Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.O[CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]1>>[O:11]=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][CH2:43][CH2:44][CH2:45][N:46]3[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:56])([CH3:58])[CH3:57])=[O:53])[CH2:48][CH2:47]3)[CH:10]=2)[C:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:7]1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1C(c2cccnc2)=C(c2ccccc2)c2ccc(O)cc21
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(c2cccnc2)=C3c2ccccc2)CC1
Reaction time: 19 h
Yield: 45 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 6-hydroxy-3-phenyl-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate instead of 4-(2-hydroxyethyl)morpholine, being stirred for 19 h, and being recrystallized with EtOAc to obtain the title compound (45%).
Reaction SMILES: [N:1]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([N:11]2[CH2:12][CH2:13][CH:8]([N:1]3[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]3)[CH2:9][CH2:10]2)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: OC1CCCN(C2CCNCC2)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCCC(O)C3)CC2)cc1

Procedure:
The compound was prepared from [1,4′]bipiperidinyl-3-ol (ChemBridge) and 4-fluoro-nitrobenzene (Aldrich) following the procedure used in Example 1. MS (m+H)+: 306.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:10]=1.Br[C:38]1[CH:39]=[C:40]([C:44]2([CH3:51])[NH:48][C:47](=[O:49])[NH:46][C:45]2=[O:50])[CH:41]=[CH:42][CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+].Cl>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C(#N)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:42]3[CH:41]=[C:40]([C:44]4([CH3:51])[NH:48][C:47](=[O:49])[NH:46][C:45]4=[O:50])[CH:39]=[CH:38][CH:43]=3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)(=[O:29])=[O:28])[CH:10]=1
Reactant: CC1(c2cccc(Br)c2)NC(=O)NC1=O
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: Cl
Solvent: CC#N
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C4(C)NC(=O)NC4=O)c3)cc12
Reaction time: 0.01 h
Yield: 50.3 %

Procedure:
To a mixture of 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.2 mmol) and 5-(3-Bromo-phenyl)-5-methyl-imidazolidine-2,4-dione (54 mg, 0.2 mmol) in a 5 mL microwave reaction flask was added THF (1 mL), acetonitrile (1 mL) and sodium carbonate (1 mL, 1 N aqueous solution, 1 mmol). The mixture was purged with nitrogen for 30 seconds. Dichloro[1,1′-bis(diphenylphoshino)ferrocene]palladium(II) dichloromethane adduct (16 mg, 0.02 mmol) was added and the purging continued for another 30 seconds. The flask was sealed and irradiated in a microwave reactor to 150° C. for 40 min. Saturated sodium chloride (5 mL) was added and the pH was adjusted to 7 using hydrochloric acid (1 N). The resulting mixture was extracted with ethyl acetate (5 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexane to afford 5-{3-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-5-methyl-imidazolidine-2,4-dione as a pale yellow solid (57 mg, 50% yield).
Reaction SMILES: O.[CH3:2][N:3]([CH3:17])[CH2:4][C@H:5]([C:14]([OH:16])=O)[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH3:18][CH:19]([CH3:34])[CH2:20][CH2:21][NH:22][C:23](=[O:33])[C@H:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH2:25]>O1CCCC1>[CH3:17][N:3]([CH3:2])[CH2:4][C@H:5]([C:14]([NH:25][C@H:24]([C:23]([NH:22][CH2:21][CH2:20][CH:19]([CH3:34])[CH3:18])=[O:33])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:16])[NH:6][C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8]
Reactant: CC(C)CCNC(=O)[C@@H](N)Cc1ccccc1
Reactant: CN(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](CN(C)C)NC(=O)OC(C)(C)C

Procedure:
By the method of part A of Example 1, in two runs, and using tetrahydrofuran instead of acetone as solvent 3-dimethylamino-N2 -(t-butoxycarbonyl)-D-alanine monohydrate (1.00 g., 716 mg.) was condensed with N-(3-methylbutyl)-L-phenylalaninamide (part D of Example 1, 1.05 g., 760 mg.). The products (2.06 g., 1.21 g.) were combined and purified by reverse phase high pressure liquid chromatography on octadecylsilated silica gel using ammonium acetate (0.2%) in methanol-water (70:30) as the eluant, affording [3-dimethylamino-N2 -(t-butoxycarbonyl)-D-alanyl]-N-(3-methylbutyl)-L-phenylalaninamide as an oil (1.96 g.).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][NH:3]1.[CH3:23][C:24]12[O:30][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29]2.[OH-].[Na+].O>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C1(C)C=CC=CC=1>[OH:30][C@:24]1([CH3:23])[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[N:3]1[C:2](=[O:1])[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4]1
Reactant: CC12CCCCC1O2
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@]1(O)CCCC[C@H]1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 25 °C
Yield: 6 %

