Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([CH3:18])[CH:10]=2)=[O:8])=[CH:5][N:4]=[CH:3]1.[NH4+].[Cl-]>CC(C)=O.O.[Zn]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([C:6]2[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)=[O:8])=[CH:10][C:11]=1[CH3:18]
Reactant: Cc1cc(C(=O)c2cncn2C)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C(=O)c2cncn2C)ccc1N
Reaction time: 1 h

Procedure:
Zn (2.66 g, 40.7 mmol) was added in 2 portions over a period of 2 minutes to a mixture of (1-methyl-1H-imidazol-5-yl)(3-methyl-4-nitrophenyl)methanone (2.0 g, 8.1 mmol, Intermediate 14: step b) and NH4Cl (2.18 g, 40.7 mmol) in acetone (18.5 mL) and water (8.2 mL) at 0° C. After stirring for 1 hour, the reaction mixture was filtered through Celite®, rinsing with EtOAc. Acetone and EtOAc were removed on a rotary evaporator and the aqueous layer was filtered and the solids dried under vacuum to provide the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([CH:19]([F:21])[F:20])[CH:15]=[CH:16][CH:17]=3)[C:12]([N:22]([S:32]([C:35]3[S:36][C:37]([Cl:40])=[CH:38][CH:39]=3)(=[O:34])=[O:33])[S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:48](OC(=O)C)(=[O:50])[CH3:49]>ClCCl>[Cl:31][C:28]1[S:27][C:26]([S:23]([N:22]([S:32]([C:35]2[S:36][C:37]([Cl:40])=[CH:38][CH:39]=2)(=[O:33])=[O:34])[C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][C:14]=3[CH:19]([F:20])[F:21])[N:10]([CH2:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:48](=[O:50])[CH3:49])[CH:8]=[CH:7][CH:6]=3)[N:11]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: NCc1cccc(Cn2nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c3c(C(F)F)cccc32)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cccc(Cn2nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c3c(C(F)F)cccc32)c1
Reaction time: 1 h

Procedure:
N-[1-{[3-(Aminomethyl)phenyl]methyl}-4-(difluoromethyl)-1H-indazol-3-yl]-5-chloro-N-[(5-chloro-2-thienyl)sulfonyl]-2-thiophenesulfonamide (for a preparation see Intermediate 70) (26 mg, 0.039 mmol) was suspended in dichloromethane (0.5 mL) and triethylamine (0.055 mL, 0.39 mmol) and then acetic anhydride (0.004 mL, 0.043 mmol) was added to the suspension. The mixture was stirred for 1 h, and concentrated under a stream of nitrogen to give N-[(3-{[3-{Bis[(5-chloro-2-thienyl)sulfonyl]amino}-4-(difluoromethyl)-1H-indazol-1-yl]methyl}phenyl)methyl]acetamide, which was used without further purification. The residue was dissolved in methanol (2 mL) and treated with NaOH (0.553 mL, 1.105 mmol) and the reaction mixture was stirred at 60° C. for 3 h. LCMS showed the reaction had gone to completion so the mixture was concentrated in vacuo and acidified with 5% citric acid. The solution was extracted with ethyl acetate and the organic layer was washed twice with water (25 mL) and once with brine (25 mL). The organic layer was dried over anhydrous magnesium sulfate before being evaporated in vacuo to give a yellow residue which was dissolved in 1:1 MeOH-DMSO (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier (Method A). The solvent was evaporated in vacuo to give the title compound (7 mg, 36%). LCMS (System A) RT=1.02 min, ES+ve m/z 525/527 (M+H)+.
Reaction SMILES: [CH:1]1(/[CH:7]=[CH:8]/[C:9]([OH:11])=O)[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.ClC(OCC)=O.C(N(CC)CC)C.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.[Cl-].[Na+]>>[CH:25]1([NH:28][C:9](=[O:11])/[CH:8]=[CH:7]/[CH:1]2[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]2)[CH2:27][CH2:26]1
Reactant: O=C(O)/C=C/C1CC=CCC1
Reactant: NC1CC1
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: O=C(/C=C/C1CC=CCC1)NC1CC1
Yield: 69 %

