Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:46])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]=[N:40][C:41]([CH3:45])=[C:42]([CH3:44])[N:43]=2)[CH:33]=1)=O)(C)(C)C>>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:28](=[O:46])[CH2:29][C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]4[N:39]=[N:40][C:41]([CH3:45])=[C:42]([CH3:44])[N:43]=4)[CH:33]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1nnc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nc1C
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1nnc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)nc1C

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (160 mg, 0.5 mmol) and 3-[3-(5,6-dimethyl-[1,2,4]triazin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K47) (180 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (26 mg).
Reaction SMILES: [Na].C(C1(CCOC2C=CN=C(C[S:24]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[N:27]=3)=O)C=2C)OCC2(OCCO2)CO1)C.[CH3:36]C1(CCO)OCC2(OCCO2)CO1>>[CH3:36][C:33]1[CH:32]=[CH:31][C:29]2[NH:30][C:26]([SH:24])=[N:27][C:28]=2[CH:34]=1
Reactant: CC1(CCO)OCC2(CO1)OCCO2
Reactant: CCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCC2(CO1)OCCO2
Agent: [Na]
Product: Cc1ccc2[nH]c(S)nc2c1

Procedure:
The same procedure as in the steps (4f) to (4j) of Example 4 was repeated using 2-(8-methyl-1,4,7,9-tetraoxaspiro[4.5]dec-8-yl)ethanol obtained in the step (73b) above and 5-methyl-1H-benzimidazole-2-thiol obtained in the step (47a) to obtain the title compound (188 mg, total 12.4% yield) as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[CH3:19][C:15]1[CH:14]=[C:13]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=2)[N:16]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(OCc3ccccc3)cc2n1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Reaction time: 1.5 h
Yield: 95.5 %

Procedure:
A solution of 13 g of 7-benzyloxy-2-methyl-4-pyrrolidin-1-yl-quinoline, product of example 1, dissolved in 750 ml of MeOH was treated with 4 g of palladium on charcoal (10%) and then hydrogenated at RT for 1.5 h until HPLC analysis indicated the completion of the reaction. The catalyst was filtered off, washed with water) and the solution was concentrated in vacuo. The solid that precipitated was collected by filtration and dried in a high vacuum to give 8.9 g (96.2%) of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol as an amorphous yellow solid. ISP mass spectrum, m/e: 229.2 (M+1 calculated for C14H16N2O: 229).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10][CH:11]=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][N:23]2[CH2:22][CH2:21][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:25][CH2:24]2)=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1ccc(CC=O)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CCc2ccc(C#N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude 2-fluoro-4-(2-oxoethyl)benzonitrile (900 mg, 5.5 mmol) in 20 mL of DCM was added N-Boc Piperazine (1.0 g, 5.5 mmol) and NaBH(OAc)3 (4.7 g, 22 mmol), the mixture was stirred at room temperature overnight. The reaction was diluted with DCM, and washed with brine, the organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative TLC to give tert-butyl 4-[2-(4-cyano-3-fluorophenyl)ethyl]piperazine-1-carboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:26]4[CH2:30][CH2:29][CH2:28][C:27]4=[O:31])=[CH:3][C:4]=3[CH3:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C)CC2)c(C)c1

