Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=1.[F:15][C:16]([F:39])([F:38])[CH2:17][CH2:18][C@@H:19](OS(C(F)(F)F)(=O)=O)[C:20]([O:22]CC1C=CC=CC=1)=[O:21]>>[C:11]([O:10][C:8](=[O:9])[C@H:7]([C@@H:19]([CH2:18][CH2:17][C:16]([F:39])([F:38])[F:15])[C:20]([OH:22])=[O:21])[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Cc1cccnc1
Reactant: O=C(OCc1ccccc1)[C@@H](CCC(F)(F)F)OS(=O)(=O)C(F)(F)F
Product: CC(C)(C)OC(=O)[C@@H](c1cccnc1)[C@@H](CCC(F)(F)F)C(=O)O

Procedure:
Intermediate S-3 was synthesized from tert-butyl 2-(pyridin-3-yl)acetate (100 mg, 0.517 mmol) and (R)-benzyl 5,5,5-trifluoro-2-(trifluoromethylsulfonyloxy)pentanoate (245 mg, 0.621 mmol) using the procedure described for Intermediate S-2 to give Intermediate S-3 (60 mg, 0.173 mmol) as a white solid containing about 30% of the (R, S) isomer. MS(ES):m/z=483.3 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1ccc(Br)cc1
Product: CC(=O)NCCc1ccc(Br)cc1

Procedure:
In close analogy to the procedure described above, 2-(4-bromo-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]2[C:18]3[N:19]=[C:20]([CH3:26])[N:21]([CH2:22][O:23][CH2:24][CH3:25])[C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:39]1[O:41][CH2:40]1>O1CCCC1>[C:28]1([CH2:27][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[C:18]3[N:19]=[C:20]([CH2:26][CH2:39][CH2:40][OH:41])[N:21]([CH2:22][O:23][CH2:24][CH3:25])[C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C1CO1
Reactant: CCOCn1c(C)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOCn1c(CCCO)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of N,N-bis(phenylmethyl)-1-ethoxymethyl-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.7 g, 3.9 mmole, Example 1 Part E) in tetrahydrofuran (50 mL) was cooled to -78° C. Butyllithium (1.6 mL of 2.5M in hexanes, 4.1 mmole) was added dropwise and the reaction mixture was stirred for 5 minutes. Ethylene oxide was run over the surface of the reaction mixture. After 10 minutes the reaction mixture was allowed to warm to ambient temperature. The ethylene oxide addition was stopped when the reaction temperature reached 0° C. The reaction was quenched with diethyl ether and water. The ether layer was separated, dried over magnesium sulfate and then concentrated under vacuum. The resulting residue was purified by column chromatography (silica gel eluting with 5-10% ethyl acetate in methylene chloride v/v) to provide 1.4 g of N,N-bis(phenylmethyl)-2-(3-hydroxypropyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [CH3:1][C@H:2]([N:9]=[C:10]=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)[N:16]=[CH:15][N:14]=[C:13]2[NH:12][C:10]([NH:9][C@@H:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:11]
Reactant: C[C@H](N=C=O)c1ccccc1
Reactant: COc1cc2c(N)ncnc2cc1OCC1CCN(C)CC1
Product: COc1cc2c(NC(=O)N[C@@H](C)c3ccccc3)ncnc2cc1OCC1CCN(C)CC1

