Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C@@H:21]4[CH2:26][CH2:25][NH:24][CH2:23][C@@H:22]4[O:27][CH3:28])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:8][C:9]=1[F:10].Cl[C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32][N:31]=1.CCN(C(C)C)C(C)C>ClCCl.O1CCOCC1>[F:3][C:4]1[CH:5]=[C:6]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C@@H:21]4[CH2:26][CH2:25][N:24]([C:30]5[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32][N:31]=5)[CH2:23][C@@H:22]4[O:27][CH3:28])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: Cc1cc(Cl)ncn1
Reactant: CO[C@H]1CNCC[C@H]1Nc1nc2c(-c3ccc(F)c(F)c3)cccn2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]1CN(c2cc(C)ncn2)CC[C@H]1Nc1nc2c(-c3ccc(F)c(F)c3)cccn2n1
Temperature: 130 °C
Yield: 61.5 %

Procedure:
8-(3,4-Difluorophenyl)-N-((3S,4R)-3-methoxypiperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine dihydrochloride (28 mg, 64.8 μmol) was extracted with dichloromethane/2 M NaOH. The organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was dissolved in dioxane (0.5 mL) and to this solution 4-chloro-6-methylpyrimidine (9.2 mg, 71.2 μmol) and DIPEA (17.0 μL, 97.2 μmol) were added. Argon was bubbled through the solution for 5 minutes, and then heated in the microwave at 130° C. for 2×30 minutes. After evaporation, purification by chromatography (silica gel, 10 g, 0 to 10% methanol in dichloromethane) afforded the title compound (18 mg, 62%) as an off white foam.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[C:12]([NH:16][C:17]([CH:19]3[CH2:23][CH2:22][C:21](=[O:24])[O:20]3)=[O:18])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][Si](C(C)(C)C)(C)C)[N:3]=1>C1COCC1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[C:12]([NH:16][C:17]([CH:19]3[CH2:23][CH2:22][C:21](=[O:24])[O:20]3)=[O:18])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[N:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1-c1cc(-c2cccc(NC(=O)C3CCC(=O)O3)c2)c(C#N)c(N)n1
Solvent: C1CCOC1
Product: N#Cc1c(-c2cccc(NC(=O)C3CCC(=O)O3)c2)cc(-c2ccccc2O)nc1N
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a cold (0° C.) solution of N-{3-[2-amino-6-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-cyano-4-pyridinyl]phenyl}-5-oxotetrahydro-2-furancarboxamide (0.400 g, 0.757 mmol) in THF (5 mL) was added dropwise a solution n-tetrabutylammonium fluoride in THF (1M, 2 mL). After being stirred for 30 minutes, the mixture was quenched with water (5 mL). The resulting precipitate was collected by filtration, washed with water and ethanol, and dried under reduced pressure to give N-{3-[2-amino-3-cyano-6-(2-hydroxyphenyl)-4-pyridinyl]phenyl}-5-oxotetrahydro-2-furancarboxamide as a white solid (0.293 g, yield 93%).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]([NH:16][O:17][P:18]([CH3:21])(=[O:20])[OH:19])=[O:15])[CH3:13])=O)C1C=CC=CC=1>CO.Cl>[NH2:11][C@H:12]([C:14]([NH:16][O:17][P:18]([CH3:21])(=[O:19])[OH:20])=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)NOP(C)(=O)O
Agent: Cl
Solvent: CO
Product: C[C@H](N)C(=O)NOP(C)(=O)O
Reaction time: 8 h
Yield: 87.5 %

Procedure:
63.2 g of [(N-benzyloxycarbonyl-L-alanyl)amino]-methylphosphonic acid in a mixture of 600 ml of methanol and 20 ml of concentrated hydrochloric acid were hydrogenated at room temperature and atmospheric pressure in the presence of 6.0 g of 10% palladium-on-charcoal catalyst until absorption of hydrogen ceased. The catalyst was filtered off and washed with methanol. The filtrate was treated with 30 ml of propylene oxide and the mixture stored overnight in a refrigerator. The solid was filtered off, washed with methanol and ether and dried over phosphorus pentoxide in vacuo. The solid was taken up in 80 ml of boiling water, filtered and treated with 120 ml of ethanol. The mixture was cooled and then refrigerated overnight. The solid was filtered off, washed well with ethanol and dried over phosphorus pentoxide in vacuo. There were obtained 31.85 g of (L-alanylamino) -methylphosphonic acid of melting point 293°-294° C (decomposition); [α]D20 = 33.8° (c =1% in water).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:22]([O:24]CC3C=CC([N+]([O-])=O)=CC=3)=[O:23])=[C:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:15][S:16][C@:11]12[O:37][CH3:38])=[O:8].C1COCC1.CO>CCOC(C)=O.[Pd]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:22]([OH:24])=[O:23])=[C:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:15][S:16][C@:11]12[O:37][CH3:38])=[O:8]
