Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]#[N:23])[CH:17]=[CH:16][C:15]=1[S:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=1>C(O)C>[C:22]([CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1)#[N:23]
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(Sc2ccc(OCC#N)cc2N)cc1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(OCC#N)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (30 mg, 0.17 mmol) was reacted in ethanol (1 mL) with the product from Example 232c (53 mg, 0.17 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (9 mg, 19%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.03 (s, 3H) 2.76 (s, 3 H), 5.23 (s, 2 H), 6.32 (d, J=6.99 Hz, 1 H), 7.18 (d, J=8.46 Hz, 2 H) 7.23 (dd, J=8.82, 2.57 Hz, 1 H), 7.31 (d, J=2.57 Hz, 1 H), 7.38 (d, J=8.82 Hz, 1 H) 7.45 (d, J=8.82 Hz, 2 H), 7.80 (d, J=8.46 Hz, 1 H), 8.41 (d, J=6.99 Hz, 1 H) 8.96 (d, J=8.46 Hz, 1 H), 10.01 (s, 1 H), 11.04 (s, 1 H), 14.42 (s, 1 H); MS (ESI+) m/z 456 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=O)[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]([C:23]([C:25]1[S:29][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:26]=1)=[O:24])[NH2:22]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:22][NH:21][C:23]([C:25]3[S:29][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:26]=3)=[O:24])[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)s1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)s1
Temperature: 110 °C
Reaction time: 12 h
Yield: 31.4 %

Procedure:
1-[5-(4-t-Butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (38.0 mg, 0.14 mmol) and methyl 5-hydrazinocarbonyl-2-thiophenecarboxylate (27.9 mg, 0.14 mmol) were dissolved in dimethylformamide (2.0 mL) and stirred at 110° C. for 12 hours. After cooling, the solvent was evaporated, and ethyl acetate was added to the resulting crude product. The precipitated solid was recovered by filtration to give 20.0 mg of the desired product as a pale yellow solid (yield 31%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH:6]=O.[CH3:12][C:13]([OH:15])=[O:14]>CC(OC(C)=O)=O>[C:13]([O:15][CH:1]1[C:2]2[C:3](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:4]=[C:5]1[CH3:6])(=[O:14])[CH3:12]
Reactant: Cc1ccccc1C=CC=O
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC1C(C)=Cc2ccccc21
Yield: 70 %

Procedure:
Using the same experimental procedure as under a), 2-methylcinnamaldehyde (21 g, 0.14 mol) in AcOH (27 g), FeCl3·6H2O (6 ml of a 0.25 M solution in Ac2O, 1.5 mmol) in Ac2O (53 g) were reacted together. After a further 2 hours at reflux the cooled mixture was treated to the same workup and purification as before to provide the title compound
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][CH3:13])OC1C=CC=CC=1)#[N:2].[NH:14]1[CH2:16][CH2:15]1>C(#N)C>[C:1]([NH:3][C:4]([N:14]1[CH2:16][CH2:15]1)=[N:12][CH3:13])#[N:2]
Reactant: C1CN1
Reactant: CN=C(NC#N)Oc1ccccc1
Solvent: CC#N
Product: CN=C(NC#N)N1CC1
Yield: 77 %

Procedure:
N-Cyano-N'-methyl-O-phenylisourea (0.471 g, 2.69 mmol) was added during 2 minutes to aziridine (0.521 g, 12.1 mmol) at 20° with stirring. Immediate solution occurred, some heat was evolved, and after 5 min a solid precipitate was formed. After 90 min excess aziridine was removed in an air stream at 20°, leaving an oily solid residue. This was dissolved in acetonitrile (10 ml) and the solution was absorbed on to silica gel (1.0 g), and remaining volatiles were removed by evaporation under reduced pressure at 20°. The solid obtained was added to the top of a column of silica gel (19.7 g, length 15 cm, diameter 2 cm) and the column eluted with acetonitrile. The elution of phenol was followed by TLC and after it was complete, subsequent eluate was collected and gave on evaporation to dryness under reduced pressure N-cyano-N'-methyl-1-aziridinoamidine (0.257 g, 77%), m.p. 130°-132.5°, Rf 0.64-0.66 (silica, acetonitrile).
