Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.[H][H]>CO.O1CCOCC1.[Pd]>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([NH:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:23])[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: O=C(Nc1ccccc1)Nc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Nc1ccccc1)Nc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Temperature: 50 °C

Procedure:
460 mg (1.1 mmol) of 1-[4′-(2,4-dioxo-thiazolidin-5-ylidenemethyl)biphenyl-3-yl]-3-phenylurea in 20 ml of a methanol/dioxane mixture (1/1) are placed in a reactor. The reaction medium is degassed and 560 mg (1.2 equivalents by mass) of 10% palladium-on-charcoal are then added. The system is placed under 3 bar of hydrogen and heated at 50° C. for hours. The reaction medium is filtered through Celite and evaporated, and the residue obtained is purified by chromatography on a column of silica with a gradual increase in the polarity of a 9/1 mixture of heptane and ethyl acetate to a 4/6 mixture of heptane and ethylacetate. After evaporation of the solvents, 150 mg (33%) of 1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-yl]-3-phenylurea are obtained in the form of a white solid with a melting point of 185° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([O:7][CH2:8][C@H:9]([OH:20])[C:10]([NH:12][C:13]2[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4]1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][C:32]=3[CH3:37])[N:29]=[CH:30][C:23]=12>C1COCC1>[CH:3]1([O:7][CH2:8][C@H:9]([O:20][C:22]2[C:23]3[CH:30]=[N:29][N:28]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][C:32]=4[CH3:37])[C:24]=3[N:25]=[CH:26][N:27]=2)[C:10]([NH:12][C:13]2[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4]1
Reactant: Cc1cnccc1-n1ncc2c(Cl)ncnc21
Reactant: Cc1cnc(NC(=O)[C@@H](O)COC2CCC2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)[C@H](COC2CCC2)Oc2ncnc3c2cnn3-c2ccncc2C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
60% Sodium hydride in mineral oil (48.8 mg, 1.22 mmol) was added in one portion to (S)-3-cyclobutoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate R1) (205 mg, 0.81 mmol) in anhydrous THF (5 mL) cooled to 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and then 4-chloro-1-(3-methylpyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate M1) (200 mg, 0.81 mmol) as suspension in dry THF (4 mL) added dropwise over 1 minute. The mixture was stirred at 0° C. for 15 mins, allowed to warm slowly to ambient temperature and stirred for 2 hours. 1M Citric mins, allowed to warm slowly to ambient temperature and stirred for 2 hours. 1M Citric combined organic extracts were washed with water (15 mL) and brine (15 mL), dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with 0 to 10% MeOH in ethyl acetate to give the product (360 mg, 96%). 1H NMR (400 (2H, m), 2.35 (3H, s), 2.54 (3H, s), 3.97-4.10 (3H, m), 6.05 (1H, t), 7.49 (1H, d), 8.12 (1H, d), 8.44 (1H, s), 8.61 (1H, s), 8.62-8.65 (2H, m), 8.69 (1H, s), 9.44 (1H, d); m/z (ESI+) (M+H)+=461; HPLC tR=1.67 min.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[N:9][C:10]([Cl:23])=[CH:11][C:12]=1[C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([F:22])[CH:18]=[CH:17][CH:16]=2)(=O)=O.[Li+].[Cl-].[CH2:28]([Sn](CCCC)(CCCC)C=C)[CH2:29]CC>CN(C=O)C.O>[Cl:23][C:10]1[CH:11]=[C:12]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([F:22])[CH:18]=[CH:17][CH:16]=3)[C:7]([CH:28]=[CH2:29])=[CH:8][N:9]=1
Reactant: O=S(=O)(Oc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1)C(F)(F)F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Temperature: 65 °C
Reaction time: 10 h
Yield: 458.4 %

Procedure:
To a solution of 6-chloro-4-(4-fluoro-1H-indol-2-yl)pyridin-3-yl trifluoromethanesulfonate (50 mg, 0.12 mmol), LiCl (8 mg, 0.19 mmol) in DMF (0.8 mL) was added tributyl(vinyl)stannane (80 mg, 0.25 mmol) dropwise at 25° C. under nitrogen. The mixture was stirred at 65° C. for 10 hours. The mixture was diluted with H2O, extracted with EtOAc, then the combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product. It was purified by column (PE:EA=5:1) to obtain the product of 2-(2-chloro-5-vinylpyridin-4-yl)-4-fluoro-1H-indole (150 mg, yield: 40%). 1H-NMR (CDCl3, 400 MHz) δ 8.45 (s, 1H), 7.41 (s, 1H), 7.15 (d, J=2.4 Hz, 1H), 6.88 (d, J=6.0 Hz, 1H), 6.79 (t, J=6.0 Hz, 1H), 6.35˜6.41 (m, 1H), 6.07˜6.10 (m, 1H), 5.77 (d, J=17.6 Hz, 1H), 5.49˜5.62 (m, 2H). MS (M+H)+: 273/275.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[C:20]([C:38]([NH2:40])=[O:39])=[N:21][CH:22]=[C:23]([N:25]5[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](N(CC)C)=[O:33])[CH2:26]5)[N:24]=4)=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Br[CH2:51][C:52]1[CH:61]=[CH:60][CH:59]=[CH:58][C:53]=1C(OC)=O>CN(C=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[C:20]([C:38]([NH2:40])=[O:39])=[N:21][CH:22]=[C:23]([N:25]5[CH2:30][CH2:29][CH2:28][C@@H:27]([N:31]6[CH2:51][C:52]7[C:53](=[CH:58][CH:59]=[CH:60][CH:61]=7)[C:32]6=[O:33])[CH2:26]5)[N:24]=4)=[CH:14][CH:13]=3)[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN(C)C(=O)N[C@@H]1CCCN(c2cnc(C(N)=O)c(Nc3ccc(C4CCN(C5CCCC5)CC4)cc3)n2)C1
Reactant: COC(=O)c1ccccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ncc(N2CCC[C@@H](N3Cc4ccccc4C3=O)C2)nc1Nc1ccc(C2CCN(C3CCCC3)CC2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
(R)-5-(3-Aminopiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (436) (50 mg, 0.1 mmol) was dissolved in 4 mL DMF. To it were added DIEA (180 μL, 1.0 mmol) and then methyl 2-bromomethylbenzoate (46 mg, 0.2 mmol) at RT. The reaction temperature was raised to 60° C. and the mixture was stirred for overnight. It was cooled to RT, quenched with 0.5 mL TFA, and directly subjected to reverse phase preparative HPLC using 5 mM HCl (aq) and nest MeCN to isolate the title compound, (R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(1-oxoisoindolin-2-yl)piperidin-1-yl)pyrazine-2-carboxamide (450), as HCl salt (19 mg). LC-MS (ESI): m/z (M+1) 580.8. UV: λ=269, 275, 304, 335, 372 nm. Proton NMR (CD3OD): δ 7.84 (1H, d, J=7.5 Hz), 7.69 (1H, s), 7.66-7.58 (2H, m), 7.56-7.52 (3H, m), 7.12 (2H, d, J=8.5 Hz), 4.67-4.57 (3H, m), 4.40-4.30 (2H, m), 3.64 (2H, m), 3.55 (1H, m), 3.27-3.06 (4H, m), 2.76 (1H, m), 2.24-1.72 (18H, m) ppm.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([CH:13]=[CH:14][C:15]=1[O:16]C)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[Cl-].[Al+3].[Cl-].[Cl-].N1C=CC=CC=1.Cl>ClCCCl>[OH:1][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([CH:13]=[CH:14][C:15]=1[OH:16])[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: COc1ccc(C(=O)c2ccccc2)c([N+](=O)[O-])c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: O=C(c1ccccc1)c1ccc(O)c(O)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 88.8 %

Procedure:
To a stirred suspension of 3-Hydroxy4-methoxy-2-nitrobenzophenone (8.3 g, 30.38 mmol) in 1,2-dichloroethane (100 ml) at room temperature under argon was added aluminium chloride (4.46 g, 33.45 mmol) in one portion followed by pyridine (9.61 g, 9.81 ml, 121.5 mmol) giving rise to an exothermic reaction. the mixture was stirred at reflux for one hour, allowed to cool to room temperature and then poured onto ice-water (300 ml). Hydrochloric acid (2N, 70 ml) was added and the mixture was stirred for one hour (initial orange precipitate gradually became yellow in appearance. The solid was removed by filtration, washed by water (30 ml) and dried under vacuum to give the product as a yellow solid 6.99 g, (89%) of melting point 153–155° C. The organic phase of the filtrate was separated and the aqueous phase was extracted by dichloromethane (20 ml). The combined organic phases were washed by brine (30 ml), dried over anhydrous sodium sulphate and the solvent removed on a rotary evaporator (bath temp. 40° C.) to leave a yellow solid (0.7 g) which was not purified further.