Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][SH:8])[NH2:6].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[C:11]1([CH:10]2[NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:9])[CH2:7][S:8]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)[C@@H](N)CS
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CSC(c2ccccc2)N1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87.3 %

Procedure:
To a suspension of L-cysteine methyl ester hydrochloride (1.717 g, 10 mmol) in tetrahydrofuran (5.0 mL) at room temperature under nitrogen was added benzaldehyde (1.02 mL, 10 mmol) followed by triethylamine (4.2 mL, 30 mmol). After stirring at room temperature for 3.5 hrs, the resulting mixture was filtered through a pad of silica gel eluting with EtOAc. Evaporation of the filtrate gave the title compound (1.95 g, 88%) as a colorless oil. TLC(EtOAc-hexane; 1:5) Rf=0.22.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([OH:22])[CH:15]=[CH:16][C:17]=2Br)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:24]([N:26](C)C)=O>CCOC(C)=O.O.[C-]#N.[Zn+2].[C-]#N.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].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([OH:22])[CH:15]=[CH:16][C:17]=2[C:24]#[N:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)N(C)C
Reactant: O=C(OCc1ccccc1)N1CCc2c(Br)ccc(O)c2C1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(O)c2c1CCN(C(=O)OCc1ccccc1)C2
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-8-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (123 mg, 0.31 mmol, 1.0 eq.) in DMAC (0.62 mL), zinc cyanide (18 mg, 0.16 mmol, 0.5 eq.), tris(dibenzylideneacetone)dipalladium(0) (6.2 mg, 7 μmol, 0.02 eq.), 1,1′-bis-(diphenylphosphino)-ferrocene (4.7 mg, 8 μmol, 0.03 eq.) and poly(methylhydrosiloxane) (6 μL) were added. The resulting mixture was stirred at 150° C. under microwave irradiation for 30 min. The reaction mixture was diluted with AcOEt and water was added. The layers were separated and the org. layer was dried over MgSO4, filtered over celite, and concentrated in vacuo. The residue was purified by flashmaster (column: 10 g, flow: 15 mL/min, 25 fractions of 15 mL, Heptane+5% AcOEt to Heptane+40% AcOEt) to yield the title compound as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:27][CH3:28])=[CH:5][C:6]2[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:16])[CH2:14]3)[N:9]=[C:8]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)[C:7]=2[CH:26]=1.Cl.[OH-].[Na+]>C(O)C.O.[Fe]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:8]2[C:7]3[CH:26]=[C:3]([O:2][CH3:1])[C:4]([O:27][CH3:28])=[CH:5][C:6]=3[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:16])[CH2:14]3)[N:9]=2)=[CH:18][CH:19]=1
Reactant: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(N)cc1

Procedure:
2,7 g of iron turnings are added to a hot solution of 2.0 g of cis-1,2,3,4,4a,10b-hexahydro-8,9-dimethoxy-2-methyl-6-(4-nitrophenyl)-benzo[c][1,6]naphthyridine in 40 cc of ethanol and 13 cc of water. A mixture of 13 cc of ethanol, 3 cc of water and 0.7 cc of 2 N hydrochloric acid is added dropwise within 40 minutes while heating, and the reaction mixture is boiled under reflux for a further 3 hours. 1 cc of a 2 N caustic soda solution is then added, filtration is effected and the filtrate is concentrated by evaporation in a vacuum. The residue is dissolved in chloroform, the solution is dried over sodium sulphate, filtered and concentrated by evaporation in a vacuum. The residue is crystallized from ethyl acetate, whereby yellowish prisms having a M.P. of 168°-170°, are obtained.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:17]O>>[I:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: Cc1ccc(I)c(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)ccc1I
Temperature: 25 °C

