Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:37]=[CH:36][C:9]([NH:10][C:11]2[N:12]=[C:13]([CH3:35])[C:14]3[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]4[CH:34]=[CH:33][C:25]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:24][CH:23]=4)[C:15]=3[N:16]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([NH:10][C:11]2[N:12]=[C:13]([CH3:35])[C:14]3[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]4[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:33][CH:34]=4)[C:15]=3[N:16]=2)=[CH:36][CH:37]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2nc(C)c3ccc(=O)n(-c4ccc(C(=O)OC(C)(C)C)cc4)c3n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(Nc2nc(C)c3ccc(=O)n(-c4ccc(C(=O)O)cc4)c3n2)cc1
Yield: 84.5 %

Procedure:
A solution of compound 3 (0.12 g; 0.2397 mmol) and trifluoroacetic acid (0.2 mL; 2.62 mmol) in 3 mL of methylene chloride was stirred at room temperature for 2 h. The reaction mixture was concentrated and the crude product taken up with ethyl acetate and n-hexane to yield compound 9 (0.09 g; 84%).
Reaction SMILES: [CH2:1]([P:8](=[O:15])([O:12]CC)[O:9][CH2:10][CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CCO>[CH2:10]([O:9][P:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:12])[OH:15])[CH3:11]
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(O)Cc1ccccc1
Temperature: 25 °C

Procedure:
Diethyl benzylphosphonate (5.0 mL, 5.5 g, 24 mmol) was dissolved in absolute EtOH (25 mL), then 50% NaOH (3 mL) was added. The reaction was heated under reflux overnight, allowed to cool to RT, then partitioned between 2N HCl and EtOAc. Washed organic layer with brine, extracted combined aqueous layers with EtOAc, dried combined organic layers over Na2SO4. After filtration and concentration recovered 4.5 g (93%). MS (DCI/NH3) 201/218 (M+H)+/(M+H+NH3)+.
Reaction SMILES: N[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.N([O-])=O.[Na+]>CC(O)=O>[NH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=2)[CH:2]=[N:3]1
Reactant: N#Cc1ccc2c(N)n[nH]c2c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 56 %

Procedure:
To a suspension of 3-amino-1H-indazole-6-carbonitrile (345 mg) in AcOH was slowly added an aqueous NaNO2 solution (301 mg) at 0° C. It was stirred at room temperature for 2.5 days, and the residue was collected by filtration, and washed with cool water. To the residue were added 0.1 M HCl and DME, followed by stirring at 80° C. for 2 hours. The reaction mixture was neutralized with a saturated aqueous NaHCO3 solution, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=80:20 to 50:50) to obtain 1H-indazole-6-carbonitrile (175 mg) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[N:29][CH:30]=[C:31]([CH:35]=1)[C:32]([NH2:34])=[O:33]>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[N:29][CH:30]=[C:31]([CH:35]=3)[C:32]([NH2:34])=[O:33])=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NC(=O)c1cncc(Br)c1
Product: NC(=O)c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (400 mg, 1.13 mmol) and 5-bromonicotinamide [CAS 28733-43-9; commercially available] (204 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (140 mg, 26%). MS (ISP) 476.2 [(M+H)+]; mp 285-287° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:8][C:9]=1[N:10]([C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[Cl:35])[CH2:11][C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[CH:15][CH:16]=1)=[O:4].[OH-].[Li+].Cl>C1COCC1.O>[Cl:35][C:29]1[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:28]=1[C:27]([N:10]([CH2:11][C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=2)=[CH:15][CH:16]=1)[C:9]1[CH:8]=[C:7]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])=[O:36]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(Cc1ccc(-c2cccc(C(F)(F)F)c2)o1)C(=O)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1sc(-c2ccccc2)cc1N(Cc1ccc(-c2cccc(C(F)(F)F)c2)o1)C(=O)c1ccc(Cl)cc1Cl
Reaction time: 5 h
Yield: 76 %

