Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[CH2:17]([O:19][C:20](=[O:31])/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[CH3:18].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:17]([O:19][C:20]([CH:21]1[CH:22]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:3][N:4]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:5]1)=[O:31])[CH3:18]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)/C=C/c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (2.46 g, 10.4 mmol) in CH2Cl2 (15 mL) was added dropwise, over a 30 minutes period, to a stirred solution of (E)-3-(3,4-dichloro-phenyl)-acrylic acid ethyl ester (2.40 g, 10.4 mmol) and trifluoroacetic acid (0.08 mL, 1 mmol) in CH2Cl2 (10 mL) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:4) afforded 2.48 g (66%) of the title compound as a yellow oil. ES-MS m/e: 379.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([OH:17])=[O:16].[C:18]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(-c2ccc(Cl)c(C(=O)O)c2)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(-c2cccc(C)c2)ccc1Cl
Yield: 98.4 %

Procedure:
A mixture of 4-chloro-3′-methylbiphenyl-3-carboxylic acid (1.70 g, 6.90 mmol), K2CO3 (7.0 g, 50.6 mmol) and CH3I (3 mL, 48 mmol) in acetone (30 mL) was heated under reflux for 1 h. After filtration and evaporation of excess CH3I, the residue was washed with water and extracted with ethyl acetate, dried over anhydrous Na2SO4, and evaporated solvent in vacuo to provide crude methyl 4-chloro-3′-methylbiphenyl-3-carboxylate (1.77 g, 98%) as a brown oil. 1H NMR (300 MHz, DMSO-d6): δ 8.04 (s, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.52-7.47 (m, 2H), 7.38 (t, J=7.8 Hz, 1H), 7.23 (d, J=7.5 Hz, 1H), 3.90 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:8]2[CH2:11][C:10]([CH3:22])([CH2:12][N:13](C(=O)C(F)(F)F)[CH2:14][CH3:15])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)C.Cl>C(O)(=O)C>[C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:8]2[CH2:11][C:10]([CH2:12][NH:13][CH2:14][CH3:15])([CH3:22])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCN(CC1(C)CN(C(c2ccccc2)c2ccccc2)C1)C(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCNCC1(C)CN(C(c2ccccc2)c2ccccc2)C1
Yield: 84.9 %

