Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[N:18]=[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22](COCC[Si](C)(C)C)[N:21]=3)[CH:16]=[N:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5].O>FC(F)(F)C(O)=O>[F:1][C:2]1[C:36]([C:37]([F:39])([F:38])[F:40])=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[N:18]=[C:17]([NH:19][C:20]3[CH:24]=[CH:23][NH:22][N:21]=3)[CH:16]=[N:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: C[Si](C)(C)CCOCn1ccc(Nc2cncc(CN3CCN(C(=O)c4cccc(C(F)(F)F)c4F)CC3)n2)n1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccc(C(F)(F)F)c1F)N1CCN(Cc2cncc(Nc3cc[nH]n3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.49 g of 6-((4-(2-fluoro-3-(trifluoromethyl)benzoyl)piperazin-1-yl)methyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazin-2-amine was dissolved in 25 ml of trifluoroacetic acid and 2.5 ml of water followed by stirring at room temperature for 2 hours. The reaction solution was concentrated in vacuo, diluted with ethyl acetate, and then washed with saturated sodium bicarbonate, water and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=5/1) to give the title compound as a solid. The resulting solid was dissolved in ethanol by heating to 80° C. The solution was charged with heptane, and heating was stopped. Then the solution was cooled slowly to room temperature. After heptane was further added, the precipitate was filtered and dried to give a crystal of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])O.[Na+].[C:15](Cl)(Cl)=[S:16]>O1CCCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:15]=[S:16])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1N=C=S
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
To a solution of 4-bromo-2-methylaniline (11.0 g, 59.0 mmol) and saturated aqueous sodium hydrogen carbonate (150 mL) in tetrahydrofuran (150 mL) was added thiophosgene (4.50 mL, 59.0 mmol), and the mixture was stirred at 0° C. for 30 min. The reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residual solid was collected by filtration and was washed with n-hexane to give the title compound as a brown powder (8.16 g, 35.8 mmol, 61%).
Reaction SMILES: [N:1]1([C:7](OC(C)(C)C)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:14][CH:15]([O:17][C:18](=[O:41])[NH:19][C@H:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]3[S:31][C:32](C=O)=[CH:33][N:34]=3)[CH:28]=2)[N:23]([C:37](=[O:39])[CH3:38])[C@@H:22]([CH3:40])[CH2:21]1)[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].C(O)(C(F)(F)F)=O>ClCCl>[C:37]([N:23]1[C:24]2[C:29](=[CH:28][C:27]([C:30]3[S:31][C:32]([CH2:7][N:1]4[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]4)=[CH:33][N:34]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:19][C:18](=[O:41])[O:17][CH:15]([CH3:14])[CH3:16])[CH2:21][C@@H:22]1[CH3:40])(=[O:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)N1c2ccc(-c3ncc(C=O)s3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1c2ccc(-c3ncc(CN4CCNCC4)s3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.3 %

Procedure:
1,1-Dimethylethyl 1-piperazinecarboxylate (48.2 mg, 0.259 mmol), 1-methylethyl[(2S,4R)-1-acetyl-6-(5-formyl-1,3-thiazol-2-yl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 106) (104 mg, 0.259 mmol) and sodium triacetoxyborohydride (220 mg, 1.036 mmol) were dissolved in dichloromethane (DCM) (4 mL) and the resulting mixture was stirred at room temperature under nitrogen for 16 h before being treated with a saturated NaHCO3 aqueous solution. The two layers were separated using a phase separator cartridge and the organic phase was concentrated in vacuo. The residue was loaded on a 20 G SCX cartridge which was eluted with MeOH then with a 2M NH3 solution in MeOH. The ammonia fractions were concentrated in vacuo to give a residue which was dissolved in DCM (3 mL) and treated with TFA (0.5 mL, 6.49 mmol). After 1 h, the mixture was concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 1 to 10% (2M NH3 in MeOH) in DCM) gave 1-methylethyl {(2S,4R)-1-acetyl-2-methyl-6-[5-(1-piperazinyl methyl)-1,3-thiazol-2-yl]-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (70 mg, 0.148 mmol, 57.3% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:27]=[N:26][CH:25]=[CH:24][N:23]=2)[CH2:21][O:20]1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:18][C:19]([C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)([OH:20])[CH3:21])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC1(c2cnccn2)CO1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2cnccn2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.1 %

