Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[C:9]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[F:24][C:21]([F:22])([F:23])[C:18]1[CH:19]=[CH:20][C:15]([O:14][C:9]2[C:10]3[CH:11]=[CH:12][CH:13]=[C:4]([NH2:1])[C:5]=3[CH:6]=[CH:7][N:8]=2)=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccc2c(Oc3ccc(C(F)(F)F)cc3)nccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c(Oc3ccc(C(F)(F)F)cc3)nccc12
Yield: 19.3 %

Procedure:
The title compound was prepared following the procedure described in Step 3 of Intermediate-1 using 5-nitro-1-(4-(trifluoromethyl)phenoxy)isoquinoline (800 mg, 2.39 mmol), iron powder (1.34 g, 23.9 mmol), and NH4Cl (1.02 g, 19.1 mmol) in EtOH (5 mL) and water (1 mL) to afford 140 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 7.81 (m, 3H), 7.72 (d, 1H), 7.46-7.40 (m, 4H), 6.94 (d, J=6.9 Hz, 1H), 6.03 (s, 2H); MS (m/z): 305.17 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13]O.C(Br)(Br)(Br)[Br:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:16][CH2:13][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc2[nH]cc(CCO)c2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2[nH]cc(CCBr)c2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(5-methoxy-1H-indol-3-yl)ethanol (4.0 g, 20.92 mmol) in DCM (30 mL), CBr4 (7.98 g, 24.06 mmol) was added, then the reaction mixture was cooled to 0° C. and PPh3 (6.3 g, 24.0 mmol) was added. After stirring at rt for 2 h, the solvent was removed under reduced pressure. Purification was performed by FC (EtOAc/hex 3:1, Rf=0.31) to yield the title compound as a brown oil which turned into a solid during storage in the freezer. LC-MS conditions B: tR=0.78 min, [M+H]+=254.06.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].CO.[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>C(N(CC)CC)C>[CH2:20]([NH:24][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCNc1c(C(=O)OCC)c(C)nc(Cl)c1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
139.5 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester (0.5 mol.) are dissolved in about 500 ml. of methanol. 60 g. of triethylamine are added and the solution is heated at reflux temperature. At this point, 36.5 g. n-butylamine are added dropwise. After the addition is completed, the heating is continued for 10 minutes. The solvent is then removed in vacuo and 500 ml. of ethyl acetate are added to the residue. The triethylamine hydrochloride is filtered off and the solvent evaporated. The resulting yellow oil, 4-butylamino-6-chloro -2methyl-5nitropyridine-3-carboxylic acid, ethyl ester is crystallized with 300 ml. of methanol, yield 110 g. (70%); m.p. 33°-35° (methanol).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:9]1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][C:40]#[N:41]>CC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:39][C:40]#[N:41])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:9]1[CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cc2ccccc2)c2cc(-c3ccc(O)cc3)ccc2n1Cc1ccccc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(Cc2ccccc2)c2cc(-c3ccc(OCC#N)cc3)ccc2n1Cc1ccccc1

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(1,3-dibenzyl-2-methyl-1H-indol-5-yl)-phenol (0.164 g, 0.406 mmol) was reacted with K2CO3 (0.073 g, 0.528 mmol) and bromoacetonitrile (0.063 g, 0.528 mmol) in acetone (5 ml) to give the product (0.164 g, 0.371 mmol, 91%) as a pale-yellow, viscous oil. 1H NMR (DMSO-d6) a 2.35 (s, 3H), 4.11 (s, 2H), 5.18 (s, 2H), 5.43 (s, 2H), 6.99 (d, J=7.2 Hz, 2H), 7.09-7.13 (m, 3H), 7.20-7.26 (m, 5H), 7.27-7.30 (m, 3H), 7.41 (d, J=8.4 Hz, 1H), 7.56-7.59 (m, 2H), 7.62 (d, J=1.7 Hz, 1H); [ESI(+)], m/z 443 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=O)[C:3]=1[C:10](=[O:25])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[C:15]([Cl:24])[CH:14]=1.[H-].[Na+].S(OC)(O[CH3:32])(=O)=O>CN(C)P(N(C)C)(N(C)C)=O>[CH3:32][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][CH2:4][C:3]=1[C:10](=[O:25])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[C:15]([Cl:24])[CH:14]=1