Reaction SMILES: [CH3:1][N:2]1[CH2:21][CH2:20][C:5]2[N:6]([CH2:14][C:15](OCC)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[CH3:1][N:2]1[CH2:21][CH2:20][C:5]2[N:6]([CH2:14][C:15]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC(C)N
Reactant: CCOC(=O)Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Product: Cc1ccc2c(c1)c1c(n2CC(=O)NC(C)C)CCN(C)C1
Temperature: 120 °C

Procedure:
A mixture of ethyl 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetate (100 mg) and isopropylamine (1 ml) was heated at 120° C. for 15 h to obtain 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-N-isopropylacetamide after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](Cl)=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[N:9][C:8]1[C:7]([C:6]=2[NH:28][CH2:27][CH2:26][N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)=[N:15][C:14]([O:16][CH3:17])=[CH:13][CH:12]=1
Reactant: CN1CCN(CCN)CC1
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2n1
Product: COc1ccc2nc3cc(Cl)ccc3c(NCCN3CCN(C)CC3)c2n1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 7,10-dichloro-2-methoxypyrido[3,2-b]quinoline and 2-(4-methylpiperazin-1-yl)ethanamine, the title compound was obtained; MS (Found M+1=386). 1H NMR (DMSO-d6, 400 Hz): 8.43-8.41 (d, 1H, J=9.2 Hz), 8.12-8.10 (d, 1H, J=9.2 Hz), 7.87 (b, 1H), 7.2 (s, 1H), 7.2.9-7.27 (d, 1H, J=9.2 Hz) 7.25-7.24 (d, 1H, J=9.2 Hz), 4.10 (m, 2H), 4.06 (s, 3H), 2.70-2.68 (m, 2H), 2.33 (b, 8H), 2.14 (s, 3H).
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[C:8]2[S:9][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:26])=[CH:28][CH:29]=2)[C:8]2[S:9][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(-c2ccccc2)sc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccccc2)sc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A solution of 4-{[cyclohexyl(3-methyl-5-phenylthiophen-2-yl)methyl]amino}benzoic acid (122 mg), ethyl 3-(methylamino)propanoate (47 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg), hydroxybenzotriazole monohydrate (55 mg) and triethylamine (50 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.6 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (121 mg, 82%).
Reaction SMILES: [CH3:1][C:2]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH2:8][CH3:9])[C:6]#[N:7].[CH2:18](N)[CH2:19][NH2:20].[S-]SS[S-].[Na+].[Na+]>O>[CH3:1][C:2]1[C:13]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([C:6]1[NH:20][CH2:19][CH2:18][N:7]=1)[CH2:8][CH3:9]
Reactant: NCCN
Reactant: CCC(C#N)Oc1cccc(C(F)(F)F)c1C
Agent: [Na+]
Agent: [S-]SS[S-]
Solvent: O
Product: CCC(Oc1cccc(C(F)(F)F)c1C)C1=NCCN1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(2-methyl-3-trifluoromethyl-phenoxy)-butyronitrile (192 mg, 0.790 mmol), ethylene diamine (0.216 ml, 3.16 mmol) and sodium tetrasulfide (7 mg, 0.04 mmol) was stirred for 4 hrs at 75° C., then cooled and stirred with water (ca 6 ml). The solid was filtered off, washed with water and dried in a vacuum to yield 2-[1-(2-methyl-3-trifluoromethyl-phenoxy)-propyl]-4,5-dihydro-1H-imidazole (m.p. 120-122° C.).
