Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[CH:14]=O.[C:16]1(=O)[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH2:17]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:2]3=[N:1][C:16]4[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[C:17]=4[CH:14]=[C:3]3[CH:4]=[N:5]2)=[CH:12][CH:11]=1
Reactant: O=C1CCCC(=O)C1
Reactant: Nc1c(C=O)cnn1-c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1CCCc2nc3c(cnn3-c3ccc(F)cc3)cc21
Temperature: 100 °C
Yield: 70 %

Procedure:
A flask was charged with 5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde (111, R1=4-Fluorophenyl) (58.15 g, 283 mmol, cyclohexane-1,3-dione (47.7 g, 425 mmol) and toluene (600 mL). The slurry was stirred then pTSA (4.8 g, 25.2 mmol) was added. The mixture was warmed in an oil bath heated to about 100° C. for about 1 h. The mixture was allowed to cool to rt and stir overnight. The mixture was concentrated to dryness under reduced pressure. Water (400 mL), sat. aq. NaHCO3 (50 mL) and ethanol (100 mL) were added to the mixture. The supernatant was decanted and the solids were triturated with water (100 mL). The supernatant was decanted and the process repeated with another portion of water (100 mL). The solids were dried under reduced pressure to remove residual water. The material was stirred with MeOH (160 mL) then the solids were collected by filtration and washed with MeOH (80 mL). The material was dried under vacuum at about 65° C. to yield 1-(4-fluorophenyl)-7,8-dihydro-1H-pyrazolo[3,4-b]quinolin-5(6H)-one (112, R1=4-Fluorophenyl) (55.5 g, 70%); LC/MS, method 3, Rt=2.37 min, MS m/z 282 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.82 (s, 1H), 8.56 (s, 1H), 8.32-8.23 (m, 2H), 7.51-7.39 (m, 2H), 3.22 (t, J=6.2 Hz, 2H), 2.76-2.69 (t, J=6.0 Hz, 2H), 2.20-2.11 (m, 2H).
Reaction SMILES: [NH3:1].C(=O)=O.CC(C)=O.[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([C:33]([CH3:36])([CH3:35])[CH3:34])[N:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[C:27]=23)[CH:20]=[CH:21][CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(O)C>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([C:33]([CH3:36])([CH3:35])[CH3:34])[N:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH2:1])[C:27]=23)[CH:20]=[CH:21][CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)c1nc(-c2cccc(OCc3ccccc3)c2)c2c(Cl)nccn12
Reactant: N
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CC(C)(C)c1nc(-c2cccc(OCc3ccccc3)c2)c2c(N)nccn12
Temperature: 110 °C

Procedure:
Gaseous NH3 is condensed into a cooled (dry ice/acetone) solution of 1-(3-benzyloxyphenyl)-3-tert-butyl-8-chloroimidazo[1,5-a]pyrazine (61.8 mg, 0.158 mmol) in iPrOH (2 mL) in a pressure tube until the volume is doubled, then the tube is sealed and heated to 110° C. (bath temp.) overnight. The seal has leaked during that time, LC indicates ≈50% conversion; therefore, ammonia is condensed in and the tube is heated as described before. The crude material is purified by preparative TLC (1000 μm silica gel layer, 20×20 cm plate), eluting once with 1% MeOH in CH2Cl2 and then three times with hexanes:EtOAc 3:1. One obtains the title compound as pale yellow solid, >95% pure by HPLC; 1H NMR (CDCl3, 400 MHz) δ 1.57 (s, 9H), 5.06 (brs, 2H), 5.14 (s, 2H), 6.99-7.04 (m, 2H), 7.22-7.26 (m, 2H), 7.31-7.42 (m, 4H), 7.44 (d, J=8.4 Hz, 2H), 7.46 (d, J=5.3 Hz, 1H). MS (ES+): m/z 373.1 (100) [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].F[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1ccccc1F
Reactant: Nc1ccccc1S
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccccc1Sc1ccccc1N
Temperature: 0 °C

