Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[N:7]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[N:8]=[CH:9][CH:10]=1)[CH3:2].CI.[C:19](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:6]1[N:7]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[N:8]=[CH:9][CH:10]=1)[CH3:19])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Cc1ccnn1-c1nccs1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccnn1-c1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (2-thiazol-2-yl-2H-pyrazol-3-yl)-acetic acid ethyl ester (100 mg, 0.42 mmol), methyl iodide (66 mg, 0.46 mmol) and cesium carbonate (151 mg, 0.46 mmol) in DMF (6 mL) is stirred at room temperature overnight. The reaction is quenched with NH4Cl (aq.) (6 mL) and ethyl acetate (30 mL). The organic layer is separated and the aqueous layer is extracted with ethyl acetate (3×30 mL). The combined organic layers are dried and the solvent removed. The crude is purified by PTLC (hexane/ethyl acetate 3:1) to give 2-(2-thiazol-2-yl-2H-pyrazol-3-yl)-propionic acid ethyl ester as an oil.
Reaction SMILES: [OH-:1].[Na+].[OH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](OC)[CH:12]=2)[O:7][C:6](=[O:16])[C:5]=1[N+]([O-])=O>O>[OH2:3].[OH:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([OH:1])=[CH:11][CH:12]=2)[O:7][C:6](=[O:16])[CH:5]=1
Reactant: COc1ccc2oc(=O)c([N+](=O)[O-])c(O)c2c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=c1cc(O)c2ccc(O)cc2o1

Procedure:
Dilute sodium hydroxide solution was added to a suspension of 4-hydroxy-6-methoxy-3-nitrocoumarin (2.0g) in water (40 ml) till the pH of the solution reached 14. Filtration gave the product m.p. 277°-8°(d); (C10H6NO6Na requires C, 46.35; H, 2.33; N, 5.41; Na, 8.87. Found: C, 46.32; H, 2.44; N, 5.50; Na, 8.34) after washing briefly with water and drying under vacuum.
Reaction SMILES: ClC(F)(F)C1N=C(C(F)(F)F)C(C(OCC)=O)=C(OCC)C=1C(O)=O.C(N(CC)CC)C.[F:33][CH:34]([F:57])[C:35]1[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[C:38]([C:45]([O:47][CH2:48]C)=[O:46])=[C:37]([O:50]CC)[C:36]=1[C:53]([O:55][CH3:56])=[O:54].[OH-].[K+].S(Cl)(Cl)=O>CCO.CCOCC.[Pd].CO.O>[F:57][CH:34]([F:33])[C:35]1[C:36]([C:53]([O:55][CH3:56])=[O:54])=[C:37]([OH:50])[C:38]([C:45]([O:47][CH3:48])=[O:46])=[C:39]([C:41]([F:44])([F:42])[F:43])[N:40]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1OCC
Agent: [Pd]
Agent: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)O)c1OCC
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OC)c1O
Yield: 32 %

Procedure:
Product of Example 18 (23.34 g, 0.032 mol), 9.0 ml (0.064 mol) of triethylamine and 0.62 g of Pd/C (10%) in 100 ml of EtOH were reacted as described by the preparation of product of Example 22 affording 9.99 g of dark orange oil. A portion of this oil (5.0 g, 0.014 mol), 4.51 g (0.070 mol) of 87% KOH, 1 ml of H2O in 30 ml of EtOH was stirred at reflux for 5 days. Reaction mixture was concentrated and the residue was poured into water and washed wlth ether. The aqueous layer was acidified with conc HCl, extracted with ether, dried (MgSO4) and concentrated in vacuo to 4.26 g of foamy oil. This oil was treated as described in Example 19: 4.26 g (0.013 mol) of this foamy oil, 25 ml of thionyl chloride and 25 ml of MeOH were reacted affording a dark solid residue which was taken up in ether and extracted with 15% K2CO3 and water, acidified with concentrated HCl, extracted with ether, dried (MgSO4) and concentraLed in vacuo to 2.7 g of solid. Recrystallization from hexane-ether afforded 1.37 g (32.0%) of product as a tan solid: mp 83°-84.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:25])[CH2:19][C:20]([O:22]CC)=[O:21])[CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[N:12]1[CH2:13][CH2:14][N:15]([C:18](=[O:25])[CH2:19][C:20]([OH:22])=[O:21])[CH2:16][CH2:17]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)N1CCN(c2ccc(Cl)cc2C(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Cl)ccc1N1CCN(C(=O)CC(=O)O)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
A mixture of ethyl 3-[4-(2-tert-butyl-4-chlorophenyl)piperazin-1-yl]-3-oxopropanoate (Example 206, 0.35 g, 0.95 mmol) and 1 M LiOH solution (5 mL, 5.0 mmol) in tetrahydrofuran (5 mL) was stirred at 0° C. for 3 h. The reaction mixture was acidified with 1 M HCl solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.32 g, 98%) as a white solid.
Reaction SMILES: [C:1]1([C:7]([C:9]2[C:10]3[S:21][CH:20]=[CH:19][C:11]=3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:23][OH:24]>N1C=CC=CC=1>[C:1]1([C:7]([C:9]2[C:10]3[S:21][CH:20]=[CH:19][C:11]=3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)=[N:23][OH:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)c1nc(C(F)(F)F)nc2ccsc12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(c1ccccc1)c1nc(C(F)(F)F)nc2ccsc12
Yield: 100.9 %