Procedure:
3.9 g (10 mmol) of 1-diphenylmethyl-3-methyl-3-[N-(ethyl)trifluoroacetylaminomethyl]azetidine in 20 ml of 5% strength sodium hydroxide and 20 ml of ethanol are stirred for one hour at 70° C. The solution is cooled, brought to pH 8 with hydrochloric acid, acidified with acetic acid and evaporated, the residue is extracted with chloroform, the organic phase is dried with anhydrous sodium sulphate, the solvent is evaporated off and 2.5 g (85%) of 1-diphenylmethyl-3-ethylaminomethyl-3-methylazetidine are obtained.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][N:6]([C:14](=[O:34])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:33])[NH:22][CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.O.O1CCOCC1.[OH-].[Na+]>C(O)C>[O:28]1[C:27]2[CH:31]=[CH:32][C:24]([CH2:23][NH:22][C:21]([C:17]3[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=3)[C:14]([N:6]([CH2:5][C:4]([OH:35])=[O:3])[CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:34])=[O:33])=[CH:25][C:26]=2[O:30][CH2:29]1
Reactant: CCOC(=O)CN(Cc1ccccc1)C(=O)c1cccc(C(=O)NCc2ccc3c(c2)OCO3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: O=C(O)CN(Cc1ccccc1)C(=O)c1cccc(C(=O)NCc2ccc3c(c2)OCO3)c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of N-benzo[1,3]dioxol-5-ylmethyl-isophthalamic acid (3.0 g, 10 mmol) in methylene chloride was added 1-hydroxy-benzotriazole monohydrate (“HOBt”) (1.35 g, 10 mmol) and ethyl N-benzylglycine (1.94 g, 10 mmol). To this was added 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (“EDAC”) (1.92 g, 10 mmol) and the mix stirred at room temperature for 24 hours. The solution treated with water (150 mL) and the organic phase separated, washed with 10% citric acid (100 mL), saturated sodium bicarbonate (100 mL) and brine (100 mL). The organic phase dried over magnesium sulfate and evaporated at reduced pressure to give ({3-[(1,3-benzodioxol-5-ylmethyl)-carbamoyl]-benzoyl}-benzyl-amino)-acetic acid ethyl ester as a solid, 3.69 g. To a solution of this ester (3.6 g, 7.6 mmol) in a mix of water (15 mL), dioxane (60 mL) and ethanol (20 mL) was added sodium hydroxide (0.72 g, 18 mmol). The mixture stirred at 50° C. for 24 hours. The solution cooled to room temperature and evaporated at reduced pressure free of solvents. The residue was diluted with water (100 mL) and washed with ether (2×50 mL). The ether discarded and the aqueous phase made acidic with 6N HCl. This was extracted with ethyl acetate (2×100 mL). The organic phases washed with brine (100 mL) and dried over magnesium sulfate. The solvent was evaporated at reduced pressure to give the title compound, 3.41 g. Microanalysis (C25H22N2O6.0.3 H2O): Calc'd: C=66.45, H=5.05, N=6.20. Found: C=66.25, H=5.15, N=5.99.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]#[N:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:22]=1)[C:17](Cl)=[O:18].O>C(#N)C>[C:11]([CH2:10][NH:9][C:17](=[O:18])[C:16]1[CH:20]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:22]=[C:14]([Cl:13])[CH:15]=1)#[N:12]
Reactant: CCCCOc1cc(C(=O)Cl)cc(Cl)n1
Reactant: N#CCN
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOc1cc(C(=O)NCC#N)cc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
3.3 g (0.033 mol) of triethylamine was added to a solution of 1.9 g (0.02 mol) of aminoacetonitrile hydrochloride in 30 ml of acetonitrile. The mixture was stirred at room temperature for 30 min. 2.5 g (0.01 mol) of 2-chloro-6-n-butoxyisonicotinoyl chloride was added dropwise thereto under cooling at 5° to 10° C. The mixture was stirred at room temperature for 1 h, poured into water and extracted with ethyl acetate. The extract was washed with a saturated aqueous common salt solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the crude product was purified according to silica gel column chromatography to obtain 1.9 g (yield: 70.9%) of white crystals having a melting point of 72° to 73° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:7][N:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[C:8]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:7][N:6]=[C:5]([C:3]([OH:4])=[O:2])[N:10]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.71 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylic acid methyl ester in 2.5 ml THF was added 937 μL of a 1M LiOH solution in water and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was acidified with 1M hydrochloric acid solution and the formed precipitate was collected by filtration washed with water and dried under high vacuum to yield 232 mg (96.71%) of the title compound as white solid, MS 331.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[N:23]=[C:22]([CH2:24][C:25](O)=[O:26])[CH:21]=[N:20][CH:19]=3)[CH:16]=2)[N:11]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:10]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:49]2[N:50]=[CH:51]C=CC=2N=N1.C(NC(C)C)(C)C.CNC>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[N:23]=[C:22]([CH2:24][C:25]([N:50]([CH3:51])[CH3:49])=[O:26])[CH:21]=[N:20][CH:19]=3)[CH:16]=2)[N:11]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:10]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cncc(CC(=O)O)n3)cc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cncc(CC(=O)N(C)C)n3)cc12
Temperature: 60 °C
Yield: 102.4 %