Procedure:
A mixture of 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (2.25 g), 1-methyl-1,2-epoxycyclohexane (1.31 g), benzyltrimethylammonium chloride (178 mg), 1N aqueous sodium hydroxide (7.8 ml), water (17 ml), and toluene was heated to reflux for 8 hours and 20 minutes. After the reaction mixture was cooled to room temperature, the precipitates were collected by filtration, washed with water, and dried. The crude material was purified by column chromatography on silica gel (CH2Cl2 :EtOAc=10:2) to give colorless crystals of 3-[2-{(1R*,2R*)-2-hydroxy-2-methylcyclohexyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]-pyridine (189 mg).
Reaction SMILES: C(O)(=O)C.[CH2:5]([N:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.BrBr.[CH2:21]([OH:24])[CH2:22][OH:23]>O>[CH2:5]([N:12]1[CH:18]([O:23][CH2:22][CH2:21][OH:24])[C:16](=[O:17])[NH:15][C:13]1=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: OCCO
Reactant: O=C1CN(Cc2ccccc2)C(=O)N1
Agent: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)N(Cc2ccccc2)C1OCCO
Temperature: 80 °C
Yield: 69.3 %

Procedure:
500 ml of acetic acid was added to 57 g of 1-benzylhydantoin and, while maintaining at 80° C. with stirring, 50.3 g of bromine was dropwise added thereto. After completion of the dropwise addition, the solution was further stirred for 2 hours. The reaction solution was then cooled and, while cooling with ice, 56 g of ethylene glycol was added thereto. After stirring for 30 minutes, the solution was further stirred for 3 hours at room temperature. One liter of water was added to the reaction solution, followed by extraction with 500 ml of ethyl acetate. The extract was further washed twice with 500 ml of water. The thus obtained ethyl acetate solution was dried with sodium sulfate, concentrated, and purified by silica gel chromatography to obtain 52 g of 1-benzyl-5-(2-hydroxyethoxy)hydantoin. (Yield: 74%)
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:6][C:7]=1[CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1)[CH3:2].[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH2:1]([C:3]1[O:4][C:5]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=2)=[CH:6][C:7]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=1)[CH3:2]
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1COc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1COc1ccc(C(=O)O)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of {2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol (324 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (228 mg) in tetrahydrofuran (10 mL) were added tributylphosphine (0.6 mL) and 1,1′-(azodicarbonyl)dipiperidine (606 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give methyl 4-({2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzoate as a white solid. The obtained methyl 4-({2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzoate was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), 2N sodium hydroxide (2.0 mL) were added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate/hexane to give the title compound (236 mg, 86%).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([C:10](=[CH:16]N(C)C)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[C:23]([NH2:31])(=[NH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.O>C(O)CCC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:31]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:30]=2)=[CH:20][CH:21]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: N=C(N)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])cc1
Yield: 86.5 %

Procedure:
A mixture of ethyl 2-(4-nitrobenzoyl)-3-dimethylaminopropenoate (3 g), benzamidine hydrochloride (1.93 g) and triethylamine (2 ml) in n-butyl alcohol (30 ml) was refluxed for 30 min. The reaction mixture was poured into water (300 ml) and the precipitate was collected by filtration. The residue was recrystallized with diethyl ether to afford ethyl 4-(4-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (3.1 g).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH:7]([CH3:11])[C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.O[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:11][CH:7]1[O:6][C:5]2[CH:12]=[CH:13][C:2]([O:1][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)=[CH:3][C:4]=2[NH:9][C:8]1=[O:10]
Reactant: CC1Oc2ccc(O)cc2NC1=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1Oc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2NC1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 55.1 %

