Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]=[N:8][CH:9]([C:13](=O)[CH3:14])[C:10](=O)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:17](=[NH:20])([NH2:19])[CH3:18].[Na]>C(O)C>[CH3:14][C:13]1[C:9]([N:8]=[N:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:10]([CH3:11])[N:20]=[C:17]([NH2:19])[CH:18]=1
Reactant: CC(=N)N
Reactant: CC(=O)C(N=Nc1ccccc1)C(C)=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1cc(N)nc(C)c1N=Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.8 %

Procedure:
To a stirred solution of 50 parts of 3-(phenylazo)-2,4-pentanedione and 35 parts of ethanimidamide monohydrochloride in 711 parts of ethanol was added a solution of 8.5 parts of sodium in 126 parts of ethanol. After stirring overnight at room temperature, the precipitate was filtered off and the filtrate was stirred for 2 days at room temperature. The mixture was evaporated and the residue was diluted with a sodium hydroxide solution 10%. The separated aqueous layer was extracted with methylbenzene. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated with methylbenzene, yielding 7.5 parts (13.8%) of 4,6-dimethyl-5-(phenylazo)-2-pyridinamine as a residue (int. 95).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]#[CH:25])[CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN(C(C)C)C(C)C.O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:11]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]#[C:25][C:2]2[N:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)[CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: Brc1cnc2cccnn12
Reactant: C#CC1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(C#Cc2cnc3cccnn23)C1
Yield: 59.7 %

Procedure:
A solution of 3-bromoimidazo[1,2-b]pyridazine (0.40 g, 2 mmol), 1-BOC-3-ethynylpiperidine (0.55 g, 2.6 mmol), Pd(PPh3)2Cl2 (70 mg, 0.1 mmol), CuI (29 mg, 0.15 mmol), and DIPEA (0.39 g, 3 mmol) in DMF (20 mL) was stirred at 80° C. under Are for 6 hrs. The mixture was poured into 100 mL water, extracted with EtOAc (60 mL×3), organic layer was washed with brine, dried with Na2SO4, filtered, and the filtrate was evaporated in vacuo. The crude product was purified by chromatography on silica gel (PE/EtOAc 7:3 to 3:2) to give 0.39 g product as yellow oil (60.0%). 1H NMR (300 MHz, CDCl3) δ: 8.50 (1H, d, J=4.2 Hz), 7.98-8.08 (2H, m), 7.13-7.17 (1H, dd, J=4.5 and 8.7 Hz), 4.09 (1H, brs), 3.76-3.82 (1H, m), 3.19 (1H, brs), 3.02-3.09 (1H, m), 2.81-2.88 (1H, m), 2.32 (1H, brs), 2.11-2.15 (1H, m), 1.67-1.81 (2H, m), 1.46 (9H, s). LCMS: m/z [M+H]+ 327.2112.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[Li]CCCC.[CH2:17]([CH:19]([C:22]1[C:23]2[N:24]([C:29](I)=[C:30]([CH3:32])[N:31]=2)[N:25]=[C:26]([CH3:28])[CH:27]=1)[CH2:20][CH3:21])[CH3:18].Cl>[Cl-].[Cl-].[Zn+2].O.C1COCC1>[CH2:17]([CH:19]([C:22]1[C:23]2[N:24]([C:29]([C:8]3[O:9][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=4[C:7]=3[CH3:10])=[C:30]([CH3:32])[N:31]=2)[N:25]=[C:26]([CH3:28])[CH:27]=1)[CH2:20][CH3:21])[CH3:18]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1coc2ccc(F)cc12
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)c1cc(C)nn2c(-c3oc4ccc(F)cc4c3C)c(C)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.7 %

