Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][OH:43])[CH2:37][CH2:36]1.O1CCN(CCO)CC1>>[CH:30]1([C:26]2[N:25]=[C:24]([CH2:23][N:18]3[C:19]4[C:15](=[C:14]([NH:13][C:11]([C:8]5[N:5]6[CH:6]=[CH:7][C:2]([O:43][CH2:42][CH2:41][N:38]7[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]7)=[CH:3][C:4]6=[N:10][CH:9]=5)=[O:12])[CH:22]=[CH:21][CH:20]=4)[C:16]([CH3:33])=[N:17]3)[CH:29]=[CH:28][CH:27]=2)[CH2:32][CH2:31]1
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Reactant: CN1CCN(CCO)CC1
Agent: OCCN1CCOCC1
Product: Cc1nn(Cc2cccc(C3CC3)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)CC5)ccn34)c12
Yield: 45 %

Procedure:
Prepared according to Example 1, Step B, substituting N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide for 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and 2-(4-methylpiperazin-1-yl)ethanol for 2-morpholinoethanol, to give the final product (45%). MS (APCI), positive scan, m/z=565.3 (M+H).
Reaction SMILES: [C:1]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:21])/[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[C:11]([CH2:22][CH3:23])[C:10]([CH3:24])=[C:9]2[C:5]=1[C:6](=[O:25])[O:7][CH2:8]2)([OH:3])=[O:2].[C:26]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:21])/[CH2:16][CH2:17][C:18]([O:20][CH3:26])=[O:19])=[C:11]([CH2:22][CH3:23])[C:10]([CH3:24])=[C:9]2[C:5]=1[C:6](=[O:25])[O:7][CH2:8]2)([OH:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCc1c(C)c2c(c(C(=O)O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Solvent: CO
Product: CCc1c(C)c2c(c(C(=O)O)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2

Procedure:
A solution of 3.88 g of (E)-6-(4-carboxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid and 0.2 g of p-toluenesulfonic acid in methanol (60 ml) is stirred at room temperature for 8 hours. The solvent is evaporated under reduced pressure. The residue is dissolved in ethyl acetate, and this solution washed twice with water, once with brine, and dried over magnesium sulfate. The solvent is evaporated under reduced pressure to give methyl (E)-6-(4-carboxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:21]([N:24](CC2C=CC(OC)=CC=2OC)CC2C=CC(OC)=CC=2OC)(=[O:23])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1([F:20])[CH2:15][CH2:14][N:13]([CH:16]2[CH2:19][O:18][CH2:17]2)[CH2:12][CH2:11]1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1([F:20])[CH2:11][CH2:12][N:13]([CH:16]2[CH2:17][O:18][CH2:19]2)[CH2:14][CH2:15]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2OC)S(=O)(=O)c2ccc(OCC3(F)CCN(C4COC4)CC3)c(Cl)c2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(OCC2(F)CCN(C3COC3)CC2)c(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 517D (0.258 g) in dichloromethane (3 mL) was added trifluoroacetic acid (2 mL) dropwise. The reaction was stirred for 1 hour then quenched by the addition of saturated NaHCO3 solution (20 mL). The reaction was extracted with dichloromethane (2×50 mL), the dichloromethane layer was concentrated, ethyl acetate (20 mL) was added and the resulting solid was filtered. The organic layer was diluted to 50 ml, washed with brine (25 mL), dried over magnesium sulfate, filtered and concentrated. The resulting oil was treated with dichloromethane and concentrated, and the solid was triturated with ethyl acetate and filtered to give the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[CH3:17][NH:18][C:19](=[O:32])[C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[CH3:17][NH:18][C:19](=[O:32])[C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][C:3]3[CH:16]=[N:15][C:6]4[C:7]5[N:8]([CH:12]=[CH:13][CH:14]=5)[C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: CNC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=c1[nH]c2cc(CO)cnc2c2cccn12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)[nH]c(=O)n3cccc43)CC2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (90.00 mg, 0.418 mmol), N-methyl-4-(piperazin-1-yl)benzamide (115 mg, 0.523 mmol) and (cyanomethyl)trimethylphosphonium iodide (163 mg, 0.669 mmol) in Propiononitrile (Volume: 2.00 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.364 mL, 2.091 mmol) at 23° C. The reaction was stirred at 95° C. for 2 hr. The suspension was cooled to 40° C., filtered warm, rinsed with ACN (3×1 mL) and dried in vacuo to provide N-methyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.152 g, 0.365 mmol, 87% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.52-2.58 (m, 4 H) 2.74 (d, J=4.55 Hz, 3 H) 3.20-3.31 (m, 4 H) 3.62 (s, 2 H) 6.71-6.77 (m, 1 H) 6.94 (d, J=8.84 Hz, 2 H) 7.08 (dd, J=3.54, 1.52 Hz, 1 H) 7.58 (d, J=1.77 Hz, 1 H) 7.68 (dd, J=3.03, 1.77 Hz, 1 H) 7.70 (d, J=8.84 Hz, 2 H) 8.14 (q, J=4.21 Hz, 1 H) 8.36 (d, J=1.77 Hz, 1 H) 11.61 (br. s., 1 H). ESI-MS: m/z 417.4 (M+H)+. mp=285.6-288.6° C.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[Cl:30].C([O-])([O-])=O.[K+].[K+].[C:37]([O:42][CH2:43][CH3:44])(=[O:41])[C:38]#[C:39][CH3:40]>CN(C=O)C.C(Cl)Cl>[Cl:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[C:16]1[N:15]2[N:14]=[C:39]([CH3:40])[C:38]([C:37]([O:42][CH2:43][CH3:44])=[O:41])=[C:20]2[CH:19]=[CH:18][C:17]=1[CH3:21]
Reactant: COc1ccc(-c2c(C)ccc[n+]2N)c(Cl)c1
Reactant: CC#CC(=O)OCC
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nn2c(-c3ccc(OC)cc3Cl)c(C)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.2 %