Reactant: Cc1cc(O)c(C(=O)C=Cc2ccc(OC(F)(F)F)c(Cl)c2)c(=O)o1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC1=C(C(=O)C=Cc2ccc(OC(F)(F)F)c(Cl)c2)COC(C)=C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 4 ml of hexamethylphosphoramide was dissolved 0.33 g of 4-hydroxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one, to this solution was added 50 mg of sodium hydride (60% oily), and the mixture was stirred at room temperature for 30 minutes. Then, 0.2 ml of dimethyl sulfate was added, and the mixture was stirred at 65° C. for 1 hour, and at room temperature overnight. Thereafter, the reaction mixture was added to ice water, and this was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.13 g of 4-methoxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran [Compound No. (2a-17)] as a pale yellow crystal.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[C:27](=[O:28])[N:5]2[C:6]([C:24]([O-:26])=[O:25])=[C:7]([CH2:10][N+:11]3[N:12]([CH2:19][CH2:20][O:21]C=O)[C:13]([NH:16]C=O)=[CH:14][CH:15]=3)[CH2:8][S:9][C@H:4]12.C(OCC)(=O)C>CO>[ClH:1].[ClH:1].[ClH:1].[NH2:2][C@@H:3]1[C:27](=[O:28])[N:5]2[C:6]([C:24]([O-:26])=[O:25])=[C:7]([CH2:10][N+:11]3[N:12]([CH2:19][CH2:20][OH:21])[C:13]([NH2:16])=[CH:14][CH:15]=3)[CH2:8][S:9][C@H:4]12
Reactant: N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(NC=O)n3CCOC=O)CS[C@H]12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](N)[C@H]3SC2)n1CCO
Reaction time: 3 h

Procedure:
Concentrated hydrochloric acid (5.67 ml) was added to a mixture of di(trifluoroacetic acid) salt of 7β-amino-3-[3-formamido-2-(2-formyloxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (10 g) in methanol (50 ml ) at ambient temperature. After being stirred at the same temperature for 3 hours, the mixture was added dropwise to ethyl acetate (500 ml). The resultant precipitate was collected by filtration to give 7β-amino-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate trihydrochloride (6.1 g).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH2:10]([O:12][P:13]([C:18]1[C:19](=[O:29])[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([Cl:28])[CH:22]=2)(=[O:17])[O:14][CH2:15][CH3:16])[CH3:11]>>[CH2:10]([O:12][P:13]([C:18]1[C:19](=[O:29])[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([N+:1]([O-:4])=[O:2])=[C:23]([Cl:28])[CH:22]=2)(=[O:17])[O:14][CH2:15][CH3:16])[CH3:11]
Reactant: CCOP(=O)(OCC)c1cc2ccc(Cl)cc2[nH]c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOP(=O)(OCC)c1cc2cc([N+](=O)[O-])c(Cl)cc2[nH]c1=O
Reaction time: 0.25 h

Procedure:
55 ml of nitric acid are added dropwise to a solution of 55 ml of 96% sulphuric acid cooled in an ice bath, and then (7-chloro-2-oxo-1,2-dihydro-3-quinolyl)phosphonic acid diethyl ester (14.7 g, 46.6 mmol) is added in portions whilst maintaining the temperature at less than or equal to 5° C. When the addition is complete, stirring is continued for 15 minutes and then the ice bath is withdrawn and the reaction mixture is brought to ambient temperature over a period of about 1 hour 30 minutes. The solution is poured into ice and the precipitate is stirred to obtain a filterable solid. Filtration is carried out, followed by washing with water to neutrality and drying in vacuo. The solid is suspended in 210 ml of ethanol at reflux; the batch is left to cool and, after drying, filtered to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[O:8][CH2:7][CH2:6][C:5]2=[O:13].C1C(=O)N([Br:21])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:12][C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:13])[CH2:6][CH2:7][O:8]2)=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2c(cc1Cl)C(=O)CCO2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1CCOc2cc(CBr)c(Cl)cc21

Procedure:
A mixture of 6-chloro-7-methyl-chroman-4-one (20 g, 101.71 mmol), NBS (19.9 g, 111.88 mmol), and AIBN (4.17 g, 25.43 mmol) in anhydrous CCl4 (300 mL) was heated at reflux in 24 h. The mixture was cooled, filtered the solid. The filtrate was concentrated and used in the next step without purification.
