Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[F:24][C:25]([F:37])([F:36])[C:26]1[CH:27]=[C:28]([CH2:32][C:33](O)=[O:34])[CH:29]=[CH:30][CH:31]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1C=CC=CC=1>C(OCC)(=O)C>[C:14]([NH:13][C:11]1[S:12][C:8]2[C:7]([C:19]#[N:20])=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:33](=[O:34])[CH2:32][C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:36])([F:24])[F:37])[CH:27]=4)[CH:23]=[CH:22][CH:21]=3)[CH:18]=[CH:17][C:9]=2[N:10]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Cc4cccc(C(F)(F)F)c4)c3)c(C#N)c2s1
Temperature: 85 °C
Reaction time: 12 h
Yield: 69.2 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (141 mg, 0.436 mmol) produced in Example 12(ii), [3-(trifluoromethyl)phenyl]acetic acid (176 mg, 0.872 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (331 mg, 0.872 mmol) and pyridine (3 mL) was stirred at 85° C. for 12 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), washed successively with saturated aqueous ammonium chloride solution (5 mL), saturated aqueous sodium hydrogen carbonate solution (5 ml) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-heptane (1/1) to give the title compound (154 mg, 69%) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH3:12])=[C:6]([N:27]2[CH:31]=[CH:30][CH:29]=[CH:28]2)[CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH3:12])=[C:6]([N:27]2[CH:31]=[CH:30][CH:29]=[CH:28]2)[CH:5]=1
Reactant: [H][H]
Reactant: COc1ccc(CCN(C)CCOc2ccc([N+](=O)[O-])cc2-n2cccc2)cc1OC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(CCN(C)CCOc2ccc(N)cc2-n2cccc2)cc1OC
Yield: 99.1 %

Procedure:
A portion (0.53 g, 1.25 mmol) of the 1-[4-nitro-2-(1H-pyrrol-1-yl)phenoxy]-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane produced in (3) above was dissolved in 50 ml of a 1:1 solvent system of ethyl acetate and methanol and 10% Pd/C (0.15 g) was slowly added to the solution, which was thereafter stirred at ordinary temperatures for 10 min as hydrogen gas was injected. Thereafter, the reaction mixture was filtered through Celite and the filtrate was evaporated, with the residue being purified by being subjected to column chromatography on silica gel using, as an eluent, ethyl acetate containing methanol (10%). The fractions containing the end product were combined and the solvent was evaporated to yield the end compound 1-[4-amino-2-(1H-pyrrol-1-yl)phenoxy]-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane (0.49 g) as a yellow oil.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][N:10]([CH:18]([C:22]1[N:31]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30](=[O:39])[C:29]2[C:24](=[CH:25][C:26]([Cl:40])=[CH:27][CH:28]=2)[N:23]=1)[CH:19]([CH3:21])[CH3:20])[C:11](=[O:17])[C:12]([CH3:16])([CH3:15])CCl)(C)(C)C.C(OC(=O)NCCNC(C1N(CC2C=CC=CC=2)C(=O)C2C(=CC(Cl)=CC=2)N=1)C(C)C)(C)(C)C.ClCC(C)(C)C(Cl)=O.CCN(CC)CC>C(Cl)Cl>[CH2:32]([N:31]1[C:30](=[O:39])[C:29]2[C:24](=[CH:25][C:26]([Cl:40])=[CH:27][CH:28]=2)[N:23]=[C:22]1[CH:18]([N:10]1[C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH2:6][NH:7][CH2:8][CH2:9]1)[CH:19]([CH3:20])[CH3:21])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N(CCNC(=O)OC(C)(C)C)C(=O)C(C)(C)CCl
Agent: CC(C)(CCl)C(=O)Cl
Agent: CC(C)C(NCCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCNCC(C)(C)C1=O
Reaction time: 48 h