Procedure:
In a 40 mL vial, 6-hydroxy-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 394C (0.200 g, 1.116 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (0.225 g, 1.116 mmol), and PPh3 (0.439 g, 1.674 mmol) were suspended in THF (5.58 mL) to give a brown solution. The mixture was cooled to 0° C. To the cooled mixture was added DEAD drop-wise. The reaction was slowly warmed to 23° C. and stirred for 18 hr. The crude material was purified by prep HPLC-MS (45-85% MeCN in water). The fractions were collected and concentrated in vacuo to give the title compound (0.223 g, 55.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33-1.44 (m, 9H) 1.44-1.59 (m, 2H) 1.86 (ddd, J=9.47, 6.32, 3.16 Hz, 2H) 3.06-3.24 (m, 2H) 3.33-3.71 (m, 5H) 4.32-4.44 (m, 1H) 4.57 (q, J=6.65 Hz, 1H) 6.48 (d, J=2.78 Hz, 1H) 6.55 (dd, J=8.84, 2.78 Hz, 1H) 6.86 (d, J=8.59 Hz, 1H) 10.56 (s, 1H). ESI-MS: m/z 307.2 and 263.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23]O)[CH2:18][CH2:17]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:23][CH2:22][N:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: CN1CCN(CCO)CC1
Product: COc1cc2c(Cl)ncnc2cc1OCCN1CCN(C)CC1

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-7-hydroxy-6-methoxy-quinazoline and 2-(4-Methyl-piperazin-1-yl)-ethanol. LC/ESI-MS: m/z=337 [M+H].
Reaction SMILES: [C:1]12([S:11][CH2:12][CH2:13][NH:14][C@H:15]([C:17]([OH:19])=[O:18])[CH3:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(O)(=O)C.[N:24]([O-])=[O:25].[Na+]>O>[C:1]12([S:11][CH2:12][CH2:13][N:14]([N:24]=[O:25])[C@H:15]([C:17]([OH:19])=[O:18])[CH3:16])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: C[C@H](NCCSC12CC3CC(CC(C3)C1)C2)C(=O)O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H](C(=O)O)N(CCSC12CC3CC(CC(C3)C1)C2)N=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 22.7 parts of N-[2-(1- adamantylthio)ethyl]alanine in 216 parts of acetic acid is cooled to 15°, then treated with a solution of 6.2 parts of sodium nitrite in 20 parts of water, added dropwise over a 15 minute period. Stirring is continued at low temperature for an additional 15 minutes, then at room temperature for another 15 minutes. The resultant clear yellow solution is added to 1000 parts of ice-water and stirring is continued. The resultant mixture is extracted with methylene chloride. The organic phase is separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to yield, as a gumlike material, N-[2-(1-adamantylthio)ethyl]-N-nitrosoalanine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([C:24](=[O:28])[C:25]([OH:27])=O)[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:10]=1.[CH3:37][NH:38][CH3:39].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([C:24](=[O:28])[C:25]([N:38]([CH3:39])[CH3:37])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:35])[CH3:36])[N:10]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(=O)C(=O)O)c3)cc12
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(=O)C(=O)N(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of {3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-oxo-acetic acid. (100 mg, 0.20 mmol), dimethylamine (2 N in THF, 0.143 mL, 0.29 mmol), and diisopropylethylamine (37 mg, 0.29 mmol) in THF (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol.). The resulting suspension was heated to 60° C. with stirring until all was dissolved. The solvent was evaporated and the residue was used in next step without purification. MS: m/z 531 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:7]=1[C:8]#[N:9].Cl[C:21]1[CH:31]=[C:25]2[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:21]2[CH:31]=[C:25]3[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]3[C:23](=[O:32])[N:22]=2)=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(F)c(Cl)c1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(F)c(Cl)c3)c(C#N)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 2-(3-chloro-4-fluorophenoxy)-5-(hydroxymethyl)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]([OH:17])=[O:16])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH3:19]O>>[CH2:2]([N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]([O:17][CH3:19])=[O:16])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CO
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Agent: Cl
Product: COC(=O)C1CN(Cc2ccccc2)CCO1
Yield: 80 %