Procedure:
A THF solution (6 mL) of 5-fluoro-3-methyl-benzofuran (187.0 mg, 1.25 mmol) is cooled to −78° C. under N2 then treated with nBuLi (1.6 M in hexane, 1.0 mL, 1.6 mmol). After 10 min at −78° C., ZnCl2 (Aldrich, 0.5 M in THF, 3.0 mL, 1.5 mmol) is added. The resulting mixture is warmed to room temperature and treated with 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (212.4 mg, 0.62 mmol) and PdCl2(dppf)-CH2Cl2 complex (Aldrich, 60 mg, 0.073 mmol). The mixture is heated to 65° C. for 18 hours, then poured into H2O, acidified with 1 N HCl then extracted with ethyl acetate. The organic extract is ished with aq. brine, dried over Na2SO4, filtered, and concentrated. The crude product is purified by chromatography using hexane-ethyl acetate gradient (100% hexane to 20% ethyl acetate in hexane) to give the title compound as a solid (121.7 mg, 54% yield).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20](OB(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1.C(O)C.O>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]3)=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cc2ccc(Br)cc2[nH]1
Reactant: Cc1ccc(OB(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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc2ccc(-c3ccc(C)cc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A mixture of ethyl 6-bromo-1H-indole-2-carboxylate (2.5 g) and 4-methylphenylboric acid (1.39 g), potassium carbonate (2.58 g) and toluene/ethanol/water (90/9/9 ml) was stirred at room temperature for one hour. Into the reaction mixture was added tetrakis(triphenylphosphine)palladium (0.32 g), and the resulting mixture was heated at reflux for 18 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to purification using column chromatography (ethyl acetate/hexane 1:5→1:2→1:1) and to recrystallization (ethyl acetate/hexane) to obtain ethyl 6-(4-methylphenyl)-1H-indole-2-carboxylate (1.92 g) as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:15][CH2:14][C:9]3([NH:13][CH2:12][CH2:11][CH2:10]3)[CH2:8]2)[CH:2]=1.[C:16](=O)(O)[O-].[Na+]>C(O)=O.C=O>[CH3:16][N:13]1[C:9]2([CH2:14][CH2:15][N:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:8]2)[CH2:10][CH2:11][CH2:12]1
Reactant: c1cncc(N2CCC3(CCCN3)C2)c1
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: CN1CCCC12CCN(c1cccnc1)C2
Temperature: 25 °C
Yield: 93.6 %

Procedure:
7-(3-Pyridyl)-1,7-diazaspiro[4.4]nonane (30 mg, 0.15 mmol) was dissolved in 98% formic acid (0.5 mL) and formaldehyde (1 mL, 28% aqueous solution). The reaction mixture was heated to reflux for 8 h. The reaction mixture was cooled to room temperature, basified with saturated aqueous sodium bicarbonate to pH 9-10 and extracted with chloroform (4×3 mL). The combined chloroform extracts were dried (K2CO3), filtered and concentrated on a rotary evaporator to afford 30 mg of the desired compound (93.6%) as a light brown liquid.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)=[O:4].[CH2:14](I)[CH3:15].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>CO>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]=[CH:5][C:3]([O:2][CH3:1])=[O:4])=[CH:12][CH:11]=1)[CH3:15]
Reactant: COC(=O)/C=C/c1ccc(O)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: CCOc1ccc(C=CC(=O)OC)cc1

Procedure:
This ester was treated with excess ethyl iodide in the presence of potassium carbonate in refluxing dry acetone for 48 hours. A moderate yield of methyl p-ethoxycinnamate was obtained as white crystals from methanol, mp 68--70° C: λmaxCCl4 5.8, 6.09, 6.22, 6.6, 8.0, 8.56, 9.53, 10.15, and 10.8 μ. Reduction of methyl p-ethoxycinnamate in benzene with LAH gave a 50% yield, after recrystallization from methanol, of p-ethoxycinnamyl alcohol, mp 85° C: λmaxCC14 2.75, 6.2, 6.61, 6.75, 8.93, 9.2, 9.55, 9.97, 10.3, 10.85, and 11.87 μ.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:12]I.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:12][N:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]1[CH3:1]
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccn(C)c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 10 g of ethyl 2-methyl-1H-pyrrole-3-carboxylate (65.3 mmol) and 8.95 mL (130.6 mmol) of methyl iodide in 70 mL of dimethylformamide placed at 0° C. there are added, in three portions, 2.61 g (65.3 mmol) of sodium hydride (NaH) 60% . The batch is then stirred at 0° C. for 1 hour. Then, the reaction mixture is hydrolysed by the addition of 420 mL of ice-cold water. The reaction mixture is then diluted with ethyl acetate, successively washed with 0.1M aqueous hydrochloric acid (HCl) solution, saturated aqueous LiCl solution and then brine. The organic phase is then dried over MgSO4, filtered, concentrated to dryness and purified by chromatography over silica gel (petroleum ether/AcOEt gradient).
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([O:36]C)=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[C:11]([O:39][CH2:40][CH3:41])=[CH:10][C:9]=2[C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=2)[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([OH:36])=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[C:11]([O:39][CH2:40][CH3:41])=[CH:10][C:9]=2[C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=2)[CH2:6][CH2:7]1
Reactant: CCCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4cccc(F)c4)cc3OCC)CC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4cccc(F)c4)cc3OCC)CC1)CC2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to a methanol (5 mL)-THF (5 mL) solution of methyl 6-(1-((2-cyclopropyl-5-ethoxy-3′-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (300 mg), and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was neutralized with 2 M hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the solvent was distilled off under reduced pressure. The deposited solid was collected by filtration and washed with diethyl ether. The obtained solid was recrystallized (ethanol/hexane) to obtain the title compound (173 mg).
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3].[OH-].[Na+].C=O.[C:17](OCC)(=[O:19])C>O>[CH2:7]([C:6]1[CH:10]=[C:1]([O:11][CH3:12])[C:2]([OH:3])=[C:4]([CH2:17][OH:19])[CH:5]=1)[CH:8]=[CH2:9]
Reactant: C=CCc1ccc(O)c(OC)c1
Reactant: CCOC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCc1cc(CO)c(O)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 2 liter round bottom flask equipped with nitrogen inlet and magnetic stirrer was dissolved eugenol, 99% (Alfa Aesar) in a solution comprised of 286 g NaOH in 1.2 L water at 0° C. A solution of formaldehyde (828 g, 10.2 mol), 37 wt. % solution in water, A.C.S. reagent (Sigma-Aldrich) was added dropwise to the stirring solution. The mixture was stirred under nitrogen at ambient temperature for 4 hours and then 55° C. for 20 h. The reaction mixture was poured into 1 L ethyl acetate and washed with 1 N HCl and deionized water. The crude product containing ˜30 mol % unreacted eugenol was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([CH3:15])[CH2:13]Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH3:15][C@H:12]([CH2:13][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: C[C@H](CCl)Cc1ccc(C(C)(C)C)cc1
Reactant: C1CCNCC1
Product: C[C@@H](Cc1ccc(C(C)(C)C)cc1)CN1CCCCC1

