Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:17][CH2:18][C:19](OCC)=[O:20])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[Cl-].[NH4+]>C1COCC1>[O:20]=[C:19]1[CH:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])[N:8]2[C:16]3[C:11]([CH:10]=[C:9]2[CH2:17][CH2:18]1)=[CH:12][CH:13]=[CH:14][CH:15]=3
Reactant: CCOC(=O)CCc1cc2ccccc2n1CC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1C(=O)CCc2cc3ccccc3n21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a stirred solution of ethyl 3-[1-(2-tert-butoxy-2-oxoethyl)-1H-indol-2-yl]propanoate from Step 4 in THF (0.06 M) at −10° C. was added 1 M potassium tert-butoxide (2.5 equiv.) dropwise. The reaction mixture was allowed to warm to rt over a period of 1 h. and then stirred at rt overnight. The reaction mixture was poured into aqueous ammonium chloride and extracted with excess EtOAc (2×). The combined organic layers were washed with brine, dried with MgSO4, filtered and concentrated under vacuum to afford the crude title compound (92%) as a dark oil. This material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16].N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1.CCOCC>[Cl:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:14]([C:15](=[O:16])[CH3:17])[C:13]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=Cc1cccc([N+](=O)[O-])c1Cl
Reactant: CCOC(=O)CC(C)=O
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1Cl)C(C)=O

Procedure:
A solution of 2-chloro-3-nitrobenzaldehyde (2.00 g., 10.8 mmole), ethyl acetoacetate (1.37 ml., 10.78 mmole), piperidine (0.25 ml.) and acetic acid (0.5 ml.) in benzene (21 ml.) under argon is fitted with a Dean-Stark trap and heated at 110° (oil bath) for 3 hours. The reaction is diluted with ether and washed with saturated sodium bicarbonate, 1N hydrochloric acid, and saturated sodium chloride, dried over anhydrous magnesium sulfate, and evaporated to give 2-[(2-chloro-3-nitrophenyl)methylene]-3-oxobutanoic acid, ethyl ester as a red oil (3.42 g.). TLC (silica gel; ether/hexanes) Rf =0.31 and 0.43.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[C@H:10]([CH:27]([CH3:29])[CH3:28])[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:30])[C@H:10]([CH:27]([CH3:28])[CH3:29])[N:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:17][CH:18]=1)[C:40](=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(=O)Cl
Reactant: CC(C)[C@H](NCc1ccc(-c2ccccc2C#N)cc1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C

Procedure:
6.2 g (15.5 mmol) of N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester and 8.0 ml of Hunig base, dissolved in 50 ml of methylene chloride, are treated with 2.3 ml of valeryl chloride with stirring and further processed analogously to Example 29b. The title compound is thus obtained as a yellow oil which is further used in crude form (Rf 0.51, toluene-methanol 19:1)
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH:8]2[N:11](C(OCC3C=CC=CC=3)=O)[CH:4]([CH2:5][CH2:6][CH2:7]2)[C:3]1=[O:22].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][N:2]1[C:9](=[O:10])[CH:8]2[NH:11][CH:4]([CH2:5][CH2:6][CH2:7]2)[C:3]1=[O:22]
Reactant: CN1C(=O)C2CCCC(C1=O)N2C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN1C(=O)C2CCCC(N2)C1=O
Yield: 91.3 %

Procedure:
A stirred suspension of benzyl 3-methyl-2,4-dioxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (742 mg, 2.454 mmol) and 10% Pd—C (100 mg) in ethyl acetate (40 ml) was hydrogenated under balloon pressure of hydrogen overnight. The suspension was filtered to remove the catalyst and the filtrate was evaporated to dryness to afford 3-methyl-3,9-diazabicyclo[3.3.1]nonane-2,4-dione as a white solid (377 mg). MS: m/e 169 (MH+).
Reaction SMILES: I.[C:2]1([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([S:17][C:18](=N)N)=[CH:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25]C[Cl:27]>[OH-].[Na+].Cl>[ClH:27].[CH3:22][N:23]([CH2:24][CH2:25][CH2:18][S:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)[CH3:28]
Reactant: N=C(N)Sc1cn(-c2ccccc2)c2ccccc12
Reactant: CN(C)CCCCl
Agent: Cl
Agent: I
Agent: [Na+]
Product: CN(C)CCCSc1cn(-c2ccccc2)c2ccccc12
Yield: 46 %