Procedure:
3-(3-Cyclohexenyl)-2E-propenoic acid 1 eq, ethyl chloroformate 1.5 eq, triethylamine 1.5 eq, cyclopropylamine 1.6 eq, quench with 10% sodium chloride solution, yield=69%.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH3:29])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1.[C:30](Cl)(=[O:33])[CH2:31][CH3:32]>>[C:30]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH3:29])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1)(=[O:33])[CH2:31][CH3:32]
Reactant: CCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c13)OCO2
Reactant: CCC(=O)Cl
Product: CCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CC)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-ethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide (example A176) and propionyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[F:25][C:26]1[CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:31]=1[F:32]>>[F:25][C:26]1[CH:27]=[C:28]([C:2]2[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)[CH:29]=[C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:31]=1[F:32]
Reactant: COc1ccc(COc2cc(B3OC(C)(C)C(C)(C)O3)cc(F)c2F)cc1
Reactant: CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COc1ccc(COc2cc(-c3nc(N4CCOCC4)c4sc(CN5CCN(C)CC5)cc4n3)cc(F)c2F)cc1

Procedure:
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with yield 2-[3,4-difluoro-5-(4-methoxy-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane in general procedure A. Purification on silica yielded 2-[3,4-difluoro-5-(4-methoxy-benzyloxy)-phenyl]-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-yl-thieno[3,2-d]pyrimidine. This was then reacted with trifluoroacetic acid in dichloromethane to yield the desired compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26][O:27][CH2:28][CH2:29]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:29][CH2:28][O:27][CH3:26])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)nc3N21
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Product: COCCOCc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to Example 15 intermediate c), from (4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and 2-bromoethyl methyl ether.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][O:7][C:8]2[C:9]([CH3:14])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][N:3]=[N:2]1.[F:15][C:16]([F:31])([F:30])[C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][CH:26](O)[CH2:25][CH2:24]2)=[N:21][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C1COCC1>[CH3:14][C:9]1[C:8]([O:7][CH2:6][C:5]2[CH:4]=[N:3][N:2]([CH:26]3[CH2:27][CH2:28][N:23]([C:20]4[N:19]=[CH:18][C:17]([C:16]([F:15])([F:30])[F:31])=[CH:22][N:21]=4)[CH2:24][CH2:25]3)[N:1]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Cc1ncccc1OCc1cnn[nH]1
Reactant: OC1CCN(c2ncc(C(F)(F)F)cn2)CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ncccc1OCc1cnn(C2CCN(c3ncc(C(F)(F)F)cn3)CC2)n1
Temperature: 25 °C

Procedure:
To a solution of 3-((1H-1,2,3-triazol-5-yl)methoxy)-2-methylpyridine (0.20 g, 1.05 mmol), in THF (2 mL) at 0° C., was added 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-ol (0.391 g, 1.58 mmol) (Intermediate 20), polymer bound triphenylphosphine (0.527 g, 1.58 mmol), and di-tert-butylazodicarboxylate (0.363, 1.58 mmol). The reaction was allowed to warm to room temperature overnight and was then filtered through a pad of celite washing with THF. The solution was concentrated in vacuo and purified by flash column chromatography on silica gel eluting with 0-60% ethyl acetate in hexane to afford the desired product. 1H NMR (DMSO-d6): δ 8.71 (2H, s), 8.00 (1H, dd), 7.89 (1H, s), 7.47 (1H, dd), 7.19 (1H, dd), 5.18 (2H, s), 4.90 (1H, m), 4.68 (2H, s), 3.31 (2H, m), 2.31 (3H, s), 2.19 (2H, m), 1.92 (2H, m).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[NH:25][CH:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27]([OH:29])=[O:28].C1C=CC2N(O)N=NC=2C=1.[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48](O)[CH2:47]2>C1COCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[NH:25][CH:26]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:27]([O:29][C@@H:48]1[CH:49]2[CH2:52][CH2:53][N:46]([CH2:51][CH2:50]2)[CH2:47]1)=[O:28]
Reactant: O=C(O)C(Nc1cc(F)ccc1F)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1cc(F)ccc1F)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
PS-DCC (914 mg, 1.301 mmol, loading: 1.33 mmol/g) was suspended in dry THF (15 ml). 2-(2,5-Difluorophenylamino)-2-phenylacetic acid hydrochloride (I20) (195 mg, 0.65 mmol), HOBT (199 mg, 1.30 mmol), and (R)-quinuclidin-3-ol (248 mg, 1.95 mmol) were added, and the suspension was shaken at RT for 16 hours (Conversion complete by UPLC-MS). PS-DCC was removed by filtration under suction, and the filtrate was evaporated. The resulting residue was dissolved in EtOAc and washed with sat. NaHCO3, water and brine. The organic layer was separated, dried over Na2SO4, filtered and evaporated. The crude was purified by filtration through a silica-pad using DCM/MeOH=95/5 as the eluent. The title compound is collected (195 mg, 80% yield, mixture of diastereomers).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([CH3:36])=[CH:30]2.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]1)[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([CH3:36])=[CH:30]2)#[N:13]
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCS(=O)(=O)CC1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2cc(Oc3ccnc4cc(OCCCN5CCS(=O)(=O)CC5)c(C#N)cc34)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.5 %