Procedure:
Crude {6-[3-(2-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrazin-2-yl}-acetic acid (0.55 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (251 mg, 0.66 mmol), and di-iso-propylamine (114.9 μL, 0.66 mmol) were dissolved in tetrahydrofuran (5 mL) and 2 M dimethylamine (412 μL, 0.825 mmol) was added. The mixture was heated to 60° C. in a capped vial for 30 minutes, cooled, diluted with ethyl acetate and washed with saturated sodium bicarbonate (1×), saturated ammonium chloride (1×) and brine (1×). The organics were dried over sodium sulfate, filtered and concentrated to yield a yellow foam (305 mg, >100%). The crude material was used without further purification in the next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[OH-].[Na+]>FC(F)(F)C(O)=O>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:18][CH2:19]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CCN(C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.1 %

Procedure:
To benzyl 4-(1-t-butoxycarbonylpiperidin-4-yl)piperazine-1-carboxylate (2.31 g) was added trifluoroacetic acid (10 ml) while cooling in an ice bath, followed by stirring at room temperature for 3 hr. The reaction mixture was poured into ice water, and a 5N aqueous solution of sodium hydroxide (26 ml) was added thereto. This was extracted with ethyl acetate:tetrahydrofuran=1:1. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed to provide the crude product of the titled compound as a pale yellow oil (1.93 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](Cl)=[O:10].C(N(CC)CC)C.[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:39]1[CH:38]=[CH:37][N:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:9](=[O:10])[CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])=[CH:41][CH:40]=3)=[O:25])[CH2:27][C:28]=12
Reactant: Cc1ccccc1CC(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1CC(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 0.05 h
Yield: 53.6 %

Procedure:
To a stirred solution of 0.334 g of 2-methylphenylacetyl chloride 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 72 hours at room temperature. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered through a pad of hydrous magnesium silicate and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give a solid which is crystallized from ethyl acetate to give 0.385 g of the desired product as white crystals, m.p. 198°-200° C.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.[B].[H-].[Na+]>C(O)CCC>[CH2:1]([O:6][CH:4]1[NH:5][C:1](=[O:7])[CH2:2][CH2:3]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1
Agent: [B]
Agent: [H-]
Agent: [Na+]
Solvent: CCCCO
Product: CCCCOC1CCC(=O)N1
Yield: 66 %

Procedure:
The operation is done as for preparation 2, replacing the isopropanol by n-butanol and employing 14.32 g of succinimide in 600 cm3 of n-butanol and 8 g of boron and sodium hydride. 7.5 g of the expected product is obtained, m.p. 36°-38° C. The product can also be prepared by anodic alkylation according to a process described in Synthesis 4, 315-317 (1980).
Reaction SMILES: O[CH2:2][C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1.P(Br)(Br)[Br:26]>COCCOC>[Br:26][CH2:2][C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: BrP(Br)Br
Reactant: CC(C(=O)O)c1cccc(Oc2ccc(C(F)(F)F)cc2CO)c1
Solvent: COCCOC
Product: CC(C(=O)O)c1cccc(Oc2ccc(C(F)(F)F)cc2CBr)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 2-[3-(2-hydroxymethyl-4-trifluoromethyl-phenoxy)-phenyl]-propionic acid (˜0.30 mmol) in DME (5 mL) was added phosphorus tribromide (0.06 mL, 0.60 mmol), and the solution was stirred at room temperature for 3 hours. After cooling to 0° C., the reaction was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the desired product.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:10]=[CH:11][C:12]([N:36]2[CH2:41][C@H:40]3[C@H:38]([CH:39]3[C:42]([OH:44])=[O:43])[CH2:37]2)=[N:13][C:14]=1[C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27](C(OC(C)(C)C)=O)[CH3:28])=[CH:22][CH:21]=2)=[N:18][N:19]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([N:36]2[CH2:37][C@H:38]3[C@H:40]([CH:39]3[C:42]([OH:44])=[O:43])[CH2:41]2)=[N:13][C:14]=1[C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][NH:27][CH3:28])=[CH:22][CH:21]=2)=[N:18][N:19]=1
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(N4C[C@@H]5C(C(=O)O)[C@@H]5C4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1ccc(-c2nnc(-c3nc(N4C[C@@H]5C(C(=O)O)[C@@H]5C4)cnc3N)o2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1R,5S)-3-[5-[bis(tert-butoxycarbonyl)amino]-6-[5-[4-[[tert-butoxycarbonyl(methyl)amino]methyl]phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (30 mg, 0.04 mmol) in DCM (0.3 mL) was added TFA (500 μL, 6.50 mmol) and reaction was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in DMSO, filtered and purified via reverse phase HPLC using a gradient of 10 to 99% MeOH—H2O (TFA modifier) to obtain (1R,5S)-3-[5-amino-6-[5-[4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid. LC/MS m/z 408.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.85 (s, 2H), 8.17 (d, J=8.2 Hz, 2H), 7.91 (s, 1H), 7.73 (d, J=8.2 Hz, 2H), 6.77 (s, 2H), 4.26 (t, J=5.7 Hz, 2H), 3.87 (d, J=10.4 Hz, 2H), 3.47-3.46 (m, 2H), 2.63 (t, J=5.2 Hz, 3H), 2.19 (s, 2H), 1.49 (t, J=2.9 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][C@H:11]([C:13]1[N:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15](=[O:24])[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[CH3:12].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:10][C@H:11]([C:13]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[CH3:12])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: Cc1cc(Cl)nc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc(N[C@@H](C)c2cc3cccc(Cl)c3c(=O)n2-c2ccccc2)nc(N)n1
Temperature: 160 °C