Procedure:
A suspension of the hydroidide salt from part (A) (27.0 g; 0.07M) in 2N aqueous sodium hydroxide (300.0 ml) was stirred under nitrogen and heated to reflux. After 10 minutes the mixture was cooled to 90° and solid 3-[dimethylamino]-propyl chloride hydrochloride (21.6 g; 0.14M) was added in small portions. A vigorous exothermic reaction occcurred and the solid dissolved. The solution was allowed to cool and was stirred at 20° for a further 17 hours. The resulting two-phase mixture was extracted with methylene chloride (3×100 ml.), and the combined organic extracts were washed with water (2×50 ml), dried (magnesium sulphate) and evaporated to give a viscous pale green oil. This was dissolved in 3.5N methanolic hydrogen chloride (50 ml.), evaporated and the residue was crystallised from acetonitrile (1200 ml.) to give the title compound as colourless leaflets, weight 11.3 g, m.p. 203°-7° (46.0% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[CH:11][CH:10]=1)=[O:8].Cl>C(O)CC(C)C>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([O:19][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:12])=[O:18])[C:12]2=[CH:11][CH:10]=1)=[O:8]
Reactant: Cn1cccc1C(=O)c1ccc2n1CCC2C(=O)O
Agent: Cl
Solvent: CC(C)CCO
Product: CC(C)CCOC(=O)C1CCn2c(C(=O)c3cccn3C)ccc21
Reaction time: 24 h

Procedure:
A solution of 300 mg. of 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 5 ml. of isoamyl alcohol is saturated with hydrogen chloride. After 24 hours, the excess alcohol is distilled off in vacuo and the residue purified by chromatography on alumina, to yield isoamyl 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo[ 1,2-a]pyrrole-1-carboxylate.
Reaction SMILES: [C:1]1(=[O:14])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][NH:2]1.[H-].[Na+].Br[CH:18]([CH3:20])[CH3:19]>>[CH3:19][CH:18]([N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[C:1](=[O:14])[NH:2][CH2:3][CH2:4][C:5]1=2)[CH3:20]
Reactant: O=C1NCCc2[nH]c3ccccc3c21
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Product: CC(C)n1c2c(c3ccccc31)C(=O)NCC2
Yield: 28.4 %

Procedure:
2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indol-1-one (931 mg) was treated with sodium hydride (73% dispersion in oil; 328 mg) and was then stirred with 2-bromopropane (615 mg) at room temperature for 72 h. Purification by FCC eluting with System A (200:8:1) gave a foam (324 mg) which was further purified by recrystallisation from ethyl acetate: hexane (1:1) to give the title compound (249 mg), t.l.c. (System A, 100:8:1) Rf 0.58.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:20])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[Cl:19])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:21]([OH:25])[CH2:22][C:23]#[CH:24].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].CCOC(C)=O.O>C(O)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([C:8]2[CH:9]=[C:4]([N:1]3[CH:24]=[C:23]([CH2:22][CH2:21][OH:25])[N:3]=[N:2]3)[CH:5]=[CH:6][C:7]=2[Cl:20])=[O:11])=[C:13]([Cl:19])[CH:14]=1
Reactant: [N-]=[N+]=Nc1ccc(Cl)c(C(=O)c2ccc(Br)cc2Cl)c1
Reactant: C#CCCO
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Br)cc1Cl)c1cc(-n2cc(CCO)nn2)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of compound 455 (1.32 g, 3.56 mmol) in ethanol (20 mL) was added but-3-yn-1-ol (0.3 mL, 3.91 mmol). A freshly prepared solution of copper(II) sulphate pentahydrate (36 mg, 0.14 mmol) and sodium ascorbate (141 mg, 0.71 mmol) in water (3.2 mL) was added to the reaction mixture. The flask was closed and stirred for 24 h at RT under argon. The reaction mixture was poured into a mixture of EtOAc/water. The organic phase was washed with water, brine and then dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 40:60 to 95:5 as the eluent to afford the title compound as white syrup.
Reaction SMILES: Br[CH:2]([CH3:11])/[C:3](/OC)=[CH:4]\[C:5]([O:7][CH3:8])=[O:6].[C:12]([NH2:20])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:11][C:2]1[O:19][C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:20][C:3]=1[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)/C=C(/OC)C(C)Br
Reactant: NC(=O)c1ccccc1
Product: COC(=O)Cc1nc(-c2ccccc2)oc1C