Reactant: CO[C@]12SCC(COC(C)=O)=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2NC(=O)Cc1cccs1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CO[C@]12SCC(COC(C)=O)=C(C(=O)O)N1C(=O)C2NC(=O)Cc1cccs1
Yield: 74.6 %

Procedure:
A mixture of 5% Pd on charcoal (120 mg., prereduced in 1:1 THF-MeOH), the major isomer of p-nitrobenzyl 7-(2-thienylacetamido)-6-methoxy-3-acetoxymethyl-ceph-3-em-4-carboxylate (60 mg.), and 1:1 THF-MeOH (3 ml.) is hydrogenated at atmospheric pressure and room temperature for 3 hrs. The mixture is filtered and the filtrate is evaporated in vacuo. Trituration of the residue with Et2O provides a white solid (50 mg.). The solid is taken up in EtOAc (5 ml.) and filtered. The EtOAc filtrate is extracted with saturated aqueous NaHCO3 (3 × 2 ml.). The combined extracts are acidified to pH 2 with 10% HCl and extracted with EtOAc (4 × 3 ml.). The EtOAc extracts are washed with brine, dried over MgSO4, filtered, and evaporated in vacuo to yield 7-(2-thienylacetamido)-6-methoxy-3-acetoxymethyl-ceph-3-em-4-carboxylic acid (34 mg.) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[C:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])#[N:14].N1CCCCC1>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[C:15](/[C:13]#[N:14])\[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CC#N
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)/C(C#N)=C1\C(=O)Nc2ccc(Cl)cc21
Reaction time: 8 h
Yield: 90 %

Procedure:
A stirred mixture of 5-chloro-1H-indole-2,3-dione, starting material VIII, (90.8 g, 0.5 mol) and methyl cyanoacetate (44.1 ml, 0.5 mol) in methanol (1000 ml) was treated with piperidine (2 ml) and heated under reflux for 5 hours before standing overnight at ambient temperature. The crude (5-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-cyanoacetic acid methyl ester was removed by filtration, washed with cold methanol (2×150 ml) and dried in vacuo to give 117.6 g (90%) of a dark purple solid. This was a 6.5:1 mixture of geometric isomers which was sufficiently pure by 1H NMR for subsequent reaction.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([N:8]=[C:9]=[O:10])=[O:7])([O-:3])=[O:2].[Br:15][C:16]1[CH:17]=[N:18][C:19]([S:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)=[N:20][CH:21]=1>O1CCOCC1.O>[Br:15][C:16]1[CH:17]=[N:18][C:19]([S:22][C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=3[N+:1]([O-:3])=[O:2])=[O:10])=[CH:27][CH:28]=2)=[N:20][CH:21]=1
Reactant: O=C=NC(=O)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccc(Sc2ncc(Br)cn2)cc1
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(Sc2ncc(Br)cn2)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 2-nitrobenzoyl isocyanate (3 g, 0.016 mol) in dry 1,4-dioxane (15 mL) was added dropwise to a solution of 4n (2.93 g, 0.01 mol) in dry 1,4-dioxane (15 mL) with stirring at room temperature. The reaction mixture was stirred for 18 hours and then diluted with water. The precipitated solid was collected by filtration and washed with water. The solid was dissolved in ethyl acetate, and the organic layer was washed with water 2-3 times, dried, and concentrated to give 1-[4-(5-bromopyrimidin-2-ylsulfanyl)-phenyl]-3-(2-nitrobenzoyl)urea (6n), yield 92%. 1H NMR (400 MHz, DMSO-d6): δ 11.32 (br, s, 1H), 10.35 (br, s, 1H), 8.78 (s, 2H), 8.22 (m, 1H), 7.91 (m, 1H), 7.77 (m, 2H), 7.67 (m, 2H), 7.57 (m 2H); EI-MS m/z 473 [M]+, 475 [M+2]+; HRMS calculated for C18H12BrN5O4SNa [M+Na]+:495.9685, found: 495.9701. Anal. (C18H12BrN5O4S) C, H, N.
