Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.C([O:18][C:19](=[O:38])[C@H:20]([CH2:34][CH:35]([CH3:37])[CH3:36])[NH:21]C(OC1C=CC([N+]([O-])=O)=CC=1)=O)(C)(C)C>CN(C=O)C>[N:8]1([C:6]([NH:21][C@H:20]([C:19]([OH:38])=[O:18])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:7])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: CC(C)C[C@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)N1CCNCC1)C(=O)O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(tert-butoxycarbonyl)piperazine (60 mg, 0.036 mmol) and N-(4-nitrophenoxycarbonyl)-L-leucine tert-butyl ester (128 mg, 0.36 mmol) in DMF was stirred at 60° C. for 1 h. concentrated in vacuo and the residue treated with 4 M HCl in dioxane (5 ml) for 16 h. The mixture was concentrated in vacuo, azeotroped with toluene and treated with 4 M HCl in dioxane (5 ml) for 16 h. The mixture was concentrated in vacuo to afford the title compound.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[O:5]1[C:9]2([CH2:14][CH2:13][CH:12]([N:15]3[CH:19]=[C:18]([C:20]4[CH:21]=[C:22]([NH:27][C:28]5[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=5)[CH:23]=[C:24]([CH3:26])[CH:25]=4)[CH:17]=[N:16]3)[CH2:11][CH2:10]2)OCC1.CS(O)(=O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH3:26][C:24]1[CH:25]=[C:20]([C:18]2[CH:17]=[N:16][N:15]([CH:12]3[CH2:11][CH2:10][NH:1][C:9](=[O:5])[CH2:14][CH2:13]3)[CH:19]=2)[CH:21]=[C:22]([NH:27][C:28]2[N:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[CH:30][N:29]=2)[CH:23]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C3CCC4(CC3)OCCO4)c2)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C3CCNC(=O)CC3)c2)c1
Temperature: 65 °C

Procedure:
Sodium azide (155 mg, 2.39 mL) was added to a solution of N-{3-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-4-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (732 mg, 1.59 mmol) in chloroform (8.0 mL) followed by methanesulfonic acid (1.24 mL, 19.1 mmol). The reaction was heated to 65° C. for 2 h. The reaction was cooled to room temperature and water was added, followed by NaOH (1N). The organic layer was extracted with EtOAc (3×). The combined layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10% methanol/dichloromethane) to afford racemic 5-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]azepan-2-one as a white solid. MS ESI calcd. for C21H21F3N6O [M+H]+ 431. found 431.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].S(=O)(=O)(O)O.[C:22]([OH:26])(=[O:25])[CH:23]=[CH2:24]>O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Pd+2]>[Cl:16][C:14]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH:24]=[CH:23][C:22]([OH:26])=[O:25])[CH:15]=1
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: C=CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: O=N[O-]
Solvent: O
Product: COC(=O)c1ccc(Cl)cc1C=CC(=O)O
Reaction time: 0.33 h

Procedure:
At 2° C., a solution of 5.96 g of sodium nitrite in 11.3 ml of water is added to a mixture of 14 g of methyl 2-amino-4-chlorobenzoate, 59 ml of water and 14.3 ml of concentrated sulfuric acid. The reaction mixture is subsequently stirred for 20 minutes and then added a little at a time to 6.9 g of acrylic acid, 57 mg of palladium acetylacetonate being added after the first portion. After 4 hours at 40° C., the precipitated solid is filtered off, giving, after washing and drying, 18.5 g of methyl 4-chloro-2-(3-hydroxy-3-oxo-1-propenyl)-benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:31][C:32]([O:34]CC)=[O:33])[CH:5]=[CH:6][C:7]=1[N:8]1[C:16](=[O:17])[C:15]2[C:14]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:13]3[CH:24]=[CH:25][CH:26]=[CH:27][C:12]3=[C:11]([O:28][CH2:29][CH3:30])[C:10]=2[CH2:9]1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:31][C:32]([OH:34])=[O:33])[CH:5]=[CH:6][C:7]=1[N:8]1[C:16](=[O:17])[C:15]2[C:14]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:13]3[CH:24]=[CH:25][CH:26]=[CH:27][C:12]3=[C:11]([O:28][CH2:29][CH3:30])[C:10]=2[CH2:9]1
Reactant: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC(F)(F)F)c4ccccc4c3OCC)C2=O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1c2c(c(OCC(F)(F)F)c3ccccc13)C(=O)N(c1ccc(CC(=O)O)cc1Cl)C2
Temperature: 25 °C
Yield: 37.5 %