Procedure:
4-Benzylmorpholine-2-carboxylic acid hydrochloride (1.00 g, 3.88 mmol) in a 10 (w/w) % hydrochloric acid/methanol solution (20 mL) was stirred at room temperature for 2 hours. The solvent was evaporated and a saturated aqueous sodium bicarbonate solution was added to the residue to make the mixture basic. The mixture was then extracted with ethyl acetate and the extract washed with brine and was dried over magnesium sulfate. Evaporation of the solvent gave 730 mg (80%) of the desired compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:27])[CH:11]=2)[CH:6]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]([OH:26])[C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:27])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc(C(=O)c2ccc(S(C)(=O)=O)cc2)c2cc(F)ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1cc(C(O)c2ccc(S(C)(=O)=O)cc2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of [6-fluoro-4-(4-methanesulfonyl-benzoyl)-naphthalen-2-yl]-acetic acid methyl ester (103.5 mg, 0.26 mmol) (example 2-1, 4th step) in methanol (3 mL) was added sodium borohydride (30 mg, 0.78 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then partitioned between ethyl acetate and water. The collected organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (RediSep® Flash column, 230-400 mesh, 0-40% ethyl acetate in hexane) gave {6-fluoro-4-[hydroxy-(4-methanesulfonyl-phenyl)-methyl]-naphthalen-2-yl}-acetic acid methyl ester (90 mg, 86%) as a yellow oil. MS (ESI+) cald. for C21H19FO5S 402 [(M+H)+], obsd. 403.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]23[CH2:21][CH:19]([CH2:20]2)[C:18](=[O:22])[N:17]([CH2:23][CH2:24][CH3:25])[C:16]3=[O:26])=[CH:11][CH:10]=1>O1CCCC1.CN(C)C1C=CN=CC=1.C(O)C>[C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]23[CH2:20][CH:19]([CH2:21]2)[C:18](=[O:22])[N:17]([CH2:23][CH2:24][CH3:25])[C:16]3=[O:26])=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCCN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCCN1C(=O)C2CC(c3ccc(NC(C)=O)cc3)(C2)C1=O
Reaction time: 0.25 h

Procedure:
A solution of 0.11 ml of acetic anhydride in 0.5 ml of tetrahydrofuran is added dropwise to a solution of 260 mg of 1-(4-aminophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione and 6 mg of 4-dimethylaminopyridine in 8 ml of tetrahydrofuran. After stirring at room temperature for 21/2 hours, two drops of ethanol are added to the reaction mixture and stirring is continued for a further 15 minutes. After concentration by evaporation and subsequent recrystallisation from ethyl acetate/petroleum ether, the title compound is obtained in the form of white crystals having a melting point of 138.5°-139.5°. Rf (methylene chloride/methanol/glacial acetic acid 40:5:1)=0.55.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(N(C(C)C)CC)(C)C>C1COCC1>[C:27]([O:26][C:24]([N:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[CH2:17][NH:16][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: Clc1cccc(Nc2nccc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1ccnc(Nc2cccc(Cl)c2)n1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
To a solution of 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine (300 mg, 1.25 mmol) and tert-butyl 2-(aminomethyl)-piperidine-1-carboxylate (540 mg, 2.50 mmol) in THF (10 mL) is added diisopropylethyl-amine (0.43 mL, 2.50 mmol). The reaction is heated at reflux for 18 hours and then cooled to room temperature. The crude reaction is partitioned between EtOAc and sat. NaHCO3. The organic layer is dried (MgSO4), concentrated in vacuo, and purified over silica (MeOH/CH2Cl2) to afford 268 mg (51% yield) of the desired compound: MS (ESI, pos. ion) m/z: 418 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>CO>[CH3:1][C:2]1[N+:7]([O-:18])=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Cc1nc(N)cc(Cl)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Product: Cc1nc(Cl)cc(N)[n+]1[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
50.23 g (0.35 mol) of 2-methyl-4-amino-6-chloropyrimidine are partially dissolved in 700 ml of methanol. The mixture is cooled to 0° C. and 131.7 g (0.42 mol) of approximately 55% m-chloroperbenzoic acid are introduced, in small fractions, with good stirring, at a rate such that the temperature remains below 5° C. After the end of the introduction, the mixture is kept below 5° C. for a further 3 hours and is then allowed to return to ambient temperature. After 4 hours at 20° C., only traces of starting material still remain. The mixture is left to freeze overnight. The following day the precipitate is drained and washed with 30 ml of cold methanol. The precipitate is taken up in 120 ml of iced methanol, with stirring. The solid is drained and dried. 27.4 g of pure product having a melting point of 191° C. are obtained.