Reaction SMILES: [BH4-].[Li+].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([O:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:12][C@H:11]1[C:20](OC)=[O:21])=[O:9])([CH3:6])([CH3:5])[CH3:4].[Cl-].[NH4+]>O1CCCC1>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([O:15][S:16]([CH3:19])(=[O:17])=[O:18])[CH2:12][C@H:11]1[CH2:20][OH:21])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Lithium borohydride (3.6 g, 163.0 mM) was added to a solution of methyl (2S,4R)-N-tert-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-carboxylate (26.5 g, 81.5 mM) in anhydrous tetrahydrofuran (300 ml) with ice-cooling in a nitrogen gas stream and the mixture was stirred at room temperature for 3 hours. The reaction mixture was ice-cooled again, the reaction was ceased by adding dropwise a saturated aqueous solution of ammonium chloride carefully and the solvent was removed. The residue was poured into water, the insoluble matters were dissolved using 1N hydrochloric acid, the mixture was extracted with ethyl acetate and the organic layer was washed with 1N hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate, water and brine in this order and dried over anhydrous magnesium sulfate. The solvent was removed to give the title compound almost quantitatively (24 g).
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.Cl.[NH2:21][CH2:22][C:23]([NH2:25])=[O:24].C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:25][C:23]([CH2:22][N:21]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]1[CH2:6][N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19])=[O:24]
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: NCC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(CN2C(=O)c3ccccc3C2=O)n1CC(N)=O

Procedure:
5.2 g (0.02 mol) of 6-phthalimido-2,5-hexanedione, 2,3 g (0.02 mol) of glycine amide hydrochloride and 1.7 g (0.02 mol) sodium acetate are stirred in 70 ml of acetic acid at 80° C. for 3 hours and the mixture is worked up as in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:29]2[CH2:33][CH:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]2=[O:39])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][CH:17]2[CH2:22][O:21][C:20]3=[N:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][N:19]3[CH2:18]2)=[CH:11][CH:10]=1.ClCC1C=CC(OC2C=CC(N3CC(CNC(=O)C)OC3=O)=CC=2F)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([N:29]2[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]2=[O:39])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][O:16][C@@H:17]2[CH2:22][O:21][C:20]3=[N:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][N:19]3[CH2:18]2)=[CH:13][CH:14]=1
Reactant: CC(=O)NCC1CN(c2ccc(Oc3ccc(COC4COc5nc([N+](=O)[O-])cn5C4)cc3)c(F)c2)C(=O)O1
Agent: CC(=O)NCC1CN(c2ccc(Oc3ccc(CCl)cc3)c(F)c2)C(=O)O1
Product: CC(=O)NC[C@H]1CN(c2ccc(Oc3ccc(CO[C@@H]4COc5nc([N+](=O)[O-])cn5C4)cc3)c(F)c2)C(=O)O1

Procedure:
N-(3-{3-Fluoro-4-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)-phenoxy]-phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide. The title compound was prepared by following the same procedure as described in the preparation of Example 4, except N-{3-[4-(4-chloromethyl-phenoxy)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide was used in place of methanesulfonic acid 6-{4-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxy}-pyridin-3-ylmethyl ester. ESI MS m/z 542.4 (M+H+).