Procedure:
Using (4-bromo-2-methylphenyl) [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (402 mg) described in Preparation Example 253 and pyrrolidin-2-one (115 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (356 mg) was obtained.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]([CH3:33])[C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[C:14]([C:27]([F:30])([F:29])[F:28])[CH:13]=1)[N:8]=[C:7]([C:31]#[N:32])[N:6]=2.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:35].[Na+].C(=O)C.C([O-])(O)=O.[Na+]>ClC(Cl)C.C(Cl)(Cl)Cl.C(O)(=O)C.C(N(CC)CC)C>[CH2:34]([N:24]1[CH2:23][CH2:22][CH:21]([CH2:20][CH2:19][O:18][C:15]2[CH:16]=[CH:17][C:12]([C:9]3[N:8]=[C:7]([C:31]#[N:32])[N:6]=[C:5]4[C:10]=3[N:11]=[C:3]([CH3:2])[N:4]4[CH3:33])=[CH:13][C:14]=2[C:27]([F:29])([F:30])[F:28])[CH2:26][CH2:25]1)[CH3:35]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1nc2c(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)nc(C#N)nc2n1C
Agent: CC=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CC(Cl)Cl
Product: CCN1CCC(CCOc2ccc(-c3nc(C#N)nc4c3nc(C)n4C)cc2C(F)(F)F)CC1
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
Triethylamine (114 μL) was added to a suspension of 8,9-dimethyl-6-{4-[2-(piperidin-4-yl)ethoxy]-3-(trifluoromethyl)phenyl}-9H-purine-2-carbonitrile monohydrochloride (128 mg) in dichloroethane (3 mL) at room temperature, and the mixture was stirred at the same temperature for 15 minutes. After the reaction mixture was ice-cooled, acetic acid (76 μL), sodium triacetoxyborohydride (113 mg), and acetaldehyde (45 μL) were added thereto, and the mixture was stirred for 1 hour under ice-cooling. After a saturated aqueous NaHCO3 solution was added to the reaction mixture, extraction thereof was performed using CHCl3, and the extract was washed with water and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (CHCl3). The obtained product was washed with diisopropyl ether, and collected by filtration, whereby 6-{4-[2-(1-ethylpiperidin-4-yl)ethoxy]-3-(trifluoromethyl)phenyl}-8,9-dimethyl-9H-purine-2-carbonitrile (79 mg) was obtained as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9](OC)=[O:10])=[N:6][C:7]=1[CH3:8].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9]=[O:10])=[N:6][C:7]=1[CH3:8]
Reactant: COC(=O)c1ccc(Br)c(C)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1nc(C=O)ccc1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A 250 mL round-bottom flask was purged with and maintained under an inert atmosphere of nitrogen then charged with methyl 5-bromo-6-methylpyridine-2-carboxylate (7.00 g, 30.6 mmol, 1.00 equiv), tetrahydrofuran (150 mL). Diisobutylaluminium hydride (60 mL, 1 mol/L in hexane) was added dropwise at −78° C. The resulting solution was stirred for 60 min at −78° C., quenched by ammonium chloride (50 mL), extracted with ethyl acetate (2×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (10/90) to provide 4.90 g (76% yield) of 5-bromo-6-methylpyridine-2-carbaldehyde as a light yellow solid. 1H NMR 300 MHz (CDCl3) δ 10.04 (s, 1H), 8.02 (d, J=8.1 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 2.78 (s, 3H). LCMS (ESI, m/z): 200 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[N:4]=[C:10]=[S:11]
Reactant: Nc1ccc(F)cc1Cl
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Fc1ccc(N=C=S)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
Into a solution of 2-chloro-4fluoroaniline (500 mg, 3.44 mmol) in a mixture of chloroform and water (10 mL/10 mL) at room temperature, thiophosgene (0.53 mL, 6.88 mmol) and sodium bicarbonate (1.09 g, 10.32 mmol) were added. The mixture was stirred at room temperature for 16 hours. The mixture was partitioned between chloroform and water. The combined organic layer was then concentrated to give the desired product (586 mg, 91%). 1H NMR (CDCl3) δ 6.98 (m, 1H), 7.20 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([F:22])[CH:21]=1)[C:16]([OH:18])=O)=[N:9][NH:8][C:7]2=[O:23].[CH3:24][O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[C:15]([C:16]([N:29]3[CH2:30][CH2:31][CH:26]([O:25][CH3:24])[CH2:27][CH2:28]3)=[O:18])[CH:19]=[C:20]([F:22])[CH:21]=1)=[N:9][NH:8][C:7]2=[O:23]
Reactant: COC1CCNCC1
Reactant: O=C(O)c1cc(F)cc(Cc2n[nH]c(=O)c3cccc(Cl)c23)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)c2cc(F)cc(Cc3n[nH]c(=O)c4cccc(Cl)c34)c2)CC1
Reaction time: 1 h