Procedure:
Using an analogous procedure to that described in Example 14, (S)-(−)-α-methylbenzyl isocyanate was reacted with 4-amino-6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazoline to give the title compound; NMR Spectrum: (CDCl3) 1.4-1.56 (m, 2H), 1.61 (d, 3H), 1.84-2.05 (m, 5H), 2.31 (s, 3H), 2.91 (d, 2H), 3.88 (s, 3H), 4.04 (d, 2H), 5.2 (m, 1H), 7.23 (d, 2H), 7.3-7.41 (m, 5H), 8.66 (s, 1H), 8.7 (s, 1H), 10.58 (s, 1H); Mass Spectrum: M+H+ 450.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[C:27]([N+:28]([O-])=O)=[CH:26][CH:25]=[CH:24][C:18]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][CH:10]=1)#[N:2]>C(O)C>[NH2:28][C:27]1[C:17]([NH:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])=[CH:10][CH:11]=2)=[C:18]([CH:24]=[CH:25][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1cccc([N+](=O)[O-])c1NCc1ccc(-c2ccccc2C#N)cc1
Solvent: CCO
Product: CCOC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a solution of ethyl 2-[(2'cyanobiphenyl-4-yl]-methyl]amino-3-nitrobenzoate (10.4 g) in ethanol (50 ml) was added stannous dichloride dihydrate (28.1 g) and the mixture was stirred at 80° C for two hours. The solvent was evaporated to dryness. To the ice-cooling mixture of the residue in ethyl acetate (300 ml) was added dropwise 2N NaOH (500 ml) with stirring. The aqueous layer was extracted with ethyl acetate (200 ml×2). The organic layers were combined, washed with water, and dried. The solvent was evaporated to dryness and the residue was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-hexane gave colorless crystals (7.3 g, 79%), m.p. 104°-105° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([CH3:20])=[C:18](I)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1COCC1.C([Mg]Cl)(C)C.CO[B:34]1[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]1.[NH4+].[Cl-]>>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([CH3:20])=[C:18]([B:34]3[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]3)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(I)cnn1[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-4-iodo-5-methyl-1H-pyrazole (1.15 g, 2.74 mmol) in THF (60 mL, 700 mmol) at rt was added 1.3 M of Isopropylmagnesium Chloride in THF (8.4 mL, 11 mmol), and the mixture was stirred for 1 h. The reaction was quenched with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.24 mL, 13.7 mmol), and allowed to stir at rt for 1 h. Sat. NH4Cl was added, and the organic solvent was removed in vacuo. The material was extracted with DCM and water. The organic layer was dry-loaded onto silica gel and purified via column chromatography, eluting with 2-7% EtOAc/heptane. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, methanol-d4): δ=0.12 (s, 6H), 0.93 (s, 9H), 1.32 (s, 12H), 1.47-1.60 (m, 2H), 1.84-2.06 (m, 6H), 2.46 (s, 3H), 3.72-3.82 (m, 1H), 4.10-4.22 (m, 1H), 7.59 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].[CH3:29][O:30][CH2:31][CH2:32][NH2:33]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:22]1)[N:14]=2)[C:5]([NH:33][CH2:32][CH2:31][O:30][CH3:29])=[O:6]
Reactant: COCCN
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Product: COCCNC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
The title compound was synthesized using the procedure described in Example 105 above, with 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzoic acid (97 mg, 0.248 mmol) and 2-methoxyethylamine (26 μl, 0.298 mmol). MS (ESI) m/z: Calculated: 447.1; Observed: 448.1 (M++1).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:11]([O:21][CH3:22])=[CH:12][CH:13]=[C:14]2[C:19]=1[C:18](=[O:20])[NH:17][CH2:16][CH2:15]2>CN(C)C=O>[NH2:9][C:10]1[C:11]([O:21][CH3:22])=[CH:12][C:13]([Cl:1])=[C:14]2[C:19]=1[C:18](=[O:20])[NH:17][CH2:16][CH2:15]2
Reactant: COc1ccc2c(c1N)C(=O)NCC2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COc1cc(Cl)c2c(c1N)C(=O)NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
N-chlorosuccinimide (20 g, 0.147 mol) was added to a solution of 8-amino-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (296c, 24 g, 0.125 mol) in N,N-dimethylformamide (250 mL) and stirred at room temperature overnight. The solution was partitioned between water (100 mL) and ethyl acetate (5×100 mL). The combined organic extracts were washed with brine (5×100 mL), dried over sodium sulfate, and concentrated to dryness. The residue was triturated with acetonitrile (200 mL), and the solids collected by filtration. After drying, 8-amino-5-chloro-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (296d, 12.5 g, 44% yield) was obtained as a blue solid. 1H NMR (400 MHz, DMSO-d6): δ 7.84 (s, 1H), 6.93 (s, 1H), 3.80 (s, 3H), 3.29-3.25 (m, 2H), 2.81-2.78 (t, J=6.6 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[CH:16]=3)[NH:11][C:10](=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[O:26])[CH:16]=2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(C(=O)c2ccc3[nH]c(=O)nc(-c4cccc(Cl)c4)c3c2)cc1
Product: Cc1ccc(C(=O)c2ccc3nc(Cl)nc(-c4cccc(Cl)c4)c3c2)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A mixture of intermediate 22 (0.041 mol) in phosphoryl chloride (105 ml) was stirred at 100° C. for 4 hours then cooled. The solvent was evaporated. The residue was taken up DCM. The solvent was evaporated. The residue was taken up in DCM. The mixture was poured out into ice water, basified with K2CO3 10% and extracted. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 11.4 g (70%) of intermediate 23. The mother layer was evaporated and purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc; 90/10; 15-40 μm). The pure fractions were collected and the solvent was evaporated, yielding 1.7 g (10.5%) of [2-chloro-4-(3-chlorophenyl)-6-quinazolinyl](4-methylphenyl)-methanone (intermediate 23), mp. 156° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5](Cl)[S:4][N:3]=1.[CH3:13][CH:14]1[CH2:19][CH2:18][C:17](B(O)O)=[CH:16][CH2:15]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[Cl:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([C:17]2[CH2:18][CH2:19][CH:14]([CH3:13])[CH2:15][CH:16]=2)[S:4][N:3]=1
Reactant: CC1CC=C(B(O)O)CC1
Reactant: CCOC(=O)c1c(Cl)nsc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1c(Cl)nsc1C1=CCC(C)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed ethyl 3,5-dichloro-1,2-thiazole-4-carboxylate (150 mg, 0.66 mmol, 1.00 equiv), (4-methylcyclohex-1-en-1-yl)boronic acid (103 mg, 0.74 mmol, 1.11 equiv), Pd(PPh3)4 (38 mg, 0.03 mmol, 0.05 equiv), K3PO4 (368 mg, 1.73 mmol, 2.61 equiv), dioxane (3 mL). The resulting solution was stirred overnight at 90° C. in an oil bath. The solids were removed by filtration. The resulting mixture was concentrated under reduced pressure. The residue was applied to a silica gel column, eluting with ethyl acetate/petroleum ether (2:98) to afford 120 mg (63%) of ethyl 3-chloro-5-(4-methylcyclohex-1-en-1-yl)-1,2-thiazole-4-carboxylate as a colorless oil.
Reaction SMILES: [N:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:22]([CH2:29][CH2:30][CH3:31])[CH2:23][C:24]([O:26]CC)=[O:25].[O-]CC.[Na+:35]>C(O)C.C(OCC)(=O)C>[N:13]1([CH2:12][CH2:11][NH:10][C:8]([C:7]2[CH:6]=[CH:5][C:4]([N:1]3[C:22]([CH2:29][CH2:30][CH3:31])=[C:23]([C:24]([O-:26])=[O:25])[N:3]=[N:2]3)=[CH:20][CH:19]=2)=[O:9])[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1.[Na+:35]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)NCCN2CCOCC2)cc1
Reactant: CCCC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCc1c(C(=O)[O-])nnn1-c1ccc(C(=O)NCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-Azido-N-(2-morpholin-4-ylethyl)benzamide obtained in Example 61a) and ethyl 3-oxohexanoate (1.07 ml, 6.35 mmol, 1.25 eq.) were dissolved in ethanol (23 ml), sodium ethoxide (480 mg, 6.35 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 20 min, and then at 60° C. for 13 hr. The resulting solid was suspended in ethyl acetate, and the insoluble material was collected by filtration, washed with ethyl acetate and dried to give the title compound as a grayish white powder (2.44 g, 5.09 mmol, quant.).
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[H-].[Na+].Cl[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][N:9]=1>C1COCC1>[Cl:14][C:13]1[C:8]([S:4][CH2:1][CH2:2][CH3:3])=[N:9][CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CCCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCSc1ncc(C(F)(F)F)cc1Cl
Temperature: 27.5 °C
Reaction time: 10 h
Yield: 99.3 %