Procedure:
A solution of crude 1-amino-2-(2-chloro-4-methoxyphenyl)-3-methylpyridinium 2,4,6-trimethylbenzenesulfonate (2.63 g, 5.9 mmol) in DMF (15 mL) was treated with K2CO3 (4.05 g, 29.3 mmol). A solution of ethyl but-2-ynoate (0.77 g, 6.9 mmol) in DMF (2 mL) was added and the reaction was stirred at ambient temperature for 16 hours then quenched with water and filtered to give a waxy yellow solid which was dissolved in CH2Cl2. The solution was washed with H2O, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to give a yellow oil (1.02 g). The original aqueous filtrate from the reaction was concentrated in vacuo to remove DMF and partitioned between CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2 and the combined organic layers was dried over MgSO4, concentrated in vacuo, combined with the yellow oil and subjected to column chromatography (30% ethyl acetate/heptane) to give 0.89 g (42%) of a yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=9.0 Hz, 1H), 7.38 (d, J=9.0 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 7.15 (d, J=2.5 Hz, 1H), 7.04 (dd, J=8.5, 2.5 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 3.92 (s, 3H), 2.63 (s, 3H), 2.17 (s, 3H), 1.46 (t, J=7.1 Hz, 3H); MS m/z 359.39 (M++H).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][CH2:29]O)=[CH:27][C:22]=2[O:21][CH2:20]1>>[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][CH2:29][O:16][C:13]3[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=3)=[CH:27][C:22]=2[O:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Reactant: OCCc1ccc2c(c1)OCO2
Product: O=C(O)CNC(=O)c1ccc(OCCc2ccc3c(c2)OCO3)cc1
Yield: 87 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (300 mg, 1.19 mmol) prepared in Example 1 (1a) and 2-(1,3-benzodioxol-5-yl)ethanol (which is the compound disclosed in Tetrahedron, (2003), 59, 3369-3378, 239 mg, 1.44 mmol) to give 356 mg of the title compound (pale red powder, yield: 87%).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11](C#N)[C:12](=[O:16])[NH:13][C:14]=1[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[C:1]([C:9]1[CH:10]=[CH:11][C:12](=[O:16])[NH:13][C:14]=1[CH3:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c(=O)c(C#N)cc1C(=O)c1ccccc1
Agent: Cl
Product: Cc1[nH]c(=O)ccc1C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
5-Benzoyl-1,2-dihydro-6-methyl-2-oxo-3-pyridine-carbonitrile (2.32 g, 0.013 mole) and concentrated HCl (50 ml) are heated and stirred at reflux under an argon atmosphere for 5 hours. Upon cooling to room temperature a solid precipitates. The solid is collected by filtration and allowed to air dry. The dry solid is heated to 280°-290° C. and maintained at this temperature for 7 minutes. The residue is allowed to cool to room temperature then extracted into methylene chloride. Concentration of the methylene chloride solution followed by flash chromatography (50% methylene chloride - ethyl acetate) gives the title compound.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:20])C=1.C(OCC)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[O:20]1[CH:8]2[CH:7]1[CH2:6][C:5]1[CH:4]=[CH:3][CH:2]=[C:1]([OH:11])[C:10]=1[CH2:9]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Oc1cccc2c1CC=CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Oc1cccc2c1CC1OC1C2