Procedure:
reacting methyl (E)-4-bromo-3-methoxy-pent-2-enoate with benzamide to give methyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate,
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:16][C:17](N)=[O:18]>C(O)(=O)C>[C:6]1([C:4]2[C:3]3[C:2](=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:1][C:17](=[O:18])[N:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: NC(N)=O
Solvent: CC(=O)O
Product: O=c1nc(-c2ccccc2)c2ccccc2[nH]1
Temperature: 25 °C

Procedure:
A solution of 2-aminobenzophenone (100 g, 0.51 mol), urea (55 g, 0.93 mol) and acetic acid (300 mL) was stirred at 110° C. for 18 h. The reaction mixture was cooled to rt and filtered. The solid was washed with water and dried under reduced pressure. 4-Phenylquinazolin-2(1H)-one was isolated as a yellow solid and was used without further purification.
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(C)=O>[C:10]1([NH:16][C:17]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1ccccc1

Procedure:
Following a procedure similar to that described in Example 23 but using 6.9 g. sodium in 300 ml. dry acetone, 41.1 g. valeramidine hydrochloride, and 35.7 g. phenyl isocyanate in 200 ml. dry acetone, there was obtained after recrystallization from ethyl alcohol 40.3 g. 1-phenyl-3-(pentanimidoyl)urea hydrochloride; m.p. 155.5°-156°C.
Reaction SMILES: S(C1CC(=O)N(O)C1=O)(O)(=O)=O.C(Cl)CCl.[CH:17]1[C:24](N)=[CH:23][CH:22]=[C:21]([OH:26])[C:19](=[O:20])[CH:18]=1>C(=O)([O-])[O-].CS(C)=O>[CH:24]1[CH:17]=[CH:18][C:19](=[O:20])[C:21]([OH:26])=[CH:22][CH:23]=1
Reactant: Nc1ccc(O)c(=O)cc1
Agent: O=C([O-])[O-]
Agent: O=C1CC(S(=O)(=O)O)C(=O)N1O
Solvent: CS(C)=O
Solvent: ClCCCl
Product: O=c1cccccc1O
Reaction time: 4 h

