Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(C)(C)C(=O)N(Br)C1=O.[CH:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)([CH3:14])[CH3:13].FC(F)(F)S(O)(=O)=O.S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:20]1[CH:19]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:17]=[CH:16][C:15]=1[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)c1ccc(C(F)(F)F)cc1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S([O-])O
Solvent: ClCCl
Product: CC(C)c1ccc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Using the general conditions described by H. Eguchi, H. Kawaguchi, S. Yoshinaga, A. Nishida, T. Nishiguchi, and S. Fujisaki (Bull. Chem. Soc. Jpn.., 1994, 67, 1918-1921), 1,3-dibromo-5,5-dimethylhydantoin (454 mg, 3.18 mmol) was added in one portion to a solution of 4-isopropyl-1-(trifluoromethyl)benzene (500 mg, 2.65 mmol) and trifluoromethanesulfonic acid (0.281 mL, 3.18 mmol) in dichloromethane (5.0 mL). The mixture was stirred in the dark at RT for 3 h. Saturated aqueous sodium bisulfite was added to the reaction mixture until the brown organic layer was decolorized. The mixture was neutralized by the addition saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was separated, dried over sodium sulfate, and evaporated. The crude material was filtered through a column packed with silica gel and eluted with hexane to isolate a mixture containing the title compound.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH2:18])[CH3:17]>O>[CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:18][CH2:16][CH3:17])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(SCc2ccccc2)n1
Reactant: CCN
Solvent: O
Product: CCNc1cccc(SCc2ccccc2)n1

Procedure:
A mixture-of 10 g of 2-benzylthio-6-bromopyridine, 70 ml of a 40% ethylamine aqueous solution, and a catalytic amount of cuprous chloride was allowed to react in an autoclave at 180° C. for 4 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane=1/19 by volume) to obtain 5.9 g of 2-benzylthio-6-ethylaminopyridine as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.Cl.[O:12]([NH2:14])[CH3:13].C([BH3-])#N.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH:14][O:12][CH3:13]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: CON
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(F)c(Cl)c1

Procedure:
Reaction of 3-chloro-4-fluorobenzaldehyde with methoxylamine hydrochloride followed by reduction with sodium cyanoborohydride as described in the preparation of Compound 44-A and 44-B gave the title hydroxylamine as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.48 (3H, s), 3.98 (2H, s), 5.72 (1H, broad s), 7.10 (1H, t), 7.22 (1H, m), 7.42 (1H, m).
Reaction SMILES: C([Li])(C)(C)C.[C:6]([Si:10]([O:13][C@H:14](/[CH:20]=[CH:21]/I)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].[CH3:23][O:24][C:25](=[O:46])[CH2:26][S:27][CH2:28][CH2:29][CH2:30][S:31][C:32]1[C:36](=[O:37])[CH2:35][C@@H:34]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH:33]=1.[NH4+].[Cl-]>CCCCC.CCOCC.C1COCC1>[CH3:23][O:24][C:25](=[O:46])[CH2:26][S:27][CH2:28][CH2:29][CH2:30][S:31][C@H:32]1[C:36](=[O:37])[CH2:35][C@@H:34]([O:38][Si:39]([C:42]([CH3:43])([CH3:45])[CH3:44])([CH3:41])[CH3:40])[C@@H:33]1/[CH:21]=[CH:20]/[C@@H:14]([O:13][Si:10]([C:6]([CH3:7])([CH3:9])[CH3:8])([CH3:11])[CH3:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCC[C@@H](/C=C/I)O[Si](C)(C)C(C)(C)C
Reactant: COC(=O)CSCCCSC1=C[C@H](O[Si](C)(C)C(C)(C)C)CC1=O
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCC[C@@H](/C=C/[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)[C@@H]1SCCCSCC(=O)OC)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
tert-Butyllithium (1.47 mL of a 1.7M solution in pentane, 2.5 mmol) was added dropwise to a solution of tert-butyl[(S)-1-((E)-2-iodovinyl) hexyloxy]dimethylsilane 6 (462.5 mg, 1.25 mmol) in Et2O (6.0 mL) at −78° C. After stirring for 30 min lithium 2-thienylcyanocuprate (6.0 mL of a 0.25M solution in THF, 1.5 mmol) was added and the reaction was stirred an additional 30 min at −78° C. A solution of enone 5 (430 mg, 1.1 mmol) in Et2O (1 mL) was added and stirring was continued for an additional 1 h. The reaction mixture was then quickly poured into saturated aqueous NH4Cl cooled to 0° C. The mixture was extracted with EtOAc and the organic portion was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was quickly purified by flash column chromatography (silica gel, 100% hexane followed by 8:1 hex/EtOAc) to afford 270 mg (39%) of the above titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:15][CH2:14][C:13]2[N:12]=[CH:11][C:10]([C:16]([O:18]CC)=O)=[C:9](Cl)[C:8]=2[CH2:7]1)=[O:5])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1>C(O)CCC>[CH2:1]([O:3][C:4]([N:6]1[CH2:15][CH2:14][C:13]2[NH:12][CH:11]=[C:10]3[C:16](=[O:18])[N:29]([C:26]4[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=4)[N:30]=[C:9]3[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(c1Cl)CN(C(=O)OCC)CC2
Reactant: NNc1ccc(Cl)cc1
Solvent: CCCCO
Product: CCOC(=O)N1CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1

