Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([CH2:19][C:20](=[O:27])[CH2:21][S:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)Cl>[CH2:1]([C@H:8]([CH2:19][C:20](=[O:27])[CH2:21][S:22]([C:23]([CH3:24])([CH3:26])[CH3:25])=[O:36])[C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)SCC(=O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)S(=O)CC(=O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Yield: 99.9 %

Procedure:
The resultant compound from Example 37 (44.4 mg, 0.115 mmol) in CH2Cl2 (2 ml) at -10° C. was treated with meta-chloroperbenzoic acid (25.0 mg, 0.116 mmol, 80% pure). After 2 h at -10°-0° C. the solvent was evaporated and the residue was dissolved in ethyl acetate which was washed with 1:1 10% Na2SO4 solution/ saturated NaHCO3 solution, saturated NaHCO3 solution and brine, and then dried over Na2SO4 and evaporated to afford 46.0 mg (99%) of a colorless oil. 1H NMR (CDCl3) δ7.05-7.40 (m,10H), 5.08 (m,2H), 3.36-3.53 (m,2H), 3.30 (m,1H), 2.95-3.18 (m,2H), 2.80 (2dd,total 1H), 2.69 (2dd,total 1H), 1.24 (s,9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1)([CH3:20])[CH3:19]>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([CH:18]([CH3:19])[CH3:20])=[CH:26][CH:25]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C(C)C)nc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)c1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.3 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.00045 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.140 g, 0.0025 mol) and allowed to stir for 10 min at RT. 2-Isopropyl-5-vinyl-pyridine (0.185 g, 0.00125 mol) was added and stirred for further 4 h. at 100 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.027 g, 15% yield). 8-Chloro-5-[2-(6-isopropyl-pyridin-3-yl)-ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.027 g, 0.00007 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.009 g, 0.00007 mol) in THF (0.5 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.027 g, 81% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]([F:10])([F:9])[F:8])=[N:4][NH:5][CH:6]=1.Cl[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][C:17]2[N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[N:22]=[CH:23][C:16]1=2)=[O:14].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[C:3]([C:7]([F:10])([F:9])[F:8])=[N:4][N:5]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][CH2:18][C:17]3[N:21]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[N:22]=[CH:23][C:16]2=3)=[O:14])[CH:6]=1
Reactant: FC(F)(F)c1n[nH]cc1Cl
Reactant: O=C(CCl)N1CCCc2c1cnn2-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cn1cc(Cl)c(C(F)(F)F)n1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 60 °C
Yield: 87.3 %

Procedure:
A mixture of 4-chloro-3-(trifluoromethyl)pyrazole (0.026 g, 0.15 mmol), 2-chloro-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridine-4-yl]ethanone (0.045 g, 0.15 mmol) and K2CO3 (0.043 g, 0.31 mmol) in THF (0.6 mL) and DMF (0.3 mL) was heated at 60° C. for 1 hr. It was then cooled to rt. The mixture was partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by flash chromatography on SiO2 with a gradient elution of 0-60% EtOAc/hexanes to afford the desired product (0.056 g, 87%). 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.70 (s, 1H), 7.45 (m, 2H), 7.16 (dd, J=8.4, 8.4 Hz, 2H), 5.17 (s, 2H), 3.81 (m, 2H), 2.87 (t, J=6.2 Hz, 2H), 2.12 (m, 2H); MS: (ES) m/z calculated for C18H14ClF4N5O [M+H]+ 428.1, found 428.1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:27])=[CH:5][C:6]([Cl:26])=[C:7]([C:9]2[NH:10][C:11](=[O:25])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=3)[N:13]=2)[CH:8]=1.[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[Cl:26][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:25])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([F:23])([F:24])[F:22])[CH:15]=3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:4]([F:27])[CH:5]=1
Reactant: NCc1cc(-c2nn(-c3ccc(F)c(C(F)(F)F)c3)c(=O)[nH]2)c(Cl)cc1F
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1cc(-c2nn(-c3ccc(F)c(C(F)(F)F)c3)c(=O)[nH]2)c(Cl)cc1F

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-81, 0.300 g), pivaloyl chloride (0.3 mL), TEA (2.0 mL), dry THF (5 mL) to afford 0.065 g of the desired product. 1H NMR (300 MHz, CDCl3): δ 1.12 (s, 9H), 4.30 (m, 2H), 7.61-7.69 (m, 3H), 8.16 (br s, 1H), 8.25 (br s, 2H), 12.73 (s, 1H); MS (m/z): 489.47 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:12]([O:16][C:17](=[O:29])[NH:18][CH2:19][C:20]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([NH2:28])=[CH:22][N:21]=1)([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>C(Cl)Cl>[C:12]([O:16][C:17](=[O:29])[NH:18][CH2:19][C:20]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([NH:28][S:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])=[CH:22][N:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: COc1cc(N)cnc1CNC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)c2cccnc2Cl)cnc1CNC(=O)OC(C)(C)C
Yield: 99 %