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27]Cl)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C-:29]#[N:30].[K+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1(C)C=CC=CC=1.O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27][C:29]#[N:30])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4CCl)ccc3o2)n1
Reactant: [C-]#N
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4CC#N)ccc3o2)n1
Yield: 85.7 %

Procedure:
A mixture of 4-tert-butyl-2-[5-(2-chloromethylphenylmethoxy)benzofuran-2-yl]thiazole (0.8 g), potassium cyanide (0.25 g) and Adogen 464 ((Aldrich phase transfer) one drop) in a mixture of toluene (8 ml) and water (8 ml) was stirred under reflux for 4 hours. After being cooled, the organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in reduced pressure. The resulting residue was subjected to column chromatography on silica gel and eluted with toluene. The fractions containing object compound were combined and concentrated under reduced pressure to give an oil of 4-tert-butyl-2-[5-(2-cyanomethylphenylmethoxy)benzofuran-2-yl]thiazole (0.67 g).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3].C=CC([O:14][CH:15]1[CH:19]2[CH:20]3CC([CH:18]2C=C1)CC3)=O>>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3].[C:15]([OH:4])(=[O:14])[C:19]([CH3:20])=[CH2:18]
Reactant: C=CC(=O)OC1C=CC2C3CCC(C3)C12
Agent: C=CC(=O)OCCCC
Product: C=C(C)C(=O)O

Procedure:
A dispersion of a core/shell polymer which had a core of n-butyl acrylate and dihydrodicyclopentadienyl acrylate (weight ratio 98:2) and a shell of n-butyl acrylate and methacrylic acid (weight ratio 98:1.5) and a core/shell weight ratio of 60:40 and which had been obtained by emulsion polymerization in a conventinal manner was mixed with red phosphorus and the sodium salt of a C12 -C18 -alkanesulfonic acid in a stirred kettle at room temperature. The mixing time was 30 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](/[CH:23]=[CH:24]/[O:25]C)[C:18]=3[CH2:27][CH3:28])=[N:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:27][CH3:28])=[C:19]([CH2:23][CH:24]=[O:25])[CH:20]=[CH:21][CH:22]=3)=[N:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(/C=C/OC)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCc1c(CC=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 70 °C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
To a solution of 2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-5-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3,4-thiadiazole (D14) (100 mg) in tetrahydrofuran (THF) (15 mL) stirred under nitrogen at room temperature was added 2M HCl/water (0.3 mL). The reaction mixture was stirred at 70° C. for 4 h. The reaction mixture was concentrated to afford the crude product [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]acetaldehyde (D15) (97 mg). MS (ES): C21H21ClN2O2S requires 400. found 401.