Procedure:
3-{(2,4-Dichloro-benzoyl)-[5-(3-trifluoromethyl-phenyl)-furan-2-ylmethyl]-amino}-5-phenyl-thiophene-2-carboxylic acid methyl ester (62 mg, 0.098 mmol) was dissolved in THF (5 mL) and water (2 mL). A solution of lithium hydroxide (13 mg, 3 eq. in 2 mL of water) was added dropwise. After first few drop, a pink color appeared and disappeared. Mixture was stirred for 5 hrs and acidified with 1N HCl-solution. The product was extracted into ethyl acetate, washed once with water, dried over magnesium sulfate. Solvent was evaporated and the residue was purified on silica gel (Bond-Elute 2 g). The product was elute with a 20 mL gradient of Hexane:EtOAc 9:1. 4:1, 7:3, 3:2, 1:1, 2:3 and EtOAc to give the desired product in 76% yield (46 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:12]1[C:11](=[O:14])[C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)=[N:13]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Reactant: ClCc1ccccc1
Product: COC(=O)c1cc(-c2ccc(F)c(C)c2)nn(Cc2ccccc2)c1=O
Yield: 71 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and benzyl chloride were reacted to yield the title compound as yellow needles (yield: 71.0%).
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:8][C:9]1[CH:10]=[C:11]([NH:12][C:1]([CH3:2])=[CH:4][C:5](=[O:7])[CH3:6])[CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)CC(C)=O
Reactant: Cc1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=C(C)Nc1cccc(C)c1
Temperature: 25 °C

Procedure:
23.36 g (233 mmol) Acetylacetone, 5.00 g (47 mmol) 3-methylaniline, and 0.8 g (4.7 mmol) 4-toluenesulfonic acid are dissolved in 50 ml toluene. The reaction mixture is refluxed overnight with a Dean-Stark trap to remove water. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethylacetate mixtures as eluent.
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]([CH3:35])([CH3:34])[CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]([C:32]#[N:33])[C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[C:17]([O:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[Cl:31])[CH:16]=2)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:31][C:25]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=1[O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:21]([OH:22])=[C:12]([C:10]([NH:9][CH2:8][C:7]([CH3:35])([CH3:34])[C:6]([OH:36])=[O:5])=[O:11])[N:13]=[C:14]2[C:32]#[N:33])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3cc(F)ccc3Cl)ccc2c1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3cc(F)ccc3Cl)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A mixture of 3-{[7-(2-chloro-5-fluoro-phenoxy)-1-cyano-4-hydroxy-isoquinoline-3-carbonyl]-amino}-2,2-dimethyl-propionic acid tert-butyl ester (19 mg), TFA (1 mL) and DCM (2 mL) was stirred at rt overnight; then concentrated, the residue was dissolved in water and added 2 M HCl solution, solids were collected via filtration, washed with water and air dried to give the desired product (17 mg). LC MS ESI+: 458 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:5]([NH2:14])=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:23](=[O:29])[C:24](OCC)=[O:25]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:14][C:24](=[O:25])[C:23](=[O:29])[N:8]([CH2:9][CH2:10][CH:11]([CH3:12])[CH3:13])[C:6]=2[N:7]=1
Reactant: CC(C)CCNc1nc(Cl)ncc1N
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)CCn1c(=O)c(=O)[nH]c2cnc(Cl)nc21
Temperature: 25 °C
Yield: 59.8 %

Procedure:
To a stirred solution of 2-chloro-N4-(3-methylbutyl)pyrimidine-4,5-diamine (2.8 g, 13.08 mmol) in toluene (40 mL) was added triethylamine (4.23 g, 41.88 mmol) and ethyl chlorooxoacetate (1.95 g, 14.33). The mixture was then heated to reflux for 16 h. It was then cooled to rt, the bulk of solvent was removed under reduced pressure to give a crude residue, which was purified by silica gel column chromatography (eluent: 70% ethyl acetate in hexane) afforded the desired product (2.1 g). 1H NMR (CDCl3, 300 MHz) δ 1.01 (d, J=6.6 Hz, 6H), 1.60-1.82 (m, 3H), 4.20-4.35 (m, 2H), 8.35 (s, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:12])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[C:26]([Br:33])[C:25]=1I.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CN(C)C=O>[Br:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[C:26]([Br:33])[C:25]=1[O:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Br)c(I)c(Br)c1
Reactant: COc1ccc(O)cc1C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2c(Br)cc([N+](=O)[O-])cc2Br)cc1C(C)C
Temperature: 0 °C