Procedure:
2-Aminothiophenol (6.26 g, 50 mmol) was dissolved in dry THF (50 ml) and sodium hydride (2 g of 60% dispersion, 1 eq) added with stirring at 0° C. under nitrogen. After stirring for 0.5 hr this mixture was added portionwise to a stirred solution of 2-fluorobenzonitrile (1 eq) in THF (30 ml). The mixture was allowed to warm to room temperature overnight and then evaporated in vacuo and the residue purified by chromatography on silica, eluting with dichloromethane. The title compound was obtained as an off-white solid (5.27 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([CH:36]([CH3:39])[CH2:37][OH:38])[C:34]=1[Cl:35])[C:30]#[N:31].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O1CCOCC1>[Cl:35][C:34]1[C:33]([CH:36]([CH3:39])[CH2:37][OH:38])=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[NH:26][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:19][CH2:20]2)[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1
Reactant: CC(CO)c1cc(C#N)cc(N)c1Cl
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C(C)CO)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 100 °C
Yield: 59.3 %

Procedure:
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (42 mg, 0.118 mmol), 3-amino-4-chloro-5-(1-hydroxypropan-2-yl)benzonitrile (24.94 mg, 0.118 mmol), palladium(II) acetate (7.97 mg, 0.036 mmol), DPPF (6.56 mg, 0.012 mmol), Xantphos (6.85 mg, 0.012 mmol), and cesium carbonate (77 mg, 0.237 mmol) were combined in a 2 dram vial and dioxane (1.2 mL) was added. The vial was evacuated and backfilled with N2 3×, then heated at 100° C. for 1.5 h. The reaction was cooled to room temperature and filtered through celite, rinsing with EtOAc. The solvent was removed in vacuo and the material was purified by flash column chromatography (0-3% MeOH/DCM; 40 g column). 2-((2-chloro-5-cyano-3-(1-hydroxypropan-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (37 mg) was obtained as a yellow glass.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1.[CH2:14]1[CH2:19]C2OCCOCCOC3C(OCCOCCOC2C[CH2:15]1)CCCC3.BrC(C)C>C1C=CC=CC=1>[CH:14]([CH:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1)[C:12]#[N:13])([CH3:19])[CH3:15]
Reactant: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Reactant: COc1ccc(CC#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)Br
Solvent: c1ccccc1
Product: COc1ccc(C(C#N)C(C)C)cc1
Temperature: 45 °C
Reaction time: 96 h

Procedure:
A solution of sodium hydroxide (50%, 300 ml) is added to a solution of p-methoxyphenylacetonitrile (147 g, 1 mol), dicyclohexyl-18-crown-6 (18.63 g, 5 mol %), 2-bromopropane (320 g, 2.6 mol) and benzene (300 ml). The reaction mixture is heated to 45° C. and held for 4 days. The organic phase is separated, washed well with water (3×200 ml), dilute hydrochloric acid (1×200 ml), water (2×200 ml) and evaporated to an oil. Vacuum distillation gives the product (175.6 g, 81% real): boiling point 96° C. to 100° C. (0.15 mm); nmr (CDCl3) shows that the distilled material contains 12.5 mol % of the starting nitrile.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([Cl:15])[C:13]=1Cl.[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([OH:30])=[CH:22][CH:21]=1>CN(C=O)C>[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([O:30][C:13]2[C:12]([Cl:15])=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[CH:9][C:8]=2[Cl:7])=[CH:22][CH:21]=1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)c(Oc2ccc(Cl)c3ccccc23)c(Cl)c1
Yield: 98.7 %

Procedure:
To a mixture containing 28.02 g (0.203 mole) of anhydrous potassium carbonate and 30.26 g (0.134 mole) of 3,4,5-trichloro-1-nitrobenzene in 300 ml dry DMF under an atmosphere of nitrogen and at room temperature was added 30.04 g (0.168 mole) of 4-chloro-1-naphthol. The flask was then placed in an oil bath which was heated. An internal reaction temperature of 105° C. was reached and maintained for 20 hours. After cooling the reaction mixture to room temperature most of the DMF was removed under vacuum. The residue was taken up in 1.5 L of 1:1 EtOAc to Et2O and 300 ml of H2O. The layers were separated and washed twice with 5% NaOH, twice with H2O, and finally once with a saturated aqueous NaCl solution. After drying over anhydrous Na2SO4 removal of the solvents afforded 48.73 g of a dark brown solid. This was recrystallized twice from hexane-ethyl acetate to afford 15.84 g of pale yellow needles; mp 121.5°-123° C. NMR (COCl3): δ6.18 (d, J=8 Hz, 1H), 7.25 (d, J=8 Hz 1H) 8.4-8.7 (m, 2H), 8.0-8.5 (m, 4H, contains 8.25 [S]).
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[F:17][CH:2]([F:1])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[C:4]=1[CH3:16]
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)F
Reactant: C1CCNCC1
Product: Cc1c(-c2ccc(C(=O)N3CCCCC3)s2)noc1C(F)F
Yield: 66 %

