Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:19][C@H:5]2[CH2:6][N:7]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:8][C@@:4]2([C:20]([N:22]2[CH2:31][CH2:30][C:29]3[N:28]=[CH:27][C:26]([C:32]([F:35])([F:34])[F:33])=[CH:25][C:24]=3[CH2:23]2)=[O:21])[CH2:3]1.[CH3:36][O:37][CH:38]1[C:43](=O)[CH2:42][CH2:41][O:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:36][O:37][CH:38]1[CH:43]([NH:1][C@@H:2]2[CH2:19][C@H:5]3[CH2:6][N:7]([C:9]([O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:10])[CH2:8][C@@:4]3([C:20]([N:22]3[CH2:31][CH2:30][C:29]4[N:28]=[CH:27][C:26]([C:32]([F:35])([F:34])[F:33])=[CH:25][C:24]=4[CH2:23]3)=[O:21])[CH2:3]2)[CH2:42][CH2:41][O:40][CH2:39]1
Reactant: N[C@@H]1C[C@H]2CN(C(=O)OCc3ccccc3)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reactant: COC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC1COCCC1N[C@@H]1C[C@H]2CN(C(=O)OCc3ccccc3)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product from Step A (difluoroacetate, 97.45 mg, 0.136 mmol), 3-methoxydihydro-2H-pyran-4(3H)-one (35.4 mg, 0.272 mmol), 4 Å molecular sieves (60 mg) and TEA (0.19 mL, 1.36 mmol) in DCM (4 mL) was stirred at rt for 2 h, followed by addition of sodium triacetoxyborohydride (46.12 mg, 0.218 mmol). The resulting mixture was stirred at rt overnight. The reaction was quenched by addition of saturated NaHCO3 aqueous solution, extracted with DCM, dried over Na2SO4. After removal of solvent, the residue was purified by column chromatography (eluent: 5% 7N NH3 in MeOH in DCM) to give the product as a yellow foam. 1H-NMR (400 MHz, CDCl3): δ 1.56-2.12 (m, 7H), 2.31 (br. s., 1H), 2.55-2.67 (m, 1H), 3.06-3.21 (m, 3H), 3.24-4.16 (m, 14H), 4.71 (br. s., 2H), 5.12 (s, 2H), 7.29-7.44 (m, 5H), 7.69 (br. s., 1H), 8.72 (br. s., 1H); LC/MS: C31H37F3N4O5: m/z 603.0 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=[C:5]2[C:4](=O)[NH:3]1.P(Cl)(Cl)([Cl:16])=O.[OH-].[NH4+]>>[Cl:16][C:4]1[C:5]2[C:6](=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=2)[N:2]([CH3:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc2c(=O)[nH]n(C)c2n1
Agent: [NH4+]
Agent: [OH-]
Product: CSc1ncc2c(Cl)nn(C)c2n1
Temperature: 0 °C
Yield: 61 %

Procedure:
1-Methyl-6-methylsulfanyl-1,2-dihydro-pyrazolo[3,4-d]pyrimidin-3-one (2.0 g, 0.01 mol) was heated with phosphorus oxychloride (8 mL) in a sealed tube at 140° C. for 6 hours. The reaction mixture was then poured into ice-water and basified with ammonium hydroxide. The formed product was isolated by filtration. The crude product was recrystalized from a 1:1 ethanol-water mixture to give 1.3 g (61%) of pure 3-chloro-1-methyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine; LC/MS (m/e)=215.0 (MH+), Rt=1.94 min.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)=[C:12]([CH3:28])[C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:11]1[C:12]([CH3:28])=[C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCC[C@@H]3c3ccnn3C)c(C)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(O[C@H]2CCC[C@@H]2c2ccnn2C)ccc(S(=O)(=O)Nc2ccncn2)c1F
Yield: 100.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2-fluoro-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.18 g, 0.31 mmol) prepared in Example 65c, triethylsilane (0.10 mL), trifluoroacetic acid (0.50 mL) and dichloromethane (2.0 mL), to yield the title compound (134 mg, 99%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].O.[C:28](Cl)(=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:28]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:37])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-aminophenoxy)piperidine-1-carboxylic acid tert-butyl ester (6.63 g) and sodium hydrogencarbonate (2.1 g) in a mixture of tetrahydrofuran (100 ml)-water (100 ml) was dropwise added benzyl chlorocarbonate (3.24 ml), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was washed with diisopropyl ether, collected by filtration, and dried under reduced pressure to give the title compound (7.189 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:21]=[C:20]([F:22])[C:19](F)=[CH:18][C:11]3=[N:12][C:13]=2[N:14]([CH2:16][CH3:17])[CH:15]=1)=[O:5])[CH3:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][NH:37][CH2:36][CH2:35][NH:34]2)=[CH:29][CH:28]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:21]=[C:20]([F:22])[C:19]([N:37]4[CH2:36][CH2:35][NH:34][CH:33]([C:30]5[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)[CH2:38]4)=[CH:18][C:11]3=[N:12][C:13]=2[N:14]([CH2:16][CH3:17])[CH:15]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(C2CNCCN2)cc1
Reactant: CCOC(=O)c1cn(CC)c2nc3cc(F)c(F)cc3cc2c1=O
Product: CCOC(=O)c1cn(CC)c2nc3cc(N4CCNC(c5ccc(OC)cc5)C4)c(F)cc3cc2c1=O
Yield: 72.8 %

