Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][C:13](=[CH2:27])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([CH3:26])[CH:18]=1)=[O:15].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>ClCCCl>[CH3:26][C:19]1[CH:18]=[C:17]([NH:16][C:14]([C:13]2([CH3:12])[CH2:27][O:6]2)=[O:15])[CH:22]=[CH:21][C:20]=1[N+:23]([O-:25])=[O:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)C(=O)Nc1ccc([N+](=O)[O-])c(C)c1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: ClCCCl
Product: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
m-Chloroperoxybenzoic acid (6.7 g, 29.9 mmol) was added in portions at 60° C. to a solution of 2-methyl-N-(3-methyl-4-nitrophenyl)acrylamide (2.9 g, 13.2 mmol) and 2,6-di-tert-butyl-4-methylphenol (66 mg) in 1,2-dichloroethane (80 ml). The string was continued at 60° C. for 6 h, and the reaction mixture was allowed to cool to room temperature. The precipitated m-chlorobenzoic acid was filtered, and the filtrate was extracted with 1 M Na2CO3 (4×60 ml). The organic phase was dried over Na2SO4 and evaporated. The yield was 3.05 g. 1H NMR (DMSO-d6): 1.54 (3H, s), 2.51 (3H, s), 2.99 (1H, d, J=5.1 Hz), 3.05 (1H, d, J=5.1 Hz), 7.79 (2H, m), 8.01 (1H, m), 9.98 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][N:54]1[NH:58][CH:57]=[CH:56][S:55]1>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:53][N:54]2[NH:58][CH:57]=[CH:56][S:55]2)=[O:7])=[CH:4][C:3]=1[B:11]1[O:12][C:13]([CH3:19])([CH3:18])[C:14]([CH3:17])([CH3:16])[O:15]1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: NN1NC=CS1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NN2NC=CS2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (2.0 g, 7.63 mmol), DIPEA (4 ml, 22.89 mmol) and HATU (3.05 g, 8.02 mmol) were dissolved in DMF (20 ml) and stirred at room temperature for 15 mins. 2-Aminothiadiazole (810 mg, 8.01 mmol) was added and the reaction stirred at room temperature for 18 hours. The solvent was evaporated under vacuum and the reaction partitioned between ethyl acetate (250 ml) and hydrochloric acid (2N, 150 ml). The aqueous was extracted with ethylacetate (2×250 ml). The combined organic extracts were dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was absorbed onto silica and purified by flash column chromatography eluting with cyclohexane/ethyl acetate (4:1 then 1:1). The solvent was evaporated from the product fractions under vacuum to 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (0.95 g). LCMS: retention time 3.34 min, MH− 346. NMR: δH [2H6]-DMSO 13.08,(1H, b), 9.22,(1H, s), 8.35,(1H, d), 8.11,(1H, dd), 7.38,(1H, d), 2.55,(3H, s), 1.34,(12H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=[O:5])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>>[NH2:10][C:9]1[C:8]2[C:7](=[CH:14][C:13]([N+:15]([O-:17])=[O:16])=[CH:12][CH:11]=2)[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:19]=1[C:20](=[O:21])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)Nc1cc([N+](=O)[O-])ccc1C#N
Reactant: O=C(CBr)c1ccccc1
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc([N+](=O)[O-])cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 2-(ethoxycarbonylamino)-4-nitrobenzonitrile (step 1) and 2-bromoacetophenone. 1H-NMR (CDCl3) δ: 9.13 (1H, d, J=1.8 Hz), 8.20 (1H, dd, J=1.8, 8.6 Hz), 7.74 (1H, d, J=8.6 Hz), 7.77-7.43 (5H, m), 5.67 (2H, br. s), 3.83 (2H, q, J=7.3 Hz), 0.89 (3H, t, J=7.3 Hz)
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[N:14]1[C:18]2=[N:19][CH:20]=[N:21][C:22](O)=[C:17]2[CH:16]=[N:15]1>>[Cl:3][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:14]([C:8]3[C:7]([Cl:6])=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:13])[N:15]=[CH:16][C:17]=12
Reactant: Oc1ncnc2c1cnn2-c1c(Cl)cccc1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Reaction time: 20 h
Yield: 86.8 %