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[C:26]1([CH2:32][CH2:33][NH2:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1C=CC=CC=1.CCCCCC>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:19](=[O:20])[C:18]1[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=1[C:16]([NH:34][CH2:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: NCCc1ccccc1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: O=C(NCCc1ccccc1)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), β-phenylethylamine (0.333 g, 2.75 mmol), and benzene (8 ml)/hexane (12 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred for 30 minutes at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-phenylethyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.840 g, 62.9% yield).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.Cl[C:36]1[N:41]=[CH:40][CH:39]=[CH:38][N:37]=1.C(N(CC)CC)C>>[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:20][CH2:21][N:22]([C:36]5[N:41]=[CH:40][CH:39]=[CH:38][N:37]=5)[CH2:23][CH2:24]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1
Reactant: Clc1ncccn1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(c2ncccn2)CC1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 63.9 %

Procedure:
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) in N,N-dimethylformade (2 mL) was added 2-chloropyrimidine (8.6 mg, 0.075 mmol) and triethylamine (21 μL, 0.15 mmol). The resulting mixture was stirred at 80° C. for 2.5 hours. After evaporation of the solvent, the crude product was directly purified by flash chromatography on silical gel, eluting with a gradient of 0-10% triethylamine in methanol to afford 2-methyl-1-{8-[2-(4-phenyl-1-pyrimidin-2-ylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole as amorphous solid (16.2 mg, 65%). 1H NMR (300 MHz, CDCl3) δ 8.30 (d, J=6.0 Hz, 2H), 7.67 (dd, J=2.6, 7.0 Hz, 1H), 7.39-7.37 (m, 4H), 7.35-7.22 (m, 3H), 7.21-7.14 (m, 2H), 6.45 (t, J=4.7 Hz, 1H), 4.64 (m, 1H), 4.17-4.09 (m, 2H), 3.61-3.52 (m, 2H), 3.28-3.25 (m, 2H), 2.59 (s, 3H), 2.44-2.33 (m, 2H), 2.29-2.22 (m, 2H), 1.97-1.85 (m, 10H), 1.62 (d, J=7.7 Hz, 2H). HRMS m/z (M+H)+ calcd: 507.3236; obsd: 507.3248.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]1)[CH:7]=[CH:6]2.C(N(CC)CC)C.[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>O1CCCC1>[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([NH:13][C@H:14]2[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]2)[CH:7]=[CH:6]3)=[O:36])=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a cooled (ice bath) and stirred solution of (6-aminomethyl-quinolin-2-yl)-(R)-indan-1-yl-amine (130 mg, 0.45 mmol) and triethyl amine (50 mg, 0.49 mmol) in tetrahydrofurane (2.6 ml) was added 4-fluorobenzoyl chloride (78 mg, 0.49 mmol) and the mixture was allowed to stir at room temperature for 1 h. Evaporation and purification by flash chromatography (ethyl acetate/heptane) on silica gel yielded the title compound as white foam (150 mg, 81%). MS: m/e=412.2 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=O)C(F)(F)F)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21].O>CN(C)C=O>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[CH:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccc(NC(=O)C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cccc(C(=O)C=CN(C)C)c1
Temperature: 150 °C
Yield: 55 %

Procedure:
8.37 g (36.21 mmol) de N-(3-acetylphenyl)-2,2,2-trifluoro-acetamide were dissolved in 80 ml of N,N-dimethyl formamide. To the resultant solution 24.23 ml (181.02 mmol) of N,N-dimethylformamide dimethyl acetal were added and heated at 150° C. for 2 h. The solvent was removed by reduced pressure distillation to yield an oil which was treated with 50 ml of water and extract with 3×100 ml of dichloromethane. The organic layers were washed with 2×200 ml of a saturated solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness by reduced pressure distillation. A solid was obtained, which precipitated from a mixture of ethanol-ethyl ether to give 4.1 g (yield=55%) of 3-(dimethylamino)-1-[3-(methylamino)phenyl]prop-2-en-1-one.