Procedure:
23.8 g (0.313 mol) of 1-propanethiol were added in the course of 30 minutes to a mixture of 7.9 g (0.313 mol) of 95% pure sodium hydride in 200 ml of THF while flushing with nitrogen and stirring, a temperature of 25-30° C. being maintained by means of cooling. After the mixture had been stirred for 1 hour, 54 g (0.25 mol) of 2,3-dichloro-5-trifluoromethylpyridine in 50 ml THF were added at 25-30° C. in the course of 20 minutes with stirring, and stirring was continued for 10 hours at 23° C. The reaction mixture was concentrated in vacuo, taken up in methylene chloride, extracted with 0.5 N sodium hydroxide solution, dried over magnesium sulfate and concentrated, yielding 63.5 g (99.4%) of the title compound of nD23=1.5120.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:28][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH3:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:28][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH3:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: COc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: [Pd]
Solvent: CO
Product: COc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (390 mg, 0.98 mmol) and 10% palladium on activated carbon (50 mg) in methanol (200 mL) was heated at 50° C. under 50 bar of hydrogen in a steel bomb pressure for 6 h. The mixture was cooled to room temperature. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (240 mg, 61.4%) as a white solid: LC/MS m/e calcd for C22H26N2O3S [M+H]+ 399.53; observed 399.2. 1H NMR (400 MHz, CDCl3) δ ppm 11.86 (s, 1H), 7.92 (d, J=8.6 Hz, 3H), 7.55 (d, J=7.8 Hz, 1H), 7.28 (s, 3H), 6.49 (s, 1H), 4.37 (t, J=7.6 Hz, 1H), 3.97 (s, 3H), 3.07 (s, 3H), 2.13-2.29 (m, 2H), 1.79 (d, J=20.0 Hz, 2H), 1.65 (m, 2H), 1.45-1.56 (m, 2H), 1.14-1.25 (m, 2H).
Reaction SMILES: C([C:3]([C:9]#[N:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6])#N.[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([Cl:22])[C:13]=1[NH:23][NH2:24].C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:8][C:7]1[N:23]([C:13]2[C:14]([Cl:22])=[CH:15][C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:12]=2[Cl:11])[N:24]=[C:3]([C:9]#[N:10])[C:4]=1[C:5]#[N:6]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: N#CC(C#N)=C(C#N)C#N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C#N
Reaction time: 0.25 h
Yield: 48.7 %