Procedure:
Phosphorus oxychloride (7.96 mL, 85.38 mmol) was added to 1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate BA4) (1.2 g, 4.27 mmol). The resulting solution was stiffed at 100° C. for 20 hours. LCMS showed reaction was complete. The reaction mixture was evaporated. Ice/water and then EtOAc were added. The organic layer to was separated and the aqueous layer re-extracted with EtOAc. The combined organics were washed with water, dried (MgSO4) and concentrated to give the product (1.110 g, 87%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.46-7.58 (3H, m), 8.45 (1H, s), 8.82 (1H, s); m/z (ES+) (M+H)+=299; HPLC tR=2.77 min.
Reaction SMILES: [C:1](=[O:6])=[N:2][C:3](Cl)=[O:4].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:23][O:24][C:25]1[CH:26]=[C:27](/[C:31](/[CH2:36][CH3:37])=[CH:32]/[CH2:33][NH:34][OH:35])[CH:28]=[CH:29][CH:30]=1.Cl>C1COCC1>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:23][O:24][C:25]1[CH:26]=[C:27](/[C:31](/[CH2:36][CH3:37])=[CH:32]/[CH2:33][N:34]2[C:3](=[O:4])[NH:2][C:1](=[O:6])[O:35]2)[CH:28]=[CH:29][CH:30]=1
Reactant: CC/C(=C\CNO)c1cccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c1
Reactant: O=C=NC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: CC/C(=C\Cn1oc(=O)[nH]c1=O)c1cccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c1
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
N-(Chlorocarbonyl)isocyanate (0.37 ml, 4.63 mmol) was added dropwise to a cold (-5° C.) mixture of (E)-N-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-enyl)-hydroxylamine (2.0 g, 4.63 mmol) in THF (20 ml). The mixture was stirred for 30 minutes, then poured into HCl (1N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on acid washed (5% H3PO4 /MeOH) silica gel (hexane/EtOAc 3/1) gave a white solid (1.48 g, 64% yield, mp 66°-67° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.C([Li])(C)(C)C.C(C1C=CC(S([N:41]=[N+:42]=[N-:43])(=O)=O)=CC=1)CCCCCCCCCCC.[NH4+].[Cl-]>O1CCCC1>[N:41]([C:4]1[C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[N+:42]=[N-:43]
Reactant: CC(C)(C)C(=O)Nc1ccc(F)cn1
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncc(F)cc1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 17 %

Procedure:
To a −78° C. solution of N-(5-fluoropyridin-2-yl)-2,2-dimethylpropanamide (1.34 g, 6.83 mmol) in tetrahydrofuran (25 mL) was added tert-butyllithium (1.31 mL of a 1.7 M solution, 20.5 mmol) dropwise. After 3 h at −78° C., 4-dodecylbenzenesulfonyl azide (3.60 g, 10.2 mmol) was added at the reaction was allowed to warm to room temperature. After 1 h, saturated aqueous NH4Cl was added, and the tetrahydrofuran was removed via rotary evaporator. Dichloromethane was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated and the residue purified by two successive silica gel chromatographies (10%→80% EtOAc/hexanes, then 5%→42% EtOAc/hexanes) to give the title compound (0.275 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][O:19]C(=O)C)[C@@:14](C(=O)C)([OH:15])[C@@:12]2(C(=O)C)[OH:13])=[C:4](Cl)[N:3]=1.[NH3:30]>>[NH2:1][C:2]1[N:3]=[C:4]([NH2:30])[C:5]2[N:6]=[CH:7][N:8]([C:9]=2[N:10]=1)[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@@](O)(C(C)=O)[C@@]1(O)C(C)=O
Reactant: N
Product: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
The 6-position of 2-amino-6-chloro-9-(2,3,5-O-triacetyl-β-D-ribofuranosyl)-9H-purine was aminated by ammonia to give 2-aminoadenosine. In the same manner as Example 1 [METHOD 1], 2-aminoadenosine was methylated to give 2-amino-2'-O-methyladenosine (Compound 30) and 2-amino-3'-O-methyladenosine (Compound 31).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:17][C:18]([F:27])([F:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1.Br.C(OCC)C>C(O)(=O)C>[NH2:11][C@@H:12]([CH2:17][C:18]([F:26])([F:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)[C@@H](N)CC(F)(F)Cc1ccccc1
Reaction time: 3 h

