Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3CCCNC3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])C.[N:33]1([C:39](=[O:50])[CH2:40][N:41]2[CH2:46][CH2:45][N:44]([C:47](Cl)=[O:48])[CH2:43][CH2:42]2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:30][CH2:29][N:28]([C:47]([N:44]4[CH2:45][CH2:46][N:41]([CH2:40][C:39]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[O:50])[CH2:42][CH2:43]4)=[O:48])[CH2:31][CH2:32]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CCN(CC(=O)N2CCOCC2)CC1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: CCN(CC)CC
Product: O=C(CN1CCN(C(=O)N2CCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)CC2)CC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (0.15 g, 0.4 mmol) (from Example 15a supra) in tetrahydrofuron (3 mL) was added triethyl amine (0.14 g, 1 mmol) (Aldrich), followed by the addition of 4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl chloride (0.17 g, 0.6 mmol) (from Example 48a supra). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-6-chloro-3-(3-chloro-benzyl)-3-{1-[4-(2-Morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-piperidine-4-yl}-1,3-dihydro-indol-2-one as a white solid. (Yield 0.12 g, 50.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:28])([F:29])[F:30])[CH:21]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(OC(F)(F)F)c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-3-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions D): tR=1.10 min.; [M+H]+: 410.4 g/mol.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([C:20]([F:23])([F:22])[F:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=O)=O)=CC=1.[OH:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=1.[H-].[Na+]>CN(C=O)C>[F:21][C:20]([F:22])([F:23])[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:11][O:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:35][CH:36]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCCCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCC(CCOc1ccc(C(=O)OCC)cc1)C(F)(F)F
Temperature: 130 °C
Yield: 60.4 %

Procedure:
345 mg of 3-trifluoromethylnonyl p-toluenesulfonate obtained in Step (1), 166 mg of ethyl p-hydroxybenzoate and 1 ml of dimethylformamdie (DMF) were placed in a round-bottomed flask, and 80 mg of sodium hydride (60%) was added thereto together with DMF, followed by 6 hours of stirring at 130° C. After the reaction, DMF was distilled off under a reduced pressure, and water was added, followed by extraction with methylene chloride. The methylene chloride solution was dried with magnesium sulfate, followed by distilling-off of the solvent and purification by thin layer chromatography with benzene as the developer to obtain 205 mg of ethyl p-(3-trifluoromethylnonyloxy)benzoate (yield: 60.5%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:6]=2[N:7]=1.[C:25]([Li])(C)(C)C.CI>O1CCCC1.CCCCC>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:8]([CH3:25])[C:6]=2[N:7]=1
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCc2c(nc(Cl)nc2N2CCOCC2)C1
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC1c2nc(Cl)nc(N3CCOCC3)c2CCN1C(=O)OC(C)(C)C
Reaction time: 0.67 h
Yield: 87 %

Procedure:
To a solution of tert-butyl 2-chloro-4-morpholino-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (dp) (501 mg, 1.41 mmol) in Tetrahydrofuran (14 mL) was added 1.7 M of tert-Butyllithium in Pentane (1.1 mL) at −78° C., which resulted orange color solution. The reaction was kept at −78° C. for 40 min before Methyl iodide (0.44 mL, 7.1 mmol) was injected. The solution was kept at −78° C. for another 40 min before quenching with water. The mixture was diluted by Dichloromethane, which was washed by water and brine till pH 7. After evaporation, the residue was purified on a silica gel column. Tert-butyl 2-chloro-8-methyl-4-morpholino-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (qe) (452 mg, 87% yield) was obtained as white solid: 1H NMR (500 MHz, CDCl3) δ 5.02 (bs, 1H), 4.26 (bs, 1H), 