Procedure:
A solution of phenyl 2-trifluoromethylthieno[3,2-d]pyrimidin-4-ylmethanone (60 mg, 0.19 mmol) and hydroxylamine hydrochloride (0.04 g, 0.58 mmol) in pyridine (2 mL) was refluxed for 1 h, concentrated in vacuo, treated with toluene (2 mL), concentrated in vacuo and the resulting solid dissolved in EtOAc (5 mL), washed with water (3 mL) and concentrated in vacuo to give the title compound (62 mg, 98%), a mixture of geometrical isomers, as an oily solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1ccc(NC2CCN(Cc3ccccc3)C2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/c1ccc(NC2CCN(Cc3ccccc3)C2)nc1
Temperature: 72.5 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
A mixture of ethyl (2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}-acrylate (830 mg) and 1N NaOH solution (4.7 ml) in MeOH (20 ml) was stirred at 70-75° C. for 2 hours. The reaction mixture was evaporated in vacuo, and the residue was dissolved with saturated NaCl solution (20 ml). The solution was adjusted to pH6.0 with aq. HCl, and the precipitate was collected by filtration to give (2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}-acrylic acid (700 mg)
Reaction SMILES: C[Si](C)(C)[N:3]([CH2:8][CH2:9][O:10][CH3:11])[Si](C)(C)C.[CH3:14][O:15][CH2:16][CH2:17][NH:18][C:19]([CH3:24])=[CH:20][C:21](=O)[CH3:22].FC(F)(F)C(F)(F)C(O)=O.CC(C)([O-])C.[Na+]>O1CCCC1>[CH3:11][O:10][CH2:9][CH2:8][NH:3][C:21](=[CH:20][C:19](=[N:18][CH2:17][CH2:16][O:15][CH3:14])[CH3:24])[CH3:22]
Reactant: COCCNC(C)=CC(C)=O
Reactant: COCCN([Si](C)(C)C)[Si](C)(C)C
Agent: CC(C)(C)[O-]
Agent: O=C(O)C(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCN=C(C)C=C(C)NCCOC
Temperature: 150 °C
Reaction time: 1 h

Procedure:
6.56 g (0.03 moles) of N,N-Bis(trimethylsilyl)-2-methoxyethylamine were mixed with 3.14 g (0.02 moles) of 4-(2-methoxyethylamino)-3-penten-2-one. To this mixture was added 4.1 g (0.026 moles) of pentafluoropropionic acid dropwise over 5 minutes with rapid stirring. The mixture darkened and became warm, eventually forming two immiscible layers, and was allowed to stir for 1 hour. 2.5 g (0.0266 moles) of sodium t-butoxide dissolved in 5 ml of tetrahydrofuran was then added dropwise over a five minute period. The mixture warmed and became one liquid phase, which was yellow. The solvent was then removed by vacuum distillation at room temperature, and the product then vacuum distilled out of the resulting residue as a clear liquid by heating>150° C. Yield of MeC(NCH2CHOMe)CHC(HNCH2CH2OMe)Me=3.9 g (91% of theoretical).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[S:22]>CCOCC>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)=[S:22]
Reactant: c1cnc(N2CCNCC2)cn1
Reactant: Fc1ccccc1N=C=S
Solvent: CCOCC
Product: Fc1ccccc1NC(=S)N1CCN(c2cnccn2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4.92 g. of 1-(2-pyrazinyl)piperazine in 50 ml. of anhydrous ether is added a solution of 4.59 g. of 2-fluorophenyl isothiocyanate in 50 ml. of anhydrous ether over a period of 10 minutes. The mixture is stirred for 30 minutes and the resulting solid is collectedand then recrystallized from 200 ml. of ethanol, giving 7.04 g. of the desired product, m.p. 151°-153° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH2:27]([OH:31])[C:28]#[C:29][CH3:30]>>[CH2:27]([O:31][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1)[C:28]#[C:29][CH3:30]
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: CC#CCO
Product: CC#CCOc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (150 mg; 0.395 mmol), intermediate 42.1, and 2-butin-1-ol (112 mg; 1.578 mmol), example 62 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: Br[CH:2]([C:4]1[N:13]([CH3:14])[C:12](=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:16]#[N:17])[CH:10]=2)[N:5]=1)[CH3:3].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(#N)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:34][CH2:33][N:32]([CH:2]([C:4]3[N:13]([CH3:14])[C:12](=[O:15])[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:16]#[N:17])[CH:10]=4)[N:5]=3)[CH3:3])[CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: COc1ccc(S(=O)(=O)N2CCNCC2)cc1
Reactant: CC(Br)c1nc2ccc(C#N)cc2c(=O)n1C
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc4ccc(C#N)cc4c(=O)n3C)CC2)cc1
Yield: 8.4 %

