Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[CH2:11]([C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH:19]=1)[CH2:12][CH2:13][CH3:14]>C(Cl)Cl>[CH2:11]([C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[C:19]=1[CH:4]=[O:5])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1cc2ccccc2o1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCc1oc2ccccc2c1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
To a solution of DMF (59 g, 0.805 mol) in anhydrous DCM (300 mL) was added slowly at 0° C. under N2 atmosphere phosphorous oxy-chloride (123 g, 0.84 mol). The mixture was stirred at rt for 2 h. To this was added slowly 2-butyl-1-benzofuran (35 g, 0.21 mol) in anhydrous DCM (100 mL). The reaction mixture was slowly heated to 60° C. for 72 h, cooled to rt and poured into ice and extracted with EtOAc. The organic layer was washed with water, brine and dried over MgSO4. The solvent was removed under vacuum and the crude product purified by column chromatography over silica gel (PetEther/EtOAc) to give 2-butyl-1-benzofuran-3-carbaldehyde (30 g, 74%) as a light brown liquid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[C:13](=[O:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Br:23]N1C(=O)CCC1=O>CN(C=O)C.CCOCC>[Br:23][C:7]1[CH:6]=[C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:4]=[C:3]([C:13](=[O:22])[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:2]=1[OH:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)CCc1ccc(O)c(C(=O)CCc2ccccc2)c1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(O)CCc1cc(Br)c(O)c(C(=O)CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The carboxylic acid 209, for example 3-[4-Hydroxy-3-(3-phenyl-propionyl)-phenyl]-propionic acid, (1.04 gm, 3.4 g mmol) was dissolved in DMF (7 mL) and N-bromosuccinimide (0.65 g, 3.66 mmol) was added to the solution. The mixture was stirred at ambient temperature for 2.5 h, diluted with ether and the organic layer was separated and washed with water and brine and then filtered through a pad of magnesium sulfate and concentrated. The residue was purified by flash chromatography (3.5:1.5:0.1 of hexane:ethyl acetate:acetic acid) to give 0.5 g of 3-[3-bromo-4-hydroxy-5-(3-phenyl-propionyl)-phenyl]-propionic acid 210 as a yellow-brown oil.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[CH:27]=[N:28][NH:29][CH:30]=1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:28]3[CH:27]=[C:26]([CH3:25])[CH:30]=[N:29]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: Cc1cn[nH]c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: Cc1cnn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)c1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (371 mg, 1.0 mmol), 4-methyl-1H-pyrazole (164 mg, 2.0 mmol) and DMAP (366 mg, 3.0 mmol) in MeCN (10 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 165 mg (40% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.41-1.58 (m, 4 H), 1.61 (s, 9 H), 2.05 (s, 3 H), 2.22-2.47 (m, 1 H), 3.30-3.40 (m, 2 H), 3.91 (m, 2 H), 4.43 (d, J=7.62 Hz, 2 H), 7.60 (s, 1 H), 7.91 (d, J=8.2 Hz, 1 H), 7.95 (dd, J=8.8, 1.8 Hz, 1H), 8.05-8.14 (m, 1 H), 8.28 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=416.8.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[C:14]([CH3:32])=[C:13]([CH3:33])[N:12]=1>COCCOCCOC>[CH3:33][C:13]1[C:14]([CH3:32])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOCCCc2nccs2)c1C
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCOCCCc2nccs2)c1C
Temperature: 110 °C
Yield: 73.1 %

Procedure:
The method described in Example 80, Part E was used with the following exceptions. A solution of phenol (2.11 g, 22.4 mmol) in diglyme (5 mL) was added to the sodium hydride dispersion (0.87 g, 22 mmol) in diglyme (10 mL). A solution of (2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}amine (4.6 g, 15 mmol) in diglyme (25 mL) was added, and the addition flask was rinsed with additional diglyme (2×5 mL), which was added to the reaction flask. The resulting amber solution was heated at 110° C. for 3.25 hours and then allowed to cool to room temperature. The volatiles were removed under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL). The solution was washed with saturated aqueous ammonium chloride (1×50 mL), 1 N potassium hydroxide (2×50 mL), and brine (2×50 mL), and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide an oil. The oil was dried for three days under high vacuum at room temperature to provide 4.7 g of (2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}amine as an oil.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:20][O:21][C:22]1[C:23]([CH3:30])=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=[O:26]>C1COCC1>[OH:26][CH:25]([C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[C:23]=1[CH3:30])[CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C:13]1=[O:19]
Reactant: COc1cccc(C=O)c1C
Reactant: O=C1CCCCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cccc(C(O)C2CCCCC2=O)c1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
To a solution of diisopropylamine (1.44 ml) in THF (8 ml) was added n-BuLi (1.56M solution in hexane, 70 ml) at −60° C. The mixture was warmed to 0° C., stirred for 10 minutes, and recooled to −60° C. To the mixture was added cyclohexanone (0.98 g) in THF (5 ml). After stirring for 1 hour, 3-methoxy-2-methylbenzaldehyde (1.5 g) was added and the mixture was stirred for 1.5 hours at the same temperature. The reaction mixture was quenched with saturated NH4Cl solution, warmed to room temperature, extracted with EtOAc. The organic layer was washed with water and brine, dried over magnesium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 4:1 to 2:1) to give 2-[hydroxy-(3-methoxy-2-methylphenyl)methyl]cyclohexanone (1.86 g) as an oil.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[C:12]([CH3:14])[N:13]=[C:9]2[N:8]([CH:15]2[CH2:24][CH2:23][C:18]3(OCC[O:19]3)[CH2:17][CH2:16]2)[C:7](=[O:25])[C:6]=1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:29][CH:28]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCCC1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[C:12]([CH3:14])[N:13]=[C:9]2[N:8]([C@H:15]2[CH2:24][CH2:23][C@H:18]([OH:19])[CH2:17][CH2:16]2)[C:7](=[O:25])[C:6]=1[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:31][CH:32]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(C)nn12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 4′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (6.4 g), 3N hydrochloric acid (40 mL) and tetrahydrofuran (40 mL) was stirred at 80° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (30 mL) and methanol (30 mL), sodium borohydride (0.67 g) was added, and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (4.9 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(P1(N(C)CCCN1)=NC(C)(C)C)CC.[CH2:30]([N:37]1[CH2:41][CH2:40][CH:39](OS(C)(=O)=O)[CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(#N)C>[CH2:30]([N:37]1[CH2:41][CH2:40][C@H:39]([O:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([NH2:1])=[N:3][CH:4]=[CH:5]3)[CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1nccc2cc(O)ccc12
Reactant: CS(=O)(=O)OC1CCN(Cc2ccccc2)C1
Agent: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Solvent: CC#N
Product: Nc1nccc2cc(O[C@H]3CCN(Cc4ccccc4)C3)ccc12
Temperature: 110 °C
Reaction time: 60 h
Yield: 40.1 %

Procedure:
1-Amino-6-hydroxyisoquinoline (50 mg, 0.312 mmol), prepared as described in WO 00/24718 (Akzo Nobel N.V.), and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (284 mg, ˜2.2 mmol.g−1, ˜0.624 mmol) were stirred at ambient temperature in acetonitrile (4 ml) for 15 min. (R) Methanesulfonic acid 1-benzylpyrrolidin-3yl ester (0.312 mmol) was added and the mixture heated to 110° C. and stirred for 60 h. The mixture was filtered and the precipitate washed with acetonitrile. The filtrate was concentrated and then purified by prep-HPLC to give (S)-6-(1-Benzylpyrrolidin-3-yloxy)-isoquinolin-1-ylamine (40 mg),
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6](=O)[CH2:7][CH3:8])[CH2:2]1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>C(OCC)(=O)C>[CH3:8][C:7]1[N:12]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:6]=1[CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1