Procedure:
The reaction of (a) with piperidine gives the novel compound (S)-fenpropidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15]1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]([CH2:34][N:35]3[CH2:38][CH2:37][CH2:36]3)[S:32][CH:33]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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]>[N:35]1([CH2:34][C:31]2[S:32][CH:33]=[C:29]([C:2]3[CH:3]=[C:4]4[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=3)[NH:7][CH:6]=[C:5]4[CH:14]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15]3)[CH:30]=2)[CH2:38][CH2:37][CH2:36]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Reactant: CC1(C)OB(c2csc(CN3CCC3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2csc(CN3CCC3)c2)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Temperature: 100 °C
Yield: 22.9 %

Procedure:
5-bromo-3-(1,1-dioxidotetrahydro-3-thienyl)-1H-indole-7-carboxamide (0.040 g, 0.112 mmol) and 1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]methyl}azetidine (0.035 g, 0.126 mmol, 1.1 eq) was dissolved in a 6:1 solution of 1,4 dioxane/water in a 20 mL microwave reaction vessel. Potassium carbonate (0.077 g, 0.560 mmol, 5 eq) was added and the solution was degassed with Argon. PdCl2(dppf) (0.014 g, 0.019 mmol) was added and the reaction was heated in a microwave at 100° C. for 20 min. Solution was passed through a StratoSphere SPE PL-Thiol MP SPE column to remove palladium and purified on Gilson preparative HPLC using Acetonitrile/Water with 0.1% TFA. The desired fractions were concentrated, giving 0.011 g (23%) of the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH2:7]([O:9][C:10]([C:12]1[N:13]=[N:14][N:15]([CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)[C:16]=1O)=[O:11])[CH3:8]>C1(C)C=CC=CC=1>[CH2:7]([O:9][C:10]([C:12]1[N:13]=[N:14][N:15]([CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)[C:16]=1[Cl:2])=[O:11])[CH3:8]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine PCl5 (5.73 g, 27.5 mmol) with a solution of 1-(3,5-bis-trifluoromethyl-benzyl)-5-hydroxy-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (5.30 g, 13.8 mmol) in toluene (150 mL) and heat to 50° C. After 2 hours, cool to RT, concentrate solution and dissolve crude material in ether (100 mL). Wash the organic solution with saturated NaHCO3 (2×100 mL) and brine (100 mL), dry, filter, and concentrate. Purify the crude material by passing through a short plug of silica gel using a linear gradient of 50% to 80% EtOAc/hexanes then recrystallize from 1:1 diethyl ether:petroleum ether (150 mL). MS (IS) 402.0 (M+H). 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.76 (s, 2H), 5.67 (s, 2H), 4.43 (q, 2H, J=7.0), 1.40 (t, 3H, J=7.0).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[N:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]2[C:9]([C:21]([C:20]3[CH:24]=[CH:25][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[O:22])=[CH:10][NH:11][C:12]2=[N:13][CH:14]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)c2c[nH]c3ncc(Br)cc23)cc1
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
Aluminum trichloride (2.7 g, 20.0 mmol) and methylene chloride (30 mL) were combined under an atmosphere of nitrogen and 5-bromo-7-azaindole (67, 400.0 mg, 2.30 mmol) in methylene dichloride (20 mL) was added. The reaction was stirred at room temperature for 70 minutes. 4-Methoxybenzoic acid chloride (0.38 g, 2.2 mmol) (prepared from the corresponding carboxylic acid using the protocol described in Example 1, Scheme 13, Step 4) in methylene dichloride (7.0 mL) was added. The reaction was stirred at room temperature for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give the compound (116, 250 mg, 34%).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:42]/[O:43]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15](/[CH:23]=[C:24]2/[C:25](=[O:41])[N:26]([C@@H:29]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)[CH2:27][CH2:28]/2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:42]/[OH:43])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15](/[CH:23]=[C:24]2/[C:25](=[O:41])[N:26]([C@@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)[CH2:27][CH2:28]/2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N2CC/C(=C\C3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\OC(c5ccccc5)(c5ccccc5)c5ccccc5)c5nsc(N)n5)[C@H]4SC3)C2=O)C1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(/C=C4\CCN([C@@H]5CCNC5)C4=O)CS[C@H]23)ns1
Yield: 97.3 %