Procedure:
prepared as described hereinbefore, by mixing a cooled solution (temperature less than about 30°C.) of 5,8-dihydro-1-naphthol in ethyl acetate with m-chloroperbenzoic acid and mixing the resulting slurry with a mixture of ethyl ether and aqueous sodium bicarbonate, to form 5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol ##SPC27##
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.Cl[C:25]1[S:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1>>[S:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[NH:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Reactant: Clc1nc2ccccc2s1
Agent: Cl
Product: NC(=O)c1cccc2c(NCc3cccc(Nc4nc5ccccc5s4)c3)ncnc12

Procedure:
The title compound was prepared according to Example 684 starting 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 2-Chloro-benzothiazole:
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[O:8][C:7]2[CH2:9][CH2:10][C:11]3[CH2:12][CH:13]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:15][C:16]=3[C:6]=2[CH:5]=1.[CH3:21][C:22]([CH3:38])([CH3:37])[CH2:23][C:24]1[C:28]2[CH:29]=[CH:30][C:31]([OH:36])=[C:32]([CH2:33][CH2:34][CH3:35])[C:27]=2[O:26][N:25]=1>>[CH3:38][C:22]([CH3:37])([CH3:21])[CH2:23][C:24]1[C:28]2[CH:29]=[CH:30][C:31]([O:36][CH2:2][CH2:3][C:4]3[O:8][C:7]4[CH2:9][CH2:10][C:11]5[CH2:12][CH:13]([C:17]([OH:19])=[O:18])[CH:14]=[CH:15][C:16]=5[C:6]=4[CH:5]=3)=[C:32]([CH2:33][CH2:34][CH3:35])[C:27]=2[O:26][N:25]=1
Reactant: CCCc1c(O)ccc2c(CC(C)(C)C)noc12
Reactant: COC(=O)C1C=CC2=C(CCc3oc(CCO)cc32)C1
Product: CCCc1c(OCCc2cc3c(o2)CCC2=C3C=CC(C(=O)O)C2)ccc2c(CC(C)(C)C)noc12

Procedure:
Using the procedure from Example 1, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)-4,5,6,7-tetrahydronaphtho[2,1-b]furan-7-carboxylate and 3-(2,2-dimethylpropyl)-7-(n-propyl )-6-hydroxybenz[4,5]isoxazole as a colorless oil.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].O=C(C1C=CC=CN=1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:4]([O:3][C:1]([NH:11][CH2:12][CH2:13][C:14](=[O:16])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(=O)c1ccccn1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Product: CCOC(=O)CC(=O)CCNC(=O)OCc1ccccc1