3.91-3.79 (m, 2H), 3.79-3.67 (m, 2H), 3.61 (m, 2H), 3.36 (m, 2H), 2.89 (bs, 1H), 2.75 (bs, 1H), 2.46 (d, J=15.0 Hz, 1H), 1.50 (d, J=7.0 Hz, 3H), 1.48 (s, 9H); LC-MS m/z=369 (M+H). Tert-butyl 2-chloro-8,8-dimethyl-4-morpholino-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (qf) (44 mg, 8% yield) was obtained as white solid: 1H NMR (400 MHz, CDCl3) δ 3.87-3.73 (m, 4H), 3.60-3.52 (m, 2H), 3.52-3.42 (m, 4H), 2.65-2.56 (m, 2H), 1.74 (s, 6H), 1.50 (s, 9H); LC-MS m/z=383 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(N(CC)CC)C.Cl[S:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])(=[O:34])=[O:33].O>ClCCl>[C:38]([O:37][C:36]([NH:35][S:32]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]([C:15](=[O:20])[C:16]([F:17])([F:18])[F:19])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(=[O:34])=[O:33])=[O:42])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)CN(Cc1cccc(N)c1)C(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)CN(Cc1cccc(NS(=O)(=O)NC(=O)OC(C)(C)C)c1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
To a solution of tert-butyl N-(3-aminobenzyl)-N-(trifluoroacetyl)glycinate (1.95 g) and triethylamine (0.981 mL) in dichloromethane (19.5 mL) was added a solution of tert-butyl (chlorosulfonyl)carbamate (1.52 g) in dichloromethane (10.0 mL) under ice-cooling, followed by stirring at room temperature for 3 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added ethyl acetate, and n-hexane was added thereto. The precipitated solid was collected by filtration to obtain tert-butyl N-(3-{[(tert-butoxycarbonyl)sulfamoyl]amino}benzyl)-N-(trifluoroacetyl)glycinate (2.19 g).
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([N+:13]1[CH:14]([C:21]([O:23][CH3:24])=[O:22])[CH2:15][CH2:16][C:17]=1OCC)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(CC)CC.[CH3:32][N+:33]([O-:35])=[O:34]>C(Cl)Cl>[CH3:24][O:23][C:21]([CH:14]1[CH2:15][CH2:16][C:17](=[CH:32][N+:33]([O-:35])=[O:34])[N:13]1[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:22]
Reactant: C[N+](=O)[O-]
Reactant: CCOC1=[N+](Cc2ccccc2)C(C(=O)OC)CC1
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCC(=C[N+](=O)[O-])N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
To the mixture obtained in Example 1C (0.2 mol) in 130 mL CH2Cl2 at ambient temperature was added Et3N (33.5 mL, 0.24 mol) followed by CH3NO2 (13 mL, 0.24 mol). The mixture stirred at ambient temperature for 8 h then was diluted with CH2Cl2, the layers were separated and the organic layer was washed with 20 mL 5% H2SO4 and 20 mL brine. The organic layer was dried over anhydrous Na2SO4, concentrated and purified via column chromatography (SiO2, 50% hexanes-EtOAc) to give 10.2 g of the title compound (36.9 mmol). MS (DCl/NH3) m/z 277 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[CH3:20][C:21]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:35][C:32]2[CH:31]=[CH:30][C:29]([C:21]([CH3:22])([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH3:20])=[CH:34][CH:33]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc(C(C)(C)c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 4-(1-methyl-1-phenyl-ethyl)-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].S(=O)(=O)(O)O.[CH3:25]O>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:25])=[O:7])=[CH:4][C:3]=1[S:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)(=[O:12])=[O:13]
Reactant: CO
Reactant: O=C(O)c1ccc(F)c(S(=O)(=O)N2CCOCC2)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(F)c(S(=O)(=O)N2CCOCC2)c1

Procedure:
4-Fluoro-3-(morpholinosulfonyl)benzoic acid (50 mg, 0.173 mmol) was refluxed overnight in the presence of concentrated sulfuric acid (1.117 mg, 8.64 μmol) in methanol (8 mL) at 70° C. The reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and compound was purified by column chromatography affording the title compound (20 mg). 1H NMR (400 MHz, CD3OD): δ 8.42 (dd, 1H, J=2.0 & 6.4 Hz), 8.33 (m, 1H), 7.49 (t, 1H, J=8.8 Hz), 3.94 (s, 3H), 3.71 (m, 4H), 3.16 (m, 4H).