Reaction SMILES: [CH:1]1[C:5]2[C:6](Cl)=[N:7][CH:8]=[N:9][C:4]=2[NH:3][CH:2]=1.[NH2:11][C:12]1[CH:16]=[CH:15][O:14][C:13]=1[C:17]([O:19][CH3:20])=[O:18].Cl>C(O)(C)(C)C.CO>[CH3:20][O:19][C:17]([C:13]1[O:14][CH:15]=[CH:16][C:12]=1[NH:11][C:6]1[C:5]2[CH:1]=[CH:2][NH:3][C:4]=2[N:9]=[CH:8][N:7]=1)=[O:18]
Reactant: Clc1ncnc2[nH]ccc12
Reactant: COC(=O)c1occc1N
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CO
Product: COC(=O)c1occc1Nc1ncnc2[nH]ccc12
Yield: 17.9 %

Procedure:
A suspension of 6-chloro-7-deazapurine (100.00 mg; 0.65 mmol), methyl 3-amino-2-furoate (138 mg; 0.98 mmol) and concentrated hydrochloric acid (55 μL; 0.65 mmol) in tert-butanol (2 mL) was microwaved at 75° C. for 3 h. The reaction mixture was diluted with methanol (2 mL) and purified by chromatography on a SP1 Biotage system, using dichloromethane and methanol as eluents to afford 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-furan-2-carboxylic acid methyl ester (30 mg, 18%) as a white solid. (HPLC: 99%, RT: 5.43 min). 1H NMR (DMSO-d6) 12.03 (br s, 1H), 8.99 (br s, 1H), 8.40 (s, 1H), 7.90 (d, J=2.2 Hz, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.38 (dd, J=3.3, 2.2 Hz, 1H), 6.60 (dd, J=3.3, 1.8 Hz, 1H), 3.90 (s, 3H); MS (m/z) 259 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[C:9]([C:18]#[N:19])=[N:10][CH:11]=[C:12]([NH:14][CH2:15][CH2:16][OH:17])[N:13]=1.Cl.[CH2:21]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][CH2:24][NH:23][CH2:22]1>CN(C)C=O>[OH:17][CH2:16][CH2:15][NH:14][C:12]1[N:13]=[C:8]([N:23]2[CH2:22][CH2:21][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][CH2:24]2)[C:9]([C:18]#[N:19])=[N:10][CH:11]=1
Reactant: N#Cc1ncc(NCCO)nc1Br
Reactant: c1ccc2c(c1)CCNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ncc(NCCO)nc1N1CCc2ccccc2CC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
0.415 g (3.00 mmol) of potassium carbonate were added slowly at room temperature to a solution of 0.243 g (1.0 mmol) of the 3-bromo-5-(2-hydroxy-ethylamino)-pyrazine-2-carbonitrile and 0.220 g (1.2 mmol) of the 2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (J. Heterocycl. Chem. 1971, 8(5), 779-83) in 10.0 ml of N,N-dimethyl-formamide. The reaction mixture was stirred at room temperature for 64 hours and at 80° C. for 5 hours. It was subsequently poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 9:1 to 0:10 v/v gradient of hexane and ethylacetate as the eluent giving 0.308 g (1.0 mmol, 100% of theory) of the 5-(2-hydroxy-ethylamino)-3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-pyrazine-2-carbonitrile as light yellow amorphous solid; MS: 310 (M+H)+.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Cl[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:2]([C:3]1[CH:11]=[CH:10][C:8]([O:9][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=2)=[C:5]([O:6][CH3:7])[CH:4]=1)=[O:1]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1Oc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
Take up vanillin (1.0 g, 6.57 mmol), 6-chloronicotinonitrile (0.911 g, 6.57 mmol) and K2CO3 (1.36 g, 9.86 mmol) in DMF (16.4 mL). Stir at room temperature overnight, then heat at 100° C. for 3 hours. Cool the reaction mixture to room temperature before quenching with water (75 mL). Extract with dichloromethane (2×150 mL). Wash the organic layer with brine (1×75 mL), dry over MgSO4, filter and concentrate to give the title compound (1.65 g, 98.8%): TOF MS ES+ 255.1 (M+H)+, HRMS calcd for C14H11N2O3 255.0770 (M+H)+, found 255.0776, time 0.38 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=12.2 min, 100% purity.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[CH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].B1C2CCCC1CCC2.[OH-:27].[Na+].OO>C1COCC1.O>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][OH:27])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: C=C1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CC(CO)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1g, 4.149 mmol) in THF (25 ml), 0.5 M solution of 9-BBN in THF (9.8 ml, 4.979 mmol) was added at 0° C. and stirred for 2 hrs at room temperature. The reaction mixture was cooled to 0° C., and then 2N NaOH (2.43 ml, 4.979 mmol) and 30% H2O2 (1.6 ml, 14.93 mmol) were added. The reaction mixture was stirred at room temperature for 4 hr and later it was poured into water. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, filtered and concentrated under vacuum. Purification by column chromatography offered 4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a yellow oil (6 g, 56%).