Procedure:
Tetracyanoethylene (1.9 g) and 2,6-dichloro-4-trifluoromethylphenylhydrazine (3.7 g) was added to a magnetically-stirred solution of sodium acetate (0.6 g) in glacial acetic acid (15 ml) at laboratory temperature. After stirring for 15 minutes, a colorless solid precipitated from the solution and stirring was continued overnight. The mixture was then filtered. The solid obtained was washed successively with acetic acid, water, aqueous sodium bicarbonate solution and water, to give 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3,4-dicyanopyrazole (2.5 g), as beige crystals, m.p. 221°-222° C.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH2:3]1.[N:9]#[C:10][N:11]=[N+]=[N-]>CCOCC>[C:10]([N:11]1[CH:3]2[CH:4]1[C:5]([CH3:8])=[CH:6][CH2:7][N:2]2[CH3:1])#[N:9]
Reactant: N#CN=[N+]=[N-]
Reactant: CC1=CCN(C)C=C1
Solvent: CCOCC
Product: CC1=CCN(C)C2C1N2C#N
Yield: 76.2 %

Procedure:
A solution of 1,4-dimethyl-1,2-dihydropyridine (9.69 g, 65 mmol) in ether (10 ml) was added slowly with stirring at 0° C. to a solution of cyanogen azide (5.1 g, 75 mmol). The reaction mixture was allowed to return to 25° C. and the solvent was removed in vacuo to give a reddish-brown product which was partitioned between 200 ml methylene chloride-water (1:1 v/v). The methylene chloride extract was dried (MgSo4) and the solvent removed in vacuo to give 7-cyano-2,5-dimethyl-2,7-diazabicyclo [4.1.0]hept-4-ene (7.39 g, 76.2%) as a tan solid with mp 117° C. 10% palladium on charcoal (400 mg) was added to a solution of 7-cyano-2,5-dimethyl-2,7-diazabicyclo[4.1.0]hept-4-ene (2.23 g, 15 mmol) in 50 ml methanol and the reduction was effected using 10% palladium on charcoal and hydrogen gas at 35 psi for 24 hours. Filtration and then removal of the solvent in vacuo gave 1,4-dimethylpiperidylidene-2-cyanamide as a white solid (2.26 g, 99.8%) with mp 94° C; IR (KBr) 2180 (C≡N) and 1598 cm-` (C=N); NMR (CDCl3) 3.44 (m, 2H, H-6), 3.05 (s, 3H, N--Me), 2.9 (m, 1H, H-3), 2.35 (m, 1H, H-3), 2.15-1.2 (m, 3H, H-4, H-5), 1.04 (d, J=5Hz, 3H, C-4 Me). Mass spectra (70 ev): Mass calc'd for C8H13N3 : 151,1109; found: 151.1107.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[CH2:15][O:16][CH3:17])=[CH:11][C:10]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:9][CH:8]=3.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:19]([O:18][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]1[CH:4]=[N:3][C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:14]([CH2:15][O:16][CH3:17])[C:13]2=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1ccccc1
Reactant: COCc1c(Br)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COCc1c(-c2ccccc2)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Reaction time: 0.08 h
Yield: 78.7 %