Procedure:
Ethyl (3-chloro-4-{4-(ethyloxy)-1-oxo-9-[(2,2,2-trifluoroethyl)oxy]-1,3-dihydro-2H-benzo[f]isoindol-2-yl}phenyl)acetate (0.041 g, 0.08 mmol) was heated to reflux in a 1:1 mixture of 2N sodium hydroxide:ethanol (10 ml) for 1 hour. The reaction was cooled to room temperature. The ethanol was evaporated and the mixture acidified with HCl (2N). The resulting white solid was collected by filtration, washed with water and dried under vacuum. This was purified by MDAP to give the title compound (0.014 g, 0.03 mmol) as a clear foam. LC/MS: Rt=3.42, [MH]+ 494.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].I[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:42])[C:40]#[CH:41])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1>C1COCC1.[Cu]I>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:42])[C:40]#[C:41][C:8]3[CH:13]=[CH:12][C:11]([C:14]4([NH:17][C:18]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])[CH2:16][CH2:15]4)=[CH:10][CH:9]=3)=[CH:34][CH:33]=2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(I)cc2)CC1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(C#CC(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.4 g (4.2 mmol) of cesium carbonate and 0.5 g (1.4 mmol) of tert-butyl [1-(4-iodophenyl)cyclopropyl]carbamate are placed in 20 mL of THF and cooled to −15° C. in the ice/methanol bath, rinsed with argon, and degassed. To this reaction mixture is added successively 160 mg (0.14 mmol) of tetrakistriphenylphosphine palladium and 30 mg (0.158 mmol) of copper (I) iodide and the mixture is again degassed. 0.5 g (1.4 mmol) of propynoic acid-(4′-chlorobiphenyl-4-yl)amide is finally added. The mixture is stirred for 24 hours at ambient temperature and the reaction mixture is then evaporated down. The residue is triturated with water and ethyl acetate, suction filtered, washed with ethyl acetate, and dried in the air. Yield: 0.4 g (59% of theory); C29H27ClN2O3 (M=486.99); calc.: molecular ion peak (M+H)+: 487/89 (Cl); found: molecular ion peak (M+H)+: 487/89 (Cl); Rf value: 0.62 (silica gel, cyclohexane/ethyl acetate (1:1)).
Reaction SMILES: OC1C=C(O)C=C[C:3]=1[CH:9]([C:20]([CH:22]([C:33]1[CH:38]=CC(O)=CC=1O)[C:23]1C=CC(OC)=[C:25]([O:31]C)[CH:24]=1)=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.C([O:43]C([O-])[O-])C.N1CCOCC1>CN(C)C=O>[OH:31][C:25]1[CH:24]=[C:23]2[C:22]([C:20](=[O:21])[C:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=3)=[CH:3][O:43]2)=[CH:33][CH:38]=1
Reactant: COc1ccc(C(C(=O)C(c2ccc(OC)c(OC)c2)c2ccc(O)cc2O)c2ccc(O)cc2O)cc1OC
Reactant: CCOC([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1OC

Procedure:
14.4 g (0.05 mole) of 2,4-dihydroxy-phenyl-(3',4'-dimethoxy-benzyl)-ketone are reacted with 10.5 g (0.07 mole) ethyl-orthoformate in 10 ml of dimethyl-formamide in the presence of 1 ml morpholine. The reaction mixture is maintained at 80°-85° C., and in the second hour a solid precipitates. After 6 hours 1OO ml of chloroform are added to the mixture, the precipitated substance is filtered and dried. 7-hydroxy-3',4'-dimethoxy-isoflavone is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[C:13](OC(=O)C)(=[O:15])[CH3:14]>O>[C:13]([NH:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(N)cc1O
Solvent: O
Product: COC(=O)c1ccc(NC(C)=O)cc1O
Temperature: 25 °C
Yield: 57.4 %

Procedure:
To a suspension of 4.17 g (0.025 mole) methyl 4-aminosalicylate (9) in 20 mL water, was added 3 mL (0.032 mole) acetic anhydride (Aldrich 11,004-3) while stirring. The mixture was heated at 80° for 30 minutes and cooled to room temperature. The precipitate was collected and added into 100 ml of 10% hydrochloric acid. This suspension was stirred at room temperature for 10 minutes, filtered and dried to give 4.3 g (82%) of a crude solid, which was recrystallized from H2O/CH3OH, yielding 3 g (70%) of 10 as white crystals, mp 153-154°. Infrared (IR) and NMR analysis gave the following results:
Reaction SMILES: Cl.CO[C:4](=[O:18])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[OH-].[NH4+:20]>>[OH:17][C:14]1[CH:15]=[C:16]2[C:11]([NH:10][CH:9]=[C:8]2[CH2:7][C@@H:5]([C:4]([NH2:20])=[O:18])[NH2:6])=[CH:12][CH:13]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccc(O)cc12
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: NC(=O)[C@@H](N)Cc1c[nH]c2ccc(O)cc12