Reactant: CCC(=O)C1CCOC1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: CCOC(C)=O
Product: Cc1c(C2CCOC2)nc2ccc([N+](=O)[O-])cn12

Procedure:
Operations similar to Production Example 1-(1) were conducted using 1-tetrahydro-3-furanyl-1-propanone in place of 3-methyl-2-butanone, and successively those of Production Example 1-(2) were conducted using 2-amino-5-nitropyridine. The resulting solid was suspended in ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to provide the title compound as yellow crystals.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[N:3]=1.[CH3:21][NH2:22]>C1COCC1.O>[I:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][NH:12][C:4]1[N:3]=[C:2]([NH:22][CH3:21])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH3:11]
Reactant: Cn1cnc2c(NCc3cccc(I)c3)nc(Cl)nc21
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNc1nc(NCc2cccc(I)c2)c2ncn(C)c2n1
Temperature: 85 °C
Reaction time: 14 h
Yield: 89 %

Procedure:
A mixture of compound 6 (25 mg, 0.06 mmol) and 2M methylamine in THF (1 mL) and 40% methylamine in water (1 mL) was stirred for 14 h at 85° C. After removal of volatiles in vacuo, the residue was triturated with methanol-water, and the solid that formed was collected by suction filtration, washed with water (10 mL), and dried to give compound 11 (22 mg, 89.0%). 1H NMR (DMSO-d6) δ 2.76 (d, J=4.6 Hz, 3 H, NHCH3), 3.55 (s, 3 H, 9-CH3), 4.59 (br s, 2 H, CH2), 6.28 (br d, J=4.3 Hz, 1 H, exchangeable with D2O, NHCH3), 7.10 (pseudo t, J=7.9 and 7.6 Hz, 1 H, H-16), 7.38 (d, J=7.6 Hz, 1 H, H-17), 7.57 (d, J=7.6 Hz, 1 H, H-15), 7.67 (s, 1 H, H-13), 7.35 (s, 1 H, H-8), 7.83 (br s, 1 H, exchangeable with D2O, NH).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:20](=[O:24])[CH:21]([CH3:23])[CH3:22]>C1COCC1>[OH:24][CH:20]([CH:21]([CH3:23])[CH3:22])[CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccccc1
Reactant: CC(C)C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C(O)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Acetophenone (11.433 gm, 95 mmol) was added dropwise over a five minute period to a solution of lithium bis(trimethylsilyl)amide (1.0M in THF, 100 ml, 100 mmol) in THF (50 ml) kept at -78° C. After 30 minutes, isobutyraldehyde (6.87 gm, 95 mmol) was added dropwise and stirring was continued for an additional hour. The mixture was quenched with saturated NH4Cl (100 ml), warmed to room temperature, diluted with H2O and extracted 2× with Et2O. The combined Et2O extracts were washed with brine, dried (Na2SO4), filtered and stripped to yield an oil. The oil was distilled (P=1.5 mm) and the fraction boiling between 120°-124° C. was chromatographed (flash, Merck SiO2, 15% EtOAc in hexane) to give the desired 3-hydroxy-4-methyl-1-phenyl-1-pentanone as a colorless liquid (9.13 gm, 50%)
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1[CH:21]1[CH2:26][CH2:25][CH2:24][C:23](=O)[CH2:22]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1[CH:21]1[CH2:26][CH2:25][CH2:24][C:23](=[CH2:1])[CH2:22]1
Reactant: COCOc1ccc(C2CCCC(=O)C2)c(OCOC)c1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCCC(c2ccc(OCOC)cc2OCOC)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
Potassium tert-butoxide (50 mg) was added to a suspension of methyltriphenylphosphonium bromide in tetrahydrofuran (4 ml) at 0° C. After 0.5 hr, a solution of (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanone (100 mg) in tetrahydrofuran (1 ml) was added, and the mixture was allowed to warm to ambient temperature. After 16 hr, the reaction mixture was partitioned between ammonium chloride (30 ml of a saturated aqueous solution) and ethyl acetate. The aqueous layer was extracted with further ethyl acetate (2×30 ml), and the combined organic extracts were washed with brine (30 ml), dried over magnesium sulfate, and evaporated in vacuo. The crude residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 4:1 v/v) to furnish the title compound as pale yellow oil (80 mg, 81%). δH (CDCl3) 1.50 (2H, m), 1.90 (2H, m), 2.05 (1H, m), 2.16 (1H, m), 2.35 (1H, m), 2.44 (1H, m), 2.97 (1H, m), 3.44 (3H, s), 3.48 (3H, s), 4.64 (1H, s), 4.69 (1H, s), 5.13 (2H, s), 5.17 (2H, s), 6.68 (1H, m), 6.77 (1H, m), 7.12 (1H, d).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:3]=1.[Br:18]N1C(=O)CCC1=O>>[Br:18][CH2:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1sc(C)cc1-c1ccc(F)cc1