Reaction SMILES: [NH2:1][C:2](=[S:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[CH:10]([CH3:21])[C:11](=O)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1>CN(C=O)C.CCOC(C)=O>[Br:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][C:11]1[N:1]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[S:8][C:10]=1[CH3:21]
Reactant: CC(Br)C(=O)Cc1cccc(Br)c1
Reactant: CCOC(=O)C(N)=S
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(Cc2cccc(Br)c2)c(C)s1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A mixture of ethyl 2-amino-2-thioxoacetate (50.9 mg, 0.38 mmol) and 3-bromo-1-(3-bromophenyl)butan-2-one (0.38 mmol, crude from previous step) in DMF (2 mL) was stirred at 70° C. for 12 h. The mixture was diluted with EtOAc and washed with H2O. The organic layer was concentrated, and purified by silica gel column chromatography(0-50% EtOAc/Hexane) to yield a yellowish solid (71 mg, 55% over 2 steps). MS (ES+) C14H14BrNO2S requires: 339, 341 found: 340, 342 [M+H]+(1:1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>C(O)(C)C>[CH3:12][N:13]([CH3:15])/[CH:14]=[CH:2]/[C:1]([C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1cncnc1
Reactant: COC(OC)N(C)C
Solvent: CC(C)O
Product: CN(C)/C=C/C(=O)c1cncnc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 68.8 %

Procedure:
5-Acetylpyrimidine (1 g, 8.2 mmol) and N,N-dimethylformamide dimethyl acetal (1.3 g, 11 mmol) were dissolved in 20 mL of isopropanol. The solution was stirred at 100° C. for 24 hours, cooled to room temperature, and concentrated under reduced pressure. Ethyl ether was then added to the residue. After being cooled in an ice bath for a couple of hours, the solid was collected by filtration, rinsed with cold ethyl ether, dried in vacuum to obtain 1 g (59% yield) of the title compound. MS (M+1)=178.0.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:20][C:21](OC(C)=O)=[O:22]>N1C=CC=CC=1>[C:21]([O:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([F:18])([F:19])[C:14]([F:15])([F:16])[F:17])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:22])[CH3:20]
Reactant: O=C(O)c1ccc(OCC(F)(F)C(F)(F)F)cc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(OCC(F)(F)C(F)(F)F)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
A solution of 2-hydroxy-4-(2,2,3,3,3-pentafluoropropoxy)benzoic acid (obtained in example 6) (0.45 g, 1.6 mmol) in pyridine (3 mL) was cooled to 0° C. and Ac2O (0.25 mL) was added. The resulting mixture was stirred for 15 min at 0° C. and for 2 h at room temperature. The mixture was then concentrated and the residue was treated with H2O (10 mL) and stirred until precipitation (2 h). The solid was collected by filtration and was purified by chromatography on silica-gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 0.2 g of the desired product as a white solid (38% yield).