Procedure:
5.2 (large scale): A suspension of 5.785 g of (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-3-[(E)-(R)-1′-tert.-butoxycarbonyl-2-oxo-[1,3′]bipyrrolidinyl-3-ylidene-methyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 1.69 ml of triethylsilane in 25 ml of dichloromethane was treated at −15° with 7.21 ml of trifluoroacetic acid and the solution was heated to 30° for 30 min after which time HPLC indicated completion of the reaction. The mixture was evaporated to dryness, the residue was digested with 60 ml of ethyl acetate, the suspension was filtered and the residue dried to give 3.43 g of the crude title compound as a brown solid, containing about 1.4 equivalents of ethylacetate. 1H-NMR (d6-DMSO): 13.9 (s, br., 1H, COOH); 11.94 (s, 1H, OH); 9.50 (d, J=8.4, 1H, NH—C(7)); 8.96 (s, br., 2H, NH2); 8.07 (s, br., 2H, NH2); 7.26 (s, br., 1H, CH—C(3)); 5.88 (dd, J=8.4 and 4.9, 1H, H—C(7)); 5.18 (d, J=4.9, 1H, H—C(6)); 4.64 (m, 1H); 3.87 (s, br., 2H H2C(4)); 3.9-2.7 (m, 8H); 2.2-2.0 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][CH2:9][O:10][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(Br)cccc1CCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1c(Br)cccc1CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(3-bromo-2-methylphenyl)ethanol [Aromatic Intermediate 22, step b] (1.67 g) and imidazole (1.60 g) in DMF (20 mL) was cooled in ice-water, treated with tert-butyldimethylchlorosilane (1.31 g), then removed from the cooling bath and stirred at room temperature overnight. The solution was poured into water and extracted twice with diethyl ether. The combined organic extracts were washed twice with water, once with brine, then dried over anhydrous magnesium sulphate and purified by flash chromatography on silica eluted with 10% dichloromethane in isohexane to afford the subtitled compound as a colourless oil. Yield 2.06 g.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[C:4]=2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[N:7]=1.[F:30][C:31]1[CH:32]=[C:33]([CH:41]=[C:42](B2OC(C)(C)C(C)(C)O2)[C:43]=1[CH3:44])[C:34]([O:36]C(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:13]([N:12]([CH2:15][CH3:16])[CH2:11][CH2:10][CH2:9][NH:8][C:6]1[N:7]=[C:2]([C:42]2[CH:41]=[C:33]([CH:32]=[C:31]([F:30])[C:43]=2[CH3:44])[C:34]([NH:17][CH:22]([CH3:27])[CH3:23])=[O:36])[C:3]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[C:4]=2[N:5]=1)[CH3:14]
Reactant: Cc1c(F)cc(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CCN(CC)CCCNc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC(C)C)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 150 °C

Procedure:
To the compound 4-chloro-2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (600 mg, 1.422 mmol) in dioxane (15 mL) and water (5 mL) were added 1,1-dimethylethyl 3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (542 mg, 2.132 mol), potassium carbonate (590 mg, 4.26 mmol) and tetrakis(triphenylphosphine)-palladium(0) (82 mg, 0.071 mmol). The mixture was heated with microwave at 150° C. for 15 minutes. The mixture was filtered. Separation by HPLC with TFA afforded the crude title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:20]1([CH:30]=O)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>[OH-].[K+].CCO>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:30][C:20]2[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1cccc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2cccc3ccccc23)CCc2cc(OCCn3ccnc3)ccc21
Yield: 87.6 %

Procedure:
According to the method of Example 6, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.475 g, 1.85 mmol) was reacted with 1-naphthaldehyde (0.448 g, 2.87 mmol) in 3.0 mL of 4% KOH in EtOH for 6 hours at room temperature to afford 0.639 g (88%) of the title compound as a bright yellow solid, mp 147-148° C.: CI-MS m/e 494 (M+), 495 (M++1);