Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[Cl:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21](B(O)O)[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:21]2[CH:20]=[N:19][CH:18]=[C:17]([Cl:16])[CH:22]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: OB(O)c1cncc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cncc(Cl)c2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 3-chloropyridine-5-boronic acid (0.381 g, 2.42 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 19.5 h to give 4-chloro-2-(5-chloropyridin-3-yl)-5,7-difluoro-3-methylquinoline as an off white solid. Mass Spectrum (ESI) m/e=325.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:24][CH3:25])=[C:5]([CH3:26])[O:4][N:3]=1.N1C=CC=CC=1.[O:33]1[CH2:38][CH2:37][CH:36]([C:39](Cl)=[O:40])[CH2:35][CH2:34]1>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])=[C:12]([NH:17][C:39]([CH:36]4[CH2:37][CH2:38][O:33][CH2:34][CH2:35]4)=[O:40])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:24][CH3:25])=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: O=C(Cl)C1CCOCC1
Reactant: COCC(C)Nc1c(N)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC(C)Nc1c(NC(=O)C2CCOCC2)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100 %

Procedure:
A solution of 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(1-methoxypropan-2-yl)quinoline-3,4-diamine (for a preparation see Intermediate 2) (9.1 g) in DCM (300 ml) was treated with pyridine (30 ml) and tetrahydro-2H-pyran-4-carbonyl chloride (5.0 ml) and the solution stirred under nitrogen at ambient temperature for 3.5 h and then left standing overnight (ambient temperature, under nitrogen). The volatiles were evaporated in vacuo and the residue partitioned between DCM and water. The organic phase was washed with water ×2 and the combined aqueous extracted with DCM. The combined organic phases were washed with brine, dried (hydrophobic frit) and reduced to dryness in vacuo. The combined aqueous including the brine wash (˜pH4) was basified with solid sodium hydrogen carbonate and the aqueous extracted with DCM ×2. The organic fractions were dried (hydrophobic frit), combined with the previous material and reduced to dryness in vacuo to give a brown foam. This foam was further dried in vacuo, triturated with diethyl ether, the suspension chilled (ice/water bath) and the solid isolated by filtration. The solid was washed with a little diethyl ether and air-dried to give N-(7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-((1-methoxypropan-2-yl)amino)quinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide as a beige solid (11.95 g, 100%).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][SH:13])=[CH:10][CH:9]=1>>[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][S:13][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1
Reactant: COc1ccc(CS)cc1
Reactant: ClCC1CO1
Product: COc1ccc(CSCC(O)CCl)cc1
Temperature: 125 °C
Reaction time: 3 h

Procedure:
2.78 ml of epichlorohydrin and 2.78 ml of p-methoxybenzylmercaptan were heated with stirring at 120 to 130° C. for three hours. After cooling, the product was purified by column chromatography using 100 g of silica gel and benzene as an eluent to obtain 1.44 g of the objective compound.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[NH:16]1[CH2:21][CH2:20][S:19][CH2:18][CH2:17]1>C(#N)C>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([NH:5][C:3](=[O:4])[CH2:2][N:16]3[CH2:21][CH2:20][S:19][CH2:18][CH2:17]3)=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: C1CSCCN1
Reactant: O=C(CCl)Nc1n[nH]c2cc(Cl)ccc12
Solvent: CC#N
Product: O=C(CN1CCSCC1)Nc1n[nH]c2cc(Cl)ccc12

