Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([CH2:10]Br)=[CH:8][CH:7]=[CH:6][C:5]=1[Br:12].[C:14]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>CC(O)C>[Br:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[C:3](=[O:13])[N:22]([C:21]1[CH:23]=[CH:24][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:19][CH:20]=1)[CH2:10]2
Reactant: COC(=O)c1c(Br)cccc1CBr
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(N2Cc3cccc(Br)c3C2=O)cc1
Reaction time: 0.08 h

Procedure:
2-Bromo-6-bromomethyl-benzoic acid methyl ester (214 mg) and 4-t-butylaniline (93 mg) were put into a microwave reaction vial along with 2 mL of iPrOH. The reaction was subjected to 170° C., 5 min of microwave. The solvent was evaporated and the residue was purified by silica gel chromatography (25 g, 10-20% EtOAc/hexanes) to afford 7-bromo-2-(4-t-butyl-phenyl)-2,3-dihydro-isoindol-1-one as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.[O:12]=[CH:13][C@@H:14]([C@H:16]([C@@H:18]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:19])[OH:17])O.C(O)C>O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C@@H:22]1[O:23][C@H:14]([CH2:13][OH:12])[C@@H:16]([OH:17])[C@H:18]([OH:19])[C@H:20]1[OH:21]
Reactant: Clc1cc(Cl)c2c(c1)NCC2
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCO
Solvent: O
Product: OC[C@H]1O[C@@H](N2CCc3c(Cl)cc(Cl)cc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
A mixture of 4,6-dichloroindoline (6.57 g) and D-glucose (10.70 g) in H2O (25 ml)-ethyl alcohol (160 ml) was refluxed for 3 days. The organic solvent was evaporated under reduced pressure, and thereto were added brine and ammonium sulfate. The mixture was extracted with ethyl acetate 5 times, and the combined organic layer was dried over sodium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure to give crude 4,6-dichloro-1-(β-D-gluco-pyranosyl)indoline, which was used in the subsequent step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH2:14][N:13]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1ccccc1)CN2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 8-tert-butoxycarbonyl-1-(4-fluoro-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]decane (12 mmol) and DMF (20 mL). Cool in an ice bath. Add NaH (18 mmol) in several portions. After the addition is complete, add benzyl bromide (18 mmol). Allow the reaction mixture to warm to ambient temperature. After 3 h, cool the reaction vessel using an ice bath and cautiously add 10% aqueous citric acid (20 mL). When gas evolution has ceased, pour into an additional 20 mL of 10% aqueous citric acid and extract using ethyl acetate (3×60 mL). Extract the combined organics with saturated aqueous NaCl, dry over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Purify to obtain the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:25]=[CH:24][C:12]([O:13][CH2:14][C:15]2[O:19][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C1COCC1>[OH:8][CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:25]=[CH:24][C:12]([O:13][CH2:14][C:15]2[O:19][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(COc2ccc(C(=O)c3ccccc3)cc2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(COc2ccc(C(O)c3ccccc3)cc2)o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A solution of methyl 5-((4-benzoylphenoxy)methyl)furan-2-carboxylate (330 mg, 1.0 mmol) in methanol (5 mL) and THF (5 mL) was cooled to 0° C. NaBH4 (58 mg, 1.53 mmol) was added in one portion and the reaction was stirred at 0° C. for 2 hours. The reaction was quenched by addition of water (0.75 mL). The mixture was stirred for 10 minutes and the majority of the solvent was removed in vacuo. The residue was partitioned between EtOAc and water and the aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered and the solvent was removed in vacuo to give the title compound (325 mg, 96.1%) as a yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:10]1[NH:11][C:12](=[O:28])[C:13](=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:14]=1)[CH2:8][CH3:9].Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[CH:43]2[N:47]([CH3:48])[N:46]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[N:45]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[N:44]2[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:33][CH:32]=1>CN(C)C=O.C(Cl)Cl>[C:22]1([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:13]2[N:14]=[C:10]([CH2:7][CH2:8][CH3:9])[N:11]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[CH:43]4[N:47]([CH3:48])[N:46]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)[N:45]([C:55]5[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=5)[N:44]4[C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)=[CH:35][CH:36]=3)[C:12]2=[O:28])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CN1C(c2ccccc2-c2ccc(CBr)cc2)N(c2ccccc2)N(c2ccccc2)N1c1ccccc1
Reactant: CCCC1=NC(=C(c2ccccc2)c2ccccc2)C(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCC1=NC(=C(c2ccccc2)c2ccccc2)C(=O)N1Cc1ccc(-c2ccccc2C2N(C)N(c3ccccc3)N(c3ccccc3)N2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.2 %