Procedure:
A mixture of 3 g of ethyl 6-ethoxycarbonyl-4-chloro-5,6,7,8-tetrahydro[1,6]naphthyridine-3-carboxylate (Example 1c) and 1.4 g of p-chlorophenylhydrazine in 100 mL of n-butanol is stirred and heated at reflux under nitrogen atmosphere for 20 hours, then cooled. Solid is collected and washed successively with n-butanol, then with ether. Solid is then dried in a vacuum oven at 80° for 24 hours obtaining 8-ethoxycarbonyl-2-p-chlorophenyl-2,3,6,7,8,9-hexahydropyrazolo[4,3-c][1,6]naphthyridine-3(5H)-one, mp 357°-359°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:21]([O:20][C:18]([C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)=[CH2:19])[CH3:22]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cccc2c(Cl)ncnc12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1ncnc2c(C)cccc12
Yield: 89.1 %

Procedure:
4-Chloro-8-methylquinazoline (5.10 g, 25.13 mmol) is dissolved in toluene (50 mL) and tributyl(1-ethoxyvinyl)tin (9.98 g, 27.64 mmol) and tetrakis(triphenylphosphine) palladium(0) (1.45 g, 1.26 mmol) are added to the solution and the reaction is refluxed for 3 h. Volatiles are evaporated under reduced pressure and the resulting mixture is diluted with brine and ethyl acetate. The phases separated and the organic phase washed with brine, dried and volatiles evaporated under reduced pressure. The residue is purified by flash chromatography (0-30% EtOAc in cyclohexane) to give 4-(1-ethoxy-vinyl)-8-methyl-quinazoline (4.80 g, 89%).
Reaction SMILES: [OH-].[Na+].[I-].[Na+].[NH:5]1[CH:9]=[CH:8][N:7]=[N:6]1.CS([O-])(=O)=O.[CH3:15][C:16](O)([CH2:18][CH3:19])C>>[CH2:19]([N:5]1[CH:9]=[CH:8][N:7]=[N:6]1)[CH2:18][C:16]#[CH:15]
Reactant: c1c[nH]nn1
Reactant: CCC(C)(C)O
Agent: CS(=O)(=O)[O-]
Agent: [I-]
Agent: [Na+]
Product: C#CCCn1ccnn1
Temperature: 25 °C
Yield: 38.9 %