Procedure:
A suspension of 4-chloro-6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)quinoline (100 mg, 0.26 mmol), (prepared as described for the starting material in Example 1), 5-hydroxy-2-methylindole (46 mg, 0.32 mmol) and cesium carbonate (129 mg, 0.39 mmol) in DMF (1 ml) was stirred for 10 minutes at ambient temperature followed by 1.5 hours at 70° C. After cooling, water (5 ml) was added. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methanol/methylene chloride/ethyl acetate (5/45/50) to give 6cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(2-methylindol-5-yloxy)quinoline (30 mg, 23%).
Reaction SMILES: C([O:8][C:9]1[C:14]2[C:15]([CH2:22][C:23]([O:25][CH2:26]C)=[O:24])([OH:21])[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:13]=2[CH:12]=[C:11]([C:28]([CH3:36])([CH3:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:10]=1)C1C=CC=CC=1.[H][H]>CO>[OH:21][C:15]1([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:14]2[C:9]([OH:8])=[CH:10][C:11]([C:28]([CH3:35])([CH3:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:12][C:13]=2[O:18][C:17]([CH3:19])([CH3:20])[CH2:16]1
Reactant: CCCCCCC(C)(C)c1cc(OCc2ccccc2)c2c(c1)OC(C)(C)CC2(O)CC(=O)OCC
Reactant: [H][H]
Solvent: CO
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)CC2(O)CC(=O)OC
Yield: 33.3 %

Procedure:
A mixture of 655 mg (1.37 mmole) 5-benzyloxy-4-ethoxycarbonylmethyl-4-hydroxy-2,2-dimethyl-7(1,1-dimethylheptyl)-3,4-dihydro-2H-benzopyran, 133 mg 5% palladium-on-calcium carbonate and 50 ml methanol was hydrogenated at 38 psi (2.7 kg/cm2) until hydrogen uptake ceased. The mixture was filtered, the filtrate evaporated in vacuo and the residual oil taken up in hexane. Upon cooling, crystals formed which were collected by filtration, 66 mg. The mother liquor was evaporated in vacuo to an oil, pentane added and the mixture refrigerated overnight. Filtration gave an additional 179 mg of product. 1H-NMR(CDCl3)ppm(delta): 3.00 (dd, 2H), 3.20 (s, 2H), 3.70 (s, 3H), 4.90 (s, 1H), 6.35 (m, 2H), 7.65 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[Li]CCCC.[O:14]1[CH2:17][C:16](=[O:18])[CH2:15]1>CCCCC.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2([OH:18])[CH2:17][O:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: O=C1COC1
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)cc2)COC1
Reaction time: 1 h
Yield: 63.2 %

