Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.FC(F)(F)C(O)=O.[F:56][C:57]([F:72])([F:71])[C:58]1[CH:70]=[CH:69][CH:68]=[CH:67][C:59]=1[O:60][CH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C.O>[O:27]=[C:25]([N:64]1[CH2:63][CH2:62][CH:61]([O:60][C:59]2[CH:67]=[CH:68][CH:69]=[CH:70][C:58]=2[C:57]([F:56])([F:71])[F:72])[CH2:66][CH2:65]1)[CH2:24][NH:23][C:21]([C:19]1[N:18]=[CH:17][N:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:20]=1)=[O:22]
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cn(-c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2C(F)(F)F)CC1)c1cn(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 58.2 %

Procedure:
DIPEA (236 mg, 1.826 mmol) was added to a stirred solution of [(1-Phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acid (prepared from Intermediate 68 by means of Step 3 of the General Scheme) (100 mg, 0.4 mmol) in DMF (5 mL) followed by HOBt (60.5 mg, 0.4 mmol) and EDCI (195 mg, 1.02 mmol). After 2 minutes of stirring, 4-(2-trifluoromethyl-phenoxy)-piperidine trifluoroacetate (126 mg, 0.45 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with cold water, and the precipitate was filtered. The precipitate was purified by recrystallisation from a mixture of 20% EtOAc in hexane (15 mL) and MeOH (0.1 mL) to afford 113 mg (58.2% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 473, 96.85%. 1H NMR (300 MHz, DMSO-d6): δ 8.4 (s, 1H), 8.3 (s, 1H), 8.08 (t, 1H), 7.8 (d, 2H), 7.68-7.6 (t, 2H), 7.6 (t, 2H), 7.4-7.34 (m, 2H), 7.14 (t, 1H), 5.0 (m, 1H), 4.2 (d, 2H), 3.7-3.4 (m, 4H), 2.1 (d, 2H), 1.8 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C@@H:8]([OH:13])[CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.CCN=C=NCCC[N+](C)(C)C.[I-].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[CH2:47]([O:54][NH2:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.Cl>CN(C=O)C>[CH2:47]([O:54][NH:55][C:10](=[O:12])[CH2:9][C@H:8]([OH:13])[CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:15][CH:14]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)C[C@H](O)COc1ccc(Br)cc1
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(C[C@H](O)COc1ccc(Br)cc1)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.7 %

Procedure:
A solution of Example 3C (121.2 g) in DMF (1 L) at 5° C. was treated sequentially with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (92.9 g), 1-hydroxybenzotriazole (68.5 g), and 4-methylmorpholine (193 mL), stirred for 5 minutes, treated with O-benzylhydroxylamine hydrochloride (73.5 g), warmed to room temperature, treated with 5% HCl (2.1 L) over 35 minutes, and filtered. The solid was washed with water and dried under vacuum (100 mm Hg) at 50° C. with a nitrogen bleed to provide 156.9 g of the desired product. 1H NMR (300 MHz, DMSO-d6) δ11.05 (s, 1H), 7.45 (m, 2H), 7.35 (m, 5H), 6.90 (m, 2H), 5.21 (d, 1H, J=5 Hz), 4.80 (s, 2H), 4.20 (m, 1H), 3.88 (m, 2H), 2.25 (dd, 1H, 6, 14 Hz), 2.15 (dd, 1H, J=8,14 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:17]2[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]2)=[N:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: COc1cnc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Yield: 78 %