Procedure:
(RS)-3-Ethoxycarbonyl-1-ethyl-7-fluoro-8-[3-(4-methoxyphenyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 33, but starting with 3-ethoxycarbonyl-1-ethyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo [b][1,8]naphthyridine (1.99 g) and (RS)-2-(4-methoxyphenyl)piperazine (2.3 g). (RS)-3-Ethoxycarbonyl-1-ethyl-7-fluoro-8-[3-(4-methoxyphenyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (2.2 g) is obtained in the form of a beige solid, m.p. 210°-212° c.
Reaction SMILES: [CH2:1]1[CH2:5][C:4]2([CH2:12][C:10](=[O:11])[O:9][C:7](=O)[CH2:6]2)[CH2:3][CH2:2]1.[NH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1>C1(C)C(C)=CC=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:13]2[C:7](=[O:9])[CH2:6][C:4]3([CH2:3][CH2:2][CH2:1][CH2:5]3)[CH2:12][C:10]2=[O:11])[CH:15]=1
Reactant: Nc1cccnc1
Reactant: O=C1CC2(CCCC2)CC(=O)O1
Solvent: Cc1ccccc1C
Product: O=C1CC2(CCCC2)CC(=O)N1c1cccnc1

Procedure:
The starting material is prepared as follows. The mixture of 16.8 g of 3,3-tetramethyleneglutaric anhydride, 9.4 g of 3-aminopyridine and 225 ml of xylene is stirred and refluxed for 48 hours while collecting the water formed. After cooling in the refrigerator the precipitate obtained is filtered off and recrystallized from 300 ml ethanol-hexane, to yield the 8-(3-pyridyl)-8-azaspiro[4,5]decan-7,9-dione melting at 153°-154°.
Reaction SMILES: [C:1]12([C:11]3O[C:13]([CH2:16][CH2:17][CH3:18])=[N:14][N:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.FC(F)(F)C([O-])=O.[CH3:26][NH3+:27]>>[C:1]12([C:11]3[N:27]([CH3:26])[C:13]([CH2:16][CH2:17][CH3:18])=[N:14][N:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CCCc1nnc(C23CC4CC(CC(C4)C2)C3)o1
Reactant: C[NH3+]
Agent: O=C([O-])C(F)(F)F
Product: CCCc1nnc(C23CC4CC(CC(C4)C2)C3)n1C

Procedure:
2-(1-Adamantyl)-5-propyl-1,3,4-oxadiazole (I) (49 mg, 0.2 mmol) and methylammonium trifluoroacetate (290 mg, 2 mmol, prepared by combining equimolar amounts of methylamine and trifluoroacetic acid in ether followed by concentration in vacuo) were stirred together in a sealed vial at 150° for 18 h. The residue was partitioned with methylene chloride and water, the organic layer washed with 10% K2CO3 and brine. The aqueous phase was extracted with methylene chloride (6×), the combined extracts dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC on a C-18 silica gel column using an acetonitrile-0.1% trifluoroacetic acid gradient to afford 3-(1-adamantyl)-4-methyl-5-propyl-4H-1,2,4-triazole (4-3). MS: 260 (M+1).
Reaction SMILES: F[C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:2]2[C:3]([C@H:8]3[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:24][CH:23]=1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: O[C@H]1CCC[C@H](c2nccnc2F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O[C@H]1CCC[C@H](c2nccnc2Oc2ccc(Nc3ccccn3)cc2)C1
Temperature: 150 °C

