Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([OH:8])[CH2:5][CH:6]=[CH2:7].CCN(C(C)C)C(C)C.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.CCOCC>[CH2:5]([C:4]1([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[O:8][C:26](=[O:28])[NH:1][CH2:2][CH2:3]1)[CH:6]=[CH2:7]
Reactant: C=CCC(O)(CCN)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC1(c2ccc(F)cc2)CCNC(=O)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 265.7 %

Procedure:
A stirred solution of 1-amino-3-(4-fluorophenyl)hex-5-en-3-ol (53 mg, 0.25 mmol) and i-Pr2NEt (0.091 mL, 0.50 mmol) in CH2Cl2 (10 mL) was cooled in an ice bath and solid triphosgene (25 mg, 0.08 mmol) was added. The ice bath was allowed to melt and the mixture was stirred at rt for 6 h. The mixture was diluted with ether (80 mL), washed with 5% aq HCl (20 mL) and satd aq NaHCO3 (20 mL), and dried over MgSO4. Removal of the solvent afforded 6-allyl-6-(4-fluorophenyl)-1,3-oxazinan-2-one (50 mg, 84%) as an oil, which was used without further purification. LC-MS Method 1 tR=1.32 min, m/z=236.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1.[N:31]1([C:37]2[N:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27][N:34]3[CH2:35][CH2:36][N:31]([C:37]4[N:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=4)[CH2:32][CH2:33]3)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1
Reactant: c1ccc2nc(N3CCNCC3)ncc2c1
Reactant: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)cc1
Product: COc1ccc(CNC(=O)C2(CCCCN3CCN(c4ncc5ccccc5n4)CC3)c3ccccc3-c3ccccc32)cc1

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-methoxy-benzylamide and 2-piperazin-1-yl-quinazoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=O)=[CH:15][CH:16]=3)[C:11](=[O:33])[NH:10][N:9]=2)[CH:7]=1.[N:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[N:38][CH:37]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:42][C:39]4[CH:40]=[CH:41][N:36]=[CH:37][N:38]=4)(=[O:21])=[O:20])=[CH:15][CH:16]=3)[C:11](=[O:33])[NH:10][N:9]=2)[CH:7]=1
Reactant: Nc1ccncn1
Reactant: COc1ccc(Cl)cc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reaction time: 2 h
Yield: 25.8 %

Procedure:
A vial was charged with perfluorophenyl 1-(5-chloro-2-methoxyphenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (From Step 6, Example 501; 126 mg, 0.236 mmol), pyrimidin-4-amine (33.7 mg, 0.355 mmol), and THF (1.18 mL). The resulting solution was cooled in an ice-water bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (591 μl, 0.591 mmol) was added drop wise. LCMS after 2 h showed complete conversion of SM to product. The reaction was quenched with 1 mL of MeOH. Purification was done via RPLC with 0.1% NH4OH in ACN and water as mobile phase to afford 1-(5-chloro-2-methoxyphenyl)-4-oxo-N-(pyrimidin-4-yl)-3,4-dihydrophthalazine-6-sulfonamide (27 mg, 25.7% yield). m/z (ESI) 444.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[C:35]4[C:40](=[CH:41][CH:42]=3)[N:39]=[CH:38][C:37]([F:43])=[CH:36]4)=[CH:29][C:28]=2[CH3:44])[C:23]([F:26])([F:25])[F:24])[N:3]=1.Br[C:46]1C=CC(C(O)=O)=C(CC)C=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:19][CH2:20]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[C:35]4[C:40](=[CH:41][CH:42]=3)[N:39]=[CH:38][C:37]([F:43])=[CH:36]4)=[CH:29][C:28]=2[CH2:44][CH3:46])[C:23]([F:24])([F:26])[F:25])[N:3]=1
Reactant: CCc1cc(Br)ccc1C(=O)O
Reactant: Cc1cc(-c2ccc3ncc(F)cc3c2)ccc1[C@@H](Oc1cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)nc(N)n1)C(F)(F)F
Product: CCc1cc(-c2ccc3ncc(F)cc3c2)ccc1[C@@H](Oc1cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)nc(N)n1)C(F)(F)F