Procedure:
The process is performed as in Example 75, starting with 500 mg of 2-chloro-N-(6-chloro-1H-indazol-3-yl)acetamide, 15 cm3 of acetonitrile and 0.62 cm3 of thiomorpholine. The reaction medium is refluxed for 2 hours, the precipitate formed is filtered off and the filtrate is concentrated to dryness under reduced pressure (2 kPa; 50° C.); the crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (50/50 by volume). The fractions containing the expected product are combined, evaporated under reduced pressure (2 kPa; 50° C.) and dried (90 Pa; 45° C.) to give 560 mg of N-(6-chloro-1H-indazol-3-yl)thiomorpholine-4-acetamide in the form of a pale yellow foam.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[N+:16]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:16][C:5]1[CH:6]=[CH:7][C:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[CH:9][C:4]=1[C:3]([NH:2][CH3:1])=[O:19]
Reactant: [H][H]
Reactant: CNC(=O)c1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)c1cc(N2CCOCC2)ccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-methyl-5-morpholino-2-nitrobenzamide (256 mg) in ethanol (20 mL) was added Pd/C (10% Pd in carbon, 50 mg, 20 wt %) under argon. A hydrogen balloon was used as the hydrogen source. The reaction was stirred at room temperature overnight. The mixture was filtered through celite and the celite pad was washed several times. The solvent was removed and the crude was purified by silica gel chromatography to obtain the desired product 2-amino-N-methyl-5-morpholinobenzamide (quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH:11]=2)=[O:9])[CH:3]=1.[F:31][C:32]([F:44])([F:43])[C:33]1[CH:34]=[C:35]([CH2:39][C:40]([OH:42])=O)[CH:36]=[CH:37][CH:38]=1>>[OH:21][CH2:20][C:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:42])[CH2:39][C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([F:31])([F:44])[F:43])[CH:34]=3)[CH:7]=[CH:6][N:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29]
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(N)ccn2)c2cnccc21
Product: CC(C)(CO)n1cc(C(=O)c2cc(NC(=O)Cc3cccc(C(F)(F)F)c3)ccn2)c2cnccc21

Procedure:
Prepared according to Method M (Example 206) using (4-aminopyridin-2-yl)[1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Preparation 27) and 3-trifluoromethylphenylacetic acid at 70° C. The residue was purified over neutral alumina eluting with 50%-60% EtOAc in hexane followed by acid deprotection using 10% HCl in dioxane at room temperature for 18 hours. The reaction was concentrated in vacuo and purified using preparative HPLC to afford the title compound.
Reaction SMILES: Cl[C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17](=[O:24])[CH2:16][CH2:15][NH:14]1.[CH2:25](N(CC)CC)C>C1(C)C=CC=CC=1>[OH:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:25])[CH:8]=2)[N:3]=[C:2]([N:14]2[CH2:15][CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:13]2)[N:11]=1
Reactant: CCN(CC)CC
Reactant: O=c1[nH]c(Cl)nc2ccccc12
Reactant: O=C1CCNCc2ccccc21
Solvent: Cc1ccccc1
Product: Cc1ccc2nc(N3CCC(=O)c4ccccc4C3)nc(O)c2c1
Yield: 80.9 %

Procedure:
To a stirred solution of 2-chloro-4(3H)-quinazolinone (580 mg, 3.0 mmol) and 1,2,3,4-tetrahydro-5H-2-benzazepin-5-one (591 mg, 3.0 mmol) in toluene (20 mL) was added triethylamine (626 μL, 4.5 mmol). After being refluxed overnight, the resulting reaction mixture was cooled and the formed solid was collected by filtration, washed with ethanol (10 mL) and ethyl acetate (10 mL), and dried in vacuo to afford 775 mg of the desired product as a white solid (yield was 81%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH2:12][CH2:13][O:14][CH3:15])[C:10](=[O:16])[N:9]([CH2:17][C:18]([O:20]CC)=[O:19])[N:8]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH2:12][CH2:13][O:14][CH3:15])[C:10](=[O:16])[N:9]([CH2:17][C:18]([OH:20])=[O:19])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1nc(-c2ccc(Cl)s2)n(CCOC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COCCn1c(-c2ccc(Cl)s2)nn(CC(=O)O)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Of the compound from Example 169A, 3.2 g (9.25 mmol) were dissolved in 28 ml of methanol. Then 2.82 ml of 20% strength aqueous potassium hydroxide solution were added. The mixture was stirred at RT for 2 h. The methanol fraction was reduced to half on a rotary evaporator. The mixture was then diluted with water and extracted once with 15 ml of ethyl acetate. The aqueous phase was acidified with 920 μl of concentrated hydrochloric acid and extracted with twice 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and freed from the solvent on a rotary evaporator. Drying in an HV gave 2.34 g (80% of theory) of the title compound.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][O:46]CC1C=CC=CC=1)[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[F:39])=[CH:28][CH:27]=1)=[O:17])C1C=CC=CC=1>[Pd].O1CCCC1>[OH:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[F:39])=[CH:28][CH:27]=1)=[O:17]
Reactant: O=C(OCCCCCCOc1ccc(-c2cccc(F)c2F)cc1)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(OCCCCCCOc1ccc(-c2cccc(F)c2F)cc1)C(CCCCCCO)CCCCCCO
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.4 %