Procedure:
1-Bromo-4-iodobenzene (0.65 g, 2.3 mmol, Lancaster) was stirred in pentane (7 mL) and then n-BuLi (1.6 M in hexane, 1.4 mL, 2.3 mmol) was added dropwise at rt. The mixture was and the stirred for 1 h. A white precipitate formed and the precipitate was allowed to settled. The pentane was removed by pipette. The mixture was diluted with pentane (7 mL) back up to the original volume. The mixture was then added to a solution of 3-oxetanone (0.315 g, 4.37 mmol) in THF (7 mL) that was cooled in an ice bath. The mixture was then allowed to come to rt and stirred for about 2 h. The mixture was quenched by the addition of saturated NH4Cl (10 mL) and allowed to stir overnight. EtOAc (15 mL) was added and the layers separated. The aqueous layer was then extracted with EtOAc (5 mL). The combined organic layers were washed with brine (5 mL), dried over MgSO4, filtered, and concentrated in vacuo. The solid was purified by flash column chromatography (40 g Silicycle™ column) eluting with 20-50% EtOAc/heptane. The solid was recrystallized by dissolving in a mixture of heptane and DCM and concentrating under reduced pressure until a precipitate had formed. The solid was collected by filtration and washed with heptane (10 mL) to provide 3-(4-bromophenyl)oxetan-3-ol (0.333 g, 63%): 1H NMR (400 MHz, DMSO) δ 7.65-7.43 (m, 4H), 6.42 (s, 1H), 4.68 (dd, J=50.6, 6.8, 4H).
Reaction SMILES: [C-:1]#[C-:2].[Na+].[Na+].CN(C)P(N(C)C)(N(C)C)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25]I)=[CH:19][CH:18]=1>CN(C)C=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][C:1]#[CH:2])=[CH:19][CH:18]=1
Reactant: Fc1ccc(CCCI)cc1
Reactant: [C-]#[C-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Product: C#CCCCc1ccc(F)cc1
Yield: 62 %

Procedure:
Subsequently, sodium acetylide (18% slurry in xylene) (50 ml) was added to hexamethylphosphoramide (20 ml) with stirring, and to the resulting mixture was furthermore added a solution of 3-(4-fluorophenyl)-1-iodopropane (7.00 g, 26.5 mmol) obtained above in dry dimethylformamide (20 ml) with stirring under ice-cooling, and then the resulting mixture was stirred at room temperature for 2 hours. After stirring, ice-cold water was added to the reaction mixture carefully with stirring under ice-cooling, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by flash chromatography on a silica gel column using hexane as the eluent to afford the title compound (2.67 g, yield: 62%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][C:9](=[O:11])[O:8][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[F:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][C:23]([CH2:27][O:28][C:29]3[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=3)[NH2:32])=[N:24]2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][C:23]([CH2:27][O:28][C:29]3[CH:30]=[C:31]([NH:32][C:9](=[O:11])[CH2:10][C:5]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([OH:8])=[O:7])[CH:33]=[CH:34][CH:35]=3)=[N:24]2)=[CH:19][CH:18]=1
Reactant: Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1
Reactant: CCCCC1(CCCC)CC(=O)OC1=O
Product: CCCCC(CCCC)(CC(=O)Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1)C(=O)O

Procedure:
The title compound is prepared analogously to the compound described in Example 20 from 2,2-dibutylsuccinic acid anhydride (prepared analogously to the instructions of H. Le Moal et al. Bull. Soc. Chim. 1964, 579 and 828) and 3-(7-fluoro-2-quinolinylmethoxy)aniline; beige crystals of m.p. 156°-157°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:9]=O.C(O)(=O)[CH2:20][C:21]([OH:23])=[O:22].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:20][C:21]([OH:23])=[O:22])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][O:17][CH3:18]
Reactant: COCCOc1ccc(C=O)cc1OCCOC
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COCCOc1ccc(C=CC(=O)O)cc1OCCOC
Temperature: 110 °C
Yield: 93.2 %