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6](=[O:42])[CH2:7][C:8]1[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[S:25]([N:28]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[C:36]=2[CH3:41])COCCOC)(=[O:27])=[O:26])=[CH:10][CH:11]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:13]=1)([CH3:4])[CH3:3].[Si](Cl)(C)(C)C.[Na+].[I-].CCOC(C)=O>CC#N>[CH3:4][C:2]([NH:5][C:6](=[O:42])[CH2:7][C:8]1[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[S:25]([NH:28][C:35]2[O:39][N:38]=[C:37]([CH3:40])[C:36]=2[CH3:41])(=[O:27])=[O:26])=[CH:10][CH:11]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:13]=1)([CH3:1])[CH3:3]
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CC(=O)NC(C)(C)C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CC(=O)NC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the title compound of Step (D) (45 mg, 0.075 mmol) in 3 ml of CH3CN, Me3SiCl (41 mg, 0.38 mmol) was added and followed by NaI (57 mg, 0.38 mmol). The mixture was stirred at room temperature for 1.5 hrs. Additional Me3SiCl (32 mg, 0.3 mmol) and NaI (46 mg, 0.3 mmol) were added in twice after stirred for 30 min and 1 hr. 3 ml H2 O and 30 ml EtOAc were added. The organic layer was washed with sat. Na2S2O3, brine, dried and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 33% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 67% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (23 mg, 60%) as a white solid, m.p. 117°-123° C. (amorphous).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB(/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])O1>C(#N)C.CCO.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>[C:11]([O:10][C:9]([NH:8][C:6]1[CH:7]=[C:2](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:3]=[CH:4][C:5]=1[Cl:16])=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)ccc1Cl
Reactant: CCOC(=O)/C=C/B1OC(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: [K+]
Solvent: CCO
Solvent: CC#N
Product: CCOC(=O)/C=C/c1ccc(Cl)c(NC(=O)OC(C)(C)C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 5-bromo-2-chlorophenylcarbamate (6-1) (1.0 equiv.) in acetonitrile (0.3 M) and EtOH (0.5 M) was added K2CO3 (2.0 equiv.). The reaction was degassed and flushed with N2, then added (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (6-2) (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.). The reaction was flushed again with N2 and stirred at 100° C. overnight. After cooling to room temperature, hexane was added, and the mixture was filtered through a pad of silica, eluting with EA/Hex (1:1) until the product was completely eluted. The filtrate was concentrated and purified on Combiflash, eluting with 0-15% EA in Hex to give (E)-ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)acrylate (6-3) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[O:8][C:7](=[O:13])[C:6]([CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26])=[O:16])=[C:5]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:35]([O:39][CH3:40])(=[O:38])[CH:36]=[CH2:37].CCN(CC)CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[CH2:14][C:6]2[C:7](=[O:13])[O:8][C:9]3[C:4]([C:5]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:3][C:2](/[CH:37]=[CH:36]/[C:35]([O:39][CH3:40])=[O:38])=[C:11]([CH3:12])[CH:10]=3)=[C:19]([C:25]([F:28])([F:26])[F:27])[CH:20]=1
Reactant: Cc1cc2oc(=O)c(CC(=O)Nc3ccc(F)cc3C(F)(F)F)c(-c3ccccc3)c2cc1Br
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)/C=C/c1cc2c(-c3ccccc3)c(CC(=O)Nc3ccc(F)cc3C(F)(F)F)c(=O)oc2cc1C
Temperature: 120 °C
Yield: 72 %

Procedure:
A solution of 2-(6-bromo-7-methyl-2-oxo-4-phenyl-2H-chromen-3-yl)-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide (Example 177) (500 mg) in DMF (5 mL) was combined with methyl acrylate (0.14 mL), Et3N (0.21 mL), Pd(OAc)2 (5 mg) and triphenylphosphine (10 mg) under argon atmosphere, and stirred with heating at 120° C. for 10 hours. The reaction solution was combined with water and extracted with ethyl acetate. The extract was washed with diluted hydrochloric acid followed by an aqueous solution of NaHCO3 and water, and then dried over magnesium sulfate, and concentrated under reduced pressure to obtain the title compound as a colorless crystal (360 mg, yield: 72%). An aliquot was recrystallized from ethyl acetate to measure a melting point. Melting point: 233-236° C.