Procedure:
3.0 g of methyl (S)-2-benzyloxycarbonylamino-4,4-difluoro-5-phenylpentanoate (8.0 mmol) were admixed with 8.0 ml (5 eq.) of a 30% HBr solution in glacial acetic acid with ice bath cooling and stirred for 3 h. 100 ml of diethyl ether were added and the resulting precipitate was filtered off with suction. The crude product thus obtained was purified by preparative HPLC (gradient: acetonitrile/water and addition of 0.05% TFA). The amorphous solid obtained after freeze-drying was taken up in dichloromethane and washed with sat. NaHCO3 solution. The organic phase was dried over MgSO4 and concentrated under reduced pressure. Thus, methyl (S)-2-amino-4,4-difluoro-5-phenyl-pentanoate was obtained as a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1Cl.ClCCl.[Cu]>[Cl:17][C:15]1[CH:16]=[C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:12]=[C:13]([Cl:18])[CH:14]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Clc1cc(Cl)cc(Br)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Product: Clc1cc(Cl)cc(-n2ccc3ccccc32)c1
Reaction time: 24 h
Yield: 68.1 %

Procedure:
A mixture of 5 g (43.7 mmol) of indole, 19.2 g (85.3 mmol) of 1-bromo-3,5-dichlorobenzene, 11.7 g (84.8 mmol) of potassium carbonate and 3.28 g (1.22 mmol) of copper powder in 14 mL of 1,2-dichlorobenzene was warmed at reflux. After 24 h, the mixture was cooled and diluted with dichloromethane and filtered through diatomaceous earth. The filter cake was washed with a 1:9 mixture of methanol-dichloromethane. The filtrate was pre-adsorbed onto silica gel and chromatographed on silica gel eluting with hexane. The partially purified material was placed under high vacuum to remove excess 1,2-dichlorobenzene and sublime excess 1-bromo-3,5-dichlorobenzene. A second chromatography on silica gel eluting with hexanes afforded 7.8 g (70%) of 1-(3,5-Dichlorophenyl)-1H-indole.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.Br.[Br:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[Na+].[Na+]>CO>[BrH:14].[N:1]1([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]3)=[CH:4][CH:3]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: Nc1ccc2c(c1)NC(=O)CC2
Reactant: BrCCNCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2ccc(N3CCNCC3)cc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
A mixture of 23 g of 7-amino-3,4-dihydrocarbostyril, 48 g of bis(β-bromoethyl)amine hydrobromide and 200 ml of methanol was refluxed with stirring for 8 hours. After cooling to room temperature, 7.52 g of sodium carbonate was added to the mixture followed by refluxing while stirring for additional 8 hours. After distilling off methanol under reduced pressure, isopropanol was added to the residue. After cooling, crystals which precipitated were collected by filtration and recrystallized from ethanol 3 times to give 15 g of 7-(1-piperazinyl)-3,4-dihydrocarbostyril hydrobromide, m.p. 174°-177° C., colorless granules.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[C@H:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([O:20][CH3:21])[CH2:16][CH2:15]3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:29][O:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=[C:33]([NH2:46])[N:32]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[NH2:46][C:33]1[N:32]=[C:31]([O:30][CH3:29])[C:36]([C:2]2[N:6]([CH:7]([CH3:8])[CH3:9])[C:5]3[CH:10]([C:22]4[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=4)[N:11]([C@H:14]4[CH2:15][CH2:16][C@H:17]([O:20][CH3:21])[CH2:18][CH2:19]4)[C:12](=[O:13])[C:4]=3[CH:3]=2)=[CH:35][N:34]=1
Reactant: CO[C@H]1CC[C@H](N2C(=O)c3cc(Br)n(C(C)C)c3[C@@H]2c2ccc(Cl)cc2)CC1
Reactant: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1nc(N)ncc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N([C@H]1CC[C@H](OC)CC1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but (S)-2-bromo-6-(4-chloro-phenyl)-1-isopropyl-5-(trans-4-methoxy-cyclohexyl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate AD) and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (Intermediate U) were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a light beige solid. tR: 4.08 min (HPLC 1); ESI-MS: tR=0.99 min, [M+H]+ 510/512 (LC-MS 1); TLC: Rf=0.10 (EtOAc).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23]C)=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:26]1SC(CC)=C(C(C)C)C=1C(OC)=O.C1(S(Cl)(=O)=O)C=CC=CC=1>>[C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]([CH2:16][CH3:17])=[C:13]([CH:19]([CH3:26])[CH3:18])[C:12]=2[C:20]([O:22][CH3:23])=[O:21])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCc1sc(N)c(C(=O)OC)c1C(C)C
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Agent: O=S(=O)(Cl)c1ccccc1
Product: CCc1sc(NS(=O)(=O)c2ccccc2)c(C(=O)OC)c1C(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from methyl 2-amino-5-ethyl-4-isopropylthiophene-3-carboxylate (Intermediate 25) and benzenesulphonyl chloride
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:10]([CH2:18][CH3:19])(C(OC)=O)[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br-].[Li+]>CN(C)C=O.O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:10]([CH2:18][CH3:19])[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCC1(C(=O)OC)C(=O)Nc2cccc(Cl)c2CC1c1ccc(OC)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC1C(=O)Nc2cccc(Cl)c2CC1c1ccc(OC)cc1
Yield: 42.7 %