Procedure:
A mixture of [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) (3.807 g, 17.463 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (3.493 g, 17.463 mmol) in chloroform (100 ml) and MeOH (5 ml) was stirred for 1 h before addition of NaBH(OAc)3 (11.11 g, 52.39 mmol). The reaction was stirred for 0.5 h before addition of water (100 ml) and sat. aq NaHCO3 (100 ml). The reaction was then extracted with 20% MeOH in DCM (3×200 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-10% MeOH/DCM gradient to provide the desired compound (5.453 g, 78%).
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[O:13][CH:14]=[C:15]([C:17](=[O:19])[CH3:18])[N:16]=2)[N:7]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:3][C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[O:13][CH:14]=[C:15]([C:17](=[O:19])[CH3:18])[N:16]=2)[N:7]=1
Reactant: CC(=O)c1coc(Cn2ncc([N+](=O)[O-])n2)n1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(=O)c1coc(Cn2ncc(N)n2)n1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 1-[2-(4-nitro-[1,2,3]triazol-2-ylmethyl)-oxazol-4-yl]-ethanone (48 mg, 0.20 mmol), iron powder (34 mg, 0.61 mmol) and NH4Cl (54 mg, 1.01 mmol) in a mixture of EtOH (2.0 mL) and water (1.0 mL) was stirred at 75° C. for 60 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. The filtrated was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a brown oil. TLC: rf (EA)=0.40. LC-MS-conditions 02: tR=0.54 min; [M+H]+=208.44.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[Br:9].[Br:10]Br.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[Fe].ClCCl>[Br:10][C:5]1[CH:4]=[C:3]([Br:9])[C:2]([F:1])=[CH:7][C:6]=1[F:8]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: BrBr
Agent: [Fe]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Fc1cc(F)c(Br)cc1Br
Reaction time: 1 h
Yield: 83.1 %

Procedure:
2,4-difluorobromobenzene (3 g, 15.5 mmol) and 260 mg of iron filings were placed in a two-neck flask, and 15 ml of dichloromethane was then added thereto. The two-neck flask was cooled in an ice bath, and a solution including bromine (1 ml, 18.7 mmol) and 15 ml of dichloromethane was added dropwise to the two-neck flask using an isobaric funnel. Next, the contents in the two-neck flask were heated under reflux for 3 hours. During heating, brown gas was produced. Then, the temperature was reduced to 20° C., and 50 ml of a sodium metabisulfite (Na2S2O5) aqueous solution (10%) was mixed with the contents in the two-neck flask by stirring for 1 hour for terminating the reaction therein. Thereafter, the contents in the two-neck flask were washed several times with deionized water to collect an organic layer, the organic layer was dehydrated using sodium sulfate (Na2SO4), and the solvent in the organic layer was removed, followed by column chromatography (SiO2, n-hexane), thereby obtaining white crystals (3.5 g, 83% yield).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[PH:11](=[O:14])([OH:13])[OH:12].[CH2:15]([C:17]([CH2:45][CH3:46])([CH:19]([OH:44])[C:20]1[N:24]=[CH:23][N:22]([C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:21]=1)[CH3:18])[CH3:16].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C.O.CCOCC>[PH:11](=[O:12])([OH:14])[OH:13].[CH2:45]([C:17]([CH2:15][CH3:16])([C:19](=[O:44])[C:20]1[N:24]=[CH:23][N:22]([C:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:21]=1)[CH3:18])[CH3:46]
Reactant: CCC(C)(CC)C(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C(Cl)C(=O)Cl
Agent: O=[PH](O)O
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCC(C)(CC)C(=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -60 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
A solution of dimethylsulphoxide (0.46 g) in dichloromethane (3 ml) was added dropwise to a stirred solution of oxalyl chloride (0.36 g) in dichloromethane (15 ml), maintaining the temperature below -60° C. After fifteen minutes, a solution of diethyl 3-hydroxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.19 g, prepared as described in Example 24) in dichloromethane (5 ml) was added, dropwise with stirring, at -60° C. After a further one hour, triethylamine (4.0 ml) was added. The stirred reaction mixture was allowed to warm to -25° C. over fifteen minutes, maintained at that temperature for fifteen minutes, then treated with ether (25 ml) and water (25 ml). The aqueous phase was reextracted twice with ethyl acetate and the combined organic layers washed with water and brine, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (19:1) as eluant, to give diethyl 3-oxo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.87 g, m.p. 99°-100° C.). NMR (CDCl3): δ1.25(6H,t), 2.1-2.25(2H,m), 3.35(2H,m), 4.1(4H,m), 7.1-7.35(15H,m), 8.05(1H,s). M/S: M+ 503. IR: 1712 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:36]([O:38][C:39](=[O:61])[C@@H:40]([NH2:60])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[C:56](=[O:57])[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][C:54]=3[CH3:58])[C:49]2=[O:59])=[CH:44][CH:43]=1)[CH3:37]>ClCCl.C(N(CC)CC)C>[CH2:36]([O:38][C:39](=[O:61])[C@@H:40]([NH:60][C:4](=[O:6])[C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])[CH2:41][C:42]1[CH:43]=[CH:44][C:45]([N:48]2[C:56](=[O:57])[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][C:54]=3[CH3:58])[C:49]2=[O:59])=[CH:46][CH:47]=1)[CH3:37]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(N2C(=O)c3cccc(C)c3C2=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(N2C(=O)c3cccc(C)c3C2=O)cc1)NC(=O)c1c(C)cccc1Cl
Temperature: 45 °C
Reaction time: 8 h