Reaction SMILES: [CH:1](=[N:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([Li])C=CC=CC=1.[Cl:25][C:26]([Cl:33])([Cl:32])[CH2:27][O:28][C:29](Cl)=[O:30].C(=O)=O>O1CCCC1.C1C=CC=CC=1.C(OCC)C>[CH:1](=[N:8][CH:9]([P:10]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])=[O:17])[C:29]([O:28][CH2:27][C:26]([Cl:33])([Cl:32])[Cl:25])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCOP(=O)(CN=Cc1ccccc1)OCC
Agent: O=C=O
Agent: [Li]c1ccccc1
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(N=Cc1ccccc1)C(=O)OCC(Cl)(Cl)Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A solution of diethyl N-benzylidene-aminomethylphosphonate (12.738 g., 50 mmole) in dry tetrahydrofuran (250 ml.) is stirred in a dry ice-acetone bath and under a nitrogen atmosphere. Phenyllithium (25 ml. of a 2.0 M solution in 7:3 benzene-ethyl ether) is added via syringe. The resulting burgundy solution is stirred for 30 minutes at -78°C., then treated dropwise over 45 minutes with a solution of 2,2,2-trichloroethyoxycarbonyl chloride (5.30 g., 25 mmole) in dry tetrahydrofuran (50 ml.). After stirring the mixture for an additional 2 hours at -78°C., the dry ice bath is replaced by an ice water bath and stirring is continued for 1 hour. Evaporation of the solvent in vacuo leaves a yellow foam which is partitioned between ethyl ether (250 ml.) and aqueous phosphate (50 ml. of 1M pH 3 phosphate + 50 ml. water). The aqueous portion is separated and extracted with ethyl ether (2 × 50 ml.). The combined ethereal solution is washed with saturated brine (100 ml.), dried over magnesium sulfate, and evaporated in vacuo to yield a cloudy, yellow oil (17.1 g.). The crude product is purified by chromatography on silica gel (430 g., packed under ethyl ether). Elution with ethyl ether affords trichloroethyl N-benzylidene-α-amino-diethylphosphonoacetate (7.058 g.) as a yellow oil.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([O:17]S(C4C=CC(C)=CC=4)(=O)=O)[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4](S(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[CH:67]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][N:70]=1)=[CH2:68]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[N:70]1[CH:71]=[CH:72][CH:73]=[CH:74][C:69]=1[CH:67]=[CH:68][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[NH:4][CH:3]=1
Reactant: C=Cc1ccccn1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(-c3cnc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)c2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Oc1cccc(-c2cnc3[nH]cc(C=Cc4ccccn4)c3c2)c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 70.5 %

Procedure:
To toluene-4-sulfonic acid 3-[3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl ester (50 mg, 0.077 mmol), tri-ortho-tolylphosphine (10 mg, 0.031 mmol), palladium (II) acetate (2 mg, 0.0077 mmol) was added DMF (0.5 mL), triethylamine (32 uL, 0.232 mmol), and 2-vinylpyridine (42 uL, 0.388 mmol). The vial was flushed with nitrogen, and the reaction was run in a Personal Chemistry® microwave reactor at 150° C. for 900 s. Water was added and the mixture was neutralized to pH 6 with 1 N aqueous HCl, then extracted with EtOAc three times. The extracts were combined and concentrated in vacuo. The crude was treated with 1 mL of EtOH and 1 mL of aqueous KOH (50 wt %). The reaction mixture was stirred at 80° C. for 15 h. The mixture was neutralized to pH 7 with 1 N aqueous HCl, and the resulting precipitate was filtered, washed with water, dried in vacuo, and adsorbed on silica gel. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded 3-[3-(2-pyridin-2-yl-vinyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenol as a yellow solid (17 mg, 35% yield). 1H NMR (500 MHz, DMSO-d6) δ 6.78 (dd, J=2.0, 8.0 Hz, 1H), 7.13 (s, 1H), 7.15-7.20 (m, 2H), 7.26 (d, J=16.0 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.73 (dt, J=2.0, 8.0 Hz, 1H), 7.90 (d, J=16.0 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.52 (d, J=5.0 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 9.56 (s, 1H), 12.1 (s, 1H). MS: m/z 314 (M+H+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=2)[N:5]=1.[CH2:25](I)[CH3:26]>CN(C=O)C>[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]([C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=2)[N:5]=1