Procedure:
Preparation of {2-[[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-(3-chloro-2,2-dimethyl-propanoyl)-amino]-ethyl}-carbamic acid tert-butyl ester: {2-[1-(3-Benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-ethyl}-carbamic tert-butyl ester (450 mg, 0.93 mmol) was treated with 3-chloropivaloyl chloride (360 μL, 2.80 mmol) and Et3N (388 μl, 2.80 mmol) in CH2Cl2 (10 mL) at room temperature. After 48 h, the mixture was diluted with CH2Cl2 (10 mL), washed with water, brine, dried and concentrated under vacuum. Purification by flash chromatography on silica gel (3–6% EtOAc in hexane) gave the title compound (413 mg) as a clear oil: MS (ES) m/e 603 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[CH2:17][CH2:18][NH:19][C:20](N1C=CN=C1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC>C1(C)C(C)=CC=CC=1>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]2[C:20](=[O:21])[NH:19][CH2:18][CH2:17][C:9]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCc1[nH]c2ccccc2c1Cc1ccccc1)n1ccnc1
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Product: O=C1NCCc2c(Cc3ccccc3)c3ccccc3n21
Yield: 62.3 %

Procedure:
A solution of N-[2-(3-benzylindol-2-yl)ethyl]-1-imidazolecarboxamide (2.4 g) in xylene (50 ml) was refluxed for 3 hours. After cooling, the mixture was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (5%-methanol-chloroform) to give a crystalline product. The product was pulverized with n-hexane to give 5-benzyl-3,4-dihydropyrimido[1,6-a]indol-1(2H)-one (1.2 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]([CH2:20][CH2:21][O:22][CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.C([O-])([O-])=O.[Cs+].[Cs+].[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>CN(C=O)C.O>[Cl:13][C:6]1[CH:5]=[C:4]([CH:14]([CH2:20][CH2:21][O:22][CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=[C:2]([C:35]2[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=2)[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(CCOC)c1cc(Cl)c(OCC2CC2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCOC)c1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 45 %

Procedure:
To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methoxybutanoate (2.3 g, 5.660 mmol) in a mixture of DMF (50 mL) and water (5 mL) were added Cs2CO3 (6.4 g, 19.815 mmol), Pd(TPP)4 (1.3 g, 1.120 mmol) and 4-(trifluoromethyl)phenyl boronic acid (1.29 g, 6.780 mmol) at RT under N2 atmosphere and the resulting mixture was stirred at 80° C. for 14 h. After completion of starting material (by TLC), filtered off the catalyst and celite bed was washed with EtOAc and extracted with EtOAc (3×100 mL). Combined organic layers were washed with water (3×50 mL), brine and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude material was purified by column chromatography to afford ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoate (1.2 g) as an off white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:11][CH2:10][CH:9]([CH3:12])[CH2:8]1)[CH2:6][C:5]2=O.C[Si]([N:22]=[C:23]=[N:24][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:11][CH2:10][CH:9]([CH3:12])[CH2:8]1)[CH2:6]/[C:5]/2=[N:24]\[C:23]#[N:22]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: CC1CCC2(CC(=O)c3cc(Br)ccc3O2)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1CCC2(C/C(=N\C#N)c3cc(Br)ccc3O2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To a solution of 6-bromo-3′-methylspiro[chroman-2,1′-cyclopentan]-4-one (216 mg, 0.73 mmol) in anhydrous DCM (5.7 mL) was added TiCl4 (1 M solution in DCM, 1.5 mL, 1.49 mmol) dropwise within 15 min at room temperature. The mixture was stirred for 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (300 mg, 0.36 mL, 1.61 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (20 g) and extracted with DCM (3×20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give (E)-N-(6-bromo-3′-methylspiro[chroman-2,1′-cyclopentane]-4-ylidene)cyanamide as light brown solid (225 mg), which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[S:19]1[CH:23]=[N:22][N:21]=[C:20]1[C:24]([OH:28])([C:26]#[CH:27])[CH3:25]>>[OH:28][C:24]([C:20]1[S:19][CH:23]=[N:22][N:21]=1)([CH3:25])[C:26]#[C:27][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: C#CC(C)(O)c1nncs1
Product: CC(O)(C#Cc1ccc2c(c1)-c1nc(C(N)=O)cn1CCO2)c1nncs1
Yield: 2 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(1,3,4-thiadiazol-2-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (1.7 mg, 2%).
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.N1C=CC=CC=1>C(#N)C>[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:14][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(Nc1ccc2oc3c(c2c1)CCCC3)c1ccc(F)cc1
Yield: 65.9 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.50 g, 2.7 mmol), 4-fluorobenzoyl chloride (0.32 mL, 2.7 mmol), and pyridine (0.54 mL, 6.7 mmol) in acetonitrile (30 mL) provided 4-fluoro-N-(6,7,8,9-tetrahydrodibenzo[b,d]furan-2-yl)benzamide (0.55 g) after filtering the precipitate from the reaction mixture. MS (ESI) m/z 310 ([M+H]+).
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[CH2:16]([C:18]1([CH2:24][CH2:25][OH:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH3:17].CC1(C)N([O])C(C)(C)CCC1.C(OCC)C>C(Cl)Cl>[CH2:16]([C:18]1([CH2:24][CH:25]=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)[CH3:17]
Reactant: CCC1(CCO)CCCCC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC1(CC=O)CCCCC1
Reaction time: 15 h
Yield: 220.4 %