Procedure:
The mixture of 88.2 mg of 2-chloro-6-methyl benzoic acid, 99.1 mg of 1-(3-dimehtylaminopropyl)-3-ethylcarbodiimide hydrochloride, 79.1 mg of 1-hydroxybenzotriazol hydrate, 107 μl of triethylamine, 100 mg of (2S)-2-amino-3-[4-(4-methyl-1,3-dioxo-1,3-dihydroisoindole-2-yl)phenyl] propionic acid ethylester hydrochloride and 1 ml of dichloromethane was stirred at 45° C. overnight. The mixture was purified by silica gel chromatography to obtain the title compound.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[C:39](=[O:40])[C:38]3[S:37][C:36]4[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=4[C:30]=3[CH:29]=[N:28]2)=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[O:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[OH:4][CH2:5][C:6]1[C:7]([N:27]2[C:39](=[O:40])[C:38]3[S:37][C:36]4[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=4[C:30]=3[CH:29]=[N:28]2)=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[O:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc(C)on3)c(=O)n(C)c2)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(Nc2cc(-c3ccnc(-n4ncc5c6c(sc5c4=O)CCCC6)c3CO)cn(C)c2=O)no1
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a solution of 291a (100 mg, 0.18 mmol) in THF/i-propanol/water (10/5/5 mL) was added lithium hydroxide (43 mg, 1.8 mmol) at room temperature. After being stirred for 1 h, MS indicated the reaction was complete. Then the mixture was concentrated under reduced pressure and the residue was partitioned between water (10 mL) and dichloromethane (15 mL). The water phase was extracted with dichloromethane (3×10 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 291 (56 mg, 60%) as white solid. MS-ESI: [M+H]+ 517.2. 1H NMR (500 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.58 (d, J=5.0 Hz, 1H), 8.48 (s, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.52 (d, J=5.0 Hz, 1H), 6.25 (s, 1H), 4.87-4.85 (m, 1H), 4.42-4.36 (m, 2H), 3.61 (s, 3H), 2.98-2.85 (m, 4H), 2.32 (s, 3H), 1.92-1.86 (m, 4H).
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH2:12]([C@@H:15]1[CH2:19]OS(=O)(=O)O1)[CH2:13][CH3:14].C([O-])(=O)CC([O-])=O>COCCOC.[Cl-].[Na+].O>[CH3:8][O:7][C:5]([C:4]1([C:3]([O:10][CH3:11])=[O:9])[CH2:14][C@@H:13]1[CH2:12][CH2:15][CH3:19])=[O:6]
Reactant: COC(=O)CC(=O)OC
Reactant: CCC[C@@H]1COS(=O)(=O)O1
Agent: O=C([O-])CC(=O)[O-]
Agent: [Cl-]
Agent: [H-]
Solvent: COCCOC
Solvent: O
Product: CCC[C@H]1CC1(C(=O)OC)C(=O)OC
Temperature: 0 °C