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.ClCCl.CN(C=O)C.[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=O)(=[O:22])=[O:21].[CH3:32][C:33]([CH3:54])([CH3:53])[CH2:34][CH2:35][NH:36][C:37](=[O:52])[C@H:38]([CH3:51])[CH2:39][C@H:40]([OH:50])[C@@H:41]([NH2:49])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C.ClCCl>[CH2:42]([C@H:41]([NH:49][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])[CH:24]=1)[C@@H:40]([OH:50])[CH2:39][C@H:38]([C:37](=[O:52])[NH:36][CH2:35][CH2:34][C:33]([CH3:32])([CH3:53])[CH3:54])[CH3:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NCCC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cccc(S(C)(=O)=O)c1)C(=O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
N-Cyclohexylcarbodiimide-N′-methyl polystyrene (100 mg @ 1.70 mmol/g; ex. Novabiochem) was treated with dichloromethane (0.5 ml) followed by a solution of 1-hydroxybenzotriazole (22 mg, 0.14 mmol) in 4:1 dichloromethane/DMF (0.5 ml). 3-Methanesulfonyl benzoic acid (28 mg, 0.14 mmol) in DMF (0.5 ml) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (3,3-dimethylbutyl)-amide (D2) (30 mg, 0.094 mmol) in dichloromethane (0.5 ml) were then added and the mixture was stirred gently overnight at room temperature. It was then diluted with dichloromethane (0.5 ml) and treated with methylisocyanate polystyrene (100 mg @ 1.80 mmol/g; ex. Novabiochem) and tris-(2-aminoethyl)-amine polystyrene (100 mg @ 3.20 mmol/g; ex. Novabiochem), and the mixture was stirred gently for a further 1.5 h. It was then filtered and the spent resins were washed with DMF (1 ml) and dichloromethane (1 ml). The combined filtrates were evaporated to dryness and the residue was triturated with diethyl ether/hexane to afford the title compound (E1) as a white solid (23 mg, 49%).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[N:9]=1.[Cl:38][C:39]1[CH:40]=[C:41]([CH2:46][C:47](O)=[O:48])[CH:42]=[CH:43][C:44]=1[Cl:45]>>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11](=[O:20])[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:47](=[O:48])[CH2:46][C:41]3[CH:42]=[CH:43][C:44]([Cl:45])=[C:39]([Cl:38])[CH:40]=3)=[CH:24][CH:23]=2)[N:9]=1
Reactant: Nc1ccc(Cn2nc(CCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n(Cc3ccccc3)c2=O)cc1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)Nc1ccc(Cn2nc(CCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n(Cc3ccccc3)c2=O)cc1

Procedure:
Prepared as for Example 7 using the compound of Example 5 and 3,4-dichlorophenylacetic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[CH3:20].C(=O)([O-])[O-].[K+].[K+].Cl>[Cu].N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:19][CH3:20])=[CH:23][CH:24]=2)=[CH:11][C:10]=1[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(Br)ccc1OCc1ccccc1
Reactant: CCOc1ccc(O)cc1
Agent: [Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Product: CCOc1ccc(Oc2ccc(OCc3ccccc3)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.1 %

Procedure:
A mixture of 10 g of 4-bromo-2-isopropylphenyl benzyl ether, 4.7 g of 4-ethoxyphenol, 4.7 g of potassium carbonate, 0.30 g of copper powder, 0.30 g of cuprous iodide and 30 ml of pyridine was stirred at 130° C. to 140° C. for 24 hours. The reaction solution was cooled to room temperature, poured into ice-water and then acidified by adding 10% hydrochloric acid. The solution was extracted with 100 ml of diethyl ether, washed in turn with 10% hydrochloric acid, an aqueous 10% sodium hydroxide solution and a saturated saline solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 4.4 g of 4-(4-ethoxyphenoxy)-2-isopropylphenyl benzyl ether (yield, 37%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.CN(C1C=CC=CN=1)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1.C(OCC)(=O)C>[C:20]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[CH3:1])(=[O:22])[CH3:21]