Reaction SMILES: [C:1]1(=[O:10])[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][NH:2]1.[Cl:11][C:12]1[N:13]=[C:14]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:15]2[S:20][C:19]([CH:21]=O)=[CH:18][C:16]=2[N:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:11][C:12]1[N:13]=[C:14]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[C:15]2[S:20][C:19]([CH2:21][N:7]3[CH2:8][CH2:9][C:4]4([C:1](=[O:10])[NH:2][CH2:3]4)[CH2:5][CH2:6]3)=[CH:18][C:16]=2[N:17]=1
Reactant: O=C1NCC12CCNCC2
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C1NCC12CCN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.8 %

Procedure:
To a solution of 1-oxo-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (150 mg, 0.624 mmol) in DCM (6 mL) was added TFA (3 mL) and the resulting solution stirred at RT for 1 h. The crude reaction mixture was loaded onto a Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to provide 2,7-diaza-spiro[3.5]nonan-1-one as a colourless oil. To a suspension of 2,7-diaza-spiro[3.5]nonan-1-one (0.624 mmol) in dichloroethane (13 mL) were added 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (130 mg, 0.458 mmol) and sodium triacetoxyborohydride (146 mg, 0.689 mmol) and the resulting suspension stirred at RT for 18 h. The reaction was quenched with water and loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH. The resulting residue was then purified by column chromatography to give the title compound as a white solid (93 mg, 50%)
Reaction SMILES: N1[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:6]1([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[C:16]([N:18]=[N+]=[N-])=[O:17])[CH:10]=[CH:9][CH:8]=[CH:7]1>ClCCl>[N:6]1([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[C:16]([N:18]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:17])[CH:10]=[CH:9][CH:8]=[CH:7]1
Reactant: [N-]=[N+]=NC(=O)c1ccsc1-n1cccc1
Reactant: C1CCNC1
Solvent: ClCCl
Product: O=C(c1ccsc1-n1cccc1)N1CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
Add 50 ml of pyrrolidine dropwise, at room temperature, to a solution of 2-(pyrrol-1-yl)thiophen-3-ylcarbonyl azide (Heterocycles, (1983), 20, 477) in 500 ml of dichloromethane. The reaction mixture is stirred for 12 hours at room temperature and then washed three times with 150 ml of 1N hydrochloric acid each time and then with 150 ml of water. The organic phase is then dried over calcium chloride and subsequently concentrated to dryness to yield the title compound in the form of an oil.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([N:18]3[C:27]4[C:22](=[CH:23][C:24]([C:28](=[O:34])/[CH:29]=[CH:30]/[N:31]([CH3:33])[CH3:32])=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([N:18]3[C:27]4[C:22](=[CH:23][C:24]([CH:28]([OH:34])[CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: CN(C)/C=C/C(=O)c1ccc2c(c1)CCCN2C(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)CCC(O)c1ccc2c(c1)CCCN2C(=O)c1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
Sodium borohydride (0.6 g) was added to a solution of (E)-[1-[(4′-chloro[1,1′-biphenyl]-4-yl)carbonyl]-1,2,3,4-tetrahydro-6-quinolinyl]-3-(dimethylamino)-2-propen-1-one (0.3 g) obtained in Reference Example 6 in methanol (30 ml), and the mixture was heated for 3 hours under reflux. After the solvent was distilled away under reduced pressure, the residues were dissolved in water-ethyl acetate and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The resultant residues were purified by alumina column chromatography (developing solvent; ethyl acetate), whereby the title compound (0.1 g) was obtained as amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6][C:5]2=[O:16].CO[CH:19](OC)[N:20](C)[CH3:21].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][C:6](=[CH:19][NH:20][CH3:21])[C:5]2=[O:16]
Reactant: CCC(=O)N1CCC(=O)c2cc(Cl)ccc21
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCC(=O)N1CC(=CNC)C(=O)c2cc(Cl)ccc21
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A solution of 6-chloro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2 g), N,N-dimethylformamide dimethyl acetal (7.009 g), and triethylamine (0.87 g) in benzene (50 m) was refluxed with stirring for 1 hour and then about three-fourths of the solvent was distilled slowly at atmospheric pressure over a period ximately 1 hour. To the residue was added benzene (100 ml) and the solvent was distilled again. The resulting solid was collected by filtration, washed with diethyl ether, and dried to give 6-chloro-3-methylaminomethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.02 g).