Procedure:
The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-fluoroquinolin-6-yl)-2-methylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 59c) starting with 4-bromo-2-ethylbenzoic acid in place of 4-bromo-2-methylbenzoic acid.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:37]=[O:38])[O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[C:8]([N:10]2[C@H:14]([C:15]([OH:17])=O)[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.CCN(C(C)C)C(C)C.[N:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[C:66]1[CH:71]=[CH:70][N:69]=[C:68]([NH2:72])[N:67]=1>C1COCC1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:37]=[O:38])[O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[C:8]([N:10]2[C@H:14]([C:15]([NH:72][C:68]3[N:67]=[C:66]([C:61]4[CH:62]=[CH:63][CH:64]=[CH:65][N:60]=4)[CH:71]=[CH:70][N:69]=3)=[O:17])[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nccc(-c2ccccn2)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OC1CCCCO1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2nccc(-c3ccccn3)n2)CCN1C(=O)OCc1ccccc1)OC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
To a solution of (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (800 mg, 1.5 mmol) in THF (10 mL) under N2 was added 2,4,6-trichlorobenzoyl chloride (477 mg, 2 mmol) and DIPEA (1.3 mL, 7.5 mmol). The mixture was stirred at rt for 2 h. THF was removed under vacuum and toluene (10 mL) was added. To this mixture was added 4-(2-pyridinyl)-2-pyrimidinamine (337 mg, 2 mmol) and DMAP (37 mg, 0.3 mmol). After being stirred at rt overnight, the mixture was diluted with EtOAc (50 mL) and washed with 5% citric acid and sat. NaHCO3. The organic solution was dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography to provide the title compound (400 mg, 39%).
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11]([CH:13](P(OC)(OC)=O)[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:12].[N+:31]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[N+:42]([O-:44])=[O:43])[CH:37]=O)([O-:33])=[O:32]>O1CCCC1>[CH3:9][O:10][C:11](=[O:12])[C:13]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])=[CH:37][C:36]1[CH:39]=[CH:40][C:41]([N+:42]([O-:44])=[O:43])=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: O=Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,1,3,3-Tetramethylguanidine (41.2 mL, 329 mmol) was added at room temperature to a solution of N-(benzyloxycarbonyl)-alpha-phophonoglycine trimethyl ester (114.1 g, 344 mmol) in tetrahydrofuran (800 mL). The mixture was stirred at room temperature for 15 min and cooled to −78° C. A solution 3,4-dinitro-benzaldehyde (61.4 g, 313 mmol) in tetrahydrofuran (200 mL) was slowly added via cannula. The resulting mixture was stirred at −78° C. for 2 h and then allowed to warm to room temperature overnight. Solvents were removed in vacuo, and the yellow residue was dissolved in 4.5 L of ethyl acetate. The solution was washed with 1.5 L of 1N sulfuric acid, water twice, brine and dried over sodium sulfate. After filtration, solvents were removed in vacuo and the residue was crystallized from ethyl acetate (20 g crude product/100 mL of ethyl acetate). The yellow crystals were collected and further purified by chromatography on silica gel using methylene chloride as eluent. The title compound was obtained a s yellow crystals (77%). 1H-NMR (CDCl3, 500 MHz) δ 7.85 (d, J=1.5 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.62 (dd, J=8.5, 1.5 Hz, 1H), 7.35-7.34 (m, 3H), 7.34 (br s, 2H), 7.23 (s, 1H), 6.95 (br s, 1H), 5.07 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:16])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4].[NH2:17][CH2:18][C:19]([OH:21])=[O:20].C[O-].[Na+]>CN(C=O)C>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7][C:6](=[O:16])[C:5]=1[C:3]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:4]
Reactant: NCC(=O)O
Reactant: COC(=O)c1c(O)c2ccccc2oc1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1c(O)c2ccccc2oc1=O
Yield: 42.5 %

