Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:23]=[CH:22][C:10]([O:11][Si](C(C)C)(C(C)C)C(C)C)=[CH:9][C:8]=2[C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:6][CH2:5]1)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4]1([C:7]2[CH:23]=[CH:22][C:10]([OH:11])=[CH:9][C:8]=2[C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC1(c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC1(c2ccc(O)cc2C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 110.8 %

Procedure:
To a solution of [4-(1-ethoxycyclopropyl)-3-tert-butyl-phenoxy]-triisopropyl-silane (Intermediate 108, 600.0 mg, 1.54 mmol) in 3 mL THF at 0° C. was added tetrabutylammonium fluoride (802.8.0 mg, 3.07 mmols; 3.1 mL of a 1 M solution in THF). The solution was stirred at 0° C. for 30 minutes and then quenched by the addition of H2O. The mixture was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound (400 mg, 88%) was isolated from the residue by column chromatography (4-10% EtOAc-hexanes) as a colorless solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.NCC([N:55]1[CH2:60][CH2:59][CH:58]([O:61][C:62]2[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=2)[CH2:57][CH2:56]1)=O>CN(C=O)C.O>[O:27]=[C:25]([N:65]1[CH2:66][CH2:67][CH:62]([O:61][C:58]2[CH:59]=[CH:60][N:55]=[CH:56][CH:57]=2)[CH2:63][CH2:64]1)[CH2:24][NH:23][C:21]([C:18]1[CH:17]=[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:20][N:19]=1)=[O:22]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: NCC(=O)N1CCC(Oc2ccncc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2ccncc2)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 34.9 %

Procedure:
DIPEA (540 mg, 4.2 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (344 mg, 1.4 mmol) in DMF (3 mL) followed by HOBt (229 mg, 1.7 mmol) and EDCI.HCl (321 mg, 1.7 mmol). After 2 minutes 2-amino-1-[4-(pyridin-4-yloxy)-piperidin-1-yl]-ethanone hydrochloride (250 mg, 1.4 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 5% MeOH in CHCl3 as eluent) afforded 198 mg (% 34.9 Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(pyridin-4-yloxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 406.18, 95.8%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (m, 1H), 8.4 (m, 2H), 8.1 (m, 1H), 7.8 (m, 2H), 7.1 (m, 1H), 7.0 (s, 2H), 4.8 (m, 1H), 4.2 (m, 2H), 3.9 (m, 1H), 3.8 (m, 1H), 3.4 (m, 1H), 3.3 (m, 1H), 2.0 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: S1C(CC2C(=O)OC(C)(C)OC2=O)=CC2C=CC=CC1=2.S1C(CC(C(O)=O)C(O)=O)=CC2C=CC=CC1=2.[CH3:38][S:39]([C:42]1[CH:58]=[CH:57][C:45]([CH2:46][CH:47]2[C:52](=[O:53])[O:51]C(C)(C)[O:49][C:48]2=[O:56])=[CH:44][CH:43]=1)(=[O:41])=[O:40]>>[CH3:38][S:39]([C:42]1[CH:43]=[CH:44][C:45]([CH2:46][CH:47]([C:48]([OH:56])=[O:49])[C:52]([OH:53])=[O:51])=[CH:57][CH:58]=1)(=[O:40])=[O:41]
Reactant: CC1(C)OC(=O)C(Cc2ccc(S(C)(=O)=O)cc2)C(=O)O1
Agent: CC1(C)OC(=O)C(Cc2cc3ccccc3s2)C(=O)O1
Agent: O=C(O)C(Cc1cc2ccccc2s1)C(=O)O
Product: CS(=O)(=O)c1ccc(CC(C(=O)O)C(=O)O)cc1

Procedure:
The title compound was prepared by substituting 5-(benzo[b]thiophen-2-ylmethyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 39: step a) with 5-(4-methylsulfonylbenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 41: step a) then following the procedure described for the preparation of 2-(benzo[b]thiophen-2-ylmethyl)malonic acid (Intermediate 39: step b).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1>>[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[O:20][C:19]([CH:21]=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[OH:8])=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ccccc1O
Reactant: O=Cc1ccc(-c2cccc(Cl)c2)o1
Product: Oc1ccccc1N=Cc1ccc(-c2cccc(Cl)c2)o1

Procedure:
Using 2-aminophenol and 5-(3-chlorophenyl)furan-2-carbaldehyde, 2.94 g of 2-{[5-(3-chlorophenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 82%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1.O>C(#N)C>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([CH2:18][C:19]3[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CCN(CC)C(=O)c1ccc(CBr)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN(CC)C(=O)c1ccc(CN2CCC3(CC2)OCCO3)cc1
Reaction time: 16 h
Yield: 96 %