Procedure:
A suspension of NaOH (37.86 g, 946.5 mmol), sodium iodide (94.65 g, 631.5 mmol) and 1H-[1,2,3]triazole (61.03 g, 883.6 mmol) in 2-methyl-2-butanol (750 mL) was refluxed for 1 h under an inert atmosphere. After cooling to room temperature the methane sulfonate (94.18 g, 631.2 mmol) was added within 5 minutes. The resulting suspension was then heated to reflux for 3 h, cooled to room temperature and concentrated in vacuo at 45° C. Water (500 mL) and dichloro methane (1 L) were added and the organic phase was separated, dried over sodium sulfate and the volatiles removed at 30° C. The residue was distilled at 1 mmHg. A forerun was collected at 20–70° C. The main fraction distilled at 123–129° C. as a colorless, turbid liquid. After filtration over Celite 1-but-3-ynyl-1H-[1,2,3]triazole was obtained as a colorless liquid (29.77 g, 38.9%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].I[CH2:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[CH3:21][C:20]([CH3:23])([CH3:22])[CH2:19][CH2:18][O:10][C:7]1[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: O=Cc1cc(O)ccc1O
Reactant: CC(C)(C)CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)CCOc1ccc(O)c(C=O)c1
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To a solution of the 2,5-dihydroxybenzaldehyde in DMF was added K2CO3 at room temperature and the mixture was stirred for 10 min. To this solution 1-iodo-3,3-dimethylbutane was added. After stirring at 70° C. for 4 h, the solvent was removed under reduced pressure and reaction mixture was diluted with ethyl acetate. After washing with water, the organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography to give desired product in 65% yield. 1H NMR: 0.97 (s, 9H), 1.73 (t, 2H, J=7.2 Hz), 4.05 (t, 2H, J=7.2 Hz), 6.88 (d, 1H, J=9.2 Hz), 7.09 (dd, 1H, J=9.2, 3.2 Hz), 7.35 (d, 1H, J=3.2 Hz), 10.39 (s, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]=[CH:8][C:7]=2[CH:12]=1.[N+](=[C:15]([C:20]([O:22][CH3:23])=[O:21])[C:16]([O:18][CH3:19])=[O:17])=[N-]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C@@H:9]3[C:15]([C:20]([O:22][CH3:23])=[O:21])([C:16]([O:18][CH3:19])=[O:17])[C@@H:8]3[C:7]=2[CH:12]=1
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Reactant: COc1ccc2c(c1)C=CCO2
Solvent: Cc1ccccc1
Product: COC(=O)C1(C(=O)OC)[C@@H]2c3cc(OC)ccc3OC[C@@H]21
Reaction time: 1.5 h

Procedure:
To stirred solution of 79 g of 6-methoxy-2H-[1]benzopyran (J. Org. Chem. 1973, 38, 3832) and 17.6 g of cuprous iodide-trimethyl phosphite (Synthesis 1971, 658) in 400 ml toluene, is added at 103° 125 g dimethyl diazomalonate (Synthesis 1971, 658) over a period of 30 min. After stirring 1.5 h, the reaction mixture is cooled, filtered through Celite, concentrated under reduced pressure and flash chromatographed with ethyl acetate/hexane (3:7) to give cis-(±)-dimethyl 1,1a,2,7b-tetrahydro-6-methoxybenzo[b]cyclopropa[d]pyran-1,1-dicarboxylate.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:21])[C@@H:6]([C:18]([OH:20])=[O:19])[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])(=[O:3])[CH3:2].[F:22][C:23]([F:41])([F:40])[C:24]([NH:26][C@H:27]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:28]O)=[O:25]>C(Cl)Cl>[C:1]([O:4][C@H:5]([CH3:21])[C@H:6]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:18]([O:20][CH2:28][C@@H:27]([C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[NH:26][C:24](=[O:25])[C:23]([F:22])([F:40])[F:41])=[O:19])(=[O:3])[CH3:2]
Reactant: O=C(OCc1ccccc1)[C@H](CO)NC(=O)C(F)(F)F
Reactant: CC(=O)O[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: ClCCl
Product: CC(=O)O[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
To a solution of O-acetyl-N-benzyloxycarbonyl-L-threonine (1 g) and benzyl N-trifluoroacetyl-L-serinate (987 mg) in methylene chloride (20 ml) was added N,N-diethylaminopropyl-N'-ethylcarbodiimide hydrochloride (1.22 g) and 4-N,N-dimethylaminopyridine (77.8 mg) at room temperature. After stirring for an hour at room temperature, the reaction mixture was washed successively with aqueous hydrogen chloride, water, 10% aqueous sodium hydrogen carbonate and brine. After drying over sodium sulfate, the methylene chloride extract was filtered and concentrated. The residue was chromatographed on silica gel (20 g) eluting successively with a mixture of hexane and methylene chloride (1:1), methylene chloride and a mixture of methylene chloride and acetone (125:1) to give benzyl O-[3(R)-acetoxy-2(S)-benzyloxycarbonylamino-1-oxo-butyl]-N-trifluoroacetyl-L-serinate (1.42 g).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[CH:28]1([N:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH2:33][CH2:32]2)[CH2:30][CH2:29]1>>[CH:28]1([N:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([C:11]([C:6]3[CH:7]=[N:8][CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=3[Cl:1])=[O:12])[CH2:33][CH2:32]2)[CH2:30][CH2:29]1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Reactant: c1ccc2c(c1)NCCN2C1CC1
Product: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCN(C2CC2)c2ccccc21