Reactant: CC(=O)Nc1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Reaction time: 12 h
Yield: 12.9 %

Procedure:
NaH (95%, 0.005 g, 0.21 mmol) was added slowly at RT to a solution of N-[4-(4-Bromo-1-oxo-1H-phthalazin-2-yl)-phenyl]acetamide (0.070 g, 0.20 mmol) in DMF (2 ml). Stirring was continued for 1 h before ethyl iodide (0.046 g, 0.29 mmol) was added. Stirring was continued for 12 h before the solvent was evaporated in vacuum. The resulting raw product was purified by chromatography over silica gel with heptane:EtOAc (3:1 up to 1:1) to give the title compound (0.010 g, 14% yield). MS (ESI+)=388.22 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:6][C:5]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>CO.O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:23])=[O:2])=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1
Reactant: COC(=O)c1ccc(Oc2ccccn2)cc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Oc2ccccn2)cc1-c1ccccc1

Procedure:
A solution of the resultant ester from Example 6B (1.0 equivalent) in aqueous methanol is treated with NaOH (2.0 equivalents) and stirred until the reaction is deemed complete by TLC analysis. The mixture is acidified, diluted with water, and extracted into ethyl acetate which is dried and evaporated. Chromatography on silica gel provides the tide product.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35]>CC#N>[Br-:23].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: COc1ccccc1OCCCBr
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: COc1ccccc1OCCC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 73 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct -4-yl(diphenyl)methanol (0.0467 g, 0.159 mmol) and 1-[(3-bromopropyl)oxy]-2-(methyloxy)benzene (0.0541 g, 0.221 mmol) in 2 CH3CN/3CHCl3 (4.0 mL) were reacted to give the desired product (0.0625 g, 73.5%). ELMS m/z 458(M+) Rt (1.96 min).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1([CH3:34])[CH2:21][C:20]([CH3:23])([CH3:22])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][N:27]=3)[CH:18]=2)[O:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]1([CH3:34])[CH2:21][C:20]([CH3:22])([CH3:23])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][N:27]=3)[CH:18]=2)[O:13]1
Reactant: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(CO)cn3)ccc2O1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(C=O)cn3)ccc2O1
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
A solution of 1.396 g (11 mmol) of freshly distilled oxalyl chloride in 25 ml of methylene chloride is placed in a 4-necked flask equipped with a stirrer, a thermometer and two pressure-equalizing addition funnels fitted with drying tubes. The solution is cooled to -60 degrees C. and then treated dropwise with a solution of 1.875 g (24 mmol) of dimethyl sulfoxide (distilled from calcium hydride) in 5 ml of methylene chloride over a five minute period. The reaction mixture is then stirred at -60 degrees C. for an additional 10 minutes. A solution of 3.10 g (10 mmol) of 2,2,4,4-tetramethyl-6-[(5-hydroxymethylpyrid-2-yl)ethynyl]-chroman (Compound 50) in 10 ml of methylene chloride is then added to the reaction mixture over a period of 5 minutes. The mixture is stirred for a further 15 minutes and is then treated with 5.06 g (50 mmol) of triethylamine. The cooling bath is then removed and the mixture is allowed to warm to room temperature. Thirty ml of water is then added to the mixture and stirring is continued for a further 10 minutes. The organic layer is then separated and the aqueous layer is extracted with 20 ml of methylene chloride. The organic layers are then combined and washed successively with dilute HCI, water and dilute Na2CO3 solution and then dried (MgSO4). The solution is then filtered and concentrated in vacuo and the residue is purified by chromatography followed by recrystallization to give the title compound.