Procedure:
A stirred solution of 2-iodo-5-methylbenzoic acid (17.3 g, 66.0 mmol) and concentrated H2SO4 (3 mL) in MeOH (200 mL) was heated at reflux for 18 h. After this time, the reaction mixture was cooled to rt, concentrated to one third volume, diluted with EtOAc (300 mL), washed with saturated NaHCO3 (2×200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was dried under high vacuum to afford methyl 2-iodo-5-methylbenzoate as a colorless oil (18.2 g, quant.). 1H NMR (300 MHz, CDCl3) δ 7.84 (d, J=8.1 Hz, 1H), 7.62 (d, J=1.9 Hz, 1H), 6.99-6.96 (m, 1H), 3.92 (s, 3H), 2.33 (s, 3H). A stirred suspension of methyl 2-iodo-5-methylbenzoate (18.2 g, 66.0 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15.2 g, 73.3 mmol), K2CO3 (27.5 g, 200 mmol), and Pd(PPh3)4 (11.5 g, 9.99 mmol) in 1,4-dioxane (150 mL) and H2O (50 mL) was heated at 100° C. for 18 h under nitrogen. After this time, the reaction mixture was cooled to rt, diluted with EtOAc (400 mL), washed with saturated NaHCO3 (2×300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 0% to 80% EtOAc/hexanes to afford methyl 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoate as a colorless oil (13.3 g, 87%). 1H NMR (300 MHz, CDCl3) δ 7.55-7.25 (m, 5H), 3.94 (s, 3H), 3.80 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[C:28]([O:29][CH2:30][CH2:31][O:32]C3CCCCO3)=[CH:27][CH:26]=[CH:25][C:24]=2[F:39])[C:19]([Cl:40])=[CH:18][N:17]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:40][C:19]1[C:20]([NH:22][C:23]2[C:28]([O:29][CH2:30][CH2:31][OH:32])=[CH:27][CH:26]=[CH:25][C:24]=2[F:39])=[N:21][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=3[CH:14]=2)=[N:17][CH:18]=1
Reactant: CN1C(=O)OCCc2cc(N)ccc21
Reactant: Fc1cccc(OCCOC2CCCCO2)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CN1C(=O)OCCc2cc(Nc3ncc(Cl)c(Nc4c(F)cccc4OCCO)n3)ccc21
Yield: 10.3 %

Procedure:
2-Amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (0.0435 g, 0.000226 mol), (2,5-Dichloro-pyrimidin-4-yl)-{2-fluoro-6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-amine (0.091 g, 0.00023 mol), 10-Camphorsulfonic acid (0.0788 g, 0.000339 mol), and Isopropyl alcohol (2 mL) were added to a 10 mL microwave tube and microwaved at 120° C. for 30 minutes. The reaction mixture was then purified by HPLC, lyophilized and neutralized with MP-carbonate to afford 2-{5-Chloro-4-[2-fluoro-6-(2-hydroxy-ethoxy)-phenylamino]-pyrimidin-2-ylamino}-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one as a yellow solid (11 mg, 10%). MP=199-201° C.; LCMS: 474 (M+H); HNMR (CDCl3): 8.07 (s, 1H), 7.36 (m, 2H), 7.10 (m, 1H), 6.84 (m, 4H), 6.64 (s, 1H), 4.42 (t, J=7.04 Hz, 2H), 4.13 (m, 2H), 3.87 (m, 2H), 3.33 (s, 3H), 2.78 (t, J=6.32 Hz, 2H).
Reaction SMILES: [NH:1]1[C:5](B(O)O)=[CH:4][CH:3]=[N:2]1.Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([N:21]([CH3:32])[CH:22]3[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]3)=[N:18][N:17]=2)=[C:12]([O:33][CH3:34])[CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:34][O:33][C:12]1[CH:11]=[C:10]([C:5]2[NH:1][N:2]=[CH:3][CH:4]=2)[CH:15]=[CH:14][C:13]=1[C:16]1[S:20][C:19]([N:21]([CH3:32])[CH:22]2[CH2:27][C:26]([CH3:28])([CH3:29])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)=[N:18][N:17]=1
Reactant: COc1cc(Cl)ccc1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Reactant: OB(O)c1ccn[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2ccn[nH]2)ccc1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Temperature: 120 °C
Yield: 23.1 %