Procedure:
A 22 L jacketed vessel equipped with mechanical stirring and a nitrogen inlet adapter was charged with dimethylformamide (4 L) and 3-isopropyl-4-methoxyphenol (462.8 g, 2.59 moles). The solution was cooled to 0° C., and KHMDS (5.50 L of 0.5M toluene solution, 2.25 moles) was added over 1.5 h while maintaining the temperature of the mixture below 2° C. The reaction mixture was stirred for 30 min at 2° C., then 1,3-dibromo-2-iodo-5-nitro-benzene (798.6 g, 1.96 moles) was added in portions, still maintaining temperature of the mixture below 2° C. After the addition was complete, the reaction mixture was allowed to stir at room temperature for 2 h or until the reaction was complete as assayed by HPLC. The reaction mixture was cooled once more to 2° C. and ethyl acetate (4.5 L) was added, followed by slow addition of saturated aqueous sodium bicarbonate (6 L) while maintaining the temperature of the reaction mixture below 28° C. The organic layer was washed with saturated aqueous sodium chloride solution, then concentrated by rotary evaporation. The black, oily residue was taken up in acetone (3.87 L). Water (0.77 L) was added to the solution over 30 min with heating to 42° C. The solution was seeded with crystals of the product, cooled to 0° C., and stirred for 15 min. The resulting crystals of 4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylanisole (665 g, 76.1%) were recovered by filtration and dried for 48 h by evaporation under air flow at room temperature.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[N:16]3[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]3)=[C:10]([C:17]#[N:18])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-:19].[K+]>>[CH3:1][C:2]1[C:7]([C:8]2[N:16]3[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]3)=[C:10]([C:17]([NH2:18])=[O:19])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: [OH-]
Reactant: Cc1ncccc1-c1cc(C#N)c2n1CCCC2
Agent: [K+]
Product: Cc1ncccc1-c1cc(C(N)=O)c2n1CCCC2
Yield: 87.2 %

Procedure:
3-(2-Methyl-3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide is prepared as described in Example 11, from 23.3 g of 3-(2-methyl-3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile and 33 g of potassium hydroxide. 21.85 g of 3-(2-methyl-3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide are thus obtained in the form of a white solid melting at 244° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([CH3:17])[CH:15]=[N:14][C:13]=3[C:18]3[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][N:19]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4]1.[H-].[Na+].[CH3:28]I>CN(C=O)C>[CH3:28][O:1][CH2:2][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([CH3:17])[CH:15]=[N:14][C:13]=3[C:18]3[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][N:19]=3)=[CH:8][CH:7]=2)[CH2:4][CH2:5]1
Reactant: CI
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(C2(CO)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1(c2ccc(-c3c(-c4cc(C#N)ccn4)ncn3C)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (30 mg, 0.09 mmol; Example 17, part A) in anhydrous DMF (2 mL) at 0° C. was added 60% NaH (6 mg, 0.136 mmol). After stirring for 10 minutes, MeI (10 μL, 0.136 mml) was added. The reaction mixture was warmed up to r.t. and stirred for 3 hr. It was then purified by ISCO flash column chromatography (MeOH/DCM=0-5%) to give the title product which was used for next step. [M+H] Calc'd for C21H20N4O, 345. Found, 345.
Reaction SMILES: Cl.[CH2:2]([O:5][NH2:6])[CH:3]=[CH2:4].[OH-].[Na+].[OH:9][C:10]1[CH2:15][CH:14]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([Br:24])[C:17]=2[CH3:25])[CH2:13][C:12](=[O:26])[C:11]=1[C:27](=O)[CH2:28][CH3:29].C(O)C>O>[CH2:2]([O:5][N:6]=[C:27]([C:11]1[C:12](=[O:26])[CH2:13][CH:14]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([Br:24])[C:17]=2[CH3:25])[CH2:15][C:10]=1[OH:9])[CH2:28][CH3:29])[CH:3]=[CH2:4]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(Br)c2C)CC1=O
Reactant: C=CCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)c(Br)c2C)CC1=O
Yield: 57.3 %