Procedure:
A mixture of potassium carbonate (83 mg, 2 eq.), 2-propyl-4-(diphenylmethylene)-1H-imidazol-5(4H)-one (90 mg, 0.3 mmol), and 4'-bromomethyl-2-(triphenyl methyl tetrazol-5-yl)biphenyl (0.21 g, 1.2 eq.) in dimethyl formamide (10 mL) was allowed to stir at room temperature for 2 days. The solvent was in vacuo, the residue was dissolved in CH2Cl2 and washed with water and brine. The organic layer was dried over MgSO4 and concentrated. The crude mixture was chromatographed over silica gel eluting with ethyl acetate-hexane (1:4) to give 3,5-dihydro-5-(diphenylmethylene)-2-propyl-3-[(2'-(triphenyl methyl tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl]-4H-imidazol-4-one (100 mg). M.S. m/e 767 (M+ +H) NMR (CDCl3 /TMS) δ0.90 (m, 3H, CH3), 1.65 (m, 2H, CH2), 2.38 (m, 2H, CH2), 4.62 (s, 2H, CH2), 6.88-7.50 (m, 30H, Harom), 7.61 (m, 2H, Harom), 7.90 (d, 1H, Harom). The above compound was detritylated following the procedure described in Example 2C, to give 61 mg of the desired product. M.S. m/e 524 (M+ +H) NMR (CDCl3 /TMS) d 1.01 (t, 3H, CH3), 1.78 (m, 2H, CH2), 2.49 (t, 2H, CH2), 4.75 (s, 2H, CH2), 7.12-7.41 (m, 15H, Harom), 7.58 (m,2H, Harom), 8.10 (d, 1H, Harom).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[CH3:13][Mg]Br.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([OH:12])[CH3:13]
Reactant: C[Mg]Br
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)C(=O)Nc2ccc(Br)cc21
Temperature: 25 °C
Yield: 28.7 %

Procedure:
A solution of 5-bromoisatin (5.0 g, 22 mmol) in dry THF (50 cm3) under N2 was cooled to 0° C. and treated drop-wise with methyl magnesium bromide (3M in diethylether, 14.7 cm3, 44 mmol) and the mixture was allowed to warm up-to room temperature. The reaction was poured into sat. ammonium chloride solution, then extracted into EtOAc (×3). The combined organic layers were then washed with water, brine, dried (MgSO4) and evaporated. The residue was then purified by column chromatography (SiO2, EtOAc:hexane, gradient elution) to afford 5-bromo-3-hydroxy-3-methyl-1,3-dihydro-indol-2-one (1.53 g, 6.32 mmol, 29%): 1H NMR (DMSO-d6) δ 1.38 (s, 3H), 5.99 (s, 1H), 6.77 (d, 1H, J=1.7 Hz), 7.38 (s, 1H, br); MS ((−) ESI) m/z 240/242 (M)−.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=O.[CH3:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1.Br[Si](C)(C)C>CN(C=O)C>[O:14]1[CH2:13][CH2:12][N:11]([C:10]2[C:5]3[N:6]([C:17]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[C:3](/[CH:1]=[CH:31]/[C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c(C=O)nc3c(N4CCOCC4)ccnn23)CC1
Reactant: Cc1ccc2ccccc2n1
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)CC1
Temperature: 25 °C

Procedure:
A solution of compound 41c (0.40 g, 0.96 mmol), 2-methylquinoline (0.17 g, 1.2 mmol) and bromotrimethylsilane (0.32 g, 2.9 mmol) in DMF (4 mL) was stirred at 80° C. for 5 h and allowed to cool to rt. The solids formed were collected by filtration, and washed with methanol (50 mL) to obtain compound 48a as a brown solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C31H36N6O3: 541.3 (M+H). Found: 541.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[C:30]([CH3:31])=[CH:29][N:28]=[C:27]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([N:39]5[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]5)=[CH:35][CH:34]=4)[N:26]=3)[CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl>[CH3:31][C:30]1[C:25]([NH:24][C:20]2[CH:19]=[C:18]([S:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)(=[O:17])=[O:16])[CH:23]=[CH:22][CH:21]=2)=[N:26][C:27]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]3)=[CH:35][CH:34]=2)=[N:28][CH:29]=1
Reactant: Cc1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1Nc1cccc(S(=O)(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1Nc1cccc(S(=O)(=O)NC2CCNCC2)c1
Reaction time: 3 h