Procedure:
To a stirred suspension of (1H-pyrazol-5-yl)boronic acid (14 mg, 0.139 mmol) and 5-(4-chloro-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (50 mg, 0.127 mmol) in dioxane (1 mL) was added Pd(PPh3)4 (7 mg, 0.006 mmol) followed by a solution of Na2CO3 (40 mg, 0.380 mmol) in water (0.25 mL). The reaction mixture was purged with nitrogen, sealed, and heated at 120° C. under microwave irradiation for 30 minutes, then again at 145° C. Additional catalyst and boronate were added and the mixture was heated for an additional 30 minutes under microwave irradiation at an increased temperature of 160° C. The reaction mixture was diluted with DCM (20 mL), washed with saturated NaHCO3(aq) (10 mL) and the organic phase was separated and concentrated in vacuo to afford the crude product as an oily residue. The crude material was purified by mass directed preparative HPLC under basic conditions (NH4OH midified) to afford the title compound as a white solid (12.5 mg, 23% yield). LC-MS: Rt 0.81 min; MS m/z 427.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.99 (br. s., 1H), 8.12 (d, J=8.08 Hz, 1H), 7.82 (br. s., 1H), 7.60 (s, 1H), 7.54 (d, J=6.06 Hz, 1H), 6.84 (d, J=2.02 Hz, 1H), 4.31-4.41 (m, 1H), 4.01 (s, 3H), 2.99 (s, 3H), 1.61 (dd, J=12.13, 3.54 Hz, 2H), 1.42 (t, J=12.13 Hz, 2H), 1.27 (br. s., 1H), 1.22 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2].[H-].[Na+].Br[CH2:16][C:17]1[CH:34]=[CH:33][C:20]2/[C:21](=[CH:30]/[C:31]#[N:32])/[C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[CH2:24][CH2:25][C:19]=2[CH:18]=1.O>CN(C=O)C>[CH2:1]([C:3]1[N:4]([CH2:16][C:17]2[CH:34]=[CH:33][C:20]3/[C:21](=[CH:30]/[C:31]#[N:32])/[C:22]4[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=4[CH2:24][CH2:25][C:19]=3[CH:18]=2)[C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: N#C/C=C1\c2ccccc2CCc2cc(CBr)ccc21
Reactant: CCc1[nH]c2ccccc2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(C)c2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
[step 1] 2-Ethyl-3-methylindole (196 mg, 1.23 mmol) was dissolved in DMF (3.2 mL), sodium hydride (60%; 49 mg, 1.23 mmol) was added, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added (E)-2-(2-bromomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetonitrile (200 mg, 0.617 mmol) obtained in Reference Example B1, and the mixture was stirred at room temperature for 2 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give (E)-[2-(2-ethyl-3-methylindol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (117 mg, 47%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH:35]=O)[CH3:30]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:32]([O:31][CH2:29][CH3:30])[CH:33]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCOc1cc(C=O)ccc1OC
Product: CCOc1cc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)ccc1OC

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 3-ethoxy-4-methoxy benzaldehyde. MS (ESI) m/z 591.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[CH:11][C:12]([F:16])=[C:13]([OH:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[N:21][CH:20]=1>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[CH:11][C:12]([F:16])=[C:13]([CH:14]=1)[O:15][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[N:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCOc1cc2nncc(Cl)c2cc1OC
Reactant: Cc1cc(F)c(O)cc1OCc1ccccc1
Solvent: c1ccncc1
Product: COCCOc1cc2nncc(Oc3cc(OCc4ccccc4)c(C)cc3F)c2cc1OC
Yield: 53.2 %

Procedure:
The starting material, 4-(5-benzyloxy-2-fluoro-4-methylphenoxy)-6-methoxy-7-(2-methoxyethoxy)cinnoline was obtained by heating a solution of 5-benzyloxy-2-fluoro-4-methylphenol (314 mg, 1.3 mmol) and 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (280 mg, 1 mmol), (prepared as described for the starting material in Example 2), in pyridine (6 ml), at reflux for 15 hours. After evaporation of the solvent, the residue was partitioned between ethyl acetate and water adjusted to pH7. The organic layer was separated, washed with water and then brine, dried (MgSO4) and the solvent evaporated. The residue was purified by flash chromatography using methylene chloride/ether (4/6 followed by 3/7) as eluent to give 4-(5-benzyloxy-2-fluoro-4-methylphenoxy)-6-methoxy-7-(2-methoxyethoxy)cinnoline as a white solid (247 mg, 53%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:10]([CH3:30])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:31]1([C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH:35]=[CH:34][N:33]=[CH:32]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>O1CCOCC1>[N:31]1([C:36]2[CH:42]=[CH:41][C:39]([NH:40][C:2]3[CH:3]=[C:4]([C:8]4[N:16]5[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]6[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=6)=[N:15]5)=[C:10]([CH3:30])[N:9]=4)[CH:5]=[CH:6][CH:7]=3)=[CH:38][CH:37]=2)[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Br)c4)n3n2)cc(OC)c1OC
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Nc5ccc(-n6ccnc6)cc5)c4)n3n2)cc(OC)c1OC
Yield: 27 %