Procedure:
To a solution of 8-chloro 2-methyl-2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indole (1.0 g, 4.54 mmol) in DMF (10 mL) was added sodium hydride (600 mg, 13.63 mmol). After stirring for 10 min at RT, 2-(2-methyl oxiranyl)pyrazine (804 mg, 5.9 mmol) was added dropwise at 0-10° C. and the reaction mixture was stirred at RT for 16 h. The reaction mixture was poured into ice water and extracted with EtOAc (3×150 mL). The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to afford crude product, which was crystallized in ether-hexane to yield a yellow solid product as the free base (1.2 g). 1H NMR (DMSO, Oxalate salt) d (ppm): 8.65 (s, 1H), 8.55 (s, 1H), 8.50 (d, 1H), 7.42 (s, 1H), 7.05 (d, 1H), 6.95 (d, 1H), 4.40 (m, 4H), 3.20 (m, 2H), 3.0 (m, 2H), 2.90 (s, 3H), 1.58 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:18]>C1COCC1.O>[C:2]1([NH:1][C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([OH:18])=[O:8])=[O:17])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCCCC(=O)O1
Reactant: Nc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.9 %

Procedure:
Aniline (0.6 g, 6.4 mmol) was added at room temperature to a stirred solution of oxonane-2,9-dione (1.0 g, 6.4 mmol) in THF anhydrous. After stirring at RT for 0.5 h, the resulting mixture was diluted with water (100 mL). The formed white solid was filtered and collected. Purification by silica gel column chromatography using as eluent EtOAc:cyclohexane=80:20 to 100:0 afforded 7-(phenylcarbamoyl)heptanoic acid as a white solid (174 mg, 11% yield).
Reaction SMILES: [OH:1][C:2]1[N:3]=[N:4][C:5]([OH:8])=[CH:6][CH:7]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13]Br>>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][N:3]1[C:2](=[O:1])[CH:7]=[CH:6][C:5](=[O:8])[NH:4]1
Reactant: Oc1ccc(O)nn1
Reactant: BrCCCCBr
Product: O=c1ccc(=O)n(CCCCBr)[nH]1

Procedure:
By the method of Example 1, 3,6-dihydroxypyridazine is reacted with 1,4-dibromobutane to yield the title product.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[I:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([CH3:19])=[CH:12][C:11]=1[F:20]>CN(C=O)C>[I:9][C:10]1[C:11]([F:20])=[CH:12][C:13]([CH:19]=[CH:3][N:4]([CH3:6])[CH3:5])=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1
Reactant: Cc1cc(F)c(I)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1cc(F)c(I)cc1[N+](=O)[O-]
Temperature: 125 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
A mixture of N,N-dimethylformamide dimethyl acetal (0.30 mL, 2.31 mmol) and 1-iodo-2-fluoro-4-methyl-5-nitro-benzene (0.50 g, 1.78 mmol) in dry DMF (3.0 mL) was stirred at 125° C. for 3 h. The resulting mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was washed with hexane to give [2-(4-iodo-5-fluoro-2-nitro-phenyl)-vinyl]-dimethyl-amine as dark red solid (0.37 mg, 62%). 1H NMR (CDCl3, 400 MHz): 2.97 (s, 6H), 5.92 (d, J=13.3 Hz, 1H), 7.02 (d, J=13.3 Hz, 1H), 7.09 (d, J=10.2 Hz, 1H), 8.30 (d, J=6.2 Hz, 1H). 13C NMR (CDCl3, 100 MHz,): 40.8, 108.9, 109.1, 137.0, 139.3, 146.0.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=[O:15])(=[O:3])[CH3:2].Cl.[CH:17]([N:20]([CH:24]([CH3:26])[CH3:25])[CH2:21][CH2:22]Cl)([CH3:19])[CH3:18]>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:22][CH2:21][N:20]([CH:24]([CH3:26])[CH3:25])[CH:17]([CH3:19])[CH3:18])[C:9](=[O:14])[C:8]2=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)C(=O)C(=O)N2
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Product: CC(=O)Nc1ccc2c(c1)C(=O)C(=O)N2CCN(C(C)C)C(C)C
Yield: 77 %