Procedure:
After adding iodobenzene diacetate (1.61 g, 4.98 mmol) to a solution of 2-(1-ethylcyclohexyl)ethanol (708 mg, 4.53 mmol) in methylene chloride (15 mL) at room temperature, 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (70.8 mg, 0.450 mmol) was added and the mixture was stirred for 15 hours. Diethyl ether was added to the reaction mixture, which was then washed with 10% aqueous sodium thiosulfate, 1N hydrochloric acid and saturated aqueous sodium hydrogencarbonate in that order. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound as an orange oil (1.54 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][C:16]2[CH:33]=[CH:32][C:19]([C:20]([NH:22][C@@H:23]([CH2:28][CH2:29][S:30][CH3:31])[C:24]([O:26]C)=[O:25])=[O:21])=[C:18]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH:17]=2)[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][C:16]2[CH:33]=[CH:32][C:19]([C:20]([NH:22][C@@H:23]([CH2:28][CH2:29][S:30][CH3:31])[C:24]([OH:26])=[O:25])=[O:21])=[C:18]([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)[CH:17]=2)[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(OC(Cn2ccnc2)c2ccc(F)cc2)cc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSCC[C@H](NC(=O)c1ccc(OC(Cn2ccnc2)c2ccc(F)cc2)cc1-c1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl (2S)-2-{4-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy]-2-(4-fluorophenyl)benzoylamino}-4-methylsulfanylbutyrate (0.037 g; 0.061 mmol) in methanol (3 ml) was treated with 2N aqueous sodium hydroxide solution (0.32 ml) and the mixture stirred at ambient temperature for 2 hours. After evaporation of the methanol, the aqueous residue was acidified to pH 7.5 with 6N HCl and purified on reverse phase silica eluting with a gradient of 50-60% methanol ammonium carbonate buffer (2 g/l, pH 7). The appropriate fractions were concentrated and freeze-dried to give the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18]CC)=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[OH-].[Na+].Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)c1ccc(-c2ccc(OC)c(Br)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cc1Br
Temperature: 90 °C

Procedure:
A stirred mixture of 3′-bromo-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid, ethyl ester (28.8 g, 86 mmol) and aqueous sodium hydroxide (35 mL of 2 M) in ethanol (690 mL) is heated at 90° C. for 2 h. The cooled mixture is then acidified with hydrochloric acid (200 mL of 1.0 M) and the resulting precipitate is filtered off and dried to give 3′-bromo-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid as a colourless crystalline solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[NH2:22][C:23]1[C:24]2[CH:35]=[C:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[S:33][C:25]=2[N:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl.CN(C)C=O>[N:7]1([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:22][C:23]3[C:24]4[CH:35]=[C:34]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[S:33][C:25]=4[N:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=3)=[O:19])=[CH:20][CH:21]=2)[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)n1nc(N)c2cc(C(=O)OC(C)(C)C)sc21
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCOCC3)cc2)c2cc(C(=O)OC(C)(C)C)sc21
Temperature: 5 °C
Yield: 41.9 %