Procedure:
A mixture of (rac)-trans-3-(3-fluoropyrazin-2-yl)cyclohexanol (35 mg, 0.178 mmol), as prepared according to Scheme 35a, 4-(pyridin-2-ylamino)phenol (66.4 mg, 0.357 mmol), and cesium carbonate (116 mg, 0.357 mmol) in NMP (1 ml) was heated in a Biotage™ microwave reactor at 150° C. for 30 min. The mixture was partitioned between H2O (10 ml) and CH2Cl2 (20 ml), the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×20 ml). The combined organic layers were dried (MgSO4), concentrated under reduced pressure, and the resulting brown oil was purified by reversed phase HPLC (Gilson Gemini-NX 10u C18 110A, 100×50.0 mm, 10% to 95% H2O/MeCN, 0.1% TFA). The product containing fractions were combined, neutralized by the addition of solid Na2CO3, and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to deliver (rac)-trans-3-(3-(4-(pyridin-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanol as a tan solid. MS (ESI, pos. ion) m/z: 363.0(M+1). IC50 (uM) 0.01049.
Reaction SMILES: C12BC(CCC1)CCC2.[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][C@@H:18]1[CH:30]=[CH2:31])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=1.[OH-].[Na+]>Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][C@@H:18]1[CH2:30][CH2:31][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: B1C2CCCC1CCC2
Agent: Cl
Product: c1ccc(CN2CCN(Cc3ccccc3)[C@@H](CCc3ccccn3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
Combine 9-borabicyclo[3.3.1]nonane (62.6 mL, 31.3 mmol, 0.5 M in THF) and (S)-1,4-dibenzyl-2-vinyl-piperazine. (2.29 g, 7.83 mmol) and stir at ambient temperature. After 18 hours, add triphenylphosphine (657 mg, 2.50 mmol), tetrakis(triphenylphosphine) palladium(0) (362 mg, 0.31 mmol), and 2-bromopyridine (1.12 mL, 11.7 mmol). Add 3M NaOH (6.4 mL, 19.3 mmol) slowly, and gas evolution will occur. Heat at reflux. After 24 hours, cool to ambient temperature, add 5N HCl (50 mL), and stir 1 hour. Dilute with 0.2 N HCl, extract with diethyl ether, and discard the diethyl ether extracts. Add 5N NaOH to the acidic aqueous solution until pH is 12–14. Extract with diethyl ether. Wash the diethyl ether extracts with water and brine, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (0.5%–3%) as the eluent to give the title compound (2.3 g, 79%): mp 83–86° C.; mass spectrum (ion spray): m/z=372 (M+1). Analysis calculated for C25H29N3: C, 80.82; H, 7.87; N, 11.31. Found: C, 80.56; H, 7.60; N, 11.30.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1Cl.[CH3:11][O-:12].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[O:12][CH3:11]
Reactant: C[O-]
Reactant: OCc1cnc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: CO
Product: COc1ncc(CO)cc1Cl

Procedure:
(5,6-Dichloro-pyridin-3-yl)-methanol was dissolved in a saturated solution of NaOMe in MeOH and heated to reflux overnight. Evaporation of MeOH, work-up (EtOAc) and evaporation gave the title compound. 1H-NMR (CDCl3) δ 8.03 (d, 1H), 7.72 (d, 1H), 4.65 (s, 2H), 4.04 (s, 3H).
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12])C.[OH:16][CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23]CC#N>>[OH:16][CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:15][C:14]1[NH:3][C:4](=[O:13])[C:5]2[C:6]([CH:12]=1)=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=2
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: N#CCCN1CCC[C@@H]1CO
Product: Cc1cccc2c(=O)[nH]c(CCN3CCC[C@@H]3CO)cc12
Yield: 12.1 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-diethyl-2,3-dimethylbenzamide (81.4 g) and (R)-3-(2-hydroxymethylpyrrolidin-1-yl)propionitrile (55.6 g), (R)-3-[2-(2-hydroxymethylpyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (12.5 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].Cl.[CH3:13]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:13])=[O:7])=[CH:4][C:3]=1[OH:11]
Reactant: CO
Reactant: Nc1ccc(C(=O)O)cc1O
Agent: Cl
Product: COC(=O)c1ccc(N)c(O)c1
Reaction time: 48 h