Procedure:
Intermediate 47 (0.2 g, 0.32 mmol) was diluted with DCM (10 mL) and treated with TEA (0.3 mL). After 3 h, reaction solvents removed and resulting residue was purified by HPLC (0.01 g, 6%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH3:14])[C:3]1=[O:15].Cl[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:24])([CH3:23])[CH3:22].CN1C2N=CN(CCCCC(=O)C)C=2C(=O)N(CCC)C1=O.C[Mg]Br.[Cl-]>O1CCCC1>[OH:24][C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH2:18][CH2:17][N:7]1[C:6]2[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH3:14])[C:3](=[O:15])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1
Reactant: CC(C)(O)CCCCCl
Reactant: CCCn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: CCCn1c(=O)c2c(ncn2CCCCC(C)=O)n(C)c1=O
Agent: C[Mg]Br
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCn1c(=O)c2c(ncn2CCCCC(C)(C)O)n(C)c1=O

Procedure:
Both alkylation of 3-methyl-1-propylxanthine with 1-chloro-5-hydroxy-5-methylhexane analogously to the following example 4 and Grignard synthesis with 3-methyl-7-(5-oxohexyl)-1-propylxanthine and methylmagnesium bromide or chloride in anhydrous tetrahydrofuran led to the same compound.
Reaction SMILES: FC(F)(F)C(OCC1C=CC=CC=1)=O.[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CS([C:35]1[N:40]=[C:39]([C:41]2[C:42]([C:48]([F:51])([F:50])[F:49])=[N:43][C:44]([NH2:47])=[N:45][CH:46]=2)[CH:38]=[CH:37][N:36]=1)=O>C1COCC1>[N:19]1[CH:20]=[CH:21][C:16]([NH:15][C:35]2[N:40]=[C:39]([C:41]3[C:42]([C:48]([F:49])([F:51])[F:50])=[N:43][C:44]([NH2:47])=[N:45][CH:46]=3)[CH:38]=[CH:37][N:36]=2)=[CH:17][CH:18]=1
Reactant: CS(=O)c1nccc(-c2cnc(N)nc2C(F)(F)F)n1
Reactant: Nc1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(OCc1ccccc1)C(F)(F)F
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ncc(-c2ccnc(Nc3ccncc3)n2)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
This compound was synthesized in an analogous manner to 21 utilizing benzyl 2,2,2-trifluoroacetate in step 1. To a solution of 4-aminopyridine (17.38 mg, 0.185 mmol) in THF (92 μl) cooled to −78° C. under nitrogen, LiHMDS (852 μl, 0.852 mmol) was added dropwise. The reaction mixture was warmed up to rt, then was stirred for 30 minutes. To the reaction mixture cooled back to −78° C., 2-(methylsulfinyl)-4′-(trifluoromethyl)-4,5′-bipyrimidin-2′-amine (14 mg, 0.046 mmol) was added, and the reaction mixture was warmed up to rt, then was stirred for 1 hour. The crude product was purified by reverse-phase HPLC [30-100% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product as a pale yellow solid (3.98 mg, 25% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.13 (d, J=4.52 Hz, 1H) 7.67 (br. s., 2H) 7.77 (d, J=6.02 Hz, 2H) 8.34 (d, J=6.02 Hz, 2H) 8.56-8.74 (m, 2H) 10.23 (s, 1H). HRMS (ES+) for C14H10F3N7.H+ [MH+]: calcd, 334.1028; found, 334.1037. UV-LC: 97.31/100% UV purity at 214/254 nm; tR=2.47 minutes over 7.75 minutes.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:16]>CN(C)C=O>[Br:1][C:2]1[C:11]([O:12][CH3:16])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Oc1c(Br)ccc2cccnc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(Br)ccc2cccnc12
Reaction time: 0.05 h
Yield: 99.8 %

Procedure:
In an oven dried round bottom flask under nitrogen, a solution of 7-bromoquinolin-8-ol (1 g, 4.46 mmol) in N,N-dimethylformamide (20 mL) at room temperature was treated with sodium hydride (60% dispersion in mineral oil, 0.268 g, 6.69 mmol) to give a bright yellow mixture and was stirred for 3 min. Iodomethane (0.307 mL, 4.91 mmol) was then added by syringe and the reaction was stirred for 30 min. The reaction was quenched carefully with water (50 mL) and diluted with ethyl acetate (100 mL). The layers were separated and the organic layer was dried over magnesium sulfate and concentrated in vacuo to give a liquid, which solidified to a white solid (1.06 g, quantitative yield) on standing overnight. MS(ES)+ m/e 237.8, 239.7 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([NH:9][C:10](=[O:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6](=O)[CH3:7].C(OC(=O)C)(=O)C.OS(O)(=O)=O>O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[N:9]=[C:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:19][C:6]=1[CH3:7]
Reactant: COC(=O)CC(NC(=O)CCc1ccccc1)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)Cc1nc(CCc2ccccc2)oc1C
Temperature: 90 °C
Yield: 34.8 %