Procedure:
In a similar manner as described in Example 63, a mixture of 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (40 mg, 0.085 mmol), 4-(1H-imidazol-1-yl)aniline (13.5 mg, 0.085 mmol), 2-(dit-butylphosphino)biphenyl (15.2 mg, 0.051 mmol), Tris(dibenzylidineacetone)-dipalladium (0) (15.6 mg, 0.017 mmol) and sodium t-butoxide (13.1 mg, 0.136 mmol) in 1,4-dioxane (1.5 mL) gave 7-(3-{[4-(1H-imidazol-1-yl)phenyl]amino}phenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)-imidazo[5,1-f][1,2,4]triazin-2-amine (0.0126 g) as a yellow solid. 1H NMR (CDCl3): δ8.80 (s, 1H), 8.24 (s, 1H), 8.05 (d, J=7.3 Hz, 1H), 7.78 (s, 1H), 7.40-7.35 (m, 1H), 7.26-7.19 (m, 7H), 6.97-6.93 (s, 3H), 6.21 (s, 1H), 3.82 (s, 9H), 2.60 (s, 3H) MS m/z 549 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(OCCO)C>>[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH:19][C:2]1[C:3]2[S:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1cccc(Br)c1
Reactant: Clc1ncnc2c1sc1ncccc12
Solvent: CCOCCO
Product: Brc1cccc(Nc2ncnc3c2sc2ncccc23)c1
Reaction time: 3 h
Yield: 39.4 %

Procedure:
A mixture of 4-chloropyrido[3′, 2′; 4,5]thieno[3,2-d]pyrimidine (72 mg, 0.32 mmol) (see previous experimental), 3-bromoaniline (0.04 mL, 0.37 mmol) and 2-ethoxyethanol (5 mL) is heated under N2 with stirring at 135 C. for 3 h. Upon cooling a solid precipitates. The solid is collected by filtration, washed with acetone and dried in a vacuum oven at ˜80 C. to give 4-(3-bromoanilino)pyrido[3′, 2′; 4,5]thieno[3,2-d]pyrimidine (45 mg, 39.4%). 1H NMR (DMSO) δ9.96 (1H, s), 8.88 (1H, dd, J=4.6, 1.7 Hz), 8.85 (1H, s), 8.72 (1H, dd, J=8.0, 1.7 Hz), 8.20 (1H, t, J=2.0 Hz), 7.84 (1H, ddd, J=8.0, 2.0, 1.3 Hz), 7.69 (1H, dd, J=8.0, 4.7 Hz), 7.39-7.31 (2H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[I:11]I.Cl>[NH4+].[OH-].O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(O)c1
Reactant: II
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(I)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
3-Hydroxybenzoic acid (13.8 g, 100 mmol) is dissolved in concentrated NH4OH (200 mL) using an overhead stirrer and is treated slowly drop-wise with a solution of iodine (23.4 g, 92 mmol) and KI (18.26 g, 110 mmol) in water (100 mL). The solution is stirred for 1 h at RT and then treated rapidly drop-wise with concentrated HCl (180 mL). The solid is collected via filtration, rinsed with water and dried overnight by pulling air through the solid to afford 13.1 g (54%) of 3-hydroxy-4-iodobenzoic acid as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ 7.13, 7.43, 7.80, 10.71, 12.98 ppm.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([NH:11][NH:12][C:13]([O:15][CH3:16])=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].CO>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][NH:12][C:13]([O:15][CH3:16])=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)NNC(=O)C=Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)NNC(=O)CCc1ccccc1
Yield: 98.1 %