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([OH:16])=O)[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[F:28])[N:24]([CH2:29][C@@H:30]1[CH2:34][O:33][C:32]([CH3:36])([CH3:35])[O:31]1)[C:23]([C:37]([CH3:42])([CH3:41])[CH2:38][CH2:39][OH:40])=[CH:22]2.NC1C=C2C(=CC=1F)NC(C(C)(C)CCO)=C2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[F:17][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:18][C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][C:27]=4[F:28])[N:24]([CH2:29][C@@H:30]4[CH2:34][O:33][C:32]([CH3:35])([CH3:36])[O:31]4)[C:23]([C:37]([CH3:42])([CH2:38][CH2:39][OH:40])[CH3:41])=[CH:22]5)=[O:16])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)OC[C@@H](Cn2c(C(C)(C)CCO)cc3cc(N)c(F)cc32)O1
Reactant: O=C(O)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Agent: CC(C)(CCO)c1cc2cc(N)c(F)cc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)OC[C@@H](Cn2c(C(C)(C)CCO)cc3cc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)c(F)cc32)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (183 mg, 0.75 mmol), (R)-3-(5-amino-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indol-2-yl)-3-methylbutan-1-ol containing some 3-(5-amino-6-fluoro-1H-indol-2-yl)-3-methylbutan-1-ol (220 mg, 0.63 mmol) and HATU (287 mg, 0.75 mmol) in DMF (3.0 mL) was added triethylamine (0.21 mL, 1.5 mmol). The reaction was stirred at room temperature overnight and then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (20-40% ethyl acetate-hexanes) to afford (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (315 mg, 87%, contains some 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide). ESI-MS m/z calc. 574.2 found 575.7 (M+1)+. Retention time 2.08 minutes.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Cc1cccc(N)c1
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccc(C)c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
To a stirred solution of 57 mg (0.20 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) (57 mg, 0.20 mmol) in ethanol (2 ml), m-toluidine (64 mg, 0.60 mmol) was added portionwise. The resulting mixture was stirred at room temperature for 30 min and the final product was collected by filtration and washed with ethanol and diethylether to yield the title compound (24 mg, 35% yield).
Reaction SMILES: [Br-].[F:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N+:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]2OCCO2)=[CH:5][CH:4]=1.C.[Cl:22]([O-:26])(=[O:25])(=[O:24])=[O:23].[Na+]>CS(O)(=O)=O>[Cl:22]([O-:26])(=[O:25])(=[O:24])=[O:23].[F:2][C:3]1[CH:4]=[CH:5][C:6]2[C:19]([CH:20]=1)=[CH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][N+:8]=1[CH:7]=2
Reactant: Fc1ccc(C[n+]2ccccc2C2OCCO2)cc1
Agent: CS(=O)(=O)O
Agent: [Br-]
Agent: [Na+]
Product: Fc1ccc2c[n+]3ccccc3cc2c1
Temperature: 105 °C
Reaction time: 16 h

Procedure:
1-(4-Fluorobenzyl)-2-(1,3-dioxolan-2-yl)pyridinium bromide (31 g, 0.091 mol) was added to a mixture of polyphosphoric acid (350 g) and methanesulfonic acid (100 mL) at 40° C. and the resulting: mixture was heated at 105° C. for 2 hours. The mixture was poured onto ice and the solution was treated with charcoal. The mixture was added to an excess of sodium perchlorate and the solution was chilled and allowed to stand for 16 hours. A precipitate formed, which was collected by filtration to afford 15.9 g (59%) of 9-fluorobenzo-[b]quinolizinium perchlorate (Formula II: R2 =9-F; R1 =H; X- =ClO4-), as a yellow solid, m.p. 168°-173° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH2:12][CH:13]=[N:14][NH:15][CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[C:28]([N+]([O-])=O)[CH2:29][CH:30]2[O:34][CH2:33][CH2:32][O:31]2)=[CH:23][CH:22]=1.CCN(CC)CC>C1COCC1>[CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH2:12][C:13]1[C:28]([CH2:29][CH:30]2[O:34][CH2:33][CH2:32][O:31]2)=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[N:15]([CH:16]([CH3:17])[CH3:18])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C(=Cc1ccc(F)cc1)CC1OCCO1
Reactant: CC(C)NN=CCCNC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)n1nc(CCNC(=O)OCc2ccccc2)c(CC2OCCO2)c1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of [3-(isopropyl-hydrazono)-propyl]-carbamic acid benzyl ester (1.0 mg, 3.8 mmol), 2-[3-(4-fluoro-phenyl)-2-nitro-allyl]-[1,3]dioxolane (0.96 mg, 3.8 mmol), and Et3N (1.53 g, 15.2 mmol) in THF (40 mL) was stirred at 60° C. for 3 days. The mixture was cooled to rt, concentrated, and the residue purified by FCC to give the title compound.