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 1-cyclopropyl-1,2,3,4-tetrahydro-quinoxaline. Light yellow foam (72%). MS (ESI): m/z=440.092 [M+H]+.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2([CH2:14][NH:15][C:16](=O)[CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].O>O1CCCC1>[OH2:21].[ClH:2].[ClH:1].[O:21]1[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][NH:15][CH2:14][C:10]2([C:5]3[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=3)[CH2:11][CH2:12][CH2:13]2)[CH2:23][CH2:22]1
Reactant: O=C(CN1CCOCC1)NCC1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccc(C2(CNCCN3CCOCC3)CCC2)cc1Cl

Procedure:
Borane-methyl sulphide complex (2 ml) was added to a refluxing solution of the morpholinoacetamide prepared in a similar manner to that described above in the form of its free base (3.6 g) in dry tetrahydrofuran (20 ml) and the mixture heated under reflux for four hours. The mixture was cooled and water (10 ml) added. Dimethylsulphide and tetrahydrofuran were removed by evaporation and excess 5N hydrochloric acid added. The solution was basified and extracted with ether. Hydrogen chloride gas was passed into the washed and dried ether extract. Evaporation to dryness gave a residue which was triturated with dry ether and recrystallised from an 8:2 mixture of propan-2-ol and ethanol to give N-(2-morpholinoethyl)-[1-(3,4-dichlorophenyl)cyclobutyl]methylamine dihydrochloride monohydrate (m.p. 230°-244° C.).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][C:13](=[O:41])[NH:14][C@H:15]([C@@H:34]1[CH2:38][C@@H:37]([CH3:39])[C:36](=[O:40])[O:35]1)[CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[CH2:19][C:18]1([CH3:33])[CH3:32])([CH3:11])([CH3:10])[CH3:9].O>C1(N)CCCC1>[C:8]([O:12][C:13](=[O:41])[NH:14][C@@H:15]([CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[CH2:19][C:18]1([CH3:33])[CH3:32])[C@@H:34]([OH:35])[CH2:38][C@H:37]([C:36](=[O:40])[NH:3][CH:4]1[CH2:2][CH2:7][CH2:6][CH2:5]1)[CH3:39])([CH3:11])([CH3:10])[CH3:9]
Reactant: Oc1ccccn1
Reactant: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](C)C(=O)O2)CC1=O
Agent: NC1CCCC1
Solvent: O
Product: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NC2CCCC2)CC1=O
Temperature: 85 °C
Reaction time: 4 h
Yield: 450.9 %

Procedure:
7.9 mg of 2-hydroxypyridine (0.08 mmol) was added to a solution of 200 mg of {(S)-2-[2,2-dimethyl-4-(5-fluoro-2-methylphenyl)-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (101b) (0.42 mmol) in cyclopentylamine (1.5 ml), and the mixture was stirred at 85° C. for four hours. The reaction mixture was cooled and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1) to obtain 203 mg of the title compound (yield: 86%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH2:27]>N1C=CC=CC=1>[NH2:20][C@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[NH:27][C:11]1[CH:12]=[C:13]2[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[CH:9][C:10]=1[F:15]
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: N[C@@H]1CCCC[C@@H]1N
Solvent: c1ccncc1
Product: N[C@H]1CCCC[C@H]1Nc1cc2c(cc1F)c(=O)c(C(=O)O)cn2C1CC1
Temperature: 115 °C
Yield: 60.5 %

Procedure:
A mixture of 1.33 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1.73 g of cis-1,2-diaminocyclohexane in 10 ml of pyridine was heated in an oil bath of 115° C. for 1 hour then filtered while hot. Cooling the filtrate afforded 1.09 g of the desired product, m.p. 270°-274° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10](F)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[F:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH:17]=O.C(O)(=O)C>C1(C)C=CC=CC=1>[F:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH:17]=[N:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2
Reactant: COc1ccc(C=O)c(F)c1
Reactant: Nc1cc(F)cc2[nH]c(=O)ccc12
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(C=Nc2cccc3[nH]c(=O)ccc23)c(F)c1