Procedure:
First, 4 g of 6-[2,3-difluorobiphenyl-4'-yl]oxyhexyl 2,2-bis(6-benzyloxyhexyl)acetate, 1.3 g of 10% Pd-C, and 150 ml of tetrahydrofuran were placed in a 300 ml autoclave. The mixture was stirred at room temperature for 2 days under a hydrogen pressure of 10 kg/cm2. The catalyst was filtered away and a filtrate was concentrated. Thereafter, the residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=2/3) to obtain 2.6 g of 6-[2,3-difluorobiphenyl-4'-yl]oxyhexyl 2,2-bis(6-hydroxyhexyl)acetate (Y: 90%). The compound thus obtained had a purity of 99.3% by HPLC.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH2:44][CH3:45])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH2:44][CH3:45])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(CC)nc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(6-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K23) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow solid (324 mg, 76%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([C:9]#[N:10])=[N:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.Cl.[NH2:19][OH:20]>CO>[OH:20][N:19]=[C:9]([C:8]1[C:3]([NH:2][CH3:1])=[N:4][CH:5]=[CH:6][N:7]=1)[NH2:10]
Reactant: CNc1nccnc1C#N
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CNc1nccnc1C(N)=NO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-methylamino-3-cyanopyrazine (J. Heterocycl. Chem. 1992, 29, 1689-92) (0.37 g, 2.8 mmol) in methanol (10 mL) was added triethylamine (0.4 mL, 2.8 mmol) followed by hydroxylamine hydrochloride (0.19 g, 2.8 mmol) and the reaction was stirred at room temperature for 4 hours. The mixture was filtered, the filtrate was then evaporated to dryness. The residue was dissolved in ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was dried (MgSO4) and the solvent was removed in vacuo to give the title compound was a white solid (0.45 g).
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH:9]([OH:25])/[CH:10]=[CH:11]/[Sn:12]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][C:4]([O:6][CH3:7])=[O:5].CO[C:28](OC)([CH3:30])[CH3:29].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[CH3:29][C:28]1([CH3:30])[O:1][CH:2]([CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH2:8][CH:9](/[CH:10]=[CH:11]/[Sn:12]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:17][CH2:18][CH2:19][CH3:20])[O:25]1
Reactant: CCCC[Sn](/C=C/C(O)CC(O)CC(=O)OC)(CCCC)CCCC
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCC[Sn](/C=C/C1CC(CC(=O)OC)OC(C)(C)O1)(CCCC)CCCC

Procedure:
A mixture of E-methyl 3,5-dihydroxy-7-tributylstannyl-6-heptenoate (4.18 g), 2,2-dimethoxypropane (18 ml) and pyridinium p-toluene sulfonate (0.227 g) is stirred in anhydrous methylene chloride (4.5 ml) at room temperature for about 20 hours, diluted with ether, washed with saturated sodium bicarbonate solution then saturated sodium chloride solution. The organic solution is dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography in 10% ether in hexane to give the desired product.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=2)[N:3]=1.[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)[CH3:14]>CC(N(C)C)=O>[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:19][N:20]1[CH2:21][CH2:22][CH:23]([NH:26][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=3)[N:3]=2)[CH2:24][CH2:25]1)[CH3:14]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: Fc1ccc2nc(Cl)ccc2c1
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3ccc4cc(F)ccc4n3)CC2)ccc1OC
Yield: 3.6 %