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH2:20])[CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].C(N(CC)CC)C.[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>ClCCl.O>[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31]([NH:20][CH:13]([C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[CH:8][CH:9]=1)[CH2:14][N:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:32]
Reactant: CCCS(=O)(=O)c1ccc(C(N)CN2CCCC2)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCS(=O)(=O)c1ccc(C(CN2CCCC2)NC(=O)c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of {1-[4-(propylsulphonyl)phenyl]-2-pyrrolidin-1-ylethyl}amine (100 mg, 0.337 mmol) in dichloromethane (5 mL) under nitrogen was added triethylamine (47 □L, 0.337 mmol) followed by 2,4-dichlorobenzoyl chloride (47 □L, 0.336 mmol). The mixture was stirred at ambient temperature for 2 h, then diluted with water and extracted with ethyl acetate (×2). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated. The product was purified by chromatography on silica eluting with 3% MeOH in dichloromethane to give the product as an off-white solid (123 mg, 78%). 1H NMR δ (400 MHz, CDCl3) δ 1.00 (3H, t, J=7.4 Hz), 1.69-1.81 (6H, m), 2.46-2.49 (2H, m), 2.58-2.62 (2H, m), 2.73 (1H, dd, J=12.5, 5.1 Hz), 2.91 (1H, dd, J=12.52, 9.5 Hz), 3.03-3.07 (2H, m), 5.01-5.09 (1H, m), 7.33 (1H, dd, J=8.3, 1.9 Hz), 7.46 (1H, d, J=1.9 Hz), 7.56 (2H, d, J=8.3 Hz), 7.64 (1H, d, J=8.3 Hz), 7.72 (1H, br d, J=3.9 Hz), 7.87 (2H, d, J=8.32 Hz); m/z (ES+) 471 (M+H), 469 (M+H), 400 (M-pyrrolidine), 398 (M-pyrrolidine).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH2:27][C:28]([F:31])([F:30])[F:29])(=O)=O)=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH2:27][C:28]([F:31])([F:30])[F:29])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(O)cc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)cc(OCC(F)(F)F)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a magnetically stirred solution of 3-chloro-5-hydroxybenzaldehyde (2.0 g, 12.8 mmol; see Example 1(ii) above) and potassium carbonate (2.3 g, 16.6 mmol) in DMF (35 mL) under nitrogen was added 2,2,2-trifluoroethyl p-toluenesulfonate (4.2 g, 16.6 mmol) at room temperature. The mixture was heated to 110° C. for 7 h and then stirred overnight at room temperature. The reaction was cooled to 0° C., poured into ice-cold 2 N HCl (100 mL) and extracted with EtOAc (2× 75 mL). The combined organic extracts were washed with 0.5 N HCl (2× 50 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The brown oil was chromatographed on silica gel eluting with Hex:EtOAc (6:1) to afford the sub-title compound (1.9 g, 61%) as a yellow oil.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6]O)[CH3:2].P(Br)(Br)[Br:16].O>ClCCl>[O:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Br:16])[CH3:2]
Reactant: COc1cc(CO)cc(OC)c1OC
Reactant: BrP(Br)Br
Solvent: O
Solvent: ClCCl
Product: COc1cc(CBr)cc(OC)c1OC
Yield: 86.7 %

Procedure:
Dissolving 3,4,5-trimethoxyl benzyl alcohol (14.05 g, 70.89 mmol) in dichlormethane (100 ml) in a three-necked bottle (250 ml); dissolving phosphorus tribromide (6.73 ml, 70.89 mmol) in dichlormethane (25 ml) for it to react at room temperature for 50 minutes, cooling in refrigeratory, slowly adding deionized water (18 ml, 1.0 mol) dropwise to quench, washing with deionized water (100 ml) twice, drying with anhydrous magnesium sulfate, filtering, washing the filter residue with dichlormethane (20 ml), conflating the filtrate, concentrating in rotarory evaporater, and vacuum drying to get 3,4,5-trimethoxyl benzyl bromine (16.05 g of faint yellow solid), yield: 84.44%.