Procedure:
To 100E6 carboxylated microspheres (previously activated with sulfo-N-hydroxysuccinimide and EDC) in 0.5 mL of carbonate buffer (pH 9) was added 2 mg of 5-aminotropolone dissolved in 25 μL of dimethyl sulfoxide. The suspension was agitated for 4 hours, and the excess reagent was washed away from the microspheres.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:21](=[O:23])[CH3:22])[C:13]4[C:18]([C:19]=3[CH:20]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([N:38]3[C:50]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[C:44]4[C:39]3=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:35]=[CH:36][CH:37]=2)O1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:40]1[C:39]2[N:38]([C:34]3[CH:33]=[C:32]([C:2]4[CH:7]=[CH:6][CH:5]=[C:4]([C:8]5[CH:9]=[CH:10][C:11]6[N:12]([C:21](=[O:23])[CH3:22])[C:13]7[C:18]([C:19]=6[CH:20]=5)=[CH:17][CH:16]=[CH:15][CH:14]=7)[CH:3]=4)[CH:37]=[CH:36][CH:35]=3)[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1
Reactant: CC(=O)n1c2ccccc2c2cc(-c3cccc(Br)c3)ccc21
Reactant: CC1(C)OB(c2cccc(-n3c4ccccc4c4ccccc43)c2)OC1(C)C
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)n1c2ccccc2c2cc(-c3cccc(-c4cccc(-n5c6ccccc6c6ccccc65)c4)c3)ccc21
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A mixture solution of 1-(3-(3-bromophenyl)-9H-carbazol-9-yl)ethanone (2.50 g, 6.86 mmol), 9-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-9H-carbazole (2.53 g, 6.86 mmol), Pd2(dba)3 (0.063 g, 0.069 mmol), (SPhos) (0.056 g, 0.137 mmol) and K3PO4 (4.74 g, 20.59 mmol) in toluene (180 mL) and water (5 mL) was refluxed under N2 overnight. After cooling to room temperature, the organic solution was isolated. Upon evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane/DCM (1/1 to 1/4, v/v) as eluent to yield 1-(3-(3′-(9H-carbazol-9-yl)-[1,1′-biphenyl]-3-yl)-9H-carbazol-9-yl)ethanone (3.2 g, 89%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].Br[CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].[Br-]>CN(C)C=O>[C:25]([O:24][C:22]([NH:21][CH2:20][CH2:19][O:17][C:13]1[CH:12]=[C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)[CH:16]=[CH:15][CH:14]=1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COC(=O)c1cccc(-c2cccc(O)c2)c1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2cccc(OCCNC(=O)OC(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
A mixture of 3′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid methyl ester (667 mg) and 2-bromo-1-[(tert-butoxycarbonyl)amino]ethane (980 mg) in N, N-dimethylformamide (15 mL) was treated with potassium carbonate (2.0 g). The mixture was stirred at room temperature for 30 min, and heated to 50° C. in an oil bath for 14 h. Additional bromide (396 mg) was added and the mixture was heated an additional 36 h. The mixture was cooled to room temperature and partitioned between 1:1 hexane ethyl acetate and water. The organic layer was separated, washed with water, dried over sodium sulfate, filtered and concentrated to give the crude product. Purification by silica gel chromatography (eluting with 5:1 hexane/ethyl acetate) afforded the title compound as a colorless oil (826 mg).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[NH:17][C:16]=2[C:24]([OH:26])=O)=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C>COCCOC.CCOC(C)=O.O(C(C)C)C(C)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[NH:17][C:16]=2[C:24]([N:2]([CH3:1])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:26])=[CH:13][CH:14]=1
Reactant: O=C(O)c1[nH]c(C(F)(F)F)cc1-c1ccc(Cl)cc1
Reactant: CNCC(C)(C)C
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(C)(C)C)C(=O)c1[nH]c(C(F)(F)F)cc1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
N-Methyl neopentyl amine (0.781 g, 5.68 mmol) and 3-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic acid (1.37 g, 4.73 mmol) were combined in DME (13 mL). DIPEA (3.47 mL, 19.87 mmol) and BOP-CI (2.53 g, 9.93 mmol) were added. The mixture was stirred at 60° C. for 1 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with aqueous 1M KHSO4 (3×20 mL), aqueous saturated NaHCO3 (3×20 mL) and brine (2×20 mL) before drying on Na2SO4 and concentration in vacuo to give an oil. The product was dissolved by heating in i-Pr2O and left to cool for 16 h. A solid had formed which was filtered off and washed with i-Pr2O (2×5 mL) to give a light yellow solid. The filtrate was combined with the residue and purified using column chromatography (silica, gradient heptane/EtOAc 95:5−>7:3) to give the desired product (604 mg, 34%) as a yellow solid. The mother liquor was concentrated in vacuo and triturated with heptane to give another batch of the desired product (271 mg, 15%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[CH2:10]([Sn](CCCC)(CCCC)CCCC)[CH:11]=[CH2:12]>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:12]([C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1)[CH:11]=[CH2:10]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1ccc(C#N)cn1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 6-chloropyridine-3-carbonitrile (7.0 g, 50 mmol), allyl tri-n-butyltin (18.2 g, 55.0 mmol) and Pd(PPh3)2Cl2 (1 g) in 80 mL DMF was stirred at 90° C. for 3 hours. The mixture was cooled down and diluted with 1 L of EtOAc, washed with water (100 mL×2) and brine (100 mL), then concentrated. The residue was purified by column chromatography (PE:EtOAc=10:1) to afford the title compound.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:21]([NH:23][C:24]5[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=5)[C:27]([OH:29])=O)=[O:22])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:36]1([NH:35][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:21]([N:17]3[CH2:16][C:15]4[CH:14]=[N:13][C:12]5[NH:8][N:9]=[CH:10][C:11]=5[C:20]=4[CH2:19][CH2:18]3)=[O:22])[CH:32]=[CH:31][CH:30]=2)=[O:29])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)Nc2cccc(C(=O)O)c2)CC4)cc1
Product: O=C(Nc1ccccc1)c1cccc(NC(=O)N2CCc3c(cnc4[nH]ncc34)C2)c1