Procedure:
A solution of 2-chloro-6-fluoro-quinoline (27.2 mg, 0.15 mmol, 1.0 equiv; intermediate D1) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (2 mL) was heated by microwave irradiation to 220° C. for 1 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 2.2 mg (4%) of the title compound. MS (ISP): 410.4 [M+H]+.
Reaction SMILES: [CH:1]([NH:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([C:26]3[C:31]([CH3:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[S:23][C:22]=2[CH:34]=1)(=[O:17])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[NH2:44][CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]1>O1CCOCC1>[CH:1]([NH:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([C:26]3[C:31]([CH3:32])=[CH:30][N:29]=[C:28]([NH:44][CH2:45][CH2:46][CH2:47][N:48]4[CH2:49][CH2:50][N:51]([CH3:54])[CH2:52][CH2:53]4)[N:27]=3)[S:23][C:22]=2[CH:34]=1)(=[O:17])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cnc(Cl)nc1-c1cc2ccc(S(=O)(=O)NC(c3ccccc3)c3ccccc3)cc2s1
Reactant: CN1CCN(CCCN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1cnc(NCCCN2CCN(C)CC2)nc1-c1cc2ccc(S(=O)(=O)NC(c3ccccc3)c3ccccc3)cc2s1
Temperature: 97 °C

Procedure:
To a stirred suspension of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-6-sulfonic acid benzhydrylamide (457 mg, 0.903 mmol) in dry 1,4-dioxane (4.5 mL) is added diisopropylethylamine (0.315 mL, 1.81 mmol) and 1-(3-aminopropyl)-4-methylpiperazine (213 mg, 1.35 mmol). The mixture is heated at 97° C. for 1 day. After concentration and subsequent chromatographic purification on silica gel, eluting with 2 M NH3/MeOH in dichloromethane: 0-10%, the title compound is obtained as a yellow solid (317 mg, 57% yield). ES+(m/z) 627 [M+H].
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3](=O)/[CH:4]=[CH:5]/[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.Cl.[S:19]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1)(=[O:22])(=[O:21])[NH2:20]>>[S:19]([C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH:5]([C:6]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][CH:7]=3)[CH2:4][C:3]([C:2]([F:17])([F:16])[F:1])=[N:30]2)=[CH:27][CH:28]=1)(=[O:22])(=[O:21])[NH2:20]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(/C=C/c1c[nH]c2ccccc12)C(F)(F)F
Agent: Cl
Product: NS(=O)(=O)c1ccc(N2N=C(C(F)(F)F)CC2c2c[nH]c3ccccc23)cc1
Yield: 82 %