Procedure:
To a stirred mixture of 2-amino-4-chloro-6-methylpyrimidine (0.266 mmol, 1.62 eq) and compound 1 (0.164 mmol, 0.164 mmol, 1 eq) in NMP (1.5 ml), DIPEA (0.656 mmol, 4 eq) was added. The mixture was heated to 160° C. for 12 hours. Then the mixture was extracted with ethyl acetate and washed with water and brine. The product was purified by silica gel column chromatography eluting with DCM/methanol (from 0 to 10%) to afford the product (S)-3-(1-((2-amino-6-methylpyrimidin-4-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one 92. ESI-MS m/z: 406.2 [M+H]+.
Reaction SMILES: [C:1]1([C:15]([O-])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].[NH4+:17].C(=O)(O)[O-].[NH4+].O>S1(CCCC1)(=O)=O>[CH:5]1[C:1]([N+:2]([O-:4])=[O:3])=[C:15]([NH2:17])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Reactant: [NH4+]
Agent: O=C([O-])O
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 177 °C
Reaction time: 2 h
Yield: 17.5 %

Procedure:
Ammonium picrate (0.18 g, 0.75 mmol) and ammonium bicarbonate (0.59 g, 7.5 mmol) are suspended in sulfolane (3 ml), stirred for 2 hr at 177° C. , cooled to ambient temperature and mixed with water (30 ml). The product is collected, washed with water and dried to yield 0.030 g (16%) of picramide (Table 1, entry 6).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[C:15]([F:21])[CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:22][C:23]1[CH:35]=[CH:34][C:26]2[O:27][C:28]([CH3:33])([CH3:32])[O:29][C:30](=[O:31])[C:25]=2[CH:24]=1>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:22][C:23]3[CH:35]=[CH:34][C:26]4[O:27][C:28]([CH3:32])([CH3:33])[O:29][C:30](=[O:31])[C:25]=4[CH:24]=3)=[C:15]([F:21])[CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)c(F)c2)cc1
Reactant: CC1(C)OC(=O)c2cc(N)ccc2O1
Product: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)c(F)c2)cc1