Procedure:
The compound N-[3-(phenylcarbamoyl)phenyl]-3,6,8,9-tetrahydro-7H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamide was prepared using 3-(3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamido)benzoic acid and aniline as described in general procedure J. The compound was obtained as a solid. LCMS [M+H]: 413.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.C(N(CC)C(C)C)(C)C.[F:37][C:38]([F:45])([F:44])[CH2:39][S:40](Cl)(=[O:42])=[O:41].C([O-])(O)=O.[Na+]>ClCCl>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:40]([CH2:39][C:38]([F:45])([F:44])[F:37])(=[O:42])=[O:41])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(CC(F)(F)F)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Temperature: 25 °C

Procedure:
To a stirred mixture of N-trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 μmol, Eq: 1.00) in dichloromethane (500 μl) was added at room temperature N,N-diisopropylethylamine (31.6 mg, 42.7 μl, 245 μmol, Eq: 3) and 2,2,2-trifluoroethanesulfonyl chloride (22.3 mg mg, 122 μmol). The mixture was allowed to stir at room temperature over night. The crude reaction diluted with 5 mL sat NaHCO3 and extracted with DCM (2×10 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 10% MeOH in DCM) to yield the title compound as an white solid (16 mg, 41.1%), MS (ISP) m/z=478.1 [(M+H)+].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[S:18][C:17]4[C:16](=[O:19])[N:15]([CH:20]5[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]5)[C:14](=[O:33])[N:13]([CH2:34][C:35]5[O:39][N:38]=[C:37]([CH2:40][CH3:41])[N:36]=5)[C:12]=4[CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[ClH:42]>O1CCOCC1>[ClH:42].[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[S:18][C:17]4[C:16](=[O:19])[N:15]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[C:14](=[O:33])[N:13]([CH2:34][C:35]5[O:39][N:38]=[C:37]([CH2:40][CH3:41])[N:36]=5)[C:12]=4[CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccc5c(c4)OCO5)cc32)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc5c(c4)OCO5)cc32)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl 4-[6-(1,3-benzodioxol-5-yl)-1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (3.75 g; compound B64) in 1,4 dioxane (130 ml) is added a solution of hydrogen chloride in 1,4-dioxane (31 ml, 4.0 M). The reaction mixture is stirred for 12 h at RT. To complete the reaction an additional amount of a solution of hydrogen chloride in 1,4-dioxane (5.0 ml, 4.0 M) is added and the mixture is stirred for 20 h at RT. Subsequently the suspension is filtered to give title compound as a solid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:21][CH3:22])[C:4]([N:6]1[CH2:20][CH2:19][C:9]2([NH:13][C:12](=[O:14])[C@H:11]([CH2:15][CH2:16][S:17][CH3:18])[NH:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[NH4+].[Cl-]>C1COCC1>[CH2:25]([N:13]1[C:9]2([CH2:8][CH2:7][N:6]([C:4](=[O:5])[CH:3]([CH2:1][CH3:2])[CH2:21][CH3:22])[CH2:20][CH2:19]2)[NH:10][C@@H:11]([CH2:15][CH2:16][S:17][CH3:18])[C:12]1=[O:14])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCC(CC)C(=O)N1CCC2(CC1)NC(=O)[C@H](CCSC)N2
Reactant: ClCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)C(=O)N1CCC2(CC1)N[C@@H](CCSC)C(=O)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 8-(2-ethylbutyryl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5]decan-2-one (420 mg, 1.3 mmol) in 20 mL of dry THF there was added sodium hydride (50 mg, 1.9 mmol) at 0° C. and under a blanket of nitrogen. Following stirring over a period of 1 h at 0° C., benzyl chloride (140 mg, 1.4 mmol) was slowly added dropwise and the mixture was then heated under reflux over a period of 24 h. Following the addition of an aqueous saturated NH4Cl solution (15 mL), the reaction mixture was isolated by filtration and the filtrate was extracted with EE (3×10 mL), and the combined organic phases were dried over Na2SO4. Following removal, by distillation, of the solvent, there was obtained the crude product as a yellow oil. Further purification was carried out by column chromatography. The product 1-benzyl-8-(2-ethylbutyryl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5]decan-2-one was obtained in a yield of 239 mg (45%).