Procedure:
3-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-5-fluorobenzoic acid (128), 4-methoxypiperidine and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate were dissolved in DMF (10 mL), to this was added DIPEA and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL) and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a white foam (67.0 mg); 1H NMR (400.132 MHz, CDCl3) δ 1.89-1.40 (4H, m), 3.17-3.06 (1H, m), 3.34 (3H, s), 3.58-3.42 (3H, m), 4.00-3.84 (1H, m), 4.67 (2H, s), 6.97-6.89 (3H, m), 7.67 (1H, t), 7.81 (1H, d), 8.49 (1H, d), 10.29 (1H, s); m/z (LC-MS, ESI+), RT=1.93 (M+H 430).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[C:4]([OH:6])=O.C(N(CC)CC)C.[Cl:23][C:24]1[CH:35]=[C:28]2[C:29](OC(=O)[NH:33][C:27]2=[CH:26][CH:25]=1)=[O:30]>O.C(#N)C>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]2[NH:33][C:4](=[O:6])[CH:3]([CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[NH:2][C:29](=[O:30])[C:28]=2[CH:35]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: NC(CCc1ccccc1Cl)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: O=C1NC(CCc2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Amino-4-(2-chlorophenyl)butanoic acid hydrochloride (1.49 g, 1 eq) was dissolved in water/acetonitrile 1:1 (24 mL:24 mL), and triethylamine (1.67 mL, 2 eq) was then added. 5-Chloroisatoic anhydride (1.18 g, 1 eq) was added in about 10 portions giving time between each addition for the previous portion to dissolve. After all of the anhydride was added the reaction was stirred at room temperature overnight. Any solids present after reaction were filtered off. The filtrate was concentrated in vacuo, azeotroped with acetonitrile, re-dissolved in AcOH (60 mL) and heated to 130° C. for 6 h. The crude mixture was then concentrated, and the residue was rinsed with NaHCO3(aq), stirring the slurry for 30 minutes before collecting the solid by filtration. The crude solid was washed with acetonitrile. 1H-NMR (300 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.74 (d, 1H), 7.68 (s, 1H), 7.59 (d, 1H), 7.40-7.03 (m, 5H), 3.66 (q, 1H), 2.75 (m, 2H), 2.03 (m, 1H), 1.83 (m, 1H). MS (ES+) m/z 371.0 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[C:15]([C:16]3[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][C:10]([C:11](O)=[O:12])=[C:9]([F:24])[CH:8]=2)=[C:4]([O:27][CH3:28])[CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:62][S:63]([NH2:66])(=[O:65])=[O:64]>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[C:15]([C:16]3[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][C:10]([C:11]([NH:66][S:63]([CH3:62])(=[O:65])=[O:64])=[O:12])=[C:9]([F:24])[CH:8]=2)=[C:4]([O:27][CH3:28])[CH:3]=1
Reactant: COc1cc(Cl)ccc1Oc1cc(F)c(C(=O)O)cc1-c1cccnc1OC
Reactant: CS(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1Oc1cc(F)c(C(=O)NS(C)(=O)=O)cc1-c1cccnc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 113.1 %