Procedure:
A solution of trans-1,1,1-trifluoro-4-(3-indolyl)-3-buten-2-one (5 mmol) and 4-sulfamylphenyl hydrazine hydrochloride (6 mmol) was subjected to Procedure 3. The title compound was obtained in 82% yield, m.p. 138-140° C.; C, H analysis (C16H14SO2N4F3):
Reaction SMILES: [N:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8](=O)[CH3:9]>>[CH:8](=[N:7]/[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)\[CH3:9]
Reactant: CC=O
Reactant: NN1CCCCC1
Product: C/C=N/N1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Piperidin-1-amine (754 mL, 6.99 mol) was added dropwise over 60 min to acetaldehyde maintained at a 0° C. (304 mL, 5.38 mol) while stirring under nitrogen. [Caution: The addition is exothermic. On this scale, the dropping funnel containing piperidin-1-amine became hot due to acetaldehyde that had vaporized and condensed in the dropping funnel]. After 1 h at 0° C. and 1 h at rt, the reaction flask was equipped with a 16-in reflux condenser and was warmed to 40° C. and stirred for 20 h. The reaction mixture was cooled to RT and partitioned between diethyl ether (700 mL) and brine (300 mL). The organic layer was washed with water and the aqueous layer was extracted with diethyl ether (2×500 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated and dried under high vacuum for 8 h to afford (E)-N-ethylidenepiperidin-1-amine (772 g) (contained impurities) as a yellow oil. The analytical data complied with data reported in the literature. The material was used without additional purification.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:61])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]=[CH:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:46]([OH:60])[CH2:45]2)[CH:7]([CH3:62])[CH:6]([OH:63])[CH2:5][C:4]1=[O:64])[CH3:2].[H][H]>[Rh]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:61])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][CH2:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:46]([OH:60])[CH2:45]2)[CH:7]([CH3:62])[CH:6]([OH:63])[CH2:5][C:4]1=[O:64])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccccc4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: [H][H]
Agent: [Rh]
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCCc4ccccc4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-cinnamyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (37 mg in 2 ml ethanol) is added 4 mg of 5% rhodium on carbon catalyst. The reaction flask is fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 1.5 hours, the mixture is filtered over diatomaceous earth, concentrated and purified by preparative TLC on silica gel
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:31][O:32][CH2:33][C:34]#[C:35][C:36](O)=[O:37]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:36](=[O:37])[C:35]#[C:34][CH2:33][O:32][CH3:31])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: COCC#CC(=O)O
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Product: COCC#CC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 24.7 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and 4-methoxybut-2-ynoic acid (Intermediate 50), to afford the title compound (9.1 mg, 24.7%). Data: UPLC (C) Rt: 1.44 min; m/z 496.2 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[N:7]=[CH:8][O:9][C:10]=1[C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1>ClCCl>[CH3:5][C:6]1[N:7]=[CH:8][O:9][C:10]=1[C:11]1[CH:19]=[CH:18][C:14]([C:15]([Cl:3])=[O:16])=[CH:13][CH:12]=1
Reactant: Cc1ncoc1-c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ncoc1-c1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Thionyl chloride (2.00 mL) is added to 4-(4-methyl-oxazol-5-yl)-benzoic acid (400 mg) in dichloromethane (5 mL) and the mixture is stirred for two days at room temperature. The solvent is evaporated to give the title compound, which is used without further purification for the next reaction step.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:6][C:7]([C:9]1[CH:13]=[C:12]([Cl:14])[S:11][C:10]=1[N:15]=[C:16]([CH2:19][CH2:20][CH2:21][CH3:22])OC)=[O:8])[CH2:4][CH3:5]>C1COCC1>[CH2:19]([C:16]1[N:6]([CH2:3][CH2:4][CH3:5])[C:7](=[O:8])[C:9]2[CH:13]=[C:12]([Cl:14])[S:11][C:10]=2[N:15]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC(=Nc1sc(Cl)cc1C(=O)NCCC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nc2sc(Cl)cc2c(=O)n1CCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a sulfonation flask, 0.36 g of 5-Chloro-2-(1-n-butyl-1-methoxymethyleneamino)thiophene-3-carboxylic-acid propylamide is dissolved in 20 ml of absolute THF and 0.085 g of a ca. 55% NaH dispersion is added in one portion. The mixture is stirred for 15 minutes at room temperature and 1 hour at reflux temperature. Then the solvent is removed in a water jet vacuum and the residue taken up in ethylacetate. The organic phase is washed twice with water and after drylng of the organic phase with sodium sulfate, the solvent is removed in a water jet vacuum. The resulting crude product is purified by column chromatography over silica gel (eluant:hexane/ethylacetate=5:1). Yield: 0.2 g 2-n-butyl-6-chloro-3-n-propyl-3H-thieno[2,3-d]pynimidin-4-one in the form of a slightly yellowish powder; m.p. 67-69° C.