Procedure:
By using 5-acetamidoisatin and 2-diisopropylaminoethyl chloride hydrochloride, a method analogous to that described in Reference Example 7 was carried out to obtain 5-acetamido-1-(2-diisopropylaminoethyl)isatin having a melting point of 187°-190° C. (yield: 77.0%, recrystallizing solvent: ethyl acetate-hexane).
Reaction SMILES: CN.O=[C:4]1[C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7][N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1.[BH3-][C:21]#[N:22].[Na+]>>[CH3:21][NH:22][CH:4]1[C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7][N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C2(CCCC2)C1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Product: CNC1CN(C(=O)OC(C)(C)C)CC12CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of CH3NH2 (33% [w/w] in EtOH, 11.70 g, 124.3 mmol) was added tert-butyl 4-oxo-2-azaspiro[4.4]nonane-2-carboxylate (5.92 g, 24.7 mmol). After addition, the reaction mixture was stirred at rt overnight, and then NaBH3CN (4.69 g, 74.6 mmol) was added portionwise. The resulting mixture was stirred at rt for 2 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc, 100%) to give the product as colorless oil (6.28 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:28])[C@@H:15]([NH2:27])[CH:16]([CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:17][C:18]([F:21])([F:20])[F:19].N1C=CC=CC=1>C(Cl)Cl>[CH3:12][O:13][C:14](=[O:28])[C@@H:15]([NH:27][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:16]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:22][C:23]([F:25])([F:26])[F:24]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)[C@@H](N)C(CC(F)(F)F)CC(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(CC(F)(F)F)CC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
4-Chlorophenyl sulphonyl chloride (211 mg, 1.00 mmol) was added to a solution of (2S)-2-amino-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-pentanoic acid methyl ester (267 mg, 1.00 mmol) and pyridine (0.45 mL, 3.00 mmol) in CH2Cl2 (5 mL) and the reaction was subsequently stirred for 18 h at 25° C. The solvent was removed in vacuo and the residue was dissolved in EtOAc (20 mL). This solution was washed with 1M HCl (2×10 mL) and brine (10 mL), dried over Na2SO4 and evaporated to afford a crude oil which was purified by flash chromatography eluting with 20:80 EtOAc:hexanes to provide the title compound (380 mg) as an oil in 86% yield. Mass Spectrum (−ESI): 446.0 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([NH2:30])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.Cl[C:32]([O:34][CH3:35])=[O:33]>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([NH:30][C:32](=[O:33])[O:34][CH3:35])=[N:9][N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:4]=2[CH:3]=1
Reactant: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A 100 mL round bottom flask charged with 6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine (1500 mg, 3.65 mmol) in DCM (30 ml) and pyridine (3 mL) was cooled to 0° C. using an ice bath. Methyl chloroformate (0.564 ml, 7.30 mmol) was added and the reaction mixture was stirred for 16 h warming to ambient temperature. The mixture was washed with saturated copper sulfate solution (2×50 mL), dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (ISCO; 40 g prepacked) eluting with ethyl acetate/hexanes to afford methyl (6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (1492 mg, 3.18 mmol, 87% yield) as a white solid. MS ESI calc'd. For C27H22ClN4O2 [M+H]+ 469. found 469.
Reaction SMILES: COC(=O)[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].NC[CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44]>CCCCCCC.C(OCC)(=O)C>[CH3:46][O:45][C:43](=[O:44])[CH2:42][CH2:41][CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36]
Reactant: COC(=O)CCCN
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)CCCNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and methyl 4-aminobutyrate (commercially available, CAS RN 3251-07-8) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Light brown foam (42%). MS (ESI): m/z=583.150 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=O)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:23])=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Reactant: C1CCNCC1
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)N3CCCCC3)cc2)=C(C)C1=O
Yield: 136.2 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (200 mg, 0.58 mmol) obtained in Example 1 and piperidine (64 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (118 mg, 0.79 mmol, yield 50%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[N:20][CH:21]=2)[CH:13]=[CH:12][N:11]=1.Cl.[F:23][CH:24]([F:42])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH2:34][N:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1)[C:28](Cl)=[O:29].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[F:42][CH:24]([F:23])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH2:34][N:35]1[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]1)[C:28]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][CH:19]=[N:20][CH:21]=3)[CH:13]=[CH:12][N:11]=2)[CH:4]=1)=[O:29]
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cncnc2)n1
Reactant: CN1CCN(Cc2ccc(C(=O)Cl)cc2C(F)F)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)F)c2)cc1Nc1nccc(-c2cncnc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
1.98 g of 4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]aniline (Reference Example 18) was dissolved in 35 ml of anhydrous pyridine and 2.90 g of 3-difluoromethyl-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride hydrochloride (Reference Example 9) was added, followed by stirring at room temperature for 2 hours. To the reaction solution, ice water and an aqueous saturated sodium hydrogen carbonate solution were added and then the mixture was subjected to extraction with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The crude crystals were washed with chloroform-diethyl ether (1:1) to obtain 2.66 g of the objective compound as pale brown crystals.
Reaction SMILES: Br[C:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[OH:10]/[N:11]=[C:12](/[C:18](=[O:20])[CH3:19])\[C:13]([O:15][CH2:16][CH3:17])=[O:14]>FC(F)(F)S([O-])(=O)=O.[Ag+]>[C:2]12([O:10]/[N:11]=[C:12](/[C:18](=[O:20])[CH3:19])\[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: BrC12CCC(CC1)CC2
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCOC(=O)/C(=N\OC12CCC(CC1)CC2)C(C)=O
Yield: 22.6 %