Procedure:
A mixture of 4-(4-chloro-2-methoxyphenoxy)-2-fluoro-5-(2-methoxypyridin-3-yl)benzoic acid (Preparation 15, 0.070 g, 0.114 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.112 g, 0.294 mmol) and N,N-diisopropylethylamine (191 μL, 1.09 mmol) in DCM (10 mL) and dimethylformamide (1.1 mL) was stirred at room temperature for 10 minutes, then methyl sulfonamide (0.0397 g, 0.417 mmol) was added. The reaction was heated at 45° C. for 18 hours under a nitrogen atmosphere, then cooled to room temperature and concentrated in vacuo to afford a pale brown residue. This was partitioned between aqueous hydrochloric acid (0.5 M, 10 mL) and DCM (25 mL). The organic extract was washed with aqueous hydrochloric acid (0.5 M, 2×10 mL), dried over sodium sulfate and concentrated in vacuo to afford a pale brown gum (0.062 g). The crude product was purified by preparative A-HPLC to afford the title compound (26.7 mg):
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([OH:39])[C:5]([C@@:7]1([CH3:38])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[OH:37])=[O:6].[C:40](OC(=O)C1C=CC=CC=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.O.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.C(Cl)Cl.CO>O1CCCC1>[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:39])[C:5]([C@@:7]1([CH3:38])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[OH:37])=[O:6].[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:39][C:40]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:47])[C:5]([C@@:7]1([CH3:38])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[OH:37])=[O:6]
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Agent: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](OC(=O)c3ccccc3)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 62 %

Procedure:
To a solution of 50 mg (91.9 μmol) of 10-deacetylbaccatin III and 13 μL (1.5 eq.) of benzoic anhydride in 2.0 mL of freshly distilled tetrahydrofuran 100 μL of a solution of 5.8 mg of commercial ytterbium trifluoromethanesulfonate hydrate in 1.0 mL of tetrahydrofuran was added. The reaction mixture was stirred at room temperature for 48 hours. Usual workup and isolation of the product by means of preparative TLC (Silica 60, CH2Cl2/MeOH 10:1) afforded 11 mg unreacted 10-deacetylbaccatin III (22%) along with 29 mg of 10-benzoyl-10deacetylbaccatin III (62%), m.p. 154°-156° C. C36H40O11 calculated C 66.66% H 6.22% measured C 66.50% H 6.23%. 1H-NMR (300 MHz, CDCl3) δ (ppm)=1.18 (s, 3H), 1.25 (s, 3H), 1.69 (s, 3H), 1.80-1.93 (m, 1H), 2.09 (s, 3H), 2.16-2.23 (m, 2H), 2.29 (s, 3H), 2.53-2.61 (m, 1H), 3.95 (d, 1H, J=6.9), 4.17 (d, 1H, J=8.3), 4.32 (d, 1H, J=8.3), 4.55 (dd, 1H, J=6.6, 10.6), 4.91 (br t, 1H, J=7.9), 5.00 (d, 1H, J=9.2), 5.67 (d, 1H, J=6.9), 6.59 (s, 1H), 7.40-7.52 (m, 4H), 7.54-7.61 (m, 2H), 8.04-8.14 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][N:11]1[C:15]([C:16](OCC)=[O:17])=[CH:14][C:13]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:12]1.C([O-])(=O)C.[NH4+:31].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:31][C:16](=[O:17])[C:15]2[N:11]([N:12]=[C:13]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:14]=2)[CH:10]=1
Reactant: CCOC(=O)c1cc(C(=O)OCC)n(CC(=O)c2ccc(Cl)cc2Cl)n1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(=O)[nH]c(-c3ccc(Cl)cc3Cl)cn2n1
Temperature: 0 °C

Procedure:
9.5 g (23.7 mmol) of diethyl 1-[2-(2,4-dichlorophenyl)-2-oxoethyl]-1H-pyrazole-3,5-dicarboxylate (Example 10A) were dissolved in 300 ml of glacial acetic acid, and 18.3 g (237 mmol) of ammonium acetate were added. The mixture was stirred at reflux for 12 h. The reaction mixture was poured into ice-water and neutralized with sodium carbonate. The precipitate was filtered off and dried under high vacuum. This gave 6.86 g (82% of theory) of the product as a solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]1([OH:27])[CH2:26][CH2:25][NH:24][CH2:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:24]3[CH2:25][CH2:26][C:22]([OH:27])([CH3:21])[CH2:23]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CC1(O)CCNC1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(O)CCN(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 3-methylpyrrolidin-3-ol (125032-87-3) in the presence of TBTU and DIEA to obtain the title compound as yellow solid; MS (EI): m/e=368.5 [MH+].
Reaction SMILES: [ClH:1].C1(C[NH:9][C@@:10]23[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][C@@H:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)C=CC=CC=1.CCOCC.C(OCC)(=O)C>CO.O1CCCC1.[Pd]>[ClH:1].[CH:23]1[C:18]2[CH2:17][C@H:16]3[C@@:10]([NH2:9])([C:19]=2[CH:20]=[CH:21][CH:22]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3
Reactant: c1ccc(CN[C@]23CCCCC[C@H]2Cc2ccccc23)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CO
Product: N[C@]12CCCCC[C@H]1Cc1ccccc12
Reaction time: 0.3 h
Yield: 54 %