Procedure:
The title compound (2.21 g, 5.15 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (1.10 g, 5.20 mmol), tert-butyl(5-amino-3-methoxypyridin-2-yl)methylcarbamate (IntC16) (1.45 g, 5.72 mmol) and pyridine (1.26 mL, 15.6 mmol) in DCM (20 mL) at rt using the methods of (IntC1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:17]3[C:18]([CH3:26])=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=34)[S:11][C:12]=2[C:13]([O:15]C)=[O:14])[CH:5]=[CH:6][CH:7]=1.O1CCCC1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:17]3[C:18]([CH3:26])=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=34)[S:11][C:12]=2[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nn2ccccc2c1-c1nc(-c2cccc(F)c2)c(C(=O)O)s1
Temperature: 70 °C
Reaction time: 1 h
Yield: 110.1 %

Procedure:
To a solution of methyl 4-(3-fluorophenyl)-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-1,3-thiazole-5-carboxylate (120 mg, 0.27 mmol) purified above in methanol (15 mL) and tetrahydrofuran (25 mL) was added 8N aqueous sodium hydroxide solution (6 mL), and the mixture was stirred at 70° C. for 1 hr. The reaction solution was cooled to 0° C., 6N hydrochloric acid was added to adjust the solution to about pH 3.0, and the reaction solution was extracted with ethyl acetate (100 mL×2). The collected organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated to give the title compound (105 mg, 91%) as a yellow solid.
Reaction SMILES: [C:1]([C:4]12[CH2:13][C:8]3([OH:14])[CH2:9][CH:10]([CH2:12][C:6]([C:15]([OH:17])=[O:16])([CH2:7]3)[CH2:5]1)[CH2:11]2)([OH:3])=[O:2].[I-].[Sm+3].[I-].[I-].[C:22](OC(C)=C)(=[O:25])[CH:23]=[CH2:24]>O1CCOCC1>[C:15]([C:6]12[CH2:7][C:8]3([O:14][C:22](=[O:25])[CH:23]=[CH2:24])[CH2:9][CH:10]([CH2:11][C:4]([C:1]([OH:3])=[O:2])([CH2:13]3)[CH2:5]1)[CH2:12]2)([OH:17])=[O:16]
Reactant: C=CC(=O)OC(=C)C
Reactant: O=C(O)C12CC3CC(O)(C1)CC(C(=O)O)(C3)C2
Agent: [I-]
Agent: [Sm+3]
Solvent: C1COCCO1
Product: C=CC(=O)OC12CC3CC(C(=O)O)(C1)CC(C(=O)O)(C3)C2
Yield: 82 %