Procedure:
The titled compound was prepared following the procedure A using 4-[(4-butylphenyl)ethynyl]-2-fluorobenzaldehyde and 6-amino-2,2-dimethyl-4H-1,3-benzodioxin-4-one as a yellow powder (66%). 1H NMR (CDCl3, 300 MHz) δ 7.41 (d, J=7.9 Hz, 2H), 7.38-7.12 (m, 6H), 6.90-6.76 (m, 2H), 4.39 (s, 2H), 2.61 (t, J=7.7 Hz, 2H), 1.68 (s, 6H), 1.65-1.52 (m, 2H). 1.41-1.17 (m, 2H), 0.92 (t, J=7.3 Hz, 3H). M− (ESI): 456.1 HPLC, Rt: 5.66 min (Purity: 97.9%).
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:38][CH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][CH:45]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:44][CH2:43]1>C(#N)C.C(N(CC)CC)C>[CH2:48]([CH:45]1[CH2:44][CH2:43][N:42]([CH2:41][CH2:40][CH2:39][NH:38][C:13]([C:5]2[S:6][C:7]3[N:12]4[C:3](=[CH:2][N:1]=[C:11]4[CH:10]=[CH:9][CH:8]=3)[CH:4]=2)=[O:15])[CH2:47][CH2:46]1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: NCCCN1CCC(Cc2ccccc2)CC1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCCCN1CCC(Cc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 2 h

Procedure:
To a suspension of 1.0 g (4.58 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 1.05 g (9.12 mM) of N-hydroxysuccinimide in acetonitrile (10 ml) was added 1.76 g (9.18 mM) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride at room temperature and the mixture was stirred at the prevailing temperature for 2 hours. To this mixture was added a suspension of 2.09 g (6.85 mM) of 1-(3-aminopropan-1-yl)-4-benzylpiperidine dihydrochloride and 3.87 ml (27.8 mM) of triethylamine in acetonitrile (5 ml) and the mixture was further stirred for 30 minutes. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (methanol/ethyl acetate 20-40-60%) to provide the title compound as red-purple amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[N:5]=[CH:6][C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:8]=1[OH:14].[BH4-].[Na+].CC(C)=O.O>O1CCCC1.C(O)C>[Br:13][C:11]1[CH:10]=[CH:9][C:8]([OH:14])=[C:7]([CH2:6][NH:5][C:4]2[CH:15]=[C:16]([Cl:18])[CH:17]=[C:2]([Cl:1])[CH:3]=2)[CH:12]=1
Reactant: Oc1ccc(Br)cc1C=Nc1cc(Cl)cc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCO
Product: Oc1ccc(Br)cc1CNc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.3 %

Procedure:
3,5-Dichloro-N-(5-bromo-2-hydroxybenzylidene)aniline (1.04 g, 3 mmol) was dissolved in tetrahydrofuran (12 mL) and ethanol (6 mL). Sodium borohydride (113 mg, 3 mmol) was added under ice cooling and argon atmosphere, and the mixture was stirred at room temperature for 12 hours. Acetone (10 mL) was added to the reaction mixture, and the residue obtained by concentration under reduced pressure was added water and extracted with dichloromethane. After the dichloromethane layer was washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give a light yellow viscous material. This was crystallized by n-hexane to give the title compound (971 mg, 93.3%) as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH2:5].CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:9])[C:4]([NH2:5])([C:29]([C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)=[O:36])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(=O)C(N)(C(=O)c1cccnc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 369.7 %

Procedure:
To a solution of L-valine methylester (3.0 g, 2.29 mmol), in DCM (30 mL) were added N-methyl morpholine (11.5 mL, 11.45 mmol), EDCI.HCl (8.7 g, 45.8 mmol) and nicotinic acid (3.3 g, 27.4 mmol). The mixture was allowed to stir at room temperature (25° C.) over 3 h under nitrogen atmosphere. The resulting mixture was diluted with ethyl acetate (200 mL), washed with water (3×100mL) and dried over sodium sulphate. The crude product obtained upon evaporation of the solvent was further purified by silica gel column chromatography to obtain required product as sticky solid (2.0 g, 38%).