Procedure:
Ethyl 5-benzyloxycarbonylamino-3-oxo-pentanoate was prepared from N-Cbz-β-alanine in the same manner as ethyl 3-oxo-3-pyridin-2-yl-propionate (Example 94).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:35][C:36]([F:59])([F:58])[C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:48][NH:47][CH2:46][CH:45]([NH:49][C:50](=[O:57])[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH2:44]2)=[CH:39][CH:38]=1>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([N:47]1[CH2:48][CH:43]([C:40]2[CH:39]=[CH:38][C:37]([C:36]([F:59])([F:58])[F:35])=[CH:42][CH:41]=2)[CH2:44][CH:45]([NH:49][C:50]([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)=[O:57])[CH2:46]1)=[O:10]
Reactant: O=C(NC1CNCC(c2ccc(C(F)(F)F)cc2)C1)c1ccccc1
Reactant: Cc1cnccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cnccc1C(=O)N1CC(NC(=O)c2ccccc2)CC(c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
38 mg (0.28 mmol) of 3-methylpyridine-4-carboxylic acid together with 131 mg (0.34 mmol) of HATU and 56 mg (0.46 mmol) of 4-dimethylaminopyridine were initially charged in 2 ml of DMF, and 80 mg (0.23 mmol) of N-{5-[4-(trifluoromethyl)phenyl]piperidin-3-yl}benzamide were added. The reaction mixture was stirred overnight at RT and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 65 mg (59% of theory)
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:16]=[CH:15][C:14]3[CH2:13][CH2:12][C:11]4[C:17]([C:21]([O-])=[O:22])=[N:18][N:19]([CH3:20])[C:10]=4[C:9]=3[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[K+].C(Cl)(=O)C(Cl)=O.Cl.[CH3:32][NH:33][OH:34].C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH:1]1([NH:6][C:7]2[N:16]=[CH:15][C:14]3[CH2:13][CH2:12][C:11]4[C:17]([C:21]([N:33]([OH:34])[CH3:32])=[O:22])=[N:18][N:19]([CH3:20])[C:10]=4[C:9]=3[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cn1nc(C(=O)[O-])c2c1-c1nc(NC3CCCC3)ncc1CC2
Reactant: CNO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(O)C(=O)c1nn(C)c2c1CCc1cnc(NC3CCCC3)nc1-2
Temperature: 25 °C
Reaction time: 6 h
Yield: 199.8 %

Procedure:
To a suspension of 400 mg (1.14 mmol) of potassium 8-(cyclopentylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate in 80 mL of dichloromethane and a few drops of dimethylformamide 0.11 mL (0.13 mmol) of oxalyl chloride were added at 0° C. The mixture was stirred at room temperature for 6 hours and then evaporated, redissolved in anhydrous dichloromethane and dropped into a solution of 344 mg (2.28 mmol) of N-methylhydroxylamine hydrochloride and 0.33 mL of triethylamine in 20 mL of the same solvent, cooled to 0° C. After 4 hours the mixture was washed with a saturated solution of sodium hydrogenocarbonate, dried over sodium sulfate and evaporated to dryness. The residue was triturated with diethylether and filtered to give 780 mg (60% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:50])[N:4]([CH2:47][CH2:48][CH3:49])[C:5](=[O:46])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]=1Cl.[CH:51]([SH:55])([CH2:53][CH3:54])[CH3:52].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:50])[N:4]([CH2:47][CH2:48][CH3:49])[C:5](=[O:46])[N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]=1[S:55][CH:51]([CH3:52])[CH2:53][CH3:54]
Reactant: CCC(C)S
Reactant: CCCn1c(=O)c(Cl)c(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCn1c(=O)c(Cl)c(SC(C)CC)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
A mixture of 5,6-dichloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.22 g), sec-butylmercaptan (0.04 g) and potassium carbonate (0.09 g) in acetonitrile (5 ml) was heated under reflux for 4 hours. The reaction mixture was concentrated to dryness. The resulting residue was dissolved in methanol (15 ml) and 1N hydrochloric acid (1.5 ml) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give yellow amorphous powders (90 mg, 56%).
Reaction SMILES: [CH2:1]([S:3]([C:5]1[O:6][C:7]2[C:12]([C:13](=[O:17])[C:14]=1[CH2:15][OH:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH3:2].[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.O>ClCCl.C(OCC)(=O)C>[CH2:1]([S:3]([C:5]1[O:6][C:7]2[C:12]([C:13](=[O:17])[C:14]=1[CH2:15][O:16][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][O:18]1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH3:2]
Reactant: C1=COCCC1
Reactant: CCS(=O)c1oc2ccccc2c(=O)c1CO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCS(=O)c1oc2ccccc2c(=O)c1COC1CCCCO1
Reaction time: 3 h

Procedure:
To 2-ethylsulfinyl-3-hydroxymethyl chromen-4-one (5 g, 19.8 mmol) dissolved in dichloromethane (20 mL) in a 25 mL round bottom flask is added dihydropyran (29.7 mmol) and toluenesulfonic acid (0.99 mol). The reaction mixture is stirred for 3 hours after which it is poured into a separatory funnel and water is added. Ethyl acetate is then added and the layers are separated. The organic layer is washed with water (3×10) and brine and dried over sodium sulfate and filtered. The filtrate is concentrated in vacuo and the residue obtained is purified by silica gel flash chromatography (ethyl ether: hexanes) to yield the above product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]3[CH2:30][CH2:29][CH2:28][CH:27]=[CH:26]3)[C:17]=2[O:31][C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[CH3:39])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:17]=2[O:31][C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[CH3:39])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2n1C1C=CCCC1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2n1C1CCCCC1
Reaction time: 8 h
Yield: 97.9 %