Procedure:
(S)-5-Hydroxytryptophan methyl ester hydrochloride (0.247 g, 0.91 mmol) was stirred overnight at room temperature in ammonium hydroxide (10 mL). After removal of volatiles under vacuum, the title compound of example 44 was obtained as a dark solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([CH3:24])[CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Br)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Br)cc12
Reaction time: 3 h
Yield: 24.5 %

Procedure:
The 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide (48.2 mg, 0.105 mmol) obtained in Example 2 was dissolved in N,N′-dimethylformamide (1.0 mL). Thereafter, potassium carbonate (43.5 mg, 0.315 mmol) and methyl iodide (30.0 mg, 0.210 mmol) were added to the above obtained solution at room temperature, and the obtained mixture was then stirred for 3 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with methylene chloride. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain the captioned compound (11.0 mg, 35%) in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.CC1(C)O[C:18](=[O:19])[CH2:17][C:15](=[O:16])[O:14]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:18](=[O:19])[CH2:17][C:15]([OH:16])=[O:14])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: Cc1ccccc1
Product: O=C(O)CC(=O)Nc1ccc(Br)cc1C(=O)O
Yield: 0.1 %

Procedure:
5-Bromoanthranilic acid (0.30 g, 1.4 mmol) was added to a solution of Meldrum's acid (0.24 g, 1.7 mmol) in toluene (5.0 mL) and treated according to Procedure 1. 5-Bromo-2-[(carboxyacetyl)amino]benzoic acid (0.34 mg, 81%) was obtained as a pale brown solid; δH (500 MHz, DMSO-d6) 3.48 (s, 2H, CH2), 7.78 (d, J3,4=8.4 Hz, 1H, H4), 8.04 (s, 1H, H6), 8.40 (d, J3,4=8.4 Hz, 1H, H3), 11.20 (s, 1H, NH), 12.80 (br s, 1H, CO2H); δC (125 MHz, DMSO-d6) 44.7, 114.5, 119.4, 122.5, 133.1, 136.4, 139.4, 164.7, 167.8, 168.9.
Reaction SMILES: [CH:1]([C@H:4]1[NH:9][CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2].Cl[C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:1]([C@H:4]1[N:9]([C:26]2[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=2)[CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Reactant: FC(F)(F)c1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1nccc(C(F)(F)F)n1)[C@@H]3C(C)C
Temperature: 150 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
A mixture of (R)-methyl 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (0.9 g, 2.56 mmol), 2-chloro-4-(trifluoromethyl)pyrimidine (1.0 g, 5.1 mmol, 2 eq.) and DIEA (1.0 g, 7.7 mmol, 3 eq.) in i-PrOH (6 mL) was stirred in a microvave oven at 150° C. for 2 h. TLC showed the starting material was consumed completely (PE:EtOAc=3:1). The solvent was removed in vacuo at 40° C., and the residue was purified by column chromatography on silica gel eluting with PE/EtOAc=6/1 to give (R)-methyl 1-isopropyl-7-(methylsulfonyl)-2-(4-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (1.0 g, 78% yield) as a white solid. LC-MS m/z 498.1 [M+H]+. 1H NMR (CDCl3 300 MHz): δ 8.52 (d, J=4.8 Hz, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 6.83 (d, J=4.8 Hz, 1H), 6.06 (d, J=7.8 Hz, 1H), 5.39-5.28 (m, 1H), 4.33-4.24 (m, 1H), 4.20-4.12 (m, 1H), 3.93 (s, 3H), 3.77-3.65 (m, 1H), 3.39 (s, 3H), 2.52-2.38 (m, 1H), 1.25 (d, J=6.9 Hz, 3H), 1.02 (d, J=6.6 Hz, 3H).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][NH:23][C:24]1[C:25]([O:36][C:37]2[CH:42]=[CH:41][C:40]([CH2:43]O)=[CH:39][CH:38]=2)=[N:26][C:27]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[N:28][CH:29]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][NH:23][C:24]1[C:25]([O:36][C:37]2[CH:42]=[CH:41][C:40]([CH2:43][F:7])=[CH:39][CH:38]=2)=[N:26][C:27]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[N:28][CH:29]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1cnc(-c2cccnc2)nc1Oc1ccc(CO)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1cnc(-c2cccnc2)nc1Oc1ccc(CF)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
To a solution of (diethylamino)sulfur trifluoride (0.036 mL; 0.28 mmol) in CH2Cl2 (2 mL), cooled to −78° C., was added a solution of Compound 18b (100 mg; 0.21 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred at −78° C. for 20 min. The resultant mixture was partitioned between EtOAc and H2O. The organic phase was washed with water and dried over Na2SO4. The mixture was filtered and the solvent removed under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 18c (50 mg; 50% yield). MS: m/z 480.2 (M+H)+.
Reaction SMILES: Cl[C@H:2]1[N:5]([C:6](=[C:11]([CH3:13])[CH3:12])[C:7]([O:9][CH3:10])=[O:8])[C:4](=[O:14])[C@@H:3]1[N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C[Si]([CH2:30][C:31](=[CH2:37])[CH2:32][C:33]([O:35][CH3:36])=[O:34])(C)C.[Cl-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C.F[B-](F)(F)F.[Ag+]>[CH3:36][O:35][C:33]([CH2:32][C:31](=[CH2:30])[CH2:37][C@H:2]1[N:5]([C:6](=[C:11]([CH3:13])[CH3:12])[C:7]([O:9][CH3:10])=[O:8])[C:4](=[O:14])[C@@H:3]1[N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])=[O:34]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](N2C(=O)c3ccccc3C2=O)[C@H]1Cl
Reactant: C=C(CC(=O)OC)C[Si](C)(C)C
Agent: [Ag+]
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=C(CC(=O)OC)C[C@@H]1[C@@H](N2C(=O)c3ccccc3C2=O)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 79.6 %