Procedure:
In a test tube containing of 2-(1-bromo-ethyl)-3-methyl-4-oxo-3,4-dihydro-quinazoline-6-carbonitrile (40.0 mg, 0.14 mmol) in acetonitrile (2 ml) was added KI (34.0 mg, 0.21 mmol), and (1-(4-Methoxy-benzenesulfonyl)-piperazine (46.4 mg, 0.21 mmol). The reaction was heated for 18 hours. The solution was concentrated under reduced pressure. The residue was partitioned between water (2 ml) and dichloromethane (5 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The solvent was removed under vacuum. The resulting residue was dissolvent in DMSO (2 ml) and purified by HPLC (Gilson-215, 0.035% TFA in acetonitrile and 0.05% water as mobile phase). The product was collected and dried under reduced pressure to give the 2-{1-[4-(4-Methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3-methyl-4-oxo-3,4-dihydro-quinazoline-6-carbonitrile compound (Yield 5.52 mg, 8.2%). 1H NMR (400 MHz, CDCl3): δ 1.64 (d, 3H, J=6.57 Hz), 3.29-3.10 (m, 6H), 3.48-3.37 (m, 2H), 3.68 (s, 3H), 3.90 (s, 3H), 4.53 (q, 1H, J=13.14, 5.81 Hz), 6.97 (d, 2H, J=2.02 Hz), 7.66 (d, 2H, J=8.84, Hz), 7.76 (d, 1H, J=8.59 Hz), 7.94 (dd, 1H J=8.59, 2.02 Hz), 8.57 (d, 1H, J=2.02 Hz). MS m/z calc. 467.16, found (ESI); 468.4 (M+1)+. Retention time 2.75 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]([CH:35]1[CH2:37][CH:36]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:13]1[C:14]2[N:25]=[N:24][N:23]([CH:26]3[CH2:30][CH:29]([CH2:31][OH:32])[CH:28]([OH:33])[CH:27]3[OH:34])[C:15]=2[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=1.N1C=CN=C1.[C:49]([Si:53](Cl)([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([CH3:52])([CH3:51])[CH3:50].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]([CH:35]1[CH2:37][CH:36]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:13]1[C:14]2[N:25]=[N:24][N:23]([CH:26]3[CH:27]([OH:34])[CH:28]([OH:33])[CH:29]([CH2:31][O:32][Si:53]([C:49]([CH3:52])([CH3:51])[CH3:50])([C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=4)[C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[CH2:30]3)[C:15]=2[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCCSc1nc(N(Cc2ccc(OC)cc2OC)C2CC2c2ccccc2)c2nnn(C3CC(CO)C(O)C3O)c2n1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCCSc1nc(N(Cc2ccc(OC)cc2OC)C2CC2c2ccccc2)c2nnn(C3CC(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)C(O)C3O)c2n1