Procedure:
To a stirred suspension of NaH 60% (873 mg, 21.81 mmol) in dry 1,2-dimethoxyethane (48 mL) is added dropwise dimethyl malonate (1.31 g, 9.92 mmol) at room temperature over 10 minutes under a nitrogen atmosphere. A solution of (VIII) (1.82 g, 10.96 mmol) in dry 1,2-dimethoxyethane (5 mL) is added slowly to the malonate anion solution, and the resulting mixture is refluxed for 2 hours and then cooled to 0° C. After adding brine (30 mL), the mixture is extracted with diethyl ether (50 mL, 25 mL). The combined organic layers are dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude is purified by column chromatography (cyclohexane: EtOAc=90:10) to afford 1.28 g of (IId) (6.40 mmol, 65%, ee=78.2%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1.Cl.Cl[CH2:14][CH2:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[O:11][CH2:14][CH2:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1
Reactant: ClCCc1c[nH]cn1
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Product: Clc1cc(Cl)cc(OCCc2c[nH]cn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
288 mg (60% in oil, 7.2 mmol) of sodium hydride are added to a solution of 2.34 g (14.4 mmol) of 3,5-dichlorophenol in 4 ml of dimethylformamide while cooling in an ice bath. The mixture is stirred at room temperature for 1 hour under nitrogen. 200 mg (1.20 mmol) 4-(2-chloroethyl)-1H-imidazole hydrochloride and tetrabutylammonium iodide (catalytic amount) are then added. The mixture is heated at 80° C. for 3 days and then the solvent is evaporated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:13]1[S:17][C:16]([C:18]([O:20]CC)=[O:19])=[N:15][C:14]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]#[N:31])[CH:24]=1.C(=O)(O)[O-].[Na+]>COCCOC.O.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:1][C:2]1[CH:3]=[C:4]([C:13]2[S:17][C:16]([C:18]([OH:20])=[O:19])=[N:15][C:14]=2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]#[N:31])[CH:24]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(C#N)c2)c(Br)s1
Reactant: OB(O)c1cc(F)cc(Cl)c1
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: COCCOC
Solvent: O
Product: N#Cc1cc(-c2nc(C(=O)O)sc2-c2cc(F)cc(Cl)c2)ccc1F

Procedure:
At room temperature, 256 mg (1.48 mmol) of (3-chloro-5-fluorophenyl)boronic acid are added to 350 mg (0.985 mmol) of the compound from Example 29A and 56.9 mg (0.049 mmol) of tetrakis(triphenylphosphine)palladium in 26 ml of DME. 252 mg (3.01 mmol) of sodium bicarbonate in 11 ml of water are subsequently added, and the mixture is stirred under reflux for 1 h. The reaction solution is subsequently concentrated under reduced pressure and the residue is taken up in ethyl acetate and washed with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 50.0 mg (13% of theory) and 41 mg (9% of theory, purity 84%) of the title compound are obtained.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11].[CH:12]([C:15]1([C:21](Cl)=[O:22])[CH2:20][CH2:19][CH:18]=[CH:17][CH2:16]1)([CH3:14])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C-:1]1([C:21]([C:15]2([CH:12]([CH3:14])[CH3:13])[CH2:20][CH2:19][CH:18]=[CH:17][CH2:16]2)=[O:22])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11]
Reactant: CC(C)C1(C(=O)Cl)CC=CCC1
Agent: [Fe+2]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)C1(C(=O)[c-]2cccc2)CC=CCC1

Procedure:
Prepared from ferrocene, 1-isopropyl-3-cyclohexene-1-carboxylic acid chloride and aluminium chloride in methylene chloride at 0° C. in a manner analogous to that described in Example 1.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=CC=CC=2)[C:5](CC2C=CC=CC=2)=[CH:4][C:3]=1[C:19]([OH:21])=[O:20].[Cl-].[Al+3].[Cl-].[Cl-].C(Br)C1C=CC=CC=1.Cl>ClCCCl>[C:19]([OH:21])(=[O:20])[C:3]1[C:2](=[CH:11][CH:6]=[CH:5][CH:4]=1)[OH:1]
Reactant: O=C(O)c1cc(Cc2ccccc2)c2ccccc2c1O
Agent: BrCc1ccccc1
Agent: Cl
Agent: [Al+3]
Solvent: ClCCCl
Product: O=C(O)c1ccccc1O
Reaction time: 2 h
Yield: 296.8 %

Procedure:
Charged were 5.50 g (0.02 mole) of 1-hydroxy-2-carboxy-4-benzylnaphthalene, 50 ml of 1,2-dichloroethane, and as a catalyst, 2.7 g of anhydrous aluminum chloride. The resultant mixture was maintained at 70° C. under stirring. Then, 5.2 g (0.03 mole) of benzyl bromide was added dropwise over 6 hours to conduct a reaction. After completion of the dropwise addition, the reaction mixture was aged for 2 hours at the same temperature and then poured into dilute hydrochloric acid. The resultant mixture was allowed to separate into layers. The lower organic layer was concentrated to obtain 8.2 g of a reddish brown resin. The weight average molecular weight of the resin was 720.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([Br:15])[C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cc(C)n(-c2ccc(Cl)nn2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nn(-c2ccc(Cl)nn2)c(C)c1Br
Reaction time: 3 h