Procedure:
Prepared from 5-(5-Difluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid (Preparative Example 26) and piperidine by the method described in Example 2 Method B. The reaction mixture was evaporated in vacuo, then chromatographed on silica gel with EtOAc/hexanes (30 then 40%) as eluant to afford product as a colorless solid (54 mg, 66%). 1H NMR (CDCl3) 1.65-1.72 (6, 3 H), 2.34 (s, 3 H), 3.67-3.70 (m, 4 H), 6.80 (t, J=53.2, 1 H), 7.30 (d, J=4.0, 1 H), 7.43 (d, J=3.5, 1 H). 13C NMR 7.7, 24.7, 26.3, ˜46 (br), 39.8 (br), 108.1 (t, J=238), 113.5, 127.6, 128.9, 131.6, 140.1, 157.8, 159.5 (q, J=29), 162.7. 19F NMR −118.2 (J=53.5). LC/MS 6.18 min, [M+1]+ 327.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]2[C:6]=1[C:7](=[O:16])[CH2:8][CH2:9][NH:10]2)(=[O:3])[CH3:2].Br[CH2:18][C:19]#[N:20]>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]2[C:6]=1[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH2:18][C:19]#[N:20])(=[O:3])[CH3:2]
Reactant: N#CCBr
Reactant: CC(=O)Nc1ccc(C)c2c1C(=O)CCN2
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C)c2c1C(=O)CCN2CC#N