Procedure:
A solution of the product of step (a) (1.11 g), imidazole (417 mg) and tert-butylchorodiphenylsilane (0.75 ml) in dry DMF (4 ml) was stirred for 18 hours. Water was added and the mixture was extracted with ethyl acetate. The organic extracts were dried, concentrated and purified (SiO2, petrol:acetone 3:1 as eluant) to give the subtitle compound (1.16 g).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH2:18][C:19](=[O:33])[NH:20][C:21]3[CH:27]=[C:26]([N:28]4[CH:32]=[CH:31][CH:30]=[CH:29]4)[CH:25]=[CH:24][C:22]=3[N:23]=2)[CH:12]=1)=[O:5])C>NCCO>[OH:5][CH2:4][CH2:6][NH:7][C:4]([C:6]1[N:7]=[CH:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH2:18][C:19](=[O:33])[NH:20][C:21]3[CH:27]=[C:26]([N:28]4[CH:32]=[CH:31][CH:30]=[CH:29]4)[CH:25]=[CH:24][C:22]=3[N:23]=2)[CH:12]=1)=[O:5]
Reactant: CCOC(=O)c1ncoc1-c1cccc(C2=Nc3ccc(-n4cccc4)cc3NC(=O)C2)c1
Solvent: NCCO
Product: O=C1CC(c2cccc(-c3ocnc3C(=O)NCCO)c2)=Nc2ccc(-n3cccc3)cc2N1
Yield: 110.5 %

Procedure:
A solution of 5-[3-(4-oxo-7-pyrrol-1-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-phenyl]-oxazole-4-carboxylic acid ethyl ester (Example 23) (35mg) in 2-amino-ethanol (1 mL) was stirred at 50° C. for 4 h. The mixture was partitioned between H2O and EtOAc. The organic layer was dried and evaporated in vacuum, and the residue was triturated with EtOAc to give the title compound (20 mg) as light-yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][CH:5](P(OCC)(OCC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:19][NH:20][C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=2)[CH:24]=[CH:25][CH:26]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:19][NH:20][C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30](/[CH:33]=[C:5](\[CH2:4][CH3:3])/[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:29][CH:28]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Reactant: CNc1cccc(-c2ccc(C=O)cc2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/c1ccc(-c2cccc(NC)c2)cc1)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
197 mg (4.9 mmol) of sodium hydride are added to a mixture of 1.2 mL (4.9 mmol) of triethyl 2-phosphonobutyrate and 415 mg of 3′-methylaminobiphenyl-4-carbaldehyde (2.0 mmol) in 10 mL of tetrahydrofuran. The reaction mixture is stirred at room temperature overnight, poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over sodium sulfate. The solvent is evaporated off and the residue (1.1 g) is purified by chromatography on a column of silica eluted with a 90/10 heptane/ethyl acetate mixture. 438 mg (72%) of ethyl 2-[1-(3′-methylaminobiphenyl-4-yl)meth-(E)-ylidene]butyrate are obtained in the form of off-white crystals.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH2:22][CH3:23])[N:13]=2)=[O:11])[CH2:4][CH2:3]1.CO>ClC(OC(Cl)C)=O>[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH2:22][CH3:23])[N:13]=2)=[O:11])[CH2:4][CH2:3]1
Reactant: CCCn1nc(C(=O)NCC2CCN(C)CC2)c2ccccc21
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Product: CCCn1nc(C(=O)NCC2CCNCC2)c2ccccc21
Yield: 20.9 %

Procedure:
A solution of N-(1-methyl-4-piperidyl)methyl-1-n-propylindazole-3-carboxamide (2.00 g) obtained in Example 7 in α-chloroethyl chloroformate (8 ml) was stirred at 70° C. for 6 hours, then methanol (20 ml) was added, and the mixture was heated under reflux for 2 hours. The reaction solution was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol:aqueous ammonia=90:10:1) to give the title compound (0.40 g) as a yellow oily substance. Yield=21%.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:11]([CH:15]1[CH2:26][CH2:25][C:18]2([O:22][CH:21]([CH2:23]Br)[CH2:20][O:19]2)[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:11]([CH:15]1[CH2:26][CH2:25][C:18]2([O:22][CH:21]([CH2:23][N:8]3[CH2:9][CH2:10][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]3)[CH2:20][O:19]2)[CH2:17][CH2:16]1)([CH3:13])([CH3:12])[CH3:14]
Reactant: CC(C)(C)C1CCNCC1
Reactant: CC(C)(C)C1CCC2(CC1)OCC(CBr)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C1CCN(CC2COC3(CCC(C(C)(C)C)CC3)O2)CC1