Procedure:
Oxalyl chloride (20.2 mL, 231 mmol) was added to a suspension of 4-morpholin-4-ylbenzoic acid (7.98 g, 38.5 mmol) in dry dichloromethane (DCM, 210 mL) and dimethylformamide (DMF, 0.04 mL). After refluxing the mixture for 6.5 hours, volatiles were carefully removed under reduced pressure (taking up the residue three times with toluene). The resulting 4-morpholin-4-ylbenzoyl chloride hydrochloride was added portion-wise (in about 0.5 hours) to a suspension of 5-tert-butyl 1-ethyl 3-amino-1H-thieno[2,3-c]pyrazole-1,5-dicarboxylate (6.0 g, 19.3 mmol) in dry DCM (200 mL) and pyridine (23.2 mL, 289 mmol), under stirring at 5° C. The resulting suspension was stirred for 20 hours at room temperature. 300 mL of DCM and 300 mL of aqueous sodium bicarbonate were then added to the reaction mixture; the organic layer was separated, washed with brine, dried over sodium sulphate and evaporated. Purification by chromatography (DCM/ethyl acetate 7:3) gave 4.05 g of the title compound.
Reaction SMILES: IC1C=C2C(=CC=1)C(=O)NC(=O)C2.[I:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[NH:20][C:19](=[O:26])[C:18]2=[CH:27]OC.[NH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([C:39]2[CH:43]=[CH:42][O:41][CH:40]=2)=[C:36]([OH:38])[CH:37]=1>>[O:41]1[CH:42]=[CH:43][C:39]([C:35]2[CH:34]=[CH:33][C:32]([CH2:31][NH:30][CH:27]=[C:18]3[C:17]4[C:22](=[CH:23][CH:24]=[C:15]([I:14])[CH:16]=4)[C:21](=[O:25])[NH:20][C:19]3=[O:26])=[CH:37][C:36]=2[OH:38])=[CH:40]1
Reactant: NCc1ccc(-c2ccoc2)c(O)c1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Agent: O=C1Cc2cc(I)ccc2C(=O)N1
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccoc2)c(O)c1
Yield: 56 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4. -ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound is prepared from 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (85 mg, 0.26 mmol) and 5-Aminomethyl-2-furan-3-yl-phenol in 56% yield: MS (ESI): 487.1 (M+1)+1.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.C([C:11]1[C:12]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])C)=[N:13][CH:14]=[CH:15][CH:16]=1)=O>C1COCC1.Cl>[CH:22]1([C:19]2[C:18]([OH:23])=[N:17][C:12]3[C:11]([CH:21]=2)=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:3][CH2:2]1
Reactant: CC(C)(C)C(=O)Nc1ncccc1C=O
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Oc1nc2ncccc2cc1C1CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution (−78° C.) of LDA (2.0 M, 251 mmol) in 600 mL THF was added ester 4-3 (prepared from cyclopropylacetic acid and methanolic HCl solution, 15 g, 131 mmol) gradually over 30 min. The reaction mixture was stirred for 30 min at −78° C. Aldehyde 4-2 (22.5 g, 109 mmol) in 40 mL THF was added. The reaction mixture was stirred at −78° C. for 1 hr, then was warmed up to room temperature over 1 hr and quenched with 200 mL NH4Cl (sat.). The mixture was extracted with ethyl acetate (×3). The combined organic layers were washed with water, brine and dried over MgSO4 and concentrated to give a viscous residue which was subsequently dissolved in 200 mL 3N HCl. The mixture was refluxed at 105° C. for 24 hr. After concentration, the residue was poured into 500 mL ice-water and quenched with K2CO3 gradually (pH=9) to yield a solid as the desired product 4-4, which was filtered and dried in vacuum.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][NH:35]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[NH:35]1[C:36]2[C:32](=[C:31]([C:2]3[N:3]=[C:4]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:5]4[O:10][C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)=[CH:8][C:6]=4[N:7]=3)[CH:39]=[CH:38][CH:37]=2)[CH:33]=[N:34]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2oc(-c3ccccc3)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3o2)cc1
Temperature: 150 °C
Reaction time: 0.42 h