Procedure:
Allyloxyamine hydrochloride (0.17 g) and then a solution of sodium hydroxide (0.06 g) in water (1 ml) were added to a stirred mixture of 3-hydroxy-2-propionyl-5-(3-bromo-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (0.50 g, 1.37 mmole) and 95% ethanol. The progress of the reaction was monitored using thin layer chromatography on silica gel (eluant dichloromethane). On completion of the reaction the ethanol was removed by evaporation under reduced pressure and the residue was extracted with dichloromethane. The organic extract was washed with aqueous 5% hydrochloric acid and then with water and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure to give the product, 2-[1-(allyloxyimino)propyl]-3-hydroxy-5-(3-bromo-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (0.33 g, 57.4%) as an oil.
Reaction SMILES: C(N1CCN([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[CH2:13][CH2:12][CH2:11]2)CC1)(=O)C.[OH-:22].[Na+]>C(O)C>[OH:22][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: [OH-]
Reactant: COc1ccc2c(c1)C(N1CCN(C(C)=O)CC1)CCC2
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1)C(O)CCC2

Procedure:
1-(4-Acetylpiperazin-1-yl)-7-methoxy-1,2,3,4-tetrahydronaphthalene (0.85 g) was dis solved in ethanol (10 ml). After adding an 8 N aqueous solution (3 ml) of sodium hydroxide, the resultant mixture was heated under reflux for 3 hr. Then the liquid reaction mixture was concentrated under reduced pressure and the residue was purified by NH-silica gel column chromatography (ethyl acetate) to give the title compound (0.6 g) as a pale brown oil. (280-4) 1-[4-(4-Fluorophenylacetyl)piperazin-1-yl]-7-methoxy-1,2,3,4-tetrahydronaphthalene
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12.[O:19]=[C:20]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:21][C:22](O)=[O:23].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:22](=[O:23])[CH2:21][C:20]([NH:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12
Reactant: O=C(O)CC(=O)Nc1ccccc1
Reactant: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(CC(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.3 %

Procedure:
To a solution of 3 (660 mg, 2.27 mmol) in MeOH (10 ml) was added conc. HCl (1 ml) and Fe (1.91 g, 34.8 mmol), and the reaction mixture was stirred at 0° C. for 3 hrs, neutralized with aqueous NaHCO3 solution and extracted with EtOAc, producing 3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)-phenylamine (4) as a dark oil (500 mg, 83%), which was used directly in the next step. To a solution of the amine 4 (200 mg, 0.69 mmol) in DMF (10 ml) was added 3-oxo-3-(phenylamino)propanoic acid (1, 155 mg, 0.89 mmol), HOBT (121 mg, 0.89 mmol) and EDC (198 mg, 1.035 mmol). The reaction mixture was stirred at room temperature overnight, evaporated to dryness and the residue was dissolved in EtOAc and washed with water. The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (eluent EtOAc:hexane 3:1) to afford the title compound 5a (30 mg, 10% yield) as a white solid (after trituration with Et2O). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.5 (s, 1H), 10.2 (s, 1H), 8.49 (d, J=5.48 Hz, 1H), 8.14 (d, J=5.48 Hz, 1H), 7.85 (dd, J=2.35 and 13.01 Hz, 1H), 7.59 (m, 3H), 7.42 (m, 2H), 7.30 (dt, J=1.96 and 7.43 Hz, 2H), 7.05 (t, J=7.24 Hz, 1H), 6.65 (d, J=5.28 Hz, 1H), 3.51 (s, 2H).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=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>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1ccccc1
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
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: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3ccccc3)c(=O)n12
Temperature: 100 °C
Yield: 44.4 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.100 g, 0.318 mmol) and phenylboronic acid (46.6 mg, 0.382 mmol) in 1,4-dioxane (2 mL) was added a 1 M solution of sodium carbonate (40.5 mg, 0.382 mmol) in water (0.38 mL) and tetrakis(triphenylphosphine)palladium (0) (18.4 mg, 0.0159 mmol). The reaction mixture was heated at 100° C. overnight. After cooling to rt, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexane, to provide the desired product (44 mg, 44.4%). LCMS calculated for C15H14N5OS (M+H)+: m/z=312.1. Found: 312.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][N:7]=[C:6]2[O:23]C1C=CC=CC=1>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][NH:7][C:6]2=[O:23]
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCCN1CCOCC1
Agent: Cl
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Yield: 89.1 %