Procedure:
17.4 g (123.6 mmol) of 4-tert-butylpiperidine, 9.0 g (30.9 mmol) of 8-tert-butyl-2-bromomethyl-1,4-dioxaspiro[4,5]decane (cis/trans mixture) and 4.3 g (30.9 mmol) of potassium carbonate in 100 ml of absolute dimethylformamide were heated at 150° C. for 8 hours. Some of the solvent was distilled off under reduced pressure, the residue was taken up with dilute aqueous sodium hydroxide solution/methylene chloride and the solution was worked up in a conventional manner.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:31]=[C:32]([Cl:38])[C:33](=[O:37])[N:34]([CH3:36])[CH:35]=1>C(Cl)Cl.CO>[Cl:38][C:32]1[C:33](=[O:37])[N:34]([CH3:36])[CH:35]=[C:30]([NH:29][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=2)[CH:31]=1
Reactant: Cn1cc(N)cc(Cl)c1=O
Reactant: CCOC(=O)c1nn(Cc2ccc(OC)cc2)cc1C(O)c1ccc(Cl)cc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1nn(Cc2ccc(OC)cc2)cc1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 1.4 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(4-methoxybenzyl)-1H-pyrazole-3-carboxylate (Step 9.3) and 5-amino-3-chloro-1-methylpyridin-2(1H)-one (Step 5.2). tR: 4.91 min (HPLC 1); tR: 1.08 min (LC-MS 2); ESI-MS: 541/543 [M+H]+ (LC-MS 2); Rf=0.32 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[CH2:6][N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:12]=1
Reactant: COC(=O)CN(CC(=O)OC)c1cccc(O)c1
Reactant: CCCCCCCC/C=C\CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCC/C=C\CCCCCCCCOc1cccc(N(CC(=O)OC)CC(=O)OC)c1
Reaction time: 72 h
Yield: 52.2 %

Procedure:
A mixture of 0.24 g (0.95 mmol) of N-(3-hydroxyphenyl)-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 0.33 g (1 mmol) of oleyl bromide, 0.15 g (1 mmol) of sodium iodide and 0.41 g (3 mmol) of potassium carbonate in 10 ml of acetone was stirred at reflux under argon for 18 hours. DMF (5 ml) was added and reflux was continued for 3 days. The solvents were removed at reduced pressure and the residue was dissolved in ethyl acetate. The extract was dried and concentrated at reduced pressure to an oil which was purified by chromatography on 230-400mesh silica gel using 25% ethyl acetate-hexane to give 0.25 g (50% yield, mp 36°-37°) of N-(2-methoxy- 2-oxoethyl)-N-[3-[(Z)-(9-octadecenyl)oxy]phenyl]glycine methyl ester. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([C:18](=[O:20])[CH3:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:28]([O:32][C:33](Cl)=[O:34])[CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C>CN(C=O)C>[CH2:28]([O:32][C:33]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:16]2[C:17]([C:18](=[O:20])[CH3:19])=[C:12]([NH:11][C:8]3[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=3)[N:13]=[CH:14][N:15]=2)[CH2:23][CH2:24]1)=[O:34])[CH:29]([CH3:31])[CH3:30]
Reactant: CC(=O)c1c(Nc2ccc(S(C)(=O)=O)nc2)ncnc1OC1CCNCC1
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1c(Nc2ccc(S(C)(=O)=O)nc2)ncnc1OC1CCN(C(=O)OCC(C)C)CC1
Temperature: 80 °C
Yield: 64.7 %

Procedure:
A mixture of 1-[4-(6-methanesulfonyl-pyridin-3-ylamino)-6-(piperidin-4-yloxy)-pyrimidin-5-yl]-ethanone (48 mg, 0.1 1 mmol), isobutylchloroformate (14.0 μL, 0.11 mmol), and triethylamine (45 μL, 0.34 mmol) in DMF (1.0 mL) was heated under microwave irradiation for 3 minutes at 80° C. The crude mixture was purified by HPLC to provide Compound A60 as a white solid (35 mg, 65%). 1H NMR (CDCl3, 400 MHz) δ 0.97 (d, 6H), 1.82-1.92 (m, 2H), 2.10-2.19 (m, 2H), 2.70 (s, 3H), 3.22 (s, 3H), 3.37 (m, 2H), 3.89-3.96 (m, 5H), 5.59 (h, 1H), 8.10 (d, 1H), 8.49-8.57 (m, 2H), 8.92 (d, 2H). Exact mass calculated for C22H29N5O6S 491.18, found 492.3 (MH+).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)ccc2c1=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)ccc2c1=O

Procedure:
7-Chloro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are reacted with piperazine to give 1-cyclopropyl-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid of decomposition point 298°-300° C. analogously to Example 87.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[C:13](=O)[NH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[CH2:1]([O:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[C:13]([Cl:25])=[N:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(COCc3ccccc3)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(COCc3ccccc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-benzyloxymethyl-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride. This oily compound is used as obtained in the following reaction.