Reactant: CC1Cc2ccccc2N1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)N1c2ccccc2CC1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a mixture of 2-methylindoline (20.0 g, 0.15 mol) and dimethylaminopyridine (500 mg, 5 mmol) in pyridine (50 mL) at room temperature is added acetic anhydride (20 mL). The mixture is stirred at ambient temperature for 18 h, diluted with ethyl acetate, washed with 1 N aqueous hydrochloric acid, water and brine, then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 26.3 g (100%) of the title compound as an amber oil. MS (ESI+) m/z 176.1 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C2C(=CC(C(NC(C(O)=O)CO)=O)=CC=2)C(NC(N)=N)=NC=1.Cl.[NH2:33][C:34]([NH2:36])=[NH:35].[C:37]([O:41][C:42](=[O:65])[CH:43]([CH2:59][O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[NH:44][C:45]([C:47]1[CH:56]=[C:55]2[C:50]([C:51]([Cl:58])=[CH:52][N:53]=[C:54]2Cl)=[CH:49][CH:48]=1)=[O:46])([CH3:40])([CH3:39])[CH3:38].O>CS(C)=O>[C:37]([O:41][C:42](=[O:65])[CH:43]([CH2:59][O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[NH:44][C:45]([C:47]1[CH:56]=[C:55]2[C:50]([C:51]([Cl:58])=[CH:52][N:53]=[C:54]2[NH:35][C:34]([NH2:36])=[NH:33])=[CH:49][CH:48]=1)=[O:46])([CH3:40])([CH3:39])[CH3:38]
Reactant: N=C(N)N
Reactant: CC(C)(C)OCC(NC(=O)c1ccc2c(Cl)cnc(Cl)c2c1)C(=O)OC(C)(C)C
Agent: Cl
Agent: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NC(CO)C(=O)O)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OCC(NC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 42.9 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-serine trifluoroacetate ##STR72## NaH (54 mg, 80% dispersion in mineral oil, 1.80 mmol) was added to a solution of guanidine hydrochloride (173 mg, 1.81 mmol) in DMSO (6 mL) and the solution was heated to 80° C. for 30 min. O-t-Butyl-N-[(1,4-dichloro-7-isoquinolinyl)carbonyl]-DL-serine t-butyl ester (330 mg, 0.70 mmol) was added and the mixture heated at 80° C. for 3 h. The cooled mixture was poured into water (50 mL) and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried (Na2SO4) and evaporated in vacuo. The residue was crystallised with i-Pr2O to give O-t-butyl-N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-serine t-butyl ester (138 mg, 0.30 mmol) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:10])=[CH:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[C:11]1([S:17][C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[C:11]1([S:17][C:18]2[CH:24]=[CH:23][C:21]([NH:22][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]=[C:2]([F:10])[F:1])=[CH:20][CH:19]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)CCCC=C(F)F
Reactant: Nc1ccc(Sc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCCC=C(F)F)Nc1ccc(Sc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
With cooling at 10°, 8.5 g of 6,6-difluorohex-5-enoic acid chloride are added to 10.0 g of 4-phenylthioaniline, 6.5 g of triethylamine and 100 mg of 4-N-pyrrolidinopyridine in 250 ml of tetrahydrofuran. The mixture is stirred for 2 hours at room temperature and then concentrated by evaporation in vacuo. The residue is taken up in toluene, the toluene phase is washed with water, dried over sodium sulfate and 90-95% of the amount of toluene is evaporated off in vacuo. While the mixture is still warm, a small amount of hexane is added, which causes the product to crystallise out. The mixture is cooled and filtered, and the filter residue is washed with hexane, yielding the title compound having a melting point of 80°-81° (compound no. 2-1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4[C:22]5[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][C:23]=5[S:29][C:20]=4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.Cl.[CH3:34][N:35]([CH:42]([CH3:44])[CH3:43])[CH2:36]/[CH:37]=[CH:38]/[C:39](O)=[O:40]>>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4[C:22]5[CH2:28][CH2:27][CH2:26][N:25]([C:39](=[O:40])/[CH:38]=[CH:37]/[CH2:36][N:35]([CH3:34])[CH:42]([CH3:44])[CH3:43])[CH2:24][C:23]=5[S:29][C:20]=4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CC(C)N(C)C/C=C/C(=O)O
Reactant: Fc1cccc(Cn2ncc3cc(Nc4ncnc5sc6c(c45)CCCNC6)ccc32)c1
Agent: Cl
Product: CC(C)N(C)C/C=C/C(=O)N1CCCc2c(sc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)C1

Procedure:
The title compound was synthesized in analogy to Example 89 from N-[1-(3-fluorobenzyl)-1H-indazol-5-yl]-6,7,8,9-tetrahydro-5H-pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-4-amine from Example 83A (100 mg, 0.23 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (61 mg, 0.32 mmol) to yield 39 mg (29%).