Procedure:
To 2 mL of dioxane were added 1.00 mmol of 1,3-dicarboxy-5-adamantanol, 0.10 mmol of samarium iodide (SmI2), 2.20 mmol of isopropenyl acrylate, and the resultant mixture was stirred at a temperature of 50° C. for 4 hours. The analysis by gas chromatography showed the formation of a 1,3-dicarboxy-5-acryloyloxyadamantane (yield: 82%, white solid) in the reaction mixture.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[N:31]=[C:30]([CH3:32])[C:29]([C:33]([OH:35])=O)=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.[CH3:45][C@@H:46]1[NH:51][CH2:50][CH2:49][N:48]([S:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=2)(=[O:54])=[O:53])[CH2:47]1>CN(C=O)C>[Cl:25][C:26]1[N:31]=[C:30]([CH3:32])[C:29]([C:33]([N:51]2[CH2:50][CH2:49][N:48]([S:52]([C:55]3[CH:56]=[CH:57][C:58]([C:61]([F:64])([F:62])[F:63])=[CH:59][CH:60]=3)(=[O:53])=[O:54])[CH2:47][C@@H:46]2[CH3:45])=[O:35])=[CH:28][CH:27]=1
Reactant: Cc1nc(Cl)ccc1C(=O)O
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
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: CN(C)C=O
Product: Cc1nc(Cl)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
HATU (460 mg, 1.21 mmol) was added to a solution of 6-chloro-2-methyl-3-pyridinecarboxylic acid (commercially available, e.g. from Anichem, or may be prepared according to known methods) (173 mg, 1.01 mmol) in DMF (4 ml) and the mixture was treated with DIPEA (0.440 ml, 2.52 mmol). This mixture was stirred for ca. 10 min at ambient temperature. (3S)-3-Methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (371 mg, 1.20 mmol) was then added and stirring was continued for one hour. The reaction mixture was partitioned between DCM and sat aq. NaHCO3 solution (20 ml each). The layers were separated and the aqueous was washed with further DCM (2×20 ml). The combined organic layers were concentrated to leave a dark brown gum. Purification by silica chromatography (Biotage SP4, 25S cartridge), eluting with 12-100% ethyl acetate in isohexane, gave the title compound (456 mg) as a pale yellow gum.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][CH2:3]1.[Br:23][CH2:24][CH2:25][CH2:26]Br>>[Br:23][CH2:24][CH2:25][CH2:26][O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][CH2:3]1
Reactant: CN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: BrCCCBr
Product: CN([C@H]1CC[C@H](OCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 11.11, trans-N-(4-Hydroxy-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide and 1,3-dibrompropane were converted to yield trans-N-[4-(3-Bromo-propoxy)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide as off-white semisolid, MS: 320 [M−C3H6BrO].
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8](=[O:28])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH2:27])[CH:10]=1.[CH3:34][N:35]([CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1)[C:36]([C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41](O)=[O:42])=[O:37].CCN=C=NCCCN(C)C.[ClH:66]>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[ClH:66].[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][CH:46]=[C:38]([C:36]([N:35]([CH3:34])[CH2:47][CH2:48][N:49]3[CH2:50][CH2:51][O:52][CH2:53][CH2:54]3)=[O:37])[CH:39]=2)[CH:10]=1)=[O:28]
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
Into a 250-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(piperidin-1-yl)phenyl)isonicotinamide (1 g, 2.09 mmol, 1.00 equiv, 95%) in dichloromethane (30 mL), 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid (960 mg, 3.12 mmol, 1.50 equiv, 95%), EDC HCl (840 mg, 4.38 mmol, 2.00 equiv), and 4-dimethylaminopyridine (540 mg, 4.43 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 25° C. The resulting solution was diluted with 200 mL of ethyl acetate. The resulting mixture was washed with 2×30 mL of NH4Cl (aq), 1×30 mL of 10% sodium bicarbonate, and 1×30 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate:methanol (20:1). This resulted in 1.30 g of N1-(2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)-N3-methyl-N3-(2-morpholinoethyl)isophthalamide as a brown oil. The brown oil was dissolved in 40 mL of methanol. HCl gas was added at 0° C. The mixture was stirred for 20 min at 0° C. The mixture was concentrated under vacuum. The product was obtained as 1.40 g (86%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6+D2O, ppm): δ 9.96 (m, 1H), 8.94 (d, J=6 Hz, 1H), 8.59 (m, 2H), 8.49 (s, 1H), 7.93-8.07 (m, 2H), 7.87-8.03 (m, 2H), 7.54-7.80 (m, 7H), 4.59 (s, 2H), 4.12 (m, 1H), 3.99-4.03 (m, 2H), 3.88 (m, 2H), 3.76-3.79 (m, 2H), 3.58 (m, 2H), 3.43 (m, 2H), 3.15-3.17 (m, 3H), 2.96 (s, 3H), 1.97 (m, 4H), 1.71 (m, 2H). MS (ES, m/z): 729 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C@H:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:4][CH2:3]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:34]1[CH2:38]O[CH2:36][CH2:35]1>>[O:1]=[C:2]1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[C@H:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:4][C@H:3]1[CH2:36]/[CH:35]=[CH:34]/[C:38]1[CH:17]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@H](C/C=C/c2ccccc2)C(=O)N1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of protected pyroglutamate 8a (1.023 g, 3.20 mmol) in 15 mL THF at −78° C., was added LiHMDS (1M THF, 3.20 mL, 3.20 mmol). The mixture was stirred at −78° C. for 1 h, then a solution of cinnamyl Br in THF (3 mL) was added. The mixture was stirred at −78° C. for 1.25 h, then was quenched with sat. NH4Cl. The mixture was diluted with H2O, then extracted with EtOAc (3×). The organic phase was washed with brine, dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography (15% EtOAc/hexanes) to afford 390 mg (28%) of 8b as a white solid. 1H NMR (300 MHz, CDCl3) δ7.43-7.22 (m, 10H), 6.46 (d, J=15.7, 1H), 6.18-6.06 (m, 1H), 5.33-5.20 (m, 2H), 4.50 (dd, J=9.3, 1.7, 1H), 2.88-2.63 (m, 1H), 2.45-2.33 (m, 1H), 2.24-2.12 (m, 2H), 1.38 (s, 9H); MS (ESI) 436.2 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([C:35]([OH:37])=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][CH:20]=1>>[C:35]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26]2[C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:23][CH:24]=1)([OH:37])=[O:36]
Reactant: NC(Cc1ccc(Nc2ncccc2C(=O)O)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cccnc1Nc1ccc(CC(Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)cc1