Procedure:
To a mixture of 4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (150 mg, 0.68 mmol) in DMF (12 mL) was added glycine (1.03 g, 13.6 mmol) and NaOMe (0.5 M in MeOH, 20.4 mL, 10.2 mmol) at rt. It was concentrated in an evaporator to remove most MeOH solvent. The resulting mixture was refluxed for 2 h. After cooled, it was diluted with water (100 mL) and acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo. Crude solid was triturated in hexanes, and solid product was collected and dried to give the title compound (76 mg). MS ESI(+) m/e: 264 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.[C:26]1(=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C:18]([C:4]2[CH:3]=[C:2]([C:26]3([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[CH:19][CH2:20]1
Reactant: O=C1CCCC1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Product: CC1(C)CC=C(c2cc(C3(O)CCCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1 step (g)) and cyclopentanone. Mass spectrum (ESI, m/z): Calcd. for C24H28N4O2, 405.2 (M+H). found 405.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:7][CH:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[C:17]([NH:19][C:20]4[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=4)[CH:16]=[C:15]([CH3:30])[CH:14]=3)=[CH:11][N:12]=2)[CH2:5][CH2:4][CH:3]1[C:31]([O:33]C)=[O:32].[OH-].[Na+].Cl>CO>[CH3:1][C:2]1([CH3:35])[CH2:7][CH:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[C:17]([NH:19][C:20]4[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=4)[CH:16]=[C:15]([CH3:30])[CH:14]=3)=[CH:11][N:12]=2)[CH2:5][CH2:4][CH:3]1[C:31]([OH:33])=[O:32]
Reactant: COC(=O)C1CCC(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3CCC(C(=O)O)C(C)(C)C3)s2)c1
Temperature: 100 °C

Procedure:
The product from Step 2 (87 mg, 0.17 mmol) was dissolved in methanol (2.9 ml) and 1 M aqueous sodium hydroxide (0.8 ml, 0.8 mmol) was added. The reaction was heated overnight at 100° C. The reaction was then cooled, acidified with hydrochloric acid (2 M in H2O, 0.4 mL) and then concentrated under reduced pressure to afford crude 2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid that was used in the next step without further purification.
Reaction SMILES: C[O-].[Na+].CO.[C:6](=[O:11])([O:9][CH3:10])OC.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:16]=[C:17]([Cl:19])[CH:18]=1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]([C:6]([O:9][CH3:10])=[O:11])[C:21]([O:23][CH3:24])=[O:22])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: COC(=O)Cc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(C(=O)OC)c1cc(Cl)cc(Cl)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A mixture sodium methoxide in methanol (28.46 g, 25%, 0.132 mol) and toluene (150 mL) was boiled with provision of a five plate Oldershaw column to remove the methanol/toluene azeotrope. The mixture was cooled to 60° C. and toluene (a volume equal to the total volume of the distillate) was added to the mixture. Dimethyl carbonate (35.95 g, 0.399 mol) was added to the reaction mixture. Methyl 3,5-dichlorobenzeneacetate (i.e. the product from Step A1b) (22.2 g, 0.101 mol) in toluene (17 mL) was added to the mixture over 70 min. When the addition was complete the mixture was stirred for a further 60 min at 60° C. The mixture was boiled and the dimethyl carbonate/methanol azeotrope was removed using the Oldershaw column. The mixture was cooled to 25° C. and acetic acid (9.5 g, 0.158 mol) was added dropwise. Water (100 mL) was added to the mixture and the organic phase separated and removed under reduced pressure. Crystallisation of the resulting residue from methanol (36 mL) gave the product as a white solid (23.9 g, 85%) melting at 72-73° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:18])[N:3]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:5]=[C:4]([Br:18])[N:3]=[C:2]([NH:31][CH2:30][CH2:29][CH2:28][CH2:27][NH:26][C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:7]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCCCNc1cc(S(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Temperature: 60 °C
Reaction time: 18 h
Yield: 72.1 %