Procedure:
In a 100 mL flask, 4-oxo-3-(3-phenyl-propionylamino)-pentanoic acid methyl ester (10 g, 36 mmol), and acetic anhydride (28 mL) were combined. Following addition of concentrated H2SO4 (1 mL), the solution was heated to 90° C. for 30 min and then cooled to ambient temperature. The reaction was slowly diluted with DI water (30 mL, potential exotherm). The reaction mixture was partitioned between CH2Cl2 and water. The organic phase was washed with DI water, 10% NaHCO3 (aq), brine (150 mL), and then dried over MgSO4 and concentrated to obtain a brown oil. The residue was purified by column chromatography (600 mL SiO2, 35% EtOAc/hexanes) to provide the desired product (3.25 g) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.33-7.20 (m, 5H), 3.72 (s, 3H), 3.47 (s, 2H), 3.08-2.96 (m, 4H), 2.24 (s, 3H); MS (EI+) 260 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:26]=[CH:25][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]([NH2:24])=O)[CH2:18][CH2:17]2)=[CH:10][CH:9]=1>O>[NH2:24][CH2:22][CH:19]1[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:8]([F:7])=[CH:26][CH:25]=2)[CH2:21][CH2:20]1
Reactant: NC(=O)C1CCN(CCCOc2ccc(F)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: NCC1CCN(CCCOc2ccc(F)cc2)CC1
Yield: 53 %

Procedure:
3.8 grams of lithium aluminum hydride are added through a solids funnel to a suspension of 26 grams of the compound obtained in stage B. The mixture is refluxed for 2 hours. The reaction medium is decomposed using 2.6 cm3 of water and then 2.1 cm3 of sodium hydroxide and finally 9.6 cm3 of water, filtered and the filtrate is then evaporated. 13.1 grams of an oil are obtained which corresponds to the expected compound and which may be used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=3)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: Nc1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridin-3-ylamine and nicotinic acid as starting materials, MS (LC/MS): 380.2 (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10]CC)=[O:9])[CH2:4][CH2:3]1.[OH-].[K+].Cl>CO>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCC(C(=O)O)CC1
Temperature: 50 °C
Yield: 91.5 %

Procedure:
A mixture of ethyl 4-oxocyclohexanecarboxylate (1.74 g, 10 mmol), methanol (25 ml), and 17% aq. KOH (5 ml) was heated at 50° C. for 1.5 h. After being cooled to room temperature, the reaction mixture was acidified to pH 3 with conc. HCl, concentrated to 10 ml under reduced pressure, and extracted with chloroform (3×15 ml). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford the desired ketone acid (1.30 g, 91%) as a colorless solid. mp 62-64° C.; 1H NMR (500 MHz, CDCl3) δ 2.05-2.10 (m, 2H), 2.23-2.27 (m, 2H), 2.35-2.41 (m, 2H), 2.49-2.54 (m, 2H), 2.80-2.84 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[NH2:11][OH:12].C([O-])(=O)C.[Na+]>C(O)C>[Br:1][C:2]1[C:7]([CH:8]=[N:11][OH:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: NO
Reactant: O=Cc1cccnc1Br
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=Cc1cccnc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of 2-bromopyridine-3-carbaldehyde (2.04 g) in ethanol (25 mL) is added hydroxylamine hydrochloride (948 mg, 13.16 mmol) and sodium ethanoate (1.09 g, 13.16 mmol). The mixture is stirred at room temperature overnight. The solvent is evaporated under reduced pressure and the residue partitioned between dichloromethane and water. The organic layer is separated, dried over sodium sulfate, filtered and solvent evaporated in vacuo to give 2 g of 2-bromopyridine-3-carbaldehyde oxime. MS (m/z): 201/203 (M+1/M+3)
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.[CH3:20][O:21][C:22]([C:24]1([CH2:30][CH:31]=O)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.ClCCl>[CH3:20][O:21][C:22]([C:24]1([CH2:30][CH2:31][NH:8][C:7]2[C:2]([CH3:1])=[N:3][C:4]([N:9]3[CH2:13][CH2:12][C@H:11]([N:14]4[CH2:18][CH2:17][CH2:16][C@@H:15]4[CH3:19])[CH2:10]3)=[CH:5][CH:6]=2)[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)=[O:23]
Reactant: COC(=O)C1(CC=O)CCOCC1
Reactant: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C1(CCNc2ccc(N3CC[C@H](N4CCC[C@@H]4C)C3)nc2C)CCOCC1
Temperature: 25 °C
Yield: 32.3 %