Procedure:
Silver tetrafluoroborate (323 mg) was added to a stirred mixture of methyl 2-[(3S,4R)-4-chloro-2-oxo-3-phthalimidoazetidin-1-yl]-3-methylbut-2-enoate (500 mg) and methyl 3-(trimethylsilylmethyl)-but-3-enoate (460 mg) in dichloromethane (2.5 ml) at -78° C. under a nitrogen atmosphere. The stirring mixture was gradually allowed to warm to 0° C. during one hour and kept at 0° C. for 1.5 hours. A saturated aqueous sodium chloride (2 ml) was added and the heterogeneous mixture was brought to pH 7 with a saturated aqueous sodium bicarbonate. After stirring for 15 minutes, the mixture was diluted with ethyl acetate and filtered through a pad of Celite. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (10 g) eluting with a mixture of benzene and acetone (5:1). Further purification on a silica gel (10 g) eluting with 10-20% ethyl acetate in dichloromethane) afforded methyl 2-[(3R,4R)-4-[2-(methoxycarbonylmethyl)allyl]-2-oxo-3-phthalimidoazetidin-1-yl]-3-methylbut-2-enoate (483 mg) as an oil.
Reaction SMILES: S(=O)(=O)(O)O.C([O:9][C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[S:24](=[O:29])(=[O:28])[N:25]([CH3:27])[CH3:26])[N:13]([CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][OH:41])[CH2:35][CH2:34]3)[C:12]=2[CH:11]=1)(C)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[OH:9][C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[S:24](=[O:28])(=[O:29])[N:25]([CH3:27])[CH3:26])[N:13]([CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][OH:41])[CH2:35][CH2:34]3)[C:12]=2[CH:11]=1
Reactant: CC(C)Oc1ccc2c(c1)N(CCCN1CCC(CCO)CC1)c1cccc(S(=O)(=O)N(C)C)c1S2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CN(C)S(=O)(=O)c1cccc2c1Sc1ccc(O)cc1N2CCCN1CCC(CCO)CC1
Temperature: 5 °C
Reaction time: 0.01 h
Yield: 38.8 %