Reaction SMILES: CS[C:3]1[NH:4][CH:5]=[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[C:7](=[O:9])[N:8]=1.[F:17][C:18]([F:36])([F:35])[C:19]1[CH:20]=[C:21]([CH:32]=[CH:33][CH:34]=1)[O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=1>C(O)C>[N:13]1[CH:12]=[C:11]([CH2:10][C:6]2[C:7](=[O:9])[N:8]=[C:3]([NH:31][CH2:30][CH2:29][C:26]3[CH:25]=[CH:24][C:23]([O:22][C:21]4[CH:32]=[CH:33][CH:34]=[C:19]([C:18]([F:17])([F:35])[F:36])[CH:20]=4)=[CH:28][CH:27]=3)[NH:4][CH:5]=2)[CH:16]=[N:15][CH:14]=1
Reactant: CSc1nc(=O)c(Cc2cncnc2)c[nH]1
Reactant: NCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Solvent: CCO
Product: O=c1nc(NCCc2ccc(Oc3cccc(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
2-Methylsulfanyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (40 mg, 0.171 mmol, 1 eq) and 2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (53 mg, 0.188 mmol, 1.1 eq) were dissolved in dry ethanol (300 μl) and stirred at 120° C. for 6 h. Ethanol was evaporated during the reaction and in the mixture was added pyridine (300 μl) and reaction was stirred for 3 h. Pyridine was evaporated and 0.5 ml of EtOH was added. Precipitate was formed and it was starting material. Mother liquor was evaporated and purified via Biotage SP-1 Snap Si 10 g in the gradient of MeOH in DCM: 1% for 1 CV, 1-5% for 18 CV; 5-10% for 20 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product which was not pure enough and it was sent to HPLC/MS Purification. After HPLC/MS purification combined fractions of desired product were collected and put on lyophilisation to obtain 5-pyrimidin-5-ylmethyl-2-{2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethylamino}-1H-pyrimidin-4-one (0.0087 mmol; yield: 5.1%, HPLC-MS/UV: [M+H]+=468.45; rt: 10.90 min; purity: 94.9%). 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.78 (t, J=7.17 Hz, 2H), 3.41-3.47 (m, 2H), 3.50 (s, 2H), 6.99 (d, J=8.40 Hz, 2H), 7.22 (d, J=8.34 Hz, 1H), 7.24-7.31 (m, 3H), 7.44 (d, J=7.82 Hz, 1H), 7.56 (s, J=7.92 Hz, 1H), 7.60 (s, 1H), 8.66 (s, 2H), 8.94 (s, 1H)
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@H:2]([C:11](O)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].C1CCC(N=C=NC2CCCCC2)CC1.[NH2:46][C@H:47]([C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59])[CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1.Cl.C(N(CC)CC)C>C(Cl)Cl>[NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@H:2]([C:11]([NH:46][C@H:47]([C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59])[CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 41 mg portion of Fmoc-Asp(Ot-Bu)-OH was dissolved in 1, ml of methylene chloride, and 12 mg of HONSu and 21 mg of DCC were added thereto at 0° C. and stirred at 0° C. for 30 minutes. Then, 1 ml of a methylene chloride solution containing 33 mg of H-Trp-OBzl hydrochloride and 14 μl of triethylamine were added thereto and stirred at 0° C. for 3 hours. The insoluble substances were removed by filtration and washed with cold methylene chloride, and the filtrate was collected. The solvent was removed from the filtrate by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (50 g of Wakogel C-200, eluted with chloroform/methanol=25/1) to obtain 67 mg of Fmoc-Asp(Ot-Bu)-Trp-OBzl as a white powder.