyl chloride (18 μL, 0.31 mmol). The reaction was stirred at room temperature for 15 minutes after which time the solvents were concentrated in vacuo and the residue purified by column chromatography (95:4.5:0.5 dichloromethane: methanol: aqueous ammonia) to afford the desired product (65 mg, 76%).