Procedure:
To a solution of the benzylamine from Example 83 in methanol (50 ml) and tetrahydrofuran (50 ml) was added 0.5 g of 20% palladium on carbon. The reaction was hydrogenated for 18 minutes and stopped. The catalyst was removed by filtration and the solvent was concentrated under reduced pressure. The residue was partitioned between 0.1N hydrochloric acid and dichloromethane. The dichloromethane was dried (MgSO4), filtered and concentrated in vacuo to yield a brown oil. The oil was slurried with ether and ethyl acetate and a white solid precipitated to afford the title compound (2.5 g, 54%), mp 224°-226° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[C:21]1([NH:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:31][CH2:30][CH2:29][CH2:28][NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: NCCCNc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCNCCCNc1ccccc1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and 3-phenylamino-propylamine in the presence of triethylamine analogously to Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:26]=[N:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:17]1[CH:26]=[N:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1cnc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1cnc2ccccc2n1

Procedure:
The title compound (0.73 g) was prepared from (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (1 ml) and 2-chloroquinoxaline (0.5 g) according to the procedure of D8.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[OH:13].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1F)[C:18]#[N:19].C([O-])([O-])=O.[K+].[K+]>C1CS(=O)(=O)CC1>[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:13][C:8]1[C:9]2[C:4](=[C:3]([CH2:2][OH:1])[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1)[C:18]#[N:19]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: OCc1cccc2c(O)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: N#Cc1ccc(Oc2cccc3c(CO)cccc23)c(F)c1
Temperature: 80 °C

Procedure:
To a solution of 5-hydroxymethylnaphthalen-1-ol (Preparation 32) (350 mg, 2.01 mmol) and 3,4-difluorobenzonitrile (279 mg, 2.01 mmol) in sulfalone (8 mL) was added K2CO3 (1.39 g, 10.05 mmol) and the mixture heated to 80° C. for 16 h before cooling to rt. The mixture was partitioned between water (50 mL) and EtOAc (3×50 mL), the organic phase was washed with water (3×50 mL), brine (50 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (SiO2, MeOH:DCM, 2:98) to give the title compound: RT=3.54 min; m/z (ES+)=276.1 [M H2O]+.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH2:28]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[CH2:29][CH3:30]>C1COCC1>[CH2:28]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:34][CH:33]=1)[CH2:29][CH3:30]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCOc1ccc(C=O)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCOc1ccc(C=CCCCC(=O)O)cc1
Yield: 75.5 %

Procedure:
This compound was synthesized from 4-carboxybutyltriphenylphosphonium bromide (8.87 g, 20 mmol) and p-propoxybenzaldehyde (3.28 g, 20 mmol, synthesized from p-hydroxybenzaldehyde and 1-iodopropane) in THF (100 mL) by a Wittig reaction. Crystallization (petroleum ether) afforded the product (3.75 g, 76%) as white crystals (mp, 49°-50° C.). IR: 3400-2500, 1725 cm-1 ; 1H-NMR: 1.00 (t, 3H), 1.75 (m, 4H), 2.35 (m, 4H), 3.90 (t, 2H), 5.55 (m, 1H), 6.35 (m, 1H), 7.00 (q, 4H), 11.30 (bs, 1H). Anal. Calcd. for C15H20O3 : C, 72.55, H, 8.12%; Found: C, 72.45, H, 8.13%. Z:E=35:65.