Procedure:
0.39 g (0.001 mol) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine was dissolved in 10 ml of dioxane and treated with 1.9 ml (0.01 mol) of N-tert.-butoxycarbonyl-1,4-diaminobutane. The mixture was stirred at 60° C. for 18 hrs., the solvent was removed and the residue was chromatographed on silica gel with ethyl acetate/hexane 1:1. There was obtained 0.36 g (77%) of tert-butyl [4-[4-(4-aminobenzenesulphonyl)-6-bromopyridin-2-ylamino]-butyl]-carbamate as a pale yellow oil. MS (ISP): me/e=501, 499 (C20H26BrN4O4S+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:4][C:3]=1[Br:16].[NH:17]1[CH2:22][CH2:21][CH:20]([N:23]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:25][C:24]2=[O:34])[CH2:19][CH2:18]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[K+].[Br-].BrBr>O.O1CCCC1>[NH2:1][C:2]1[C:3]([Br:16])=[CH:4][C:5]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[CH:27]=[C:26]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:25][C:24]3=[O:34])[CH2:21][CH2:22]2)=[O:14])=[CH:6][C:7]=1[Br:8]
Reactant: Nc1c(Br)cc(C(=O)CCC(=O)O)cc1Br
Reactant: O=c1[nH]c(-c2ccccc2)cn1C1CCNCC1
Agent: BrBr
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c(Br)cc(C(=O)CCC(=O)N2CCC(n3cc(-c4ccccc4)[nH]c3=O)CC2)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.0 g (2.849 mmol) of 4-amino-3,5-dibromo-γ-oxo-benzenebutanoic acid, 1.04 g (2.91 mmol) of 1,3-dihydro-1-(4-piperidinyl)-4-phenyl-2(2H)-imidazolone, 0.935 g (2.912 mmol) of TBTU, 1.02 ml (5.77 mmol) of DIEA and 50 ml of tetrahydrofuran was stirred for 1 hour at ambient temperature. The reaction mixture was diluted with 300 ml of water and acidified slightly with citric acid. The precipitate formed was suction filtered and washed carefully with water, then with 3 ml of tetrahydrofuran, and finally dried in a circulating air dryer at a temperature of 60° C. 1.3 g (79% of theoretical) of a colourless, crystalline product were obtained, Rf 0.47 (El A). IR (KBr): 1679.9 cm−1 (C═O) MS: M+=574/576/578 (Br2)
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][CH:20]=2)=[N:9][S:10][C:11]=1[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=O)=O.O[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[C:30]([CH3:41])[C:29]=1[CH3:42]>>[CH2:25]([C:22]1[CH:23]=[CH:24][C:19]([C:8]2[C:7]([CH2:6][O:5][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[C:30]([CH3:41])[C:29]=3[CH3:42])=[C:11]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[S:10][N:9]=2)=[CH:20][CH:21]=1)[CH3:26]
Reactant: CCc1ccc(-c2nsc(C(F)(F)C(F)(F)F)c2COS(C)(=O)=O)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: CCc1ccc(-c2nsc(C(F)(F)C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 following Step 5 and 6 by coupling [3-(4-ethylphenyl)-5-(pentafluoroethyl)-1,2-thiazol-4-yl]methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate to afford the desired product as an off-white solid. 1H-NMR (300 MHz, CD3OD) δ 7.60 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 6.97 (d, J=8.4 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H), 5.03 (s, 2H), 2.91 (t, J=8.1 Hz, 2H), 2.68 (q, J1=15.3 Hz, J2=7.5 Hz, 2H), 2.51 (t, J=8.4 Hz, 2H), 2.23 (s, 3H), 2.03 (s, 3H), 1.02 (t, J=7.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C25H24F5NO3S, 514.1 (M+H). found 514.1.
Reaction SMILES: Br.[CH3:2][O:3][C:4]([C:6]1[CH2:7][NH:8][CH2:9][CH2:10][CH:11]=1)=[O:5].C(N(C(C)C)C(C)C)C.Br[CH2:22][CH:23]1[O:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[O:25][CH2:24]1>CN(C)C=O>[CH3:2][O:3][C:4]([C:6]1[CH2:7][N:8]([CH2:22][CH:23]2[O:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[O:25][CH2:24]2)[CH2:9][CH2:10][CH:11]=1)=[O:5]
Reactant: BrCC1COc2ccccc2O1
Reactant: COC(=O)C1=CCCNC1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1=CCCN(CC2COc3ccccc3O2)C1
Reaction time: 16 h
Yield: 74.3 %