Procedure:
22.0 g (0.1 mole) of methyl 3-(β-phenylacryloyl)-carbazate are dissolved in 300 ml. of methanol and the solution is hydrogenated in the presence of 0.2 g. of a palladium-charcoal catalyst. The solution is evaporated. Thus 21.8 g of the white crystalline desired compound are obtained. Yield: 98.2%. M.p.: 118° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:17])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16])[C:5](O)=[O:6].C(N1C=CN=C1)([N:20]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:17])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16])[C:5]([NH2:20])=[O:6]
Reactant: C#CCCCOc1c(C)cc(C(=O)O)cc1C
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C#CCCCOc1c(C)cc(C(N)=O)cc1C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a solution of 4.7 g 3,5-dimethyl-4-(3-ethynylpropoxy)benzoic acid in 100 ml dry tetrahydrofuran was added 3.7 g carbonyldiimidazole and the mixture was stirred 2 hrs. at room temperature. To the latter was added 10 ml concentrated ammonium hydroxide, and the mixture was stirred for 30 min., poured onto water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated to give 4.7 g 3,5-dimethyl-4-(3-ethynylpropoxy)benzamide, m.p. 81°-84° C.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([C:23]([O:25][CH3:26])=[O:24])[CH3:22])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[N+](C1C=CC([CH2:36][C:37]([O-])=[O:38])=CC=1)([O-])=O>CN(C)C=O>[C:37]([NH:1][C@H:2]([C:11]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([C:23]([O:25][CH3:26])=[O:24])[CH3:22])=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)(=[O:38])[CH3:36]
Reactant: O=C([O-])Cc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(C)=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.73 g (2.0 mmol) of methyl L-tyrosyl-L-valyl-L-alaninate (Example 1, Step A3) is dissolved in 5 ml of dimethylformamide, then 0.4 g (2.2 mmol) of p-nitro-phenyl-acetate is added. The reaction mixture is stirred at room temperature overnight then is evaporated at a pressure of 2.0-2.5 kPa. The residue is dissolved in 15 ml of ethyl acetate, the solution is washed with 3×5 ml of water, 5 ml of 1 M KHSO4 and 3×5 ml of water, then dried over anhydrous sodium sulfate and evaporated at a pressure of 2.0-2.5 kPa. The residue is rubbed with diethyl ether, filtered, washed with diethyl ether and dried in a vacuum desiccator.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:34]1([C:40](=[O:42])[CH3:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[C:40]([N:34]1[CH2:39][CH2:38][N:37]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:36][CH2:35]1)(=[O:42])[CH3:41]
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 14 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1 equivalent of 1-(piperazin-1-yl)ethanone as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7](=[O:10])[CH2:8][CH3:9])[CH2:3]1.[H-].[Na+].[CH2:13]([N:20]1[CH2:30][CH2:29][C:23]2[N:24]=[CH:25][N:26]=[C:27](Cl)[C:22]=2[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([N:20]1[CH2:30][CH2:29][C:23]2[N:24]=[CH:25][N:26]=[C:27]([O:1][C@H:2]3[CH2:6][CH2:5][N:4]([C:7](=[O:10])[CH2:8][CH3:9])[CH2:3]3)[C:22]=2[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Reactant: CCC(=O)N1CC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=O)N1CC[C@H](Oc2ncnc3c2CN(Cc2ccccc2)CC3)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
To a solution of 1-((S)-3-hydroxy-pyrrolidin-1-yl)-propan-1-one (intermediate 2) (358 mg, 2.503 mmol) in 5 mL of THF was added NaH (108 mg, 2.70 mmol) under Ar. The mixture was stirred at rt for 15 min, then 6-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (500 mg, 1.925 mmol) and 5 mL of THF were added and stirred at rt for 5 h. The reaction was quenched with H2O and extracted with ethylacetate, the org. layer was washed with brine, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by flash-chromatography using Isco Companion system (12 g of SiO2) CH2Cl2/MeOH (95/5). The collected fractions were combined, evaporated and dried over high vacuum to give 1-[(S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-propan-1-one. (m=560 mg, yield 78%) MS: [M+H]+=367.6, Rt(7)=0.64 min.