Procedure:
The compound of example 22, step 4 (66.0 mg, 124 μmol) was dissolved in ethanol (5 ml), and palladium on activated carbon (20 mg, 10%) was added. The mixture was hydrogenated overnight at room temperature and a hydrogen pressure of 4.5 bar. The mixture was filtered over celite and evaporated under reduced pressure to give 65.0 mg of the crude title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C:4]([CH2:6][N:7]([CH3:9])[CH3:8])=[CH2:5].CO[CH2:13][N:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][Si](C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C:3]([C:4]1([CH2:6][N:7]([CH3:9])[CH3:8])[CH2:5][CH2:13][N:14]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15]1)=[O:10]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(CN(C)C)C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(CN(C)C)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.8 %

Procedure:
To a cold solution of 2-dimethylaminomethyl-acrylic acid methyl ester (0.266 g, 1.86 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzyl-amine (1.43 ml, 5.59 mmol) in dichloromethane (25 ml) was added at 0° C. trifluoroacetic acid (83 μl, 1.12 mmol). The resulting solution was warmed to room temperature and stirred for 72 hours. Saturated aq. NaHCO3 (60 ml) was added to the reaction mixture and stirred for 10 minutes. Diluted with dichloromethane (50 ml) and the organic layer was separated. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica get eluting with a solution of ethyl acetate in hexanes (1:2) followed by CH2Cl2/MeOH/NH4OH (9/1/0.01) to give the title compound (400 mg, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=4[Cl:28])[C:22](O)=[O:23])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:60][CH2:61][C@H:62]([OH:64])[CH3:63]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([C:22](=[O:23])[NH:60][CH2:61][C@H:62]([OH:64])[CH3:63])[CH:25]=[CH:26][C:27]=4[Cl:28])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1
Reactant: C[C@@H](O)CN
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)O)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)CNC(=O)c1ccc(Cl)c(N(C)C(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c1
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a mixture of 3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoic acid (3 g, 6.09 mmol) in THF (50 mL) was added EDCI (2.34 g, 12.18 mmol), HOBt (1.23 g, 9.13 mmol), DIPEA (5 mL) and (R)-1-amino-propan-2-ol (0.69 g, 9.13 mmol) by sequence under nitrogen atmosphere at room temperature. The reaction mixture was stirred overnight, diluted with water. The resulting precipitate was washed with water and EtOAc to give 8-bromo-N-(2-chloro-5-((R)-2-hydroxypropylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (2.7 g, yield 81%). 1H NMR (DMSO-d6, 400 MHz): δ8.62 (t, J=5.2 Hz, 1H, NH), 8.11-6.11 (m, 7H, ArH), 4.77 (d, J=4.4 Hz, 1H, OH), 4.18 (br s, 2H, CH2), 3.81-3.75 (m, 1H, CH), 3.32 (s, 3H, NCH3), 3.19 (br s, 2H, CH2), 2.94 (br s, 2H, CH2), 1.05 (d, J=6.0 Hz, 3H, CH3). LC-MS: (ESI, m/z)=549 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31]O)[CH2:25][CH2:24]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([O:20][CH2:31][CH2:30][CH2:29][N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[CH3:21])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1CCN(CCCO)CC1
Reactant: Cc1ccc(O)cc1NC(=O)CNc1ccc(F)c(Cl)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(OCCCN2CCN(C)CC2)cc1NC(=O)CNc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.4 %

Procedure:
To a solution of 2-(3-chloro-4-fluoro-phenylamino)-N-(5-hydroxy-2-methyl-phenyl)-acetamide (0.400 g) and 4-methyl-1-piperazinepropanol (0.270 g) in tetrahydrofuran (20 ml) under a nitrogen atmosphere was added tributylphosphine (0.64 ml) and 1,1′-(azodicarbonyl)dipiperidine (0.656 g) and the mixture stirred at ambient temperature for 20 hours. The reaction mixture was poured into diethylether and filtered through Celite. After concentration, the residue was purified by NPHPLC (eluting with 75% ethanol in dichloromethane) to afford the title compound (0.334 g).