Procedure:
1,4-Dioxa-8-azaspiro[4.5]-decane (200 mmol, 28.6 g, 25.6 mL) is dissolved in 160 ml of dry acetonitrile under nitrogen and treated with K2CO3 (220 mmol, 30.3 g) followed by dropwise addition over 1.5 hours of 4-(bromomethyl)-N,N-diethylbenzamide (200 mmol, 54.01 g) as a solution in 81 mL of acetonitrile. After 16 hours, the reaction mixture is poured into 250 mL of water and extracted twice with 150 mL of methylene chloride. The pooled extracts were washed with 250 mL of brine, dried over Na2SO4 and concentrated in vacuo affording 63.9 g (192 mmol, 96% yield) of the product as a yellow-orange oil.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:45][S:46][CH2:47][CH2:48][CH2:49][NH2:50].C(=O)([O-])O.[Na+]>CN(C=O)C>[C:1]([C:5]1[N:10]=[C:9]([NH:50][CH2:49][CH2:48][CH2:47][S:46][CH3:45])[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:34])[CH3:35])[C@@H:15]2[CH2:20][NH:19][CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CSCCCN
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2Cl)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1CNC[C@@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2NCCCSC)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 1-tert-butyl 3-methyl (3R*,5S*)-5-{[(2-tert-butyl-4-chloropyrimidin-5-yl)carbonyl](isobutyl)amino}piperidine-1,3-dicarboxylate (51.1% mg) and diisopropylethylamine (38 mg) in DMF (0.5 ml) was added a solution of 3-methylthiopropylamine (21 mg) in DMF (0.5 ml), and the mixture was stirred at 80° C. overnight. To the reaction mixture was added 2% aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate, and the extract was concentrated by a nitrogen gas blower. The residue was purified by reversed-phase preparative HPLC, and the object fraction was concentrated by a nitrogen gas blower. The residue was dissolved in trifluoroacetic acid/acetonitrile solution (20% (V/V), 1.0 ml), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated by a nitrogen gas blower. The residue was neutralized with triethylamine (1 ml), saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was concentrated by a nitrogen gas blower. The residue was purified by reversed-phase preparative HPLC, and the object fraction was concentrated by a nitrogen gas blower to give the object compound (6.4 mg).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])[CH:13]=1)[C:7]([O:9]C)=[O:8])=[O:3].[OH-].[Na+].Cl.O>CO>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])[CH:13]=1)[C:7]([OH:9])=[O:8])=[O:3]
Reactant: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(C(=O)O)c1
Temperature: 22.5 °C
Reaction time: 24 h

Procedure:
To a mixture of methyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate (XXII, PREPARATION 5, 0.197 g, 0.64 mmol) in methanol (5.0 mL) is added sodium hydroxide (1N, 3.0 mL). The mixture is stirred at 20-25 degrees C. for 24 hours. The mixture is acidified to about pH 5 with hydrochloric acid (10%). Water (50 mL) is added and the mixture is washed twice with ethyl acetate (2×50 mL). The organic extracts are combined and dried over anhydrous magnesium sulfate and concentrated to give the title compound, NMR (DMSO-d6) delta 0.66, 0.930, 1.48, 1.62, 3.12, 3.35, 7.54, 7.98, 8.22 and 8.51.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C:13]([CH3:33])([CH3:32])[CH2:14][O:15][S:16]([CH2:19][CH2:20][CH2:21][S:22]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:24])=[O:23])(=[O:18])=[O:17])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](Cl)(=O)[C:35](Cl)=O.CN(C)C=O>ClCCl>[CH2:1]([O:8][C@H:9]([C:13]([CH3:33])([CH3:32])[CH2:14][O:15][S:16]([CH2:19][CH2:20][CH2:21][S:22]([O:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:23])=[O:24])(=[O:17])=[O:18])[C:10]([O:12][CH2:34][CH3:35])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(COS(=O)(=O)CCCS(=O)(=O)Oc1ccccc1)[C@@H](OCc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCS(=O)(=O)Oc1ccccc1
Reaction time: 1 h

Procedure:
To a stirred 0° C. solution of (2R)-2-benzyloxy-3,3-dimethyl-4-(3-phenoxysulfonylpropylsulfonyloxy)butanoic acid (Example 8(a), Step 3) (0.8 g) in dichloromethane (10 mL), was added oxalyl chloride (0.28 mL) followed by a drop of N,N-dimethylformamide. The reaction mixture was stirred for 1 hour and concentrated in vacuo. The resulting residue was dissolved in dichloromethane (10 mL), to which was added ethanol (2 mL). The reaction mixture was stirred overnight at room temperature. The volatiles were removed, and the residual material was purified by silica gel chromatography (hexanes/ethyl acetate 70:30) to afford ethyl (2R)-2-benzyloxy-3,3-dimethyl-4-(3-phenoxysulfonylpropylsulfonyloxy)butanoate (0.70 g).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([O:11][CH2:12][C:13]([F:26])([F:25])[C:14]([F:24])([F:23])[C:15]([F:22])([F:21])[C:16]([F:20])([F:19])[CH2:17][OH:18])=[C:5]([F:27])[C:4]=1[F:28].Cl[C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:32]=1[N+:40]([O-:42])=[O:41].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[CH3:1][N:2]([CH3:29])[C:3]1[C:4]([F:28])=[C:5]([F:27])[C:6]([O:11][CH2:12][C:13]([F:26])([F:25])[C:14]([F:23])([F:24])[C:15]([F:21])([F:22])[C:16]([F:19])([F:20])[CH2:17][O:18][C:35]2[CH:36]=[CH:31][C:32]([N+:40]([O-:42])=[O:41])=[CH:33][C:34]=2[N+:37]([O-:39])=[O:38])=[C:7]([F:10])[C:8]=1[F:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)c1c(F)c(F)c(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CN(C)c1c(F)c(F)c(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)COc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c(F)c1F
Yield: 73.2 %

Procedure:
N,N-Dimethyl-4-(6-hydroxy-2,2,3,3,4,4,5,5-octafluorohexyloxy)-2,3,5,6-tetrafluorobenzeneamine (1.05 g) was treated with 1-chloro-2,4-dinitrobenzene (0.51 g) and potassium carbonate (0.35 g) in NMP (5 mL) at 80° C. for 21.5 hrs. The mixture was diluted with water and extracted with ethyl ether. The extracts were washed with water and brine, dried (K2CO3), and concentrated to an orange oil. The oil was purified by chromatography to give N,N-dimethyl-4-[6-(2,4-dinitrophenoxy)-2,2,3,3,4,4,5,5-octaflurohexyloxy]-2,3,5,6-tetrafluorobenzeneamine (1.05 g) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19]Cl.C(=O)([O-])[O-].[K+].[K+].[I-:27].[Na+]>CC(=O)CC>[I:27][CH2:17][CH2:18][CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: [I-]
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=C(c1ccccc1)c1ccc(OCCCI)cc1
Temperature: 70 °C
Yield: 90.1 %

Procedure:
A 1000 mL three-neck flask was charged with 4-hydroxybenzophenone (50.00 g; 252.2 mmol), 1-bromo-3-chloropropane (79.41 g; 504.4 mmol) and 2-butanone (500 mL). After flushing with nitrogen, anhydrous potassium carbonate (104.6 g; 756.5 mmol) was added and the reaction mixture was stirred at reflux for 24 h. Full consumption of the starting 4-hydroxybenzophenone was confirmed by TLC. The reaction mixture was filtered, the filtrate evaporated, the oily residue dissolved in dichloromethane (300 mL) and extracted with water (3×100 mL). The organic phase was separated, evaporated, and the unreacted 1-bromo-3-chloropropane was removed by heating to 70° C. in vacuo. The residue was dissolved in 2-butanone (500 mL) and sodium iodide (45.36 g; 302.6 mmol) was added. The reaction mixture was refluxed for 6 h. The reaction mixture was filtered, the filtrate evaporated, the oily residue dissolved in dichloromethane (300 mL) and extracted with water (3×100 mL). The organic phase was separated, evaporated, the light brown oily residue dried in vacuo to give crude 4-(3-iodopropoxyl)benzophenone (light brown solid; 83.2 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[C:19]1([CH2:25]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:25]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[N:8]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:25]([N:8]1[CH2:7][C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)CN(Cc1ccccc1)N2
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 84 h

Procedure:
To a solution of 5-nitroindazole (10 g, 61.3 mmol) in DMF (100 mL) was added K2CO3 (12.7 g, 91.9 mmol) and PhCH2Br (7.29 mL, 61.3 mmol). The resulting mixture was stirred at RT for 3.5 days, then poured into 400 mL of H2O. The resulting slurry was filtered, rinsed once with water and dried in vacuo giving a beige solid. A portion of this crude material (2.5 g) was purified by chromatography (SiO2, elution with 1:2 EtOAc-hexanes) giving 1-benzyl-5-nitro-1H-indazole and 2-benzyl-5-nitro-1H-indazole.
Reaction SMILES: O.[OH-].[Na+].[CH2:4]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([C:21]([O:23]CC)=[O:22])[C:12]1=[O:26])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[CH2:4]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([C:21]([OH:23])=[O:22])[C:12]1=[O:26])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
Water (15 ml) and sodium hydroxide (1.3 g) were added to a methanol (30 ml) solution of ethyl 4-benzyl-3,4-dihydro-3-oxo-2-quinoxalinecarboxylate (3.5 g). The reaction mixture was stirred at room temperature for 2 hours and concentrated. 2N Hydrochloric acid was added to the residue to adjust the pH to 4, which was extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain the entitled compound (2.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([CH3:13])[CH3:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1.[Na].O>C(O)CC>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:11]([CH3:13])([CH3:12])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([OH:9])[CH2:10][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)=[CH:16][CH:17]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Agent: [Na]
Solvent: CCCO
Solvent: O
Product: CC(C)(Oc1ccc(Cl)cc1)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Yield: 18.4 %

Procedure:
A solution of 30 g (0.093 mole) of 2-(4-chlorophenyl)-2-[2-(p-chlorophenoxy)-2-propyl]oxirane in 40 ml of n-propanol is added dropwise, at room temperature, to a solution of 7.6 g (0.107 mole) of 1,2,4-triazole-sodium in 60 ml of n-propanol. The reaction mixture is allowed to stir at reflux temperature for 48 hours, then cooled, water is added and the mixture is extracted with methylene chloride. The organic phase is dried over sodium sulphate and evaporated in vacuo. The oily residue is purified by column chromatography. 6.7 g (18.4% of theory) of 3-(4-chlorophenoxy)-2-(4-chlorophenyl)-3-methyl-1-(1,2,4-triazol-1-yl)-2-butanol are obtained. This is vigorously stirred with 20 ml of saturated hydrogen chloride/ether solution at room temperature. The precipitate which separates out is filtered off with suction, washed with a little ether and dried in vacuo at 40° C. 6.5 g (89% of theory relative to base employed) of 3 -(4-chlorophenoxy)-2-(4-chlorophenyl)-3-methyl-1-(1,2,4-triazol-1-yl)-2-butanol hydrochloride of melting point 135° C. are obtained.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].[CH2:14]1[NH:19][CH2:18][CH2:17][N:16]2[CH2:20][CH2:21][CH2:22][CH2:23][CH:15]12.C(=O)([O-])[O-].[Na+].[Na+].[F:30][C:31]([F:40])([F:39])[C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35]>ClCCl.CO>[CH2:14]1[N:19]([C:8]([C:7]2[CH:6]=[C:5]([S:2]([NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[C:32]([C:31]([F:30])([F:39])[F:40])[CH:33]=3)(=[O:4])=[O:3])[CH:13]=[CH:12][CH:11]=2)=[O:9])[CH2:18][CH2:17][N:16]2[CH2:20][CH2:21][CH2:22][CH2:23][CH:15]12
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: C1CCN2CCNCC2C1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(c1cccc(S(=O)(=O)Nc2cccc(C(F)(F)F)c2)c1)N1CCN2CCCCC2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 3-(chlorosulfonyl)benzoyl chloride (0.36 g 1.5 mmol) in anhydrous dichloromethane (50 mL) was added octahydro-1H-pyrido[1,2-α]pyrazine (0.21 g, 1.5 mmol) in dichloromethane (4 mL) slowly over 10 minutes at room temperature. Then sodium carbonate (0.32 g, 3 mmol) was added. The mixture was stirred at room temperature for 5 hours. Then 3-(trifluoromethyl)aniline (2.9 g, 18 mmol) was added. The mixture was stirred at room temperature for 5 days, then sodium carbonate (0.32 g, 3 mmol) and methanol (5 mL) were added, the mixture was stirred for 20 minutes, then filtered, and concentrated. The residue was purified by chromatography on silica gel (methanol/ethyl acetate=1:10) to give the titled compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.27 (m, 3H), 1.42-2.10 (m, 7H), 2.70-3.40 (m, 4H), 4.25-4.40 (m, 1H), 7.40 (m, 3H), 7.50 (m, 1H), 7.70 (m, 3H), 7.85 (m, 1H), 10.80 (br s, 1H); MS (ESI) m/z 468 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:8]([OH:10])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[Cl-].[F:25][C:26]1[CH:27]=[C:28]([CH:51]=[C:52]([F:54])[CH:53]=1)[CH2:29][NH2+:30][CH2:31][C:32]([NH:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[CH2:40][C@@:39]1([C:47](=[O:48])[NH:46][C:45](=[O:49])[N:44]1[CH3:50])[CH2:38]2)=[O:33]>C(Cl)Cl.CN(C=O)C>[F:25][C:26]1[CH:27]=[C:28]([CH:51]=[C:52]([F:54])[CH:53]=1)[CH2:29][N:30]([CH2:31][C:32]([NH:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[CH2:40][C@@:39]1([C:47](=[O:48])[NH:46][C:45](=[O:49])[N:44]1[CH3:50])[CH2:38]2)=[O:33])[C:8]([C:2]1([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:10]
Reactant: CN1C(=O)NC(=O)[C@@]12Cc1ccc(NC(=O)C[NH2+]Cc3cc(F)cc(F)c3)cc1C2
Reactant: CC1(C(=O)O)CCCCC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C(=O)NC(=O)[C@@]12Cc1ccc(NC(=O)CN(Cc3cc(F)cc(F)c3)C(=O)C3(C)CCCCC3)cc1C2
Temperature: 0 °C

Procedure:
To a solution of 1-methylcyclohexanecarboxylic acid (32.0 mg, 0.222 mmol) in DCM (1.5 mL) was added one drop of DMF (cat.), followed by oxalyl chloride (37.0 mg, 0.228 mmol), while at ambient temperature and under a constant stream of nitrogen. Upon cessation of gas evolution, the reaction mixture was cooled to 0° C. prior to the introduction of triethylamine (34.0 mg, 0.333 mmol) as a solution in DCM (2.0 mL), and then N-(3,5-difluorobenzyl)-2-{[(4S)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl]amino}-2-oxoethanaminium chloride (50.0 mg, 0.111 mmol, Intermediate 1). After 1 hour the reaction mixture was applied directly to a silica gel column for purification, eluting with DCM:MeOH—99:1 to 95:5. Product containing fractions were pooled and concentrated in vacuo to give the title compound. MS: m/z=561 (M+23(Na+)). HRMS: m/z=539.2477; calculated m/z=539.2464 for C29H33N4O4F2.
Reaction SMILES: [N-:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[Na+].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13](F)[C:10]=1[C:11]#[N:12]>CN(C(N1CC1)=O)C>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[C:10]=1[C:11]#[N:12]
Reactant: c1cn[n-]c1
Reactant: COc1cccc(F)c1C#N
Agent: CN(C)C(=O)N1CC1
Agent: [Na+]
Product: COc1cccc(-n2cccn2)c1C#N
Temperature: 60 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
At 50° C. and under a nitrogen blanket, a solution of 0.273 mol of sodium pyrazolide (prepared from equimolar amounts of pyrazole and sodium hydride) in 140 ml of N,N-dimethylethyleneurea is dripped into a solution of 41,2 g (0.273 mol) of 2-methoxy-6-fluorobenzonitrile (preparation: J. Heterocycl. Chem., 25, 1173, 1988) in 50 mi of N, N-dimethylethyleneurea, and the mixture is stirred for 2 hours at 60° C. The batch is cooled and stirred into 4 liters of ice water, and the crystals which precipitate are suction filtered and dried; there is obtained 37.1 g of the product of m.p. 93°-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[C@H:18]([NH:19][C:20]([C:22]3[S:23][C:24]4[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=4[N:30]=3)=[O:21])[CH2:17][N:16]([S:32]([CH2:35][C:36]([O:38]C)=[O:37])(=[O:34])=[O:33])[CH2:15]1)=[O:12])=[CH:5]2.O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[C@H:18]([NH:19][C:20]([C:22]3[S:23][C:24]4[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=4[N:30]=3)=[O:21])[CH2:17][N:16]([S:32]([CH2:35][C:36]([OH:38])=[O:37])(=[O:34])=[O:33])[CH2:15]1)=[O:12])=[CH:5]2
Reactant: COC(=O)CS(=O)(=O)N1C[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCc2nc(C(=O)N[C@@H]3CN(S(=O)(=O)CC(=O)O)C[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reaction time: 4 h
Yield: 89.1 %

Procedure:
The compound (100 mg) obtained in Example 100 was dissolved in tetrahydrofuran (4 mL)-water (1 mL), and the mixture was cooled with ice. Lithium hydroxide monohydrate (7.8 mg) was added thereto. The temperature of the resultant mixture was returned to room temperature, and the mixture was stirred for 4 hours. After the reaction mixture was neutralized with 1N hydrochloric acid, it was concentrated. Precipitates were collected by filtration, washed with water and 50% ethanol and dried overnight at 50° C. under reduced pressure to give the title compound (87 mg).