Product: COC(=O)c1sc(CBr)cc1-c1ccc(F)cc1

Procedure:
A solution of methyl 1-[5-methyl-3-(4-fluorophenyl)-thien-2-yl]methanoate (12.9 g; 0.05 mol), N-bromosuccinimide (11.02 g; 0.0619 mol) and 2-2′-azobisisobutyronitrile (0.339 g; 2.06 mmol) in Cl4 (300 ml) was reflux under argon atmosphere for 90 minutes under UV irradiation. After filtration of the precipitate, the filtrate was evaporated to dryness to give methyl 1-[5-bromomethyl-3-(4-fluorophenyl)-thien-2-yl]methanoate as a solid which was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:27]5[CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:23][C:22]=5[C:21]([C:32]5[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=5)=[N:20]4)[CH2:12][CH2:11]3)=[C:8]([C:42]([OH:44])=O)[S:7][C:6]=2[CH:45]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:79][CH2:80][CH2:81][N:82]1[CH2:87][CH2:86][O:85][CH2:84][CH2:83]1>CN(C=O)C>[N:82]1([CH2:81][CH2:80][NH:79][C:42]([C:8]2[S:7][C:6]3[CH:45]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[C:9]=2[CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:27]4[CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:23][C:22]=4[C:21]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][CH:33]=4)=[N:20]3)[CH2:14][CH2:15]2)=[O:44])[CH2:87][CH2:86][O:85][CH2:84][CH2:83]1
Reactant: NCCN1CCOCC1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCC(c3c(C(=O)O)sc4cc(F)ccc34)CC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCC(c3c(C(=O)NCCN4CCOCC4)sc4cc(F)ccc34)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
A stirred solution of 20 mg (0.03 mmol) of 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carboxylic acid in 0.3 mL of dry DMF was treated with 14 mg (0.036 mmol) of HBTU and 8 μL (0.045 mmol) of DIEA. The solution was stirred for 5 min before the addition of 20 μL (0.15 mmol) of 4-(2-aminoethyl)morpholine. The reaction was stirred at room temperature for 30 min then partitioned between EtOAc (30 mL) and saturated NaHCO3 (20 mL). The aqueous layer was further extracted with EtOAc (2×20 mL). The combined organic layers were then washed with brine, dried over Na2SO4, and concentrated. Purification by column chromatography (silica, 5-10% of (2 N NH3 in MeOH)/CH2Cl2) afforded 15 mg (65%) of a white solid. MS (electrospray), exact mass calculated for C37H44F4N6O4S2: 776.28; m/z found, 777.3 [M+H]+. 1H NMR (CDCl3, 400 MHz): 8.07 (br s, 1H), 7.73 and 7.66 (A and B of AB quartet, J=8.41 Hz, 4H), 7.50 (dd, J=8.41, 2.35 Hz, 1H), 7.14 (dt, J=8.61, 2.54 Hz, 1H), 6.64 (t, J=4.70 Hz, 1H), 4.56 (s, 2H), 4.16 (t, J=6.85 Hz, 2H), 3.80-3.67 (m, 7H), 3.53 (q, J=5.48 Hz, 2H), 3.03 (br m, 2H), 2.98 (t, J=5.67 Hz, 2H), 2.90 (s, 3H), 2.60 (t, J=5.87 Hz, 2H), 2.38 (br m, 4H), 2.12 (br m, 4H), 1.86-1.73 (br m, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[OH2:20].[OH-].[Na+]>Cl>[NH2:14][C:11]1[N:10]=[C:9]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[C:8]([C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:20])[CH:7]=2)=[CH:13][N:12]=1
Reactant: O
Reactant: Nc1ncc(-c2ccnc(F)c2)c(-c2ccco2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncc(-c2cc[nH]c(=O)c2)c(-c2ccco2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A suspension of 5-(2-fluoro-4-pyridyl)-4-(2-furyl)-2-pyrimidinylamine (3.00 g, 11.70 mmol) in concentrated hydrochloric acid (15 ml)-water (15 ml) was stirred at 100° C. for 2 hours. After cooling as it was, the reaction mixture was neutralized with a 5N aqueous sodium hydroxide solution. The resulting solid was collected by filtration, washed with water and dried at 60° C. for 22 hours, to give the title compound (2.19 g, 70%) as a pale brown solid.