Procedure:
Through a solution of 4-amino-3-hydroxybenzoic acid (75 g, 0.49 mol) in 2.0 L of dry methanol at room temperature was bubbled anhydrous HCl gas until the solution was saturated. The solution was stirred for 48 hours, then concentrated in vacuo. The product was partitioned between EtOAc and saturated aq. NaHCO3 solution, and the organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to provide the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:14]=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].FC(F)(F)C1C=CC(C2(CO)CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=CC1(c2ccc(Cl)c(Cl)c2)CCCC1
Agent: OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Product: OCC1(c2ccc(Cl)c(Cl)c2)CCCC1

Procedure:
(1-(3,4-Dichlorophenyl)cyclopentyl)methanol (483) was synthesized from 1-(3,4-dichlorophenyl)phenyl)cyclopentanecarbaldehyde (482) following the procedure described for 1-(4-trifluoromethyl-phenyl)-cyclopentane-methanol (239).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22]O>S(=O)(=O)(O)O>[CH3:22][O:9][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.33 g, 4.18 mmol) in methanol (10 mL) was treated slowly with 4 drops of concentrated sulfuric acid. The resulting reaction mixture was heated under reflux for 36 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The residue was diluted with ethyl acetate (200 mL). The organic phase was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 97/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid methyl ester (1.37 g, 99%) as a light yellow oil: EI-HRMS m/e calcd for C16H19F3O2S (M+) 332.1058, found 332.1052.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]3)=[CH:11][C:10]=2[O:20][CH3:21])[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)([Cl:24])=O.CN(C=O)C>C1(C)C=CC=CC=1>[Cl:24][C:13]1[C:12]2[C:17](=[CH:18][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[C:10]([O:20][CH3:21])[CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCn1ccnc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCn1ccnc1
Temperature: 0 °C
Yield: 59 %

Procedure:
A mixture of 7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (412 mg, 1.44 mmol), thionyl chloride (5 ml) and DMF (0.2 ml) was heated at reflux for 1 hour. The mixture was diluted with toluene and the volatiles were removed by evaporation. The residue was suspended in methylene chloride, cooled to 0° C. and aqueous sodium hydrogen carbonate solution was added. The resulting precipitate was collected by filtration and dried under vacuum to give 4-chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (258 mg, 59%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([C:20]([CH:22]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23]2)=O)[CH3:19])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([C:20]2([CH:22]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:23]3)[CH2:2][CH2:1]2)[CH3:19])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC[Mg]Br
Reactant: CN(C(=O)C1CCN(Cc2ccccc2)C1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1(C2CCN(Cc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 37.7 %

Procedure:
The solution of ethylmagnesium bromide (3.0 M in ethyl ether, 2.1 mL, 6.3 mmol) in THF (17.0 mL) was cooled to −78° C. To this solution was added the solution of titanium (IV) isopropoxide (0.76 mL, 2.6 mmol) in THF (1.7 mL) dropwise with the temperature below −70° C. After stirred for three minutes, the solution of 4-[(1-benzyl-pyrrolidine-3-carbonyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.5 mmol) in THF (1.7 mL) was added. The resulting solution was warmed to room temperature, heated at reflux for one hour and then cooled to 8° C. Ethylmagnesium bromide (3.0M in ethyl ether, 1.8 mL, 5.4 mmol) was added followed by the solution of titanium (IV) isopropoxide (0.66 mL, 2.2 mmol) in THF (1.0 mL) rapidly. The reaction mixture was stirred at room temperature for one hour and partitioned between ethyl acetate and water. The separated organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (60% ethyl acetate in hexane with 0.5% triethylamine) to give pale yellow oil (390 mg, 38%). ESI MS m/z 414.3 (M+H+).
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][CH2:8][NH:9][C:10](=[O:31])[C:11]1[C:12](=[CH:14][CH:15]=[C:16]([NH:18][C:19](=[O:30])[CH2:20][CH2:21][NH:22]C(OC(C)(C)C)=O)[CH:17]=1)[NH2:13])(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[NH2:22][CH2:21][CH2:20][C:19]([NH:18][C:16]1[CH:17]=[C:11]([C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:32])=[O:5])=[O:31])[C:12]([NH2:13])=[CH:14][CH:15]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1cc(NC(=O)CCNC(=O)OC(C)(C)C)ccc1N
Solvent: O=C(O)C(F)(F)F
Product: NCCC(=O)Nc1ccc(N)c(C(=O)NCCC(=O)O)c1