Procedure:
476 mg of 3-bromo-6-benzyloxy-4-methoxymethyl-β-carboline is introduced in 10 ml of toluene and 5 ml of ethanol, mixed with 41 mg of tetrakis(triphenylphosphine)-palladium(0) and stirred for 5 minutes. Then 177 mg of phenylboronic acid and 1.5 ml of a 2 m- soda solution are added and then heated for 3 hours to 95° C. After concentration by evaporation it is taken up in a lot of ethyl acetate and washed once each with water and saturated common salt solution. After drying, filtration and concentration by evaporation, it is recrystallized. 372 mg of 6-benzyloxy-3-phenyl-4-methoxymethyl-β-carboline of a melting point of 205°-206° C. (ethanol, methylene chloride, hexane) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([C:15](OCC)=[O:16])[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[NH3:23]>CO>[NH2:23][C:15]([C:13]1[NH:12][C:8]2[N:9]=[CH:10][N:11]=[C:6]([NH:5][C:4]3[CH:20]=[CH:21][CH:22]=[C:2]([Cl:1])[CH:3]=3)[C:7]=2[CH:14]=1)=[O:16]
Reactant: CCOC(=O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reactant: N
Solvent: CO
Product: NC(=O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1

Procedure:
90 mg (0.285 mmol) of 4-(3-chloroanilino)-6-ethoxycarbonyl-7H-pyrrolo-[2,3-d]pyrimidine (stage 1.4) in 30 ml of methanol and≈5 g of ammonia are heated at 120° C. for 48 h in an autoclave. The reaction mixture is treated with silica gel, evaporated, applied to a silica gel column as a powder and finally eluted with methylene chloride/methanol/THF (210:35:10). Filtration with methanol through an alumina column (basic) and stirring in ethyl acetate yields 6-aminocarbonyl-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine; HPLC: tRet(Grad20)=8.1; TLC-Rf=0.18 (CH2Cl2/methanol [10:1]); high resolution MS: (M+H)+=288.0669 (calc. 288.0652).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:15]([O-])=O)[CH:10]=3)[NH:5][C:4]=2[CH2:3]1>CCO.[Pd]>[NH2:15][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4]1[CH2:3][N:2]([CH3:1])[CH2:14][CH2:13][C:12]2=1
Reactant: CN1CCc2c([nH]c3ccc([N+](=O)[O-])cc23)C1
Agent: [Pd]
Solvent: CCO
Product: CN1CCc2c([nH]c3ccc(N)cc23)C1
Reaction time: 20 h
Yield: 107 %

Procedure:
To a solution of 2-methyl-6-nitro-2,3,4,9-tetrahydro-1H-β-carboline (description 1) (1.42 g, 6.13 mmol) in EtOH (300 mL), 570 mg of (5%) Pd/C were added. The mixture was hydrogenated under 20 psi at room temperature for 20 h and filtered through a pad of Celite. The EtOH was evaporated to dryness to yield 1.32 g of 6-amino-2-methyl-2,3,4,9-tetrahydro-1H-β-carboline that were used directly to synthesize compounds of formula I.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:20])[C@@H:5]([NH2:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[Br:21][C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26]([CH:30]=1)[C:27](O)=[O:28].Cl>CCOC(C)=O>[CH3:2][O:3][C:4](=[O:20])[C@@H:5]([NH:19][C:27](=[O:28])[C:26]1[CH:30]=[C:22]([Br:21])[CH:23]=[CH:24][C:25]=1[OH:31])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1O
Yield: 35.2 %

Procedure:
3-Biphenyl-4-yl-(2S)-(5-bromo-2-hydroxy-benzoylamino)-propionic acid methyl ester (2.75 g, 35%) was prepared from (2S)-amino-3-biphenyl-4-yl-propionic acid methyl ester-hydrochloride (5.0 g, 17.2 mmol), 5-bromo-2-hydroxy-benzoic acid (3.7 g, 17.2 mmol) as described in general procedure A except for an adapted work-up. After reaction completion, the reaction mixture was poured onto 150 mL of 1N HCl and 150 mL of EtOAc. The organic layer was washed with 1N HCl, saturated sodium bicarbonate, dried over sodium sulfate and evaporated. The crude material was purified over silica gel (7:3, DCM-hexanes).