Reaction SMILES: N#N.Br[C:4]([F:13])([F:12])[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[CH2:14]([Sn](CCCC)(CCCC)CCCC)[CH:15]=[CH2:16].CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[F:12][C:4]([F:13])([CH2:16][CH:15]=[CH2:14])[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(N1CCCC1)C(F)(F)Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: N#N
Solvent: Cc1ccccc1
Product: C=CCC(F)(F)C(=O)N1CCCC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 2-bromo-2,2-difluoro-1-(pyrrolidin-1-yl)ethanone (600 mg, 2.63 mmol) in dry toluene (18 mL) was added allyltributyltin (0.84 mL, 2.63 mmol) and AIBN (9 mg, 0.05 mmol) at rt. The reaction mixture was stirred at 100° C. for 1 h. AIBN (9 mg, 0.05 mmol) was then added again and the reaction mixture further stirred at 100° C. for 30 h. The solvent was removed under reduced pressure and the crude residue purified by FC (SiO2 containing 10% KF, hept-EA, 1:0→4:1) to give the title compound as a colorless oil. LC-MS-conditions 08: tR=0.73 min; [M+H]+=190.30.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][N:6]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:23][CH2:22][CH2:21]4)[CH2:16][CH2:15]3)=[O:13])[CH2:7][CH2:8][C:9]=2[N:10]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC>C1(C)C=CC=CC=1.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:29]([C:2]1[S:3][C:4]2[CH2:5][N:6]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:23][CH2:22][CH2:21]4)[CH2:16][CH2:15]3)=[O:13])[CH2:7][CH2:8][C:9]=2[N:10]=1)(=[O:31])[CH3:30]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(CN1CCc2nc(Br)sc2C1)N1CCN(C2CCC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1nc2c(s1)CN(CC(=O)N1CCN(C3CCC3)CC1)CC2
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-bromo-5-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine (300 mg, 0.75 mmol), tributyl(1-ethoxy-vinyl)tin (361 mg, 1 mmol) and Pd(PPh3)4 (92 mg, 0.08 mmol) in toluene (15 mL) is degassed with argon and heated at 110° C. in a sealed tube overnight. The mixture is cooled and saturated KF solution (10 mL) is added. The mixture is stirred at rt for 30 min, and then the layers are separated. The aqueous layer is extracted with EtOAc (15 ml) and the combined extracts are dried and evaporated. The residue is dissolved in THF (10 mL), 2N HCl (10 mL) is added and the mixture is stirred at rt for 30 min. Solid Na2CO3 is added until pH>7 and the layers are separated. The aqueous layer is extracted with EtOAc (15 ml) and the combined extracts are dried and evaporated. The residue is purified by PTLC to give the title compound as a white solid. MS (M+1): 363.0; 1H NMR (δ, CDCl3): 3.88 (s, 2H), 3.52-3.62 (m, 4H), 3.41 (s, 2H), 2.99 (s, 4H), 2.62-2.77 (m, 4H), 2.29 (q, 4H), 1.66-2.08 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:6]([C:8]2(Cl)[NH:13][C:12]([NH2:14])=[N:11][CH:10]=[CH:9]2)[CH:7]=1.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:6]([C:8]2[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([NH:33][C:30]3[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=3)[CH:9]=2)[CH:7]=1
Reactant: Cc1ccc(N)cc1
Reactant: COc1ccccc1COc1ccc(Br)cc1C1(Cl)C=CN=C(N)N1
Product: COc1ccccc1COc1ccc(Br)cc1-c1cc(Nc2ccc(C)cc2)nc(N)n1
Yield: 36 %

Procedure:
Following the method described in Example 4, 6-[5-bromo-2-(2-methoxy-benzyloxy)-phenyl]-6-chloro-pyrimidin-2-ylamine and 4-methyl-phenylamine provided the title compound (36% yield). 1H NMR (CD3OD) δ 3.82 (s, 3H, CH3), 5.25 (s, 2H, CH2), 6.32 (s, 1H, Ar), 6.89-6.98 (m, 2H, Ar), 7.21-7.30 (m, 6H, Ar), 7.59-7.72 (m, 3H, Ar).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[CH3:31][N:32]([CH3:44])[CH2:33][CH:34]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1)[CH3:35]>C1COCC1>[CH3:44][N:32]([CH3:31])[CH2:33][CH:34]([NH:36][C:37]1[CH:38]=[CH:39][C:40]([NH:43][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])=[CH:41][CH:42]=1)[CH3:35]
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: CC(CN(C)C)Nc1ccc(N)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(NC(C)CN(C)C)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 40.3 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 116 mg, 0.288 mmol) and THF (2 mL). To the resulting solution was added N-(2-Dimethylamino-1-methyl-ethyl)-benzene-1,4-diamine (prepared below, 61.4 mg, 0.314 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture and the reaction mixture was vacuum filtered. The black solid collected was set aside. The filtrate was then concentrated in vacuo and then redissolved into EtOAc and then Hexanes were added causing a precipitate to form. The precipitate was then filtered and washed with ˜1 mL of i-prOH yielding 40% (0.067 g, 0.116 mmol) of the title compound.