Procedure:
To a solution of 3,4-Bis-(2-methoxy-ethoxy)-benzaldehyde (19 g, 72.4 mmol) in pyridine (60 ml), malonic acid (11.3 g, 108.6 mmol) was added, followed by piperidine (2 ml), the resulting mixture was heated at 110° C. for 6 hs under N2. After removal of most of pyridine, the residue was poured into water (200 ml) and acidified to PH=3 by aq.HCl. The precipitate was collected and dried to give product (20 g, 93.3%). LC-MS: m/e 295 (M−1)
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([NH:9][C@H:10]([C:15](O)=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4].[NH4+].[Cl-].C1C=CC2N(O)N=[N:36]C=2C=1.C(Cl)CCl>CN(C=O)C>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([NH2:36])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4]
Reactant: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(N)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
Boc-Gly-Pro-Nleu-OH (4.1 g, 0.0106 mol.), NH4Cl (1.7 g, 0.032 mol.) and HOBt (1.76 g, 0.013 mol.) were dissolved in 100 ml DMF and the solution was chilled to 0° C. TEA (4.5 ml) was added to the solution slowly while stirring the solution. After a while, EDC (2.6 g, 0.013 mol.) was added to the solution. The stirring was continued overnight. The DMF was removed under reduced pressure and the resulting mixture was poured into 350 ml chloroform. The chloroform solution was washed by H2O 2×20 ml, saturated NaHCO3 2×20 ml, brine 2×20 ml, saturated NaHSO4 2×20 ml and brine again until the pH of the brine layer was approximate 7. The organic layer was dried using Na2SO4 and the chloroform was distilled under reduced pressure to obtain the product (3.5 g, 84%). TLC Rf=0.36 (developing solvents: CMA, 85:15:3).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[S:17][C:15]=2[N:16]=1>>[Cl:10][C:11]1[N:12]=[C:13]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[CH:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[S:17][C:15]=2[N:16]=1
Reactant: NCc1ccc(F)cc1
Reactant: FC(F)(F)c1cc2c(Cl)nc(Cl)nc2s1
Product: Fc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1

Procedure:
Following the procedure of Example 1, the reaction of 4-fluorobenzylamine with 2,4-dichloro-6-trifluoromethyl-thieno-[2,3-d ]-pyrimidine yields 2-chloro-6-trifluoromethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10](=[N:13][C:14](=O)[CH3:15])SC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N)C[NH2:30]>CCCCCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[NH:30][CH2:15][CH2:14][N:13]=1
Reactant: CSC(=NC(C)=O)Nc1cc(Cl)ccc1Cl
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCO
Product: Clc1ccc(Cl)c(NC2=NCCN2)c1

Procedure:
2.8 g (0.01 M) of N-(2,5-dichlorophenyl)-N'-acetyl-S-methylisothiourea and 7.0 g (0.03 M) of ethylenediamine mono-p-toluenesulphonate are boiled with 30 ml of n-amyl alcohol for 5 hours. The reaction solution is washed with 50 ml of a saturated solution of sodium carbonate and 50 ml of water. The amyl alcohol is distilled off under vacuum until a dry residue is obtained which after being recrystallized from ethylacetate gives 1.5 g (65% of the theoretical yield of 2-(2',5'-dichlorophenylamino)-imidazoline (2) with a melting point of 179°-182° C. The hydroiodide salt of the above compound has a melting point of 275°-277° C. According to the U.S. Pat. No. 2,899,426 the melting point of 2-(2',5'-dichlorophenylamino)-imidazoline-(2) hydroiodide is 275.4°-277°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17](=[O:18])[N:16]([CH3:19])[CH:15]=[C:14](Br)[N:13]=2)=[CH:7][CH:6]=1)[CH3:2].[C:22]([C:26]1[CH:50]=[CH:49][C:29]([C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[C:34]=2[CH3:48])=[O:31])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17](=[O:18])[N:16]([CH3:19])[CH:15]=[C:14]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([NH:32][C:30](=[O:31])[C:29]4[CH:28]=[CH:27][C:26]([C:22]([CH3:23])([CH3:24])[CH3:25])=[CH:50][CH:49]=4)[C:34]=3[CH3:48])[N:13]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2nc(Br)cn(C)c2=O)cc1
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
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: CCOC(=O)c1ccc(Nc2nc(-c3cccc(NC(=O)c4ccc(C(C)(C)C)cc4)c3C)cn(C)c2=O)cc1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
A mixture of 4-(6-bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzoic acid ethyl ester (2) (340 mg; 0.97 mmol), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (5) (457 mg; 1.16 mmol), tetrakis(triphenylphosphine)palladium (56 mg; 0.05 mmol), 1N sodium carbonate (2.9 mL; 2.9 mmol), and 1,2-dimethoxyethane (30 mL) was heated at 100 degrees in a sealed pressure vessel for 16 hr. The mixture was cooled to room temperature, treated with water (70 mL) and extracted with ethyl acetate (3×60 mL). The combined organic extracts were washed with water (2×40 mL) and brine (1×40 mL), dried over magnesium sulfate, and evaporated under reduced pressure. The resulting residue was triturated with diethyl ether/dichloromethane to give 4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoic acid ethyl ester (6) as a gray solid (330 mg), MS 539.49 (M+H).