Procedure:
To 600 mg (3.9 mmol) 5-Amino-7-fluoro-1H-quinolin-2-one and 624 mg (3.9 mmol) 2-fluoro-4-methoxybenzaldehyde in 12 ml toluene are added 18 μl acetic acid and 2 g molecular sieve. The mixture is heated over 25 hours under reflux and filtrated through a path of cellites after cooling. The solvent is evaporated and the residue is two times azeotrophed with small portions of toluene to obtain 5-{[1-(2-fluoro-4-methoxyphenyl)-methylidene]amino}-1H-quinolin-2-one are quantitatively. 0.81 ml (11.6 mmol) 1,1,1-trifluoroepoxypropane in 12 ml THF and 3.5 ml hexane are cooled to −100° C. and 3.75 ml of a 2.5 M n-butyl lithium solution (9.4 mmol) in hexane are added over 10 minutes while the temperature does not exceed −95° C. 10 Minutes after complete addition 1.11 g (12 mmol) 5-{[1-(2-fluoro-4-methoxyphenyl)-methylidene]amino}-1H-quinolin-2-one in 10 ml THF are added over 15 minutes while the temperature does not exceed −95° C. After tree hours at −100° C. 3.75 ml diethyl ether are added and the reaction mixture is warmed to −10° C. over one hour. The reaction is quenched by addition of saturated ammonium chloride solution. The phases were separated and the aqueous layer is extracted twice with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated. Flash chromatography on silica gel (acetone in hexane 0 to 80%) yields 410 mg of 5-{[(2-Fluoro-4-methoxyphenyl)(2-trifluoromethyl-oxiranyl)methyl]amino}-1H-quinolin-2-one.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([CH3:32])=[N:28][NH:29]2)=[CH:25][CH:24]=1.C(N(CC)CC)C.O>C(O)CCC.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[C:30]3[C:26]([C:27]([CH3:32])=[N:28][NH:29]3)=[CH:25][CH:24]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1n[nH]c2cc(N)ccc12
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5c(C)n[nH]c5c4)nc(Cl)nc32)cc1
Temperature: 110 °C
Yield: 98.1 %

Procedure:
A mixture of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.585 mmol), 6-amino-3-methylindazole (94 mg, 0.64 mmol) and triethylamine (TEA) (0.200 mL, 1.44 mmol) in n-butyl alcohol (n-BuOH) (5 mL) was heated at 110° C. overnight. After cooling down, H2O and EtOAc were added. The organic phase was separated, washed with 1N HCl, followed by 5% NaHCO3, before being dried over Na2SO4 and concentrated in vacuo to give 2-chloro-N-(3-methyl-1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (260 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[C:25]([N:29]1[C:33]([C:34](Cl)=[O:35])=[CH:32][C:31]([CH3:37])=[N:30]1)([CH3:28])([CH3:27])[CH3:26].C(OCC)(=O)C.O1CCCC1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[C:25]([N:29]1[C:33]([C:34]([NH:1][C:2]2[CH:3]=[C:4]([O:5][C:6]3[CH:7]=[CH:8][C:9]4[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]5[CH2:20][CH2:19]5)=[O:17])[N:14]=4)[N:11]=3)[CH:21]=[CH:22][C:23]=2[CH3:24])=[O:35])=[CH:32][C:31]([CH3:37])=[N:30]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1cc(C(=O)Cl)n(C(C)(C)C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)n(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.4 %

Procedure:
To a solution of N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (210 mg, 0.65 mmol) in N,N-dimethylacetamide (5 mL) was added a solution of 1-tert-butyl-3-methyl-1H-pyrazole-5-carbonylchloride (160 mg, 0.78 mmol) in N,N-dimethylacetamide (1 mL), and the mixture was stirred at room temperature for 30 min. Ethyl acetate/tetrahydrofuran and saturated aqueous sodium hydrogencarbonate solution were added to the mixture, the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4). Combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→90/10) to give the title compound (14 mg, 4%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:10]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O)#[N:11].[BH4-].[Na+]>C1(C)C=CC=CC=1>[C:10]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])#[N:11]
Reactant: CC(C)(C)OC(=O)CN
Reactant: N#Cc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CNCc1cccc(C#N)c1
Temperature: 140 °C
Reaction time: 12 h
Yield: 86.5 %

Procedure:
To a stirred solution of glycine-ter-butyl ester (5 g, 0.038 mol) in toluene (100 mL). was added 3-cyanobenzaldehyde (5 g, 0.0381 mol) under N2 and refluxed at 140° C. for 2 h. After complete evaporation of the toluene, the reaction mass was cooled to RT and dissolved in dry methanol. Sodium borohydride (2.17 g, 0.0571 mol) was added in portions at 0° C. After 12 h, the reaction mass was evaporated under vacuum, washed with water (100 mL), extracted in DCM (100 mL), dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as a yellow liquid (8.1 g, 86%). 1H NMR (DMSO-d6, 400 MHz) δ 7.71-7.72 (m, 2H), 7.63-7.65 (m, 1H), 7.53-7.55 (m, 1H), 5.40-5.41 (m, 1H), 4.53-4.54 (m, 2H), 3.17 (s, 2H), 1.39 (s, 9H).