Procedure:
2-Chloro-4-morpholino-6-phenylfuro[3,2-d]pyrimidine (50 mg, 1.0 eq) was dissolved in toluene/ethanol/water (4:2:1, 2.8 ml) and treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (97 mg, 2.5 eq), PdCl2(PPh3)2 (13.3 mg, 0.12 eq) and sodium carbonate (59 mg, 3.5 eq). The vial was sealed and heated with stirring in the microwave to 150° C. for 25 minutes. The crude reaction mixture was concentrated and purified by reverse phase HPLC to afford 233 MS (Q1) 398 (M)+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3C(=O)CCC3=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N[C@@H:26]([CH2:36][CH2:37][CH2:38][CH3:39])[C@H:27]([OH:35])[C:28]([O:30]C(C)(C)C)=[O:29].C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:26]([CH2:36][CH2:37][CH2:38][CH3:39])[C@H:27]([OH:35])[C:28]([OH:30])=[O:29])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCCC[C@H](N)[C@H](O)C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@H](O)C(=O)O
Yield: 64.1 %

Procedure:
1.37 g (4.07 mmol) of N-[(9-fluorenyl)-methoxycarbonyl]-succinimide were added to a solution of 0.93 g (4.3 mmol) of tert-butyl 3(S)-amino-2(S)-hydroxyheptanoate in 40 ml of water/dioxan (1:1). The stirred mixture was adjusted to pH 9-10 with saturated sodium carbonate solution. After 17 hours the dioxan was removed by evaporation under a vacuum. The residual aqueous phase was washed with ethyl acetate, acidified with 2M hydrochloric acid and partitioned in ethyl acetate (three 100 ml aliquots). The three ethyl acetate aliquots were combined and washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and the solvent was removed by evaporation to give crude tert-butyl 3(S)-[(9-fluorenyl)methoxyformamido]-2(S)-hydroxyheptanoate in the form of a pale yellow oil. This oil was chromatographed on silica gel using 20% ethyl acetate in hexane followed by 40% ethyl acetate in hexane for the elution. The chromatographed material was then stirred with 10 ml of trifluoroacetic acid/dichloromethane (1:1). After 30 minutes the solvent was removed by evaporation and the residual oil was triturated with 15 ml of diethyl ether/petroleum ether (1:2). There was obtained 1 g of 3(S)-[(9-fluorenyl)methoxyformamido]-2(S)-hydroxyheptanoic acid as a white solid MS m/e 384.1 [M+H].
Reaction SMILES: [C:1]1([CH2:7][CH:8]([NH2:11])[C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.CC(C[AlH]CC(C)C)C.[OH-].[Na+]>ClCCl>[C:1]1([CH2:7][CH:8]([NH2:11])[CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC(N)Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: NCC(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
A solution of 2 (18.25 g, 0.125 mol) in dichloromethane (150 mL) was added over 30 min to a 1M solution diisobutylaluminum hydride of DIBAL (500 mL, 0.5 mol) cooled to −10°. The temperature raised to −5° and returned to −10°. The starting material was gone after 15 min (GC). The cooled reaction mixture was treated with 500 mL of aqueous 2N sodium hydroxide at a rate, which kept the temperature under 20°. The resulting mixture was stirred at room temperature for 1 hr and then it was filtered through 1PS filter paper. The solvent was evaporated under reduced pressure and the residue was distilled through a short path column to give 12.7 g (68% yield) of 3-phenyl-1,2-diamino-propane, 3 (b.p. 78–83° C., 0.2–0.3 mm) which was 90% pure by glpc. NMR (CDCl3) δ 7.4 (s, 5H), 2.4–3.2 (m, 5H), 1.4 (s, 4H).