Procedure:
1-Bromobicyclo[2.2.2]octane (4.6 g, 24.3 mmol), ethyl (Z)-2-hydroxyimino-3-oxobutyrate (3.78 g, 24.3 mmol) and silver trifluoromethanesulphonate (6.32 g, 24.6 mmol) were reacted under similar conditions to that described in Example 31a to give the title compound (1.47 g, 22%); νmax (CH2Cl2) 2950, 2925, 2860, 1735, 1685, 1370 and 1325 cm-1 ; δH (60 MHz, CDCl3) 1.30 (3H, t, J ca 7 Hz), 1.64 (S) and 1.75 (s) (together 13H), 2.36 (3H, s), and 4.30 (2H, q); [Ammonia CI mass spectrum Found MH+ (288)].
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].CC(C)([O-])C.[K+].Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24]>C1COCC1>[C:2]([CH:3]([CH2:22][C:23](=[O:24])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)c1ccccc1)C(=O)c1ccccc1
Reaction time: 0.17 h
Yield: 66.7 %

Procedure:
To a stirring solution of ethyl 3-oxo-3-phenylpropanoate 67 (0.754 g, 3.92 mmol) in THF cooled to 0° C. was added potassium tert-butoxide (0.556 g, 4.71 mmol) and the reaction mixture was stirred for 10 minutes followed by the addition of 2-bromo-1-phenylethanone 68 (0.859 g, 4.32 mmol). The reaction mixture was allowed to stir at room temperature for 90 minutes then quenched with ethanol (2) and poured into ethyl acetate and layer separated. The organic layer was washed with water, brine, dried over Na2SO4, then purified by ISCO (40 g column, 0 to 35% ethyl acetate in hexane) to afford compound 69 (0.812 g, 67% yield) as a yellow oil. LRMS (ESI): (calc.) 310.12 (found) 311.08 (MH)+
Reaction SMILES: COC([N:5]1[C:9]2=[N:10][C:11]([Cl:14])=[CH:12][CH:13]=[C:8]2[CH:7]=[C:6]1[CH3:15])=O.[OH-].[Na+]>CO>[Cl:14][C:11]1[N:10]=[C:9]2[NH:5][C:6]([CH3:15])=[CH:7][C:8]2=[CH:13][CH:12]=1
Reactant: COC(=O)n1c(C)cc2ccc(Cl)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2ccc(Cl)nc2[nH]1

