Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[Na+].[Cl:6][CH2:7][C:8](Br)=[O:9].[CH:11]1([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12]1>O.C(Cl)Cl>[Cl:6][CH2:7][C:8]([N:18]1[CH2:19][CH2:20][N:15]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[CH2:16][CH2:17]1)=[O:9]
Reactant: O=C(Br)CCl
Reactant: C1CC(N2CCNCC2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)N1CCN(C2CCC2)CC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of sodium bicarbonate (15 mmol) in water (5 mL) and DCM (30 mL) at 0° C. is added chloroacetyl bromide (12 mmol), followed by immediate addition of 1-cyclobutylpiperazine (10 mmol). The mixture is stirred at 0° C. for an additional 40 min. To the mixture is added aqueous sodium bicarbonate (15 mL) and DCM (30 mL). The layers are separated and the organic layer is dried (MgSO4) and solvent is removed in vacuo to give 2-chloro-1-(4-cyclobutyl-piperazin-1-yl)-ethanone, which is used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 4.07 (2H, s), 3.64 (2H, t), 3.52 (2H, t), 2.74 (1H, m), 2.36 (2H, t), 2.31 (2H, t), 1.72-2.08 (6H, m); MS (+VE) m/z 217.1 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:19]=[N+:20]=[N-:21])=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CN=[N+]=[N-])cc1-c1ccccc1
Temperature: 75 °C
Yield: 77.1 %

Procedure:
A mixture of 4-bromomethyl-2-phenylbenzoic acid methyl ester (1.5 g, 4.9 mmol), sodium azide (1.28 g, 19.7 mmol) and tetrabutylammonium iodide (1.3 g, 4.9 mmol) in DMF (16 mL) was heated at 75° C. for 18 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (15% ethyl acetate-hexanes) to give the desired azide as a colorless oil (1.01 g).
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:28])[C:5]([N:7]([CH3:27])[C:8]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][N:10]1[C:17](=[O:26])[C:18]([OH:25])=[C:19]([C:21]([O:23]C)=O)[N:20]=[C:9]21)=[O:6])[CH3:3].[Br:29][C:30]1[C:35]([CH3:36])=[C:34]([F:37])[CH:33]=[C:32]([Br:38])[C:31]=1[CH2:39][NH2:40].CCN(CC)CC>CCO>[Br:29][C:30]1[C:35]([CH3:36])=[C:34]([F:37])[CH:33]=[C:32]([Br:38])[C:31]=1[CH2:39][NH:40][C:21]([C:19]1[N:20]=[C:9]2[C:8]3([N:7]([CH3:27])[C:5](=[O:6])[C:4]([N:2]([CH3:1])[CH3:3])=[O:28])[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]3)[CH2:11][N:10]2[C:17](=[O:26])[C:18]=1[OH:25])=[O:23]
Reactant: Cc1c(F)cc(Br)c(CN)c1Br
Reactant: COC(=O)c1nc2n(c(=O)c1O)CC1CCC2(N(C)C(=O)C(=O)N(C)C)CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1c(F)cc(Br)c(CNC(=O)c2nc3n(c(=O)c2O)CC2CCC3(N(C)C(=O)C(=O)N(C)C)CC2)c1Br
Yield: 56.1 %

Procedure:
A solution of methyl 10-(((dimethylamino)(oxo)acetyl)(methyl)amino)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (0.10 g, 0.246 mmol), (2,6-dibromo-4-fluoro-3-methylphenyl)methanamine (0.225 g, 0.758 mmol) and Et3N (0.279 mL, 2 mmol) in EtOH (5 mL) was heated at reflux for 48 h. Then, cooled and purified by preparative HPLC to afford the title compound (0.0906 g, 0.138 mmol, 56% yield) as a white solid after crystallization from methanol/H2O. 1H NMR (500 MHz, CDCl3) δ: 12.18 (1 H, s), 9.08 (1 H, s), 7.32 (1 H, d, J=8.5 Hz), 4.96 (2 H, d, J=8.2 Hz), 4.78-4.90 (1 H, m), 3.57-3.72 (1 H, m), 3.36-3.49 (1 H, m), 2.94 (3 H, s), 2.93 (3 H, s), 2.76 (3 H, s), 2.48-2.54 (1 H, m), 2.34 (3 H, d, J=2.1 Hz), 2.00-2.10 (4 H, m), 1.71-1.87 (2 H, m), 1.45-1.53 (1 H, m). LCMS (M+H) calcd for C25H29Br2FN5O5: 656.05; found: 656.24.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OC(=O)C)(=O)C>>[OH:20][CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cccnc1C
Reactant: O=Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1cccnc1CC(O)c1ccccc1

Procedure:
In carrying out the reaction, an appropriate ethyl 2-methylnicotinate and benzaldehyde compound and acetic anhydride are refluxed together under nitrogen for about 24 hours. Thereafter, the excess anhydride is removed in vacuo and the residue poured into water and extracted with ether. The ether solution extracted with dilute acid, the acid solution then made basic with ammonia to obtain a lactone of 2-(2-hydroxy-2-phenylethyl)nicotinic acid. The lactone is reduced to 2-phenylethylnicotinic acid adding the lactone to a freshly prepared mixture of phosphorus and iodine and the resulting mixture heated at reflux temperature for 3 to 10 hours with stirring. The acid is recovered from the reaction mixture by filtering to remove the phosphorus and cooling to recover the hydroiodic acid salt which is collected, dissolved in water and the solution neutralized with ammonia to obtain the 2-phenethylnicotinic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]([C:31]5[CH:36]=[CH:35][C:34]([C:37]#[C:38][Si](CC)(CC)CC)=[CH:33][CH:32]=5)=[N:23][N:22]=4)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:37]([C:34]1[CH:35]=[CH:36][C:31]([C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21]([NH:20][C:17]3[CH:16]=[CH:15][C:14]([O:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][N:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:19][CH:18]=3)=[N:22][N:23]=2)=[CH:32][CH:33]=1)#[CH:38]
Reactant: CC[Si](C#Cc1ccc(-c2nnc(Nc3ccc(Oc4ccnc5cc(OC)cnc45)cc3)c3ccccc23)cc1)(CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(-c2nnc(Nc3ccc(Oc4ccnc5cc(OC)cnc45)cc3)c3ccