Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].[CH:12]([Cl:15])([Cl:14])[Cl:13].[OH-].[K+]>CN1CCCC1=O.CO>[Cl:13][C:12]([CH:7]([OH:8])[C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([Cl:15])[Cl:14]
Reactant: ClC(Cl)Cl
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc(C(O)C(Cl)(Cl)Cl)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
To a solution of 3-nitrobenzaldehyde (80 g, 0.53 mol) and chloroform (95 ml, 1.17 mol) in 320 ml of N-methylpyrrolidinone cooled to -10° C. under nitrogen was added dropwise a solution of potassium hydroxide (24 g, 0.43 mol) in 80 ml of methanol over a 40 minute period. The deep purple reaction mixture was aged for 4 hours at -5° C. before quenching into 640 ml of lN HCl and 500 ml of methylene chloride cooled to 0° C. The quench mixture was stirred and cooled for an additional 0.5 hour and then brought to ambient temperature. The methylene chloride layer was separated and washed twice with 720 ml of water, 720 ml of 10% sodium bisulfite, and again with 720 ml of water. After treatment with 9.0 g of Darco G-60 charcoal for 1 hour and filtration through Super-Cel, the organic layer was washed with 450 ml of aqueous 5% sodium bicarbonate solution and then 720 ml of water, with 65 ml of saturated salt solution added. The resulting methylene chloride solution contained 140.2 g (98.4% yield) of TMBA.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][NH:8][S:7]1(=[O:13])=[O:12].C([O-])([O-])=O.[Cs+].[Cs+].F[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:28]=1[N+:36]([O-:38])=[O:37]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][N:8]([C:31]2[CH:32]=[CH:27][C:28]([N+:36]([O-:38])=[O:37])=[CH:29][C:30]=2[N+:33]([O-:35])=[O:34])[S:7]1(=[O:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1ccc(CN2C(=O)CN(c3ccc([N+](=O)[O-])cc3[N+](=O)[O-])S2(=O)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the title B compound, 2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (303 mg, 1.05 mmol) in dry 1,4-dioxane (5 mL) is treated with Cs2CO3 (342 mg, 1.05 mmol). 1-Fluoro-2,4-dinitrobenzene (197 mg, 1.05 mmol) is added and the mixture is stirred at RT for 16 h. The solvent is evaporated and the residue is partitioned between EtOAc and 1N aqueous HCl. The organic layer is dried over anhydrous Na2SO4 and concentrated. The residue is chromatographed on silica gel using 10%→100% EtOAc in hexanes as the eluent to afford 2-(2,4-dimethoxybenzyl)-5-(2,4-dinitrophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a yellow solid: [M−1]−=451.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Br:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][C:36]=1[NH:37][CH:38]=[C:39]1[C:44](=[O:45])OC(C)(C)OC1=O)[C:30]([O:32][CH3:33])=[O:31]>>[Br:26][C:27]1[CH:28]=[C:29]([C:30]([O:32][CH3:33])=[O:31])[CH:34]=[C:35]2[C:36]=1[NH:37][CH:38]=[CH:39][C:44]2=[O:45]
Reactant: COC(=O)c1ccc(NC=C2C(=O)OC(C)(C)OC2=O)c(Br)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: COC(=O)c1cc(Br)c2[nH]ccc(=O)c2c1
Temperature: 25 °C

Procedure:
To a flask with DOWTHERM (35 mL) at 210° C. was added methyl 3-bromo-4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)benzoate (3.3 g, 8.59 mmol) in portions. The resulting solution was heated for 20 min and cooled down to room temperature. Solids were precipitated from the solution. To the reaction mixture was then added hexanes and the precipitate filtered. The solids were washed thoroughly with Et2O and hexanes and dried under vacuum to yield methyl 8-bromo-4-oxo-1,4-dihydroquinoline-6-carboxylate. (M+H)+: 282, 284
Reaction SMILES: [P:1]([O:9]CC)([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[O:2].COC(=O)[O-].[CH2:17]([N+:19]1[CH:23]=[CH:22][N:21]([CH3:24])[CH:20]=1)[CH3:18]>CO>[CH2:4]([O:3][P:1]([O-:9])([O:6][CH2:7][CH3:8])=[O:2])[CH3:5].[CH2:17]([N+:19]1[CH:23]=[CH:22][N:21]([CH3:24])[CH:20]=1)[CH3:18]
Reactant: CCOP(=O)(OCC)OCC
Agent: CC[n+]1ccn(C)c1
Agent: COC(=O)[O-]
Solvent: CO
Product: CCOP(=O)([O-])OCC

Procedure:
By adding 50 parts of triethyl phosphate (TEP: produced by Daihachi Chemical Industries Co., Ltd.) to the methanol solution of 50 parts of 1-ethyl-3-methylimidazolium methyl carbonate salt obtained in Production Example 7 and carrying out a salt exchange reaction, there was obtained a methanol solution of 1-ethyl-3-methylimidazolium diethyl phosphate monoanion. The above-described solution was heated under reduced pressure of 1.0 kPa or less at 50° C. to distill methanol until no distillate of methanol was observed. Thereafter, the temperature was raised from 50° C. to 100° C. and heating was continued for 30 minutes to distill and remove monomethyl carbonate (HOCO2CH3), methanol, and carbon dioxide (slight amounts of methanol and carbon dioxide are formed by thermal decomposition of monomethyl carbonate. Hereinafter, these are abbreviated as by-products). Thus, 1-ethyl-3-methylimidazolium diethyl phosphate monoanion, electrolyte (C-4), was obtained. The yield was 99 parts (yield based on the weight of 50 parts of 1-ethyl-3-methylimidazolium methyl carbonate salt; hereinafter the same shall apply). The molecular weight of the electrolyte (C-4) was 266.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:31])=[C:18]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][CH2:13]2)=[CH:8][CH:7]=1>C(OCC)(=O)C.CCCCCC>[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:31])=[C:18]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:27])([CH3:28])[CH3:29])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:1]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C3OCCO3)cc1)CO2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C=O)cc1)CO2
Yield: 95 %

Procedure:
Using N-(3-(4-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 82, the title compound was synthesized in the same manner as in Example 173. Yield: 95%. Melting point: 195-196° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[N:7][NH:8]2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[CH:22]1[C:27](O)=[CH:26][CH:25]=[C:24]([CH3:29])[CH:23]=1.C(N(CC)CC)C>S(Cl)(Cl)=O>[C:24]1([CH3:29])[CH:25]=[CH:26][C:27]([O:12][C:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[C:3]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)[CH:4]=3)[NH:8][N:7]=2)=[O:13])=[CH:22][CH:23]=1
Reactant: Cc1ccc(O)cc1
Reactant: COc1ccc(-c2cc3c(C(=O)O)n[nH]c3cc2Cl)cc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COc1ccc(-c2cc3c(C(=O)Oc4ccc(C)cc4)n[nH]c3cc2Cl)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
A mixture of 6-chloro-5-(4-methoxyphenyl)-1H-indazole-3-carboxylic acid (547 mg, 1.81 mmol) in thionyl chloride (10 mL) was heated to 60° C. for 4 hours, cooled to room temperature and concentrated in vacuo. The residue was dissolved in CH2Cl2 (20 mL) and treated with p-cresol (399 mg, 3.61 mmol) followed by triethylamine (369 mg, 3.61 mmol). The reaction mixture was stirred for 16 hours and quenched with water (20 mL). The layers were separated and the organic phase was concentrated in vacuo. The residue was purified by flash chromatography (25-50% EtOAc/heptane) to give the title compound (192 mg, 27% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2C(=O)[O:12][N:11]=[C:10]2[C:15]2[C:16]([NH:20][CH2:21][CH2:22][NH:23][S:24]([NH2:27])(=[O:26])=[O:25])=[N:17][O:18][N:19]=2)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O.[OH-].[Na+].Cl>C1COCC1>[NH2:27][S:24]([NH:23][CH2:22][CH2:21][NH:20][C:16]1[C:15]([C:10](=[N:11][OH:12])[NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=2)=[N:19][O:18][N:17]=1)(=[O:25])=[O:26]
Reactant: NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)NCCNc1nonc1C(=NO)Nc1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 336.1 %

Procedure:
To a crude mixture of N-[2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)ethyl]sulfamide (2.4 mol) containing residual amounts of trifluoroacetic acid stirring in a 22 L flask was added THF (5 L). The resulting solution was cooled to 0° C. using an ice bath and 2 N NaOH (4 L) was added at a rate so that the temperature did not exceed 10° C. After stirring at ambient temperature for 3 h (LCMS indicated no starting material remained), the pH was adjusted to 3-4 with concentrated HCl (˜500 mL). The THF was removed in vacuo, and the resulting mixture was extracted with ethyl acetate (15 L). The organic layer was washed with water (5 L), brine (5 L), and the solvents removed in vacuo to afford a solid. The solid was triturated with MTBE (2×2 L), combined with three other reactions of the same size, and dried overnight in a convection oven to afford a white solid (3535 g). The solid was recrystallized (3×22 L flasks, 2:1 water:ethanol, 14.1 L each flask) and dried in a 50° C. convection oven to a constant weight to furnish the title compound as an off-white solid (3290 g, 78%). LCMS for C11H14BrFN7O4S (M+H)+: m/z=437.9, 439.9. 1H NMR (400 MHz, DMSO-d6): δ 11.51 (s, 1H), 8.90 (s, 1H), 7.17 (t, J=8.8 Hz, 1H), 7.11 (dd, J=6.1, 2.7 Hz, 1H), 6.76 (m, 1H), 6.71 (t, J=6.0 Hz, 1H), 6.59 (s, 2H), 6.23 (t, J=6.1 Hz, 1H), 3.35 (dd, J=10.9, 7.0 Hz, 2H), 3.10 (dd, J=12.1, 6.2 Hz, 2H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][C@H:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])[CH3:29])[CH:20]=3)[C:12]=2[CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][C@H:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:37])([F:38])[F:39])[CH3:29])[CH:20]=3)[C:12]=2[CH:11]=1
Reactant: C[C@H](Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 230 mg of 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{(1S)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide in 5 ml THF is cooled to 0° C. At 0° C. 0.14 ml tetra-n-butylammonium fluoride (˜75% in H20) are added. The reaction mixture is allowed to warm to room temperature and stirred for 90 minutes.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:42](=[O:43])[C:41]1[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=1[CH2:39][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:19]1=[O:18])[CH3:2]
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: CCc1ccccc1N
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: CCc1ccccc1NC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-ethylaniline to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2-ethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (95%) as a colorless solid: mp 184-186° C.; 1H NMR (300 MHz, DMSO-d6) δ10.06 (s, 1H), 7.69-7.61 (m, 1H), 7.50-7.34 (m, 3H), 7.31-7.13 (m, 6H), 7.01 (dd, J=7.5, 7.5 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.40 (s, 1H), 5.20-5.01 (m, 2H), 4.86 (d, J=8.9 Hz, 1H), 4.72 (d, J=8.9 Hz, 1H), 4.47 (t, J=8.7 Hz, 2H), 2.93 (t, J=8.7 Hz, 2H), 2.68 (q, J=7.5 Hz, 2H), 1.16 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ177.9, 168.1, 161.6, 161.2, 142.8, 139.8, 136.4, 135.8, 134.5, 132.7, 130.8, 129.1, 129.0, 128.3, 127.9, 127.8, 127.0, 126.9, 126.5, 124.2, 123.6, 120.9, 120.4, 119.6, 109.7, 92.9, 80.4, 72.6, 57.5, 41.4, 28.8, 24.5, 14.8; MS (ES+) m/z 517.2 (M+1).
Reaction SMILES: C(OC([NH:8][N:9]1[CH2:17][C:16]2[C:11](=[C:12]([CH3:19])[CH:13]=[CH:14][C:15]=2[CH3:18])[CH2:10]1)=O)(C)(C)C>Cl>[NH2:8][N:9]1[CH2:10][C:11]2[C:16](=[C:15]([CH3:18])[CH:14]=[CH:13][C:12]=2[CH3:19])[CH2:17]1
Reactant: Cc1ccc(C)c2c1CN(NC(=O)OC(C)(C)C)C2
Agent: Cl
Product: Cc1ccc(C)c2c1CN(N)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
20 g of N-(t-butyloxycarbonylamino)-4,7-dimethylisoindoline are introduced into 200 ml of concentrated hydrochloric acid and stirred for 2 hours at room temperature. A yield of 17 g of the hydrochloride of 2-Amino-4,7-dimethylisoindoline precipitates in the form of crystals.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4]([OH:6])=O.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.C([Li])CCC.[CH:33]([C@H:36]1[CH2:40][O:39][C:38](=[O:41])[NH:37]1)([CH3:35])[CH3:34].O1CCNC1=O>C1COCC1.O>[CH3:7][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:1])[CH2:3][C:4]([N:37]1[C@@H:36]([CH:33]([CH3:35])[CH3:34])[CH2:40][O:39][C:38]1=[O:41])=[O:6]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: CC(C)(CC(=O)O)c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C1NCCO1
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1C(=O)CC(C)(C)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
3-Methyl-3-phenylbutanoic acid (2, 1.00 g, 5.61 mmol) was dissolved in 70 mL of THF and cooled to −78° C. Triethylamine (1.17 mL, 8.42 mmol) and trimethylacetyl chloride (0.760 mL, 6.17 mmol) were added to the reaction flask producing a white solid. The resulting mixture was warmed to 0° C. for 1 h and then cooled back down to −78° C. In a second flask butyllithium (6.84 mL, 1.6 M in hexanes, 10.9 mmol) was added dropwise with vigorous stirring to a solution of (4S)-(−)-4-isopropyl-2-oxazolidinone (1.45 g, 11.2 mmol) at −78° C. in THF (60 mL) producing a white precipitate. The resulting suspension of the lithiated oxazolidinone was added via cannula to the reaction flask. Stirring was continued for 2 h, water was added and the reaction mixture was warmed to room temperature, whereupon it was extracted three times with diethyl ether. The combined organic extracts were dried over magnesium sulfate, and concentrated in vacuo. The product was purified by radial chromatography (4 mm plate, 3:7 diethyl ether-pet. ether) affording compound 3 as a clear, colourless oil in 84% yield (1.37 g, 4.74 mmol). 1H-NMR (400 MHz, CDCl3) 7.38 (d, 2H, J=7.3 Hz, H-19 and H-15) 7.28 (t, 2H, J=7.3 Hz, H-18 and H-16), 7.16 (t, 1H, J=7.3 Hz, H-17), 4.22-4.18 (m, 1H, H-4), 4.05 (dd, 1H, J=9.0 and 2.8 Hz, 1H-5), 4.00 (t, 1H, J=9.0 Hz, 1H-5), 3.38-3.30 (m, 2H, H-10), 2.16-2.12 (m, 1H, H-6), 1.48 (s, 3H, H-13 or H-12), 1.47 (s, 3H, H-13 or H-12), 0.79 (d, 3H, J=7.1 Hz, H-8 or H-7), 0.71 (d, 3H, J=6.9 Hz, H-8 or H-7); Mass spectrum (EI) 289 (8, M.+), 119 (100, [C9H11]+). Optical rotation obtained was [α]D25 +69.5 (c 1.16, CHCl3). Compound 3 was prepared according to D. A. Evans et al. (1988) Tetrahedron 44:5525.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[S:16])[C:12]([F:15])([F:14])[F:13].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.[Cu](I)I>[CH3:9][O:8][C:7]1[C:2]2[S:16][C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccc(NC(=S)C(F)(F)F)c1Br
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: COc1cccc2nc(C(F)(F)F)sc12
Temperature: 80 °C

Procedure:
To a solution of N-(2-bromo-3-methoxyphenyl)-2,2,2-trifluoroethanethioamide (C25) (748 mg, 2.38 mmol) in 1,2-dimethoxyethane (11.9 mL) was added 1,10-phenanthroline (88.4 mg, 0.48 mmol), cesium carbonate (1.55 g, 4.76 mmol), and copper iodide (45.3 mg, 0.24 mmol). Nitrogen was bubbled through the reaction for 30 minutes and the reaction was heated to 80° C. for 48 hours. The mixture was cooled to room temperature, filtered and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 30% diethyl ether in hexanes) afforded the title compound as a colorless solid. Yield: 398 mg, 1.71 mmol, 72%. GCMS m/z 233 (M+). 1H NMR (400 MHz, CDCl3) δ 4.03 (s, 3H), 6.97 (br d, J=7.9 Hz, 1H), 7.56 (dd, J=8.3, 8.0 Hz, 1H), 7.82 (dd, J=8.3, 0.6 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[OH:24]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:14][C:15]2[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=2[OH:24])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)Nc2cc([N+](=O)[O-])ccc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
4-Dimethylaminopyridine (2.62 g, 21.4 mmol) was added portionwise with stirring to a solution of 4-tert-butylbenzoyl chloride (3.8 ml, 19.5 mmol) and 2-amino-4-nitrophenol (3.0 g, 19.5 mmol) in 60 ml methylene chloride. The resulting solution was stirred overnight at room temperature. The reaction solution was diluted with 60 ml methylene chloride and washed with 3×50 ml water. The methylene chloride solution was separated, filtered to remove precipitated solid, dried (anhydrous sodium sulfate) and concentrated to dryness under reduced pressure to yield the title compound as a brownish solid (5.01 g, 82% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:31])[N:17]3[C:22](=[C:23]([C:25]([OH:27])=O)[CH:24]=2)[C:21]2[S:28][CH:29]=[CH:30][C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.CN(C=O)C.[CH:41]([NH:44][CH2:45][CH2:46][O:47][CH3:48])([CH3:43])[CH3:42]>C1(C)C=CC=CC=1.O1CCOCC1.C(N(CC)CC)C>[CH:41]([N:44]([CH2:45][CH2:46][O:47][CH3:48])[C:25]([C:23]1[CH:24]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[C:16](=[O:31])[N:17]2[C:22]=1[C:21]1[S:28][CH:29]=[CH:30][C:20]=1[CH:19]=[CH:18]2)=[O:27])([CH3:43])[CH3:42]
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Reactant: COCCNC(C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12)C(C)C

Procedure:
From 8-[p-(benzyloxy)phenyl]-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid with SOCl2 and DMF in toluene. Then treatment with triethylamine and isopropyl-(2-methoxy-ethyl)-amine in dioxan.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[N:20][C:15]4=[N:14][CH:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:25][O:26][CH2:27][CH2:28][OH:29].Cl.C([O-])(O)=O.[Na+]>CO.O>[OH:29][CH2:28][CH2:27][O:26]/[N:25]=[C:21](/[C:18]1[CH:19]=[N:20][C:15]2[N:16]([C:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[CH:13][N:14]=2)[N:17]=1)\[CH3:22]
Reactant: CC(=O)c1cnc2ncc(Cc3ccc4ncccc4c3)n2n1
Reactant: NOCCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C/C(=N\OCCO)c1cnc2ncc(Cc3ccc4ncccc4c3)n2n1
Yield: 74.3 %

Procedure:
A solution of 1-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)ethanone (40 mg, 0.13 mmol), 2-(aminooxy)ethanol hydrochloride (30 mg, 0.26 mmol) and HCl (4 N in 1,4-dioxane, 0.1 mL) in methanol (5 mL) was stirred at room temperature for 48 h. The reaction mixture was neutralized with saturated aqueous NaHCO3 solution and diluted with water, extracted with dichloromethane, dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography in silica gel eluting with a ethyl acetate/methanol gradient to afford 35 mg (74%) of the title compound as yellow solid. 1H-NMR (400 MHz, d6-DMSO) δ ppm 8.94 (s, 1H), 8.84 (d, 1H), 8.28 (d, 1H), 7.97-7.91 (m, 3H), 7.77 (d, 1H), 7.49 (dd, 1H), 4.77 (t, 1H), 4.56 (s, 2H), 4.30-4.27 (m, 2H), 3.71-3.70 (m, 2H), 2.25 (s, 3H). LCMS (method B): [MH]+=363, IR=2.08 min.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=[O:6])=[CH2:3].[C:10]([OH:13])(=[S:12])[CH3:11]>C(OC(C)C)(C)C>[C:10]([S:12][CH2:3][CH:2]([CH2:4][C:5]([OH:7])=[O:6])[C:1]([OH:9])=[O:8])(=[O:13])[CH3:11]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: CC(O)=S
Solvent: CC(C)OC(C)C
Product: CC(=O)SCC(CC(=O)O)C(=O)O
Temperature: 95 °C
Reaction time: 2.5 h
Yield: 91.9 %

Procedure:
400 g (3.07 mol) of itaconic acid (VIII) are added in portions within a period of approximately 30 minutes to 280 g (3.68 mol) of thioacetic acid, with simultaneous heating of the heating bath to 95° C. After 2.5 hours' stirring at 90°-100° C., the reaction mixture is cooled to room temperature and diluted with 300 ml of diisopropyl ether (DIPE), whereupon the product crystallises out within a period of approximately 12 hours. There are obtained 582 g of crystals having a melting point of 89°-91° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:42])[C:15]2([CH:18]3[CH2:22][CH2:21][N:20]([C:23]4[C:24]([F:41])=[CH:25][N:26]5[C:31]([C:32]=4[CH3:33])=[C:30]([CH:34]4[CH2:36][CH2:35]4)[CH:29]=[C:28]([C:37]([OH:39])=[O:38])[C:27]5=[O:40])[CH2:19]3)[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClC(Cl)C.CC(O)C.ClCCl>[CH:34]1([C:30]2[CH:29]=[C:28]([C:37]([OH:39])=[O:38])[C:27](=[O:40])[N:26]3[C:31]=2[C:32]([CH3:33])=[C:23]([N:20]2[CH2:21][CH2:22][CH:18]([C:15]4([N:14]([CH3:42])[CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH2:16][CH2:17]4)[CH2:19]2)[C:24]([F:41])=[CH:25]3)[CH2:36][CH2:35]1
Reactant: Cc1c(N2CCC(C3(N(C)C4CCN(C(=O)OC(C)(C)C)CC4)CC3)C2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: Cc1c(N2CCC(C3(N(C)C4CCNCC4)CC3)C2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a stirred solution of 8-(3-{1-[(1-tert-butoxycarbonyl-piperidin-4-yl)-methyl-amino]-cyclopropyl}-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (14 g) in dichloroethane (100 mL) was added trifluoroacetic acid (30 mL) at 0° C. slowly. The resulting solution was stirred at 0° C. to room temperature for one hour. The solvent was removed in vacuo to yield yellow oil, which was dissolved in 20% IPA in dichloromethane and the solution was neutralized by sat. aq NaHCO3 resulting two clear phases, and the two phases were well shaken. The organic layer was separated, and the aqueous phase was extracted with 20% IPA/CH2Cl2. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to give yellow solid (10 g), the solid was crystallized from methanol/water to give crystalline solid (8 g). ESI MS m/z 483.3 (M+H+). 1H NMR (400 MHz, CD3OD) δ 8.88 (d, J=10.0 Hz, 1H), 7.93 (s, 1H), 4.03-3.98 (m, 1H), 3.79-3.75 (m, 1H), 3.66-3.62 (m, 1H), 3.58-3.52(m, 1H), 3.47-3.44 (m, 2H), 3.05-2.88 (m, 4H), 2.62 (s, 3H), 2.49 (s, 3H), 2.35-2.23 (m, 3H), 2.06-2.02 (m, 1H), 1.70-1.58 (m, 2H), 1.51-1.44 (m, 1H), 0.93-0.64 (m, 8H).