Procedure:
293 mg of N-[5-[[N-(t-butoxycarbonyl)-β-alanyl]amino]anthraniloyl]-β-alanine t-butyl ester are stirred at 20° C. for 3 hours in 1.3 ml of trifluoroacetic acid. The solvent is evaporated in a vacuum, the residue is dissolved in water and evaporated in a vacuum. There are obtained 324 mg of N-[5-(β-alanylamino)anthraniloyl]-β-alanine trifluoroacetate (1:2), MS: 295 (100, M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([N:20]([CH3:22])[CH3:21])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16](Br)=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:42][C:43]([OH:47])([C:45]#[CH:46])[CH3:44]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].[Cu]I>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([N:20]([CH3:22])[CH3:21])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:46]#[C:45][C:43]([OH:47])([CH3:44])[CH3:42])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: C#CC(C)(C)O
Reactant: COC(=O)c1nc2c(s1)C(N(C)C)COc1ccc(Br)cc1-2
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1nc2c(s1)C(N(C)C)COc1ccc(C#CC(C)(C)O)cc1-2
Temperature: 80 °C
Yield: 41.7 %

Procedure:
To a stirred mixture of 9-Bromo-4-dimethylamino-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (120 mg, 0.31 mmol) in TEA (5 mL) and DMF (1 mL) were added Pd(OAc)2 (7.0 mg, 0.03 mmol), PPh3 (24.6 mg, 0.09 mmol), CuI (11.9 mg, 0.06 mmol), 2-methylbut-3-yn-2-ol (131.5 mg, 1.56 mmol). The reaction mixture was degassed with N2 and heated in autoclave at 80° C. overnight. Then the mixture was cooled to room temperature, and EtOAc was added. The mixture was filtered though Celite, and the filtrate was washed with saturated brine, dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash column chromatography (silica gel, EtOAc in hexane from 10% to 20%) to afford 4-Dimethylamino-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (50 mg, 41%) as a light yellow solid. LC-MS (ESI & APCI): 387.5 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][C:27]1=[O:32]>CN1C(=O)CCC1.CC#N>[F:22][C:21]1[CH:20]=[C:19]2[C:15]([CH:16]=[N:17][N:18]2[CH3:23])=[CH:14][C:13]=1[C@@H:11]([C:8]1[N:6]2[N:7]=[C:2]([N:29]3[CH2:30][CH2:31][NH:26][C:27](=[O:32])[CH2:28]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:12]
Reactant: C[C@@H](c1cc2cnn(C)c2cc1F)c1cnc2ccc(Cl)nn12
Reactant: O=C1CNCCN1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: C[C@@H](c1cc2cnn(C)c2cc1F)c1cnc2ccc(N3CCNC(=O)C3)nn12
Temperature: 180 °C
Reaction time: 3 h

Procedure:
6-Chloro-3-[(S)-1-(6-fluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (Intermediate E, 66.0 mg, 0.2 mmol), KF (59.3 mg, 1.0 mmol) and piperazin-2-one (61.9 mg, 0.6 mmol) were suspended in NMP (0.5 mL). The RM was stirred at 180° C. for 3 h. The mixture was diluted with CH3CN and purified by reverse phase chromatography (Büchi MPLC: 5-24% CH3CN, 0.1% HCOOH). The fractions was combined, concentrated and neutralized with NaHCO3, extracted with EtOAc. The combined organics layers were tried over Na2SO4, filtered, concentrated to afford the title compound as a yellow foam (tR 3.53 min (conditions 4), (tR 8.25 (conditions 5), MH+=394.3, 1H-NMR in DMSO-d6: 8.04 (s, 1H); 7.92 (s, 1H); 7.81 (d, 1H); 7.50 (m, 1H); 7.46 (d, 1H); 7.06 (d, 1H); 4.78 (m, 1H); 3.95 (s, 3H); 3.95 (d, 1H); 3.80 (d, 1H); 3.58 (m, 2H); 3.22 (m, 2H); 1.71 (d, 3H)).