Procedure:
First 11.1 g (50 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrobromide (guvacoline hydrobromide) and then 22.6 g (175 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 11.45 g (50 mmol) of 2-bromomethylbenzo-1,4-dioxan (U.S. Pat. No. 2,366,102) in 100 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 50° and then concentrated by evaporation under a high vacuum. Water is added to the residue and extraction is carried out with diethyl ether. The organic phases are washed with water and extracted by shaking with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 10.75 g (74.4%) of 1-(benzo-1,4-dioxan-2-ylmethyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester are obtained in the form of a yellow oil. The 1-(benzo-1,4-dioxan-2-ylmethyl)-1,2,5,6-tetrahydropyridine- 3-carboxylic acid methyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from methanol/diethyl ether and decomposes at 215°-217°.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:25])[C:9]=1[NH:10][C:11]1[C:20]2[C:15](=[C:16]([OH:23])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[O:14][C:13](=[O:24])[CH:12]=1.[Br:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.OP([O-])(O)=O.[K+]>CS(C)=O>[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][O:23][C:16]1[C:17]([O:21][CH3:22])=[CH:18][CH:19]=[C:20]2[C:15]=1[O:14][C:13](=[O:24])[CH:12]=[C:11]2[NH:10][C:9]1[C:8]([Cl:25])=[CH:7][N:6]=[CH:5][C:4]=1[Cl:3]
Reactant: BrCCCCBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCBr
Reaction time: 0.08 h

Procedure:
Sodium hydride (31 mg, 0.78 mmol) was added to a solution of 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (111 mg, 0.31 mmol, Example 29) and DMSO (2 mL) at rt under N2. After 5 min, 1,4-dibromobutane (0.05 mL, 0.42 mmol) was added. After 3 h, the reaction was poured into 1M KH2PO4 (30 mL) and extracted with ethyl acetate (40 mL×2). The combined extracts were dried, filtered, concentrated, and purified by silica gel chromatography (3:2→1:4; hexanes:ethyl acetate) to give 8-(4-bromobutoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one: 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.81 (s, 2H), 7.95 (d, 1H), 7.21 (d, 1H), 4.64 (s, 1H), 4.01 (t, 2H), 3.92 (s, 3H), 3.63 (t, 2H), 2.05 (m, 2H), 1.80 (m, 2H); MS (ESI): 486.8.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:27])=[CH:11][C:12]([NH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:13]([CH:19]=1)[C:14]([O:16]CC)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)(C)C.O>[CH2:1]([O:8][C:9]1[C:10]([F:27])=[CH:11][C:12]([NH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:13]([CH:19]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)c(F)cc1NC1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1cc(OCc2ccccc2)c(F)cc1NC1CCOCC1
Yield: 98.4 %

Procedure:
A mixture of 1.0 g of the compound obtained in Step 4.3 and 0.45 g of KOH in 16 ml of isopropanol and 4 ml of water is irradiated in a microwave field for 20 minutes at 130° C. The reaction medium is evaporated under reduced pressure. Water is added, the resulting mixture is acidified with aqueous 1N HCl solution to pH 3 and this mixture is extracted with EtOAc. The organic phase is dried over Na2SO4 and filtered, and the filtrate is evaporated under reduced pressure to give 0.91 g of the expected product.
Reaction SMILES: Cl.[CH3:2][C@H:3]([O:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[C:13]([O:28]C)[N:14]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:10]([NH2:30])[N:9]=1)[CH2:4][CH2:5][CH3:6]>O1CCOCC1.CO>[NH2:30][C:10]1[N:9]=[C:8]([O:7][C@@H:3]([CH3:2])[CH2:4][CH2:5][CH3:6])[N:16]=[C:15]2[C:11]=1[NH:12][C:13](=[O:28])[N:14]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCN3CCCCC3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCC[C@H](C)Oc1nc(N)c2[nH]c(=O)n(CCCCCN3CCCCC3)c2n1
Reaction time: 8 h
Yield: 83.3 %

Procedure:
A solution of hydrogen chloride in dioxane (4M, 0.71 ml) was added to a solution of 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[5-(1-piperidinyl)pentyl]-9H-purin-6-amine (0.046 g, 0.126 mmol) in methanol (3 ml). The resultant mixture was allowed to stand overnight at room temperature and then blown down under nitrogen. The residue was dissolved in methanol and loaded onto a 2 g aminopropyl SPE cartridge (pre-conditioned with methanol), eluted with methanol and the resultant solution blown down under nitrogen to give the title compound as a yellow solid (40.97 mg).