Procedure:
6-Chloro-2-methyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid methyl ester (0.225 g, 1 mmol) is dissolved in methanol (30 ml) and 1M NaOH (10 ml) and stirred at room temperature overnight. The methanol is removed in vacuo and the resulting white suspension is extracted with chloroform (3×20 ml), dried (MgS04) and concentrated in vacuo to yield a white powder which is dried under high vacuum to yield the titled product. (MH+167).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[CH:4][C:3]=1[CH3:11]>P(Cl)(Cl)(Cl)=O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]#[N:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(N)=O)ccc1F
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C#N)ccc1F

Procedure:
10.00 g (65.29 mmol) 4-fluoro-3-methyl-benzoic acid amide are stirred together with 50 ml phosphorus oxychloride for 4 hours at 60° C. and then evaporated down i. vac. The residue is poured into ice water, the resulting precipitate is filtered off and washed with water. After being taken up in ethyl acetate the organic phase is washed with sat. potassium carbonate solution, dried over sodium sulphate and evaporated down completely i. vac.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][N:7]([CH2:26][C:27]1[N:28]=[C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]2[CH:39]=1)[C:8]([C:10]1[NH:11][CH:12]=[C:13]([C:15](=[O:25])[C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])[CH:14]=1)=[O:9].CC#N.O>CS(O)(=O)=O>[F:22][C:21]1[CH:20]=[C:19]([F:23])[CH:18]=[C:17]([F:24])[C:16]=1[C:15]([C:13]1[C:14]2[CH:2]=[CH:6][N:7]([CH2:26][C:27]3[N:28]=[C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:32]=[CH:31][N:30]4[CH:39]=3)[C:8](=[O:9])[C:10]=2[NH:11][CH:12]=1)=[O:25]
Reactant: O=C(c1c[nH]c(C(=O)N(Cc2cn3ccc(C(F)(F)F)cc3n2)CC2OCCO2)c1)c1c(F)cc(F)cc1F
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CC#N
Product: O=C(c1c(F)cc(F)cc1F)c1c[nH]c2c(=O)n(Cc3cn4ccc(C(F)(F)F)cc4n3)ccc12
Temperature: 85 °C
Yield: 62.6 %

Procedure:
The product from Step B (744 mg, 1.40 mmol) was dissolved in methanesulfonic acid (6.0 mL) and heated to 85° C. for 50 min. After cooling in an ice-water bath, the reaction mixture was taken up in 2:3 MeCN—H2O (10 mL) and purified by reverse phase HPLC (C-18 column) to give the title compound (430 mg). LC/MS: m/z 491(M+H). 1H-NMR (d6-DMSO, 500 MHz): δ 5.40 (s, 2H), 6.96 (d, 1H), 7.20 (dd, 1H), 7.33 (t, 2H), 7.57 (d, 1H), 7.88 (d, 1H), 8.01 (s, 1H), 8.03 (s, 1H), 8.71 (d, 1H), 13.09 (s, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH:14]([C:18]1[CH:35]=[CH:34][C:21]2[NH:22][C:23]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([O-])=[O:30])=[CH:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1)[C:15]([CH3:17])=[O:16]>>[NH:14]([C:18]1[CH:35]=[CH:34][C:21]2[NH:22][C:23]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([NH:11][C:10]4[CH:12]=[CH:13][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:8][CH:9]=4)=[O:30])=[CH:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1)[C:15]([CH3:17])=[O:16]
Reactant: CC(=O)Nc1ccc2[nH]c(-c3ccc(C(=O)[O-])cc3)nc2c1
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: CC(=O)Nc1ccc2[nH]c(-c3ccc(C(=O)Nc4ccc(N5CCOCC5)cc4)cc3)nc2c1

Procedure:
Compound 454 was prepared from 4-morpholinoaniline and 4-(5-acetamino-1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C26H25N5O3: 456.20; found: 455.95.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[OH:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21].C(N(C(C)C)CC)(C)C>ClCCl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([CH:24]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1cncc(O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cncc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
4-Nitrophenyl chloroformate (7.0 g) was added to a dichloromethane (100 ml) solution of methyl 5-hydroxynicotinate (5.3 g) and diisopropylethylamine (6.1 ml), followed by stirring at room temperature for 1 hour. The reaction liquid was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting solid was washed with EtOAc/hexane and dried under reduced pressure to obtain methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (8.4 g).