Procedure:
A mixture of 2.09 g (0.01 moles) of 3-chloro-6-(3,5-dimethyl-1-pyrazolyl)-pyridazine, 21 ml of carbon tetrachloride and 1.96 g (0.011 moles) of N-bromosuccinimide is boiled under stirring for 3 hours. After cooling the precipitate is filtered, washed with carbon tetrachloride and recrystallized from ethanol. Yield: 1.44 g (50.5%); m.p.: 143°-145° C.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=4)[CH2:14][CH2:13]3)[C:7](=[O:22])[CH:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1.[CH3:27][NH:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)=[O:30]>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2([N:8]3[C:7](=[O:22])[CH:6]4[CH2:23][O:24][CH2:25][CH2:26][N:5]4[C:4]4[N:3]=[C:2]([C:35]5[CH:34]=[CH:33][C:32]([NH:31][C:29]([NH:28][CH3:27])=[O:30])=[CH:37][CH:36]=5)[N:11]=[CH:10][C:9]3=4)[CH2:14][CH2:13]2)=[CH:16][CH:17]=1
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1C1(c2ccc(Cl)cc2)CC1
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc(-c2ncc3c(n2)N2CCOCC2C(=O)N3C2(c3ccc(Cl)cc3)CC2)cc1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 84 using 2-chloro-5-(1-(4-chlorophenyl)cyclopropyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x36, 100 mg, 0.256 mmol), 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (141 mg, 0.511 mmol), and PdCl2(dppf) (18.70 mg, 0.026 mmol) in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL). 1H NMR (400 MHz, DMSO-d6) δ 1.10-1.24 (m, 2H), 1.46-1.60 (m, 2H), 2.54-2.60 (d, 3H), 2.84-3.03 (m, 1H), 3.46-3.57 (m, 2H), 3.91-4.00 (m, 1H), 4.08-4.20 (m, 1H), 4.33-4.55 (m, 2H), 5.98-6.07 (m, 1H), 7.01-7.17 (m, 2H), 7.23-7.34 (m, 2H), 7.36-7.46 (m, 2H), 7.68-7.73 (m, 1H), 8.02-8.13 (m, 2H), 8.61-8.70 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C26H25ClN6O3, 505.17. found 505.4.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:6])[CH:4]=[CH2:5].C(N(CC)CC)C.[CH3:14][Si:15](Cl)([CH3:17])[CH3:16]>C(#N)C>[CH3:1][N:2]([Si:15]([CH3:17])([CH3:16])[CH3:14])[C:3](=[O:6])[CH:4]=[CH2:5]
Reactant: C[Si](C)(C)Cl
Reactant: C=CC(=O)NC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 45 %

Procedure:
N-methylacrylamide (50.9 g, 0.6 mole) and triethylamine (67 g, 0.67 mole) were added to 300 mL of acetonitrile in a 500 mL round-bottomed flask. The reaction vessel was fitted with a reflux condenser topped with a rubber stopper that contained two needles, one connected to a source of nitrogen gas and other to an oil bubbler. A solution of trimethylsilyl chloride (72.4 g, 0.67 mole) in a 50 mL acetonitrile was added dropwise to this mixture. A white precipitate formed almost immediately. The amount of precipitate continued to increase throughout the addition and the color of the solution changed from colorless to orange. After the addition was completed, the resulting slurry was allowed to stir at room temperature for six hours. The mixture was filtered using vacuum filtration in a dry bag filled with nitrogen. The white precipitate was collected as a filter cake. NMR-T60 analysis indicated the filter cake was the triethylammonium chloride, the expected by-product. The orange colored filtrate concentrated in vacuo gave a dark red material. The crude mixture was subjected to vacuum fractional distillation. The first fraction distilled at 22°-35° C. at 0.3 mm Hg. NMR analysis showed it was mostly acetonitrile and a small amount of product. The second fraction distilled at 35°-45° C. at 0.3 mm Hg and appeared to be the desired pure product on NMR analysis. The third fraction distilled at 70°-80° C. at 0.3 mm Hg. NMR analysis showed it was N-methyl acrylamide. The pot contained uncharacterized polymerized material as a black viscous material. The reaction gave about 45% yield.