Reaction SMILES: [C:1]1(=O)O[C:4](=O)[CH:3]=[CH:2]1.C1CC=CC=1.[CH2:13]1[CH:17]2C(C(O)=O)[CH:19](C(O)=O)[CH:14]1[CH:15]=[CH:16]2>O>[CH2:1]1[CH:19]2[C@@H:14]3[CH:13]=[CH:17][C@H:16]([CH:4]2[CH:3]=[CH:2]1)[CH2:15]3
Reactant: O=C1C=CC(=O)O1
Reactant: O=C(O)C1C2C=CC(C2)C1C(=O)O
Agent: C1=CCC=C1
Solvent: O
Product: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
Maleic anhydride (88.3 g, 0.90 mole) and water (150.0 g) was stirred at 20°-30° C. under nitrogen, cyclopentadiene (30.0 g, 0.45 mole) was added by dropping in 1 hour and stirred at 25° C. for 6 hours and heated to 101° C. and held for 20 hours until 92% of nadic acid was converted to NBLCO2H as detected by GC. The wet crystal was filtered out and recrystallized from water to obtain 40.3 g of NBLCO2H with a yield of 49%.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:12]=3[S:13][C:7]=2[N:6]=[CH:5]1.[N:19]1([C:25]2[C:29]3[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:28]=3[O:27][N:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C.[Br-].[Na+]>CN1CCCC1=O>[CH3:18][N:15]1[CH2:16][CH2:17][C:11]2[C:8]3[C:9](=[O:10])[N:4]([CH2:3][CH2:2][N:22]4[CH2:23][CH2:24][N:19]([C:25]5[C:29]6[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:28]=6[O:27][N:26]=5)[CH2:20][CH2:21]4)[CH:5]=[N:6][C:7]=3[S:13][C:12]=2[CH2:14]1
Reactant: Cc1ccc2onc(N3CCNCC3)c2c1
Reactant: CN1CCc2c(sc3ncn(CCCl)c(=O)c23)C1
Agent: [Br-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccc2onc(N3CCN(CCn4cnc5sc6c(c5c4=O)CCN(C)C6)CC3)c2c1
Yield: 16.9 %

Procedure:
3-(2-Chloroethyl)-7-methyl-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4(3H)-one (2.5 g, 8.81 mol; preparation: Example A3) was stirred together with 3-piperazin-1-yl-5-methyl-1,2-benzisoxazole (2.49 g, 11.45 mmol), diisopropylethylamine (15.4 ml, 88.1 mmol), sodium bromide (4.53 g, 44.05 mmol) and N-methyl-2-pyrrolidone (40 ml) at 70° C. for 4 days. After cooling, N-methyl-2-pyrrolidone and excess diisopropylethylamine were removed under high vacuum, the residue was added to water, the aqueous phase was extracted several times with ethyl acetate, and the organic phases were washed with water, dried over magnesium sulfate and concentrated in vacuo. The very impure crude product was chromatographed on silica gel (eluent: methylene chloride with slowly increasing methanol content (0-50%)). This resulted in 0.9 g of 7-methyl-3-{2-[4-(5-methyl-1,2-benzisoxazol-3-yl)piperazin-1-yl]ethyl}-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4(3H)-one (yield: 22%) being obtained as a solid product which was converted into the corresponding dihydrochloride with ethereal hydrochloric acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[F:46][C:47]([F:52])([F:51])[CH2:48][CH2:49][NH2:50]>C(#N)C>[F:46][C:47]([F:52])([F:51])[CH2:48][CH2:49][NH:50][C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][N:9]=1)=[O:13]
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: NCCC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccc(C(=O)NCCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 25 %

Procedure:
5-(methoxycarbonyl)pyridine-2-carboxylic acid (100 mg, 0.55 mmol) was dissolved in acetonitrile (1 mL). Triethylamine (0.230 mL, 1.66 mmol) and O-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (314 mg, 0.83 mmol) were added. The reaction mixture was stirred at rt for 5 min. 3,3,3-trifluoropropylamine hydrochloride (83 mg, 0.55 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo and the crude was pardoned between ethyl acetate and 1M sodium hydroxide. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude was purified by column chromatography using a gradient of ethyl acetate in heptane yielded 38 mg (25%) of the title compound as a white solid; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (t, 1 H), 9.11 (d, 1 H), 8.48 (dd, 1 H), 8.18 (d, 1 H), 3.92 (s, 3 H), 3.53-3.60 (m, 2 H), 2.54-2.66 (m, 2 H); MS (ESI) m/z 277[M+H+], m/z 275[M−H+];