Procedure:
The compound prepared in (1) above (1.95 gm) was dissolved into 40 ml of DMF, and 6 ml of bromoacetonitrile was added to the solution. After heating under reflux for 3 hours, the reaction mixture was concentrated, and chloroform was added to the residue. The residue, after washing with saturated brine, was dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography using a chloroform-methanol (100:1) mixed solvent as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 605 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]3)=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[CH3:28]C(C)([O-])C.[K+].CI.C(OCC)(=O)C>CS(C)=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([N:17]([C@H:18]3[CH2:23][CH2:22][C@H:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]3)[CH3:28])=[O:16])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)N2CCN(c3ccc(C#N)cc3)CC2)CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CC[C@H](N(C)C(=O)N2CCN(c3ccc(C#N)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2.50 g of 1-(4-cyanophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-piperazine and 0.76 g of potassium tert.butoxide in 30 ml of dimethylsulphoxide is stirred for 30 minutes at ambient temperature. Then 0.5 ml of methyliodide is added dropwise and the mixture is stirred for 1.5 hours at ambient temperature. The reaction solution is diluted with 100 ml of water and the aqueous phase is extracted three times with ethyl acetate. The organic phases are washed with saturated saline solution and dried over sodium sulphate. The solvent is removed under reduced pressure and the residue remaining is chromatographed over silica gel with ethyl acetate/cyclohexane (3:1) as eluant. Yield: 1.0 g (39% of theory). The product contains about 20% of cis compound Rf value: 0.58 (silica gel; ethyl acetate) 1.0 g of starting material are obtained as a further fraction. Rf value: 0.45 (silica gel; ethyl acetate)
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=1.[NH:29]1[C:33](B(O)O)=[CH:32][CH:31]=[N:30]1.C([O-])([O-])=O.[Cs+].[Cs+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:11][C:8]1[N:7]([CH2:12][C:13]2[C:22]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:16]=[CH:15][CH:14]=2)[C:6]2[CH:5]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:3]=[C:2]([C:31]3[NH:30][N:29]=[CH:33][CH:32]=3)[C:10]=2[N:9]=1
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Reactant: OB(O)c1ccn[nH]1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2c(-c3ccn[nH]3)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 4-bromo-2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole (200 mg, 0.46 mmol), 1H-pyrazol-5-ylboronic acid (100 mg, 0.92 mmol), Pd(dba)2 (40 mg, 0.046 mmol), Cs2CO3 (300 mg, 0.92 mmol) and P(t-Bu)3 (10 wt % in hexane, 20 mg, 0.092 mmol) in dioxane (20 mL) and water (10 mL), was stirred at 100° C. for 18 h under a nitrogen atmosphere. The reaction mixture was cooled and then concentrated. The resulting residue was purified by silica gel chromatography eluted with EtOAc to give the product (140 mg 72%), as a white solid. 1H NMR showed this compound is in a form of tautomeric mixture (major tautomer/minor tautomer=5/3) 1H NMR of the major tautomer (300 MHz, DMSO-d6) δ ppm 2.45 (s, 3H), 3.08 (s, 4H), 3.71 (s, 4H), 6.00 (s, 2H), 6.37 (d, 1H, J=7.2 Hz), 6.96 (s, 1H), 7.24-7.72 (m, 6H), 7.83-7.87 (m, 1H), 8.01 (d, 1H, J=7.2 Hz), 8.25 (d, 1H, J=4.2 Hz), 13.24 (br s, 1H); LC-MS: m/e=424 [M+1]+
Reaction SMILES: [CH:1]1([NH:4][NH2:5])[CH2:3][CH2:2]1.CN(C)[CH:8]=[CH:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH:1]1([N:4]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=[N:5]2)[CH2:3][CH2:2]1
Reactant: NNC1CC1
Reactant: CCOC(=O)C(=O)C=CN(C)C
Product: CCOC(=O)c1ccnn1C1CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 17.3 using cyclopropylhydrazine (Step 17.2) and ethyl 4-(Dimethylamino)-2-oxobut-3-enoate at 125° C. for 8 hr. The crude product was purified by silica gel column chromatography (hexane/EtOAc 2.5-45%). tR: 4.40 min (HPLC 1); tR: 0.91 min (LC-MS 2); ESI-MS: 181 [M+H]+ (LC-MS 2); Rf=0.85 (hexane/EtOAc 1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](Cl)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:15][C:16](=[N:22]O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)C(C)C)(C)C.O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[CH2:11][C:12]1[O:13][N:22]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=1
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: CCOC(=O)C(N)=NO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1noc(Cc2ccc(OC)c(OC)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
2-(3,4-dimethoxyphenyl)acetyl chloride (0.650 mL; 3.78 mmol) was added to a mixture of ethyl 2-amino-2-(hydroxyimino)acetate (0.500 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (18 mL) at −15° C. The reaction mixture was stirred at room temperature overnight and poured into a mixture of ice and water. The formed precipitate was filtered off, suspended in pyridine (18 mL) and refluxed in a sealed tube for 20 h and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.395 g (36%) of ethyl 5-(3,4-dimethoxybenzyl)-1,2,4-oxadiazole-3-carboxylate as a yellow solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:26])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]([O:24]C)=[O:23])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:27])[C:6]([C:28]([OH:30])=[O:29])=[CH:5]2)[CH2:3][CH2:2]1>C(O)(=O)C.O.S(=O)(=O)(O)O>[C:22]([CH2:21][CH2:20][N:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:27])[C:6]([C:28]([OH:30])=[O:29])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:26])[CH2:15][CH2:16]1)([OH:24])=[O:23]
Reactant: COC(=O)CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 82.1 %