Procedure:
Concentrated sulphuric acid (109 g.) cooled to 5°C. is added over the course of 30 seconds to a solution, kept at 5°C, of 2-isopropoxy-6-dimethylsulphamoyl-10-[3-(4-hydroxyethylpiperidino)propyl]-phenothiazine (10.9 g.) in anhydrous chloroform (150 cc.). After stirring for 30 seconds at 5°C., the reaction mixture is poured onto crushed ice (150 g.). The pH of the solution is brought to 7.5 by addition of sodium hydroxide solution (d = 1.33), whilst cooling, and extraction is effected using chloroform (total 350 cc.). The chloroform solution is dried over anhydrous sodium sulphate (5 g.), the solvent evaporated under reduced pressure and the product obtained dried under reduced pressure (0.05 mm. Hg) at 20°C. The resulting amorphous product (5.1 g.) is dissolved in boiling acetonitrile (35 cc.). After cooling, the crystals which have formed are filtered off, washed with acetonitrile (5 cc.) and dried at 50°C. under reduced pressure (0.05 mm. Hg) for 20 hours. 2-Hydroxy-6-dimethylsulphamoyl-10-[3-(4-hydroxyethylpiperidino)propyl]phenothiazine (3.9 g.), melting at 163°-165°C., is obtained.
Reaction SMILES: [OH-].[NH4+].O[C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1O)[CH2:7][C@@H:8]([C:19]([OH:21])=[O:20])[NH:9][C:10](=[O:18])[CH:11]([CH2:16][SH:17])[C:12]([F:15])([F:14])[F:13].S(=O)(=O)(O)[O-].[K+].CO>O>[F:13][C:12]([F:14])([F:15])[C@@H:11]([CH2:16][SH:17])[C:10]([NH:9][C@@H:8]([CH2:7][CH:6]1[CH2:22][CH2:23][CH2:24][CH2:4][CH2:5]1)[C:19]([OH:21])=[O:20])=[O:18]
Reactant: O=C(N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O)C(CS)C(F)(F)F
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: O=C(O)[C@H](CC1CCCCC1)NC(=O)[C@H](CS)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Concentrated ammonium hydroxide (3.1 mL) was added to a suspension of the title (S) isomer product from part (a) (1.734 g., 4.69 mmol.) in deoxygenated water (3.1 mL) at room temperature. Dissolution occurred almost immediately and the reaction mixture was stirred for 10 minutes at room temperature. The pH was adjusted to 1.5 with saturated potassium bisulfate solution and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with brine, dried (MgSO4), and concentrated to a residue which was chromatographed on a 5×15 cm silica gel column. Elution with hexane:ethyl acetate:acetic acid, 80:20:2, concentration of the pure fractions, and coevaporation from heptane afforded a white solid which was triturated with hexane. This solid was dried under high vacuum for 18 hours to afford 1.28 g. of the title (S,S) isomer product; m.p. 141°-143° C., [α]D =+13.6° (c=0.85, methanol).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1([F:28])[CH2:27][CH2:26][NH:25][CH2:24]1>C(#N)C>[F:22][C:23]1([F:28])[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:24]1
Reactant: CCOC(=O)c1cccc(OCCBr)c1
Reactant: FC1(F)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cccc(OCCN2CCC(F)(F)C2)c1
Temperature: 70 °C
Reaction time: 36 h

Procedure:
To a suspension of ethyl 3-[(2-bromoethyl)oxy]benzoate D46 (476 mg) and potassium carbonate (481 mg, 3.48 mmol) in Acetonitrile (20 mL) stirred at 20° C. was added 3,3-difluoropyrrolidine (250 mg, 1.741 mmol). The reaction mixture was stirred at 70° C. for 36 h. After cooled to room temperature the mixture was filtrated and the filtrate was concentrated. The crude product was added to a silica gel column and was eluted with Hexane/EtOAc/TEA in ratio 50/50/0.5. Fractions isolated and solvent evaporated to afford the title product D49 in 400 mg as a yellow oil. LCMS Retention time=1.20 mins, [M+H]+300 (5 min run)
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][CH:28]([CH2:31][O:32][C:33](=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[O:29][CH3:30])(C(C)(C)C)(C)C>C1COCC1>[C:33]([O:32][CH2:31][CH:28]([CH2:27][OH:26])[O:29][CH3:30])(=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(CO[Si](C)(C)C(C)(C)C)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(CO)OC
Yield: 82 %

Procedure:
1M TBAF (6 mL, 6.0 mmol) was added to a solution of compound Compound 43 (2.4 g, 5.0 mmol) in THF (50 mL). After 30 nun, TLC analysis showed that all the staring material had been consumed. Then, the reaction mixture was partitioned between diethyl ether (100 mL) and sat. NaCl solution (30 mL). The organic extract was dried (MgSO4), concentrated and subjected to silica-gel column chromatography [eluent: hexane/ethyl acetate, 75/25, v/v] to give glycerol derivative Compound 44 (1.52 g, 79%) as an oil
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[CH2:12]1[C@H:21]2[C@H:16]([CH2:17][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=32)[NH:15][CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([N:15]2[C@@H:16]3[C@@H:21]([C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH2:18][CH2:17]3)[CH2:12][CH2:13][CH2:14]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: Nc1cc(C(=O)O)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1cc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)ccc1F
Yield: 47 %

Procedure:
The title compound is prepared from 3-amino-4-fluoro-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 47% of theory; LC (method 4): tR=1.94 min; Mass spectrum (ESI+): m/z=325 [M+H]+.