Procedure:
In close analogy to the procedure described in Example 104b, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-{[4-(2-amino-2-carboxyethyl)phenyl]amino}pyridine-3-carboxylic acid (prepared by reaction of 2-amino-3-(4-aminophenyl)-propionic acid with 2-chloronicotinic acid as in Example 104a) to provide the title compound in good yield.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([CH3:16])[NH:3]1.S(Cl)([Cl:20])(=O)=O.O>C1C=CC=CC=1>[CH3:1][N:2]1[C:6](=[O:7])[C:5]([Cl:20])([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]([CH3:16])=[N:3]1
Reactant: Cc1[nH]n(C)c(=O)c1C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: CC1=NN(C)C(=O)C1(Cl)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8 %

Procedure:
To a solution of 2.16 g of 1,3-dimethyl-4-benzoyl-5-pyrazolone in 20 ml of dry benzene was added 1.62 g of sulfuryl chloride and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, water was added to the reaction mixture and after shaking an organic layer was separated. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate and the solvent was distilled off from the solution. The so obtained residue was recrystallized from n-hexane to give 0.2 g of the desired product melting at 70.5° - 72° C. (Yield 7.6%)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([C:16]3[N:20]([C:21]4[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=4)[N:19]=[C:18]([C:28]([F:31])([F:30])[F:29])[CH:17]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(Cl)Cl>[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][O:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([N:20]2[C:16]([C:14]3[S:15][C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=4)=[CH:12][CH:13]=3)=[CH:17][C:18]([C:28]([F:31])([F:29])[F:30])=[N:19]2)[CH:22]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3cccc(O)c3)s2)c1
Reactant: CN(C)CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)CCOc1cccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)c1
Temperature: 0 °C
Yield: 43.8 %

Procedure:
3-(5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenol (120 mg, 0.26 mmol), 2-(dimethylamino)ethanol (46 mg, 0.52 mmol) and triphenylphosphine (138 mg, 0.52 mmol) were dissolved in a mixture solvent of anhydrous THF (2.5 mL) and DCM (2.5 mL) and cooled off at 0° C. under nitrogen atmosphere. To this solution was added diisopropyl azodicarboxylate (111 mg, 0.52 mmol). The reaction mixture was stirred vigorously and warmed up to mom temperature overnight. The solvent was evaporated in vacuo and the residue was purified by HPLC, providing the product (61 mg, 44%). 1H-NMR (Acetone-d6): δ 8.13 (m, 1H), 7.93 (m, 1H), 7.90 (m, 1H), 7.71 (m, 1H), 7.60 (m, 1H), 7.47 (m, 1H), 7.17-7.09 (br, 5H), 4.12 (t, J=5.8 Hz, 2H), 3.18 (s, 3H), 2.65 (t, J=5.8 Hz, 2H), 2.21 (s, 6H). MS (ES): 536 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.O.[CH3:19]O>>[CH3:19][O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: CO
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(B(O)O)cc1

Procedure:
A solution of 4-carboxyphenylboronic acid (2.0 g) and sulfuric acid (0.1 ml) in methanol (50 ml) was refluxed overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over MgSO4. The solvent was evaporated in vacuo to give 4-methoxycarbonylphenylboronic acid (1.7 g) as colorless prisms.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1ccc(Cl)cc1
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (67 mg, 82%), MS (ISP) m/z=329.4 [(M+H)+], mp 209.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[N:19]([CH3:30])[C:20](=[O:29])[C:21]5[CH:27]=[CH:26][NH:25][C:24](=[O:28])[C:22]=5[N:23]=4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].S(C1C=CC(C)=CC=1)(O[CH2:41][CH2:42][F:43])(=O)=O>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[N:19]([CH3:30])[C:20](=[O:29])[C:21]5[CH:27]=[CH:26][N:25]([CH2:41][CH2:42][F:43])[C:24](=[O:28])[C:22]=5[N:23]=4)=[CH:14][CH:13]=3)[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2c(=O)[nH]ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2c(=O)n(CCF)ccc2c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 3.7 %

Procedure:
2-{4-[(1-Cyclobutylpiperidin-4-yl)oxy]phenyl}-3-methyl-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (24 mg, 0.06 mmol) and potassium carbonate (33 mg, 0.24 mmol) were stirred in DMF (0.5 mL) at room temperature, then 2-fluoroethyl tosylate (40 mg, 0.18 mmol) was dropwise added thereto and stirred at room temperature for 20 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline water in that order, and the organic layer was dried with magnesium sulfate. The solvent was evaporated off, and the residue was purified through silica gel thin-layer chromatography (chloroform/methanol=9/1) to obtain the intended compound (1.0 mg, 4%) as a pale yellow solid.