Procedure:
2.9 g of the compound from Example 9 are dissolved in a mixture of 14 ml of acetic acid and 9.5 ml of water, and 1.4 ml of concentrated sulphuric acid are added. The mixture is heated at 150° to 160° C. for 1.5 hours and poured into 90 ml of water. The precipitate is filtered off with suction, washed with water and methanol and dried. 2.3 g (72% of theory) of 7-[4-(2-carboxyethyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid semisulphate semihydrate of decomposition point 258° to 261° C. are isolated.
Reaction SMILES: [CH:1]1([C:4](=[O:21])[C:5](=[CH:17][N:18](C)C)[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([S:15][CH3:16])[CH:9]=2)=[O:7])[CH2:3][CH2:2]1.Cl.NO.O>C(O)C>[CH:1]1([C:4]2[O:21][N:18]=[CH:17][C:5]=2[C:6](=[O:7])[C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([S:15][CH3:16])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: CSc1cc(C(=O)C(=CN(C)C)C(=O)C2CC2)ccc1C
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: CSc1cc(C(=O)c2cnoc2C2CC2)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
A mixture of 3-cyclopropyl-2-(N,N-dimethylaminomethylene)-1-(4-methyl-3-methylsulphenylphenyl)propan-1,3-dione (10.6 g) and hydroxylamine hydrochloride (2.92 g) in ethanol was stirred at room temperature overnight. Water was added and the mixture was evaporated to remove the ethanol. It was extracted with ethyl acetate, washed with aqueous sodium chloride solution, dried (sodium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluted with a mixture of ether and cyclohexane to give 5-cyclopropyl-4-(4-methyl-3-methylsulphenylbenzoyl)isoxazole (2.77 g) as a white solid, m.p. 85.5°-86.1° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH2:35][CH2:36][CH3:37])[C:32]([OH:34])=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].[NH:38]1[CH2:43][CH2:42][CH:41]([OH:44])[CH2:40][CH2:39]1>C(Cl)Cl>[OH:44][CH:41]1[CH2:42][CH2:43][N:38]([C:32](=[O:34])[C@@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:35][CH2:36][CH3:37])[CH2:39][CH2:40]1
Reactant: OC1CCNCC1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(O)CC1
Reaction time: 3 h
Yield: 106 %

Procedure:
TBTU (7.09 g, 22.09 mmol) was added to a solution of (S)-2-(tert-butoxycarbonylamino)pentanoic acid (4 g, 18.41 mmol), which is commercially available, and piperidin-4-ol (2.235 g, 22.09 mmol) in DCM (50 mL). The reaction was stirred for 3 h and was then quenched by addition of NaHCO3 (aq., 8%, 25 mL). The aqueous phase was extracted with DCM. The organic phases were combined, dried (MgSO4), filtered and evaporated. The residue was added H3PO4 (aq) (1 M, 25 mL) and the aqueous phase was extracted with Et2O. The organic phases were pooled, dried (MgSO4), filtered and evaporated to give the title product (5.86 g, 106%) as a yellow oil. The obtained crude product was used in the next step without characterization.
Reaction SMILES: [K].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:20][Cl:21]>CN(C=O)C>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([O:15][CH2:20][Cl:21])=[O:14])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: ClCBr
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(OCCl)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To the potassium salt of 3-benzyloxybenzoic acid (2.39 g, 8.91 mmol) was added the bromochloromethane (8.7 ml, 15 eq.) and DMF (10.7 mL). The mixture was then stirred at room temperature for 12-18 hours. The mixture was then filtered and the filtrate concentrated. Purification of the crude product via flash chromatography (EtOAc:Hexanes 1:10) yielded 1.2 g of the title compound as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ=5.12 (s, 2H), 5.96 (s, 2H), 7.22-7.25 (m, 1H), 7.26-7.47 (m, 6H), 7.68-7.72 (m, 2H), MS(ESI) 276.
Reaction SMILES: [NH:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>CC(C)=O>[CH2:19]([N:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: C1CCC2NCCCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN1CCCC2CCCCC21
Temperature: 5 °C
Yield: 74.6 %

Procedure:
To a 500 mL 3-necked round-bottomed flask, was added 24.0 g of decahydroquinoline dissolved in 150 mL acetone. To this mixture was added 29.7 g of powdered anhydrous potassium carbonate. The reaction mixture was cooled to 5° C. with an ice bath. While stirring, 20.8 g of allyl bromide in 50 mL acetone was added slowly to the reaction mixture. After addition was complete, the reaction mixture was allowed to stir at room temperature for 24 hours. The reaction mixture was filtered, and the solvent was removed from the filtrate under reduced pressure using a rotary evaporator yielding 23.0 g of N-allyl decahydroquinoline as a viscous liquid. To a 500 mL 3-necked round-bottomed flask was added 22.0 g of N-allyl decahydroquinoline dissolved in 100 mL diethyl ether. After cooling to 5° C. with an ice bath, 15.5 g of allyl bromide in 20 mL diethyl ether was added slowly. After completion of addition of allyl bromide, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 24 hours. The solid residue thus formed was collected by filtration and was washed with diethyl ether (2×500 mL). The washed solid was recrystalled from acetonitrile. After removal of acetonitrile by filtration, the residue was dried under vacuum yielding 24.0 g of N,N-diallyl decahydroquinolinium bromide as a white solid.