Procedure:
6-Chloro-1,3,4,5-tetrahydro-3-ethyl-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (2.67 g, 6.88 mmole) and lithium bromide (3.05 g, 35.1 mmole) in dimethylformamide (40 ml) and water (2 drops) were heated at 130° C. for 4 hours. The cooled mixture was dissolved in ethyl acetate, washed with water, dried (magnesium sulfate), and concentrated. The residue was triturated with hexane to obtain 0.97 g of crude tan solid. Additional product was present in the mother liquor.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]=[C:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].O>CC(O)=O.[Pd].[H][H]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1=CNCCN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1CNCCN1C(=O)OC(C)(C)C
Yield: 97.9 %

Procedure:
Ethyl 1-tert-butoxycarbonyl-1,4,5,6-tetrahydropyrazinecarboxylate (60 g) was dissolved in AcOH (400 ml), and the solution was subjected to catalytic reduction using 10% palladium on carbon (12 g)-H2O (30 ml), in hydrogen at 3 atm for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in AcOEt (1000 ml), and the organic layer was washed with saturated aqueous NaHCO3 solution by stirring carefully to avoid foaming. The organic layer was further washed with saturated brine, and dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure to give 59.2 g of ethyl 1-tert-butoxycarbonyl-2-piperazinecarboxylate as an oil (yield 97.9%).
Reaction SMILES: [C:1]([O:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11](=O)[C:12]([CH3:15])([CH3:14])[CH3:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23]C(N)=S>CN(C)C=O>[C:2]1([C:1]2[O:9][C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:23]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: CC(C)(C)C(=O)C(OC(=O)c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(-c2ccccc2)oc1-c1ccccc1
Temperature: 160 °C

Procedure:
0.15 g of 3,3-dimethyl-2-oxo-1-phenylbutyl benzoate is dissolved in 8 ml of dimethylformamide in a reactor. 0.2 g of thiourea (5 eq.) is subsequently added and the reaction mixture is left to react at reflux (160° C.) for 15 hours.
Reaction SMILES: ClC1C=CC2N(C(CNC3N=C([O:26][C@@H:27]4[CH2:31][CH2:30][N:29](C)[CH2:28]4)C=CN=3)=C(C3C=CC(F)=CC=3)N=2)C=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41]=[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]3[C:48]=2[CH2:49][C:50]2[CH:55]=[N:54][CH:53]=[C:52](Cl)[N:51]=2)=[CH:36][CH:35]=1.N1CCC(O)C1>>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41]=[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]3[C:48]=2[CH2:49][C:50]2[CH:55]=[N:54][CH:53]=[C:52]([O:26][CH:27]3[CH2:31][CH2:30][NH:29][CH2:28]3)[N:51]=2)=[CH:36][CH:35]=1
Reactant: Clc1ccc(-c2nc3ccccn3c2Cc2cncc(Cl)n2)cc1
Reactant: CN1CC[C@@H](Oc2ccnc(NCc3c(-c4ccc(F)cc4)nc4ccc(Cl)cn34)n2)C1
Agent: OC1CCNC1
Product: Clc1ccc(-c2nc3ccccn3c2Cc2cncc(OC3CCNC3)n2)cc1