Procedure:
6-Methoxy-7-(3-morpholinopropoxy)-4-phenoxyquinazoline (33.08 g, 84 mmol) was dissolved in 6M aqueous hydrochloric acid (800 ml) and heated at reflux for 1.5 hours. The reaction mixture was decanted and concentrated to 250 ml then basified (pH9) with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with dichloromethane (4×400 ml), the organic layer was separated and filtered through phase separating paper. The solid was triturated with ethyl acetate to give 6-methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (23.9 g, 89%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C@@H:4]([N:29]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([NH:17]C(OCC2C=CC=CC=2)=O)=[CH:13][CH:12]=1.C1COCC1>[Pd].C(O)(C)C>[CH3:1][O:2][C:3](=[O:42])[CH:4]([N:29]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:28])[C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1
Reactant: COC(=O)[C@H](CCCCNC(=O)c1ccc(NC(=O)OCc2ccccc2)cc1)n1c2ccccc2c2ccccc21
Agent: [Pd]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COC(=O)C(CCCCNC(=O)c1ccc(N)cc1)n1c2ccccc2c2ccccc21
Reaction time: 4 h
Yield: 97.6 %

Procedure:
10% Pd/C (0.035 g) was added in one portion to a stirred solution of (S)-6-(4-benzyloxycarbonylamino-benzoylamino)-2-carbazol-9-yl-hexanoic acid methyl ester 11 (0.350 g, 0.62 mmol) in a 1:1 mixture of THF (5 mL) and isopropanol (5 mL) and nitrogen atmosphere. The reaction mixture was subsequently stiffed under hydrogen atmosphere for 4 h at room temperature. The reaction mixture was passed through a celite pad, and the filtrate was concentrated in under reduced pressure to give (S) 6-(4-amino-benzoylamino)-2-carbazol-9-yl-hexanoic acid methyl ester (12) (0.260 g, 98%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5]([CH3:7])=[C:4]([CH3:8])[C:3]=1[CH3:9].C([Li])CCC.Br[CH2:16][CH2:17][Cl:18].O>C(OCC)C>[CH3:1][C:2]1[CH:6]([CH2:16][CH2:17][Cl:18])[C:5]([CH3:7])=[C:4]([CH3:8])[C:3]=1[CH3:9]
Reactant: ClCCBr
Reactant: CC1=C(C)C(C)=C(C)C1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC1=C(C)C(CCCl)C(C)=C1C
Temperature: 2 °C
Reaction time: 18 h

Procedure:
A 1-liter three-necked flask, provided with a dropping funnel, condenser, mechanical stirrer and nitrogen inlet, was charged with 30.5 g of 1,2,3,4-tetramethylcyclopentadiene (0.25 mol), dissolved in 700 mL of ethoxyethane, and cooled to 2° C. Then 160 mL of n-butyllithium (1.6 M in hexane; 0.26 mol) were added dropwise in two hours, followed by 18 hours of stirring at room temperature with the aid of a mechanical stirrer. Then 36.0 g of 1-bromo-2-chloroethane (0.25 mol) were added all at once. The reaction mixture was stirred at room temperature for 10 days. GC analysis of a sample showed that the conversion of the tetramethylcyclopentadiene was 91%. One hundred ml of water were added to the reaction mixture, followed by separation of the water phase and the organic phase. The organic layer was washed once with 50 mL of saturated aqueous sodium chloride solution, dried with sodium sulphate, filtered and boiled down. The residue (43.9 g) proved to have the following composition according to gas chromatography (GC) analysis: apart from the starting materials, 1-bromo-2-chloroethane (9 wt %) and 1,2,3,4-tetramethylcyclopentadiene (9 wt %). Only non-geminally coupled product (84%) and geminally coupled product (16%) were found to be present.