Procedure:
To a solution of 2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine (0.075 g, 0.288 mmol) in 1-2 dichloroethane (DCE, 6 mL) was added a solution of 4-(2-oxo-ethyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (0.053 g, 0.288 mmol) in DCE (2 mL), acetic acid (3.1 eq) and allowed to stir at room temperature for an hour. NaBH(OAc)3 (3 eq.) was then added in one portion and reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane (DCM, 5.0 mL), quenched with 2 M of NH4OH in water. Aqueous layer was extracted with DCM (5.0 mL×2). Combined organics were washed with aqueous NaHCO3 (15 mL), brine (30 mL), and dried over Na2SO4, and concentrated under vacuum. Purification by column chromatography on silica gel eluting with methanol in dichloromethane (0-10%) afforded 0.04 g (35%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([OH:28])=[O:27])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[CH2:8][CH2:7]2.[Cl:29][C:30]1[N:35]=[C:34](Cl)[C:33]([Cl:37])=[CH:32][N:31]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[C:6]([O:27][C:26]([N:23]1[CH2:22][CH2:21][N:20]([CH:17]2[CH2:18][CH2:19][N:14]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:32]4[C:33]([Cl:37])=[CH:34][N:35]=[C:30]([Cl:29])[N:31]=4)=[C:11]4[C:6]=3[CH2:7][CH2:8][N:9]([CH3:13])[C:10]4=[O:12])[CH2:15][CH2:16]2)[CH2:25][CH2:24]1)=[O:28])([CH3:11])([CH3:7])[CH3:5]
Reactant: CN1CCc2c(N3CCC(N4CCN(C(=O)O)CC4)CC3)ccc(N)c2C1=O
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCc2c(N3CCC(N4CCN(C(=O)OC(C)(C)C)CC4)CC3)ccc(Nc3nc(Cl)ncc3Cl)c2C1=O
Temperature: 25 °C
Yield: 72 %

Procedure:
A mixture 4-[1-(8-amino-2-methyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-5-yl)-piperidin-4-yl]-piperazine-1-carboxylic acid #tert!-butyl ester (9.20 g, 20.7 mmol), 2,4,5-trichloropyrimidine (5.96 mL, 51.8 mmol), K2CO3 (7.17 g, 51.8 mmol) in DMSO (200 mL) was stirred at 60° C. for 12 hours. After cooling to room temperature, 700 mL of water was added with stirring. The mixture was filtrated. The resulting brown solids were suspended in CH3CN (ca. 200 mL), stirred for a while and filtrated. The residue was further washed with CH3CN and dried under reduced pressure to give 8.75 g of 4-{1-[8-(2,5-dichloro-pyrimidin-4-ylamino)-2-methyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-5-yl]-piperidin-4-yl}-piperazine-1-carboxylic acid tert-butyl ester as pale beige solids in 72% yield.
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]=[C:9]=[O:10])=O)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[CH:16][C:15]=1[NH:27][NH:28]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[CH:16][C:15]=1[N:27]1[C:9](=[O:10])[NH:8][C:6]([C:5]2[CH:11]=[CH:12][C:2]([I:1])=[CH:3][CH:4]=2)=[N:28]1
Reactant: O=C=NC(=O)c1ccc(I)cc1
Reactant: CC(C)C(=O)NCc1ccc(Cl)c(NNC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c1
Yield: 34.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 4-iodobenzoyl isocyanate (Intermediate-67, 1.500 g), tert-butyl 2-(2-chloro-5-{[(2-methylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate (Intermediate-97, 1.0 g), DCM (20 mL), and trifluoro acetic acid (5.0 mL) to afford 0.500 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 1.02 (d, J=6.9 Hz, 6H), 2.44 (m, 1H), 4.28 (d, J=8.7 Hz, 2H), 7.28 (br s, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.44 (s, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.91 (d, J=8.1 Hz, 2H), 8.38 (m, 1H), 12.61 (m, 1H); MS (m/z): 495.7 (M−H)−.