Procedure:
The title compound was prepared according to the experimental for compound 183 from 2-(4-chlorophenyl)-3-((6-chloropyrazin-2-yl)methyl)imidazo[1,2-a]pyridine and pyrrolidin-3-ol. M/e+ 406 for C22H21ClN5O (M+H)−; 1H-NMR (400 MHz, CDCl3) δ 8.20 (d, J=6.9 Hz, 1H), 7.91 (dd, J=6.6, 1.8 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.62 (d, J=9.1 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.20 (m, 1H), 6.79 (td, J=6.9, 1.1 Hz, 1H), 4.59 (s, 1H), 4.35 (s, 2H), 3.54 (m, 3H), 2.09 (m, 2H), 1.55 (s, 1H) ppm
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@@H:20]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22]>>[CH3:25][N:23]([CH3:24])[C:21]([C@@H:20]([NH:19][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:26][CH:27]([CH3:28])[CH3:29])=[O:22]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)C[C@H](N)C(=O)N(C)C
Agent: Cl
Product: CC(C)C[C@H](NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)N(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42 a) and (2S)-2-amino-N,N,4-trimethyl-pentanamide hydrochloride (1:1) (CAN 207595-81-1) as starting materials, LC-MS (UV peak area/ESI) 100%, 374.2240 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:5][C:3]=1[NH2:4].ClOC(C)(C)C.[CH3:22][S:23][CH2:24][C:25](=O)[CH3:26].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:26][C:25]1[NH:4][C:3]2[C:5]([C:24]=1[S:23][CH3:22])=[C:6]([N:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)[C:7]([F:9])=[CH:8][C:2]=2[Br:1]
Reactant: CSCC(C)=O
Reactant: Nc1cc(N2CCOCC2)c(F)cc1Br
Agent: CC(C)(C)OCl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1c(C)[nH]c2c(Br)cc(F)c(N3CCOCC3)c12
Yield: 79.2 %

Procedure:
A solution of 145 g of 2-bromo-4-fluoro-5-morpholinoaniline in 1 l of methylene chloride and the solution was cooled to a temperature of not higher than -50° C. on a dry ice-acetone bath. At the same temperature as above 60 g of tert-butyl hypochlorite was added dropwise to the solution during which operation the reaction system changed from heterogeneous mixture to homogeneous solution. Then, 67 g of methylthio-2-propanone was added dropwise to the solution and the mixture was reacted at the same temperature as above for 2 hours followed by adding dropwise 80 ml of triethylamine. After completion of addition, the temperature of the mixture was elevated slowly to room temperature. After room temperature was attained 1 l of water was added to separate the methylene chloride layer which then was dried over sodium sulfate and concentrated under reduced pressure to give 150 g of 2-methyl-3-methylthio-5-fluoro-4-morpholino-7-bromoindole.
Reaction SMILES: C([O:4][C:5](=[O:62])[C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:61])[NH:24][CH2:25][CH2:26][C@H:27]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[C:28](=[O:52])[NH:29][CH2:30][CH2:31][S:32][C:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:18][CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])C=C.C(N(CC)CC)C.C(O)=O>O1CCCC1.O>[C:11]([O:10][C:8]([NH:7][C@H:6]([C:5]([OH:62])=[O:4])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][C:23](=[O:61])[NH:24][CH2:25][CH2:26][C@H:27]([NH:53][C:54]([O:56][C:57]([CH3:59])([CH3:58])[CH3:60])=[O:55])[C:28](=[O:52])[NH:29][CH2:30][CH2:31][S:32][C:33]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:20][CH:21]=1)=[O:9])([CH3:12])([CH3:13])[CH3:14]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: O=CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)C(=O)O
Temperature: 25 °C

Procedure:
98 mg (0.1 mmol) of the compound from example 15A was dissolved in approx. 4 ml tetrahydrofuran. 70 μl (0.5 mmol) Triethylamine, 19 μl (0.5 mmol) formic acid and 11 mg (0.01 mmol) tetrakis(triphenylphosphin)palladium(0) were added. The reaction mixture was stirred over night at room temperature. The reaction was diluted with approx. 5 ml water and twice extracted with approx. 5 ml dichloromethane. The combined organic phases were extracted with brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The raw product was purified by preparative RP-HPLC on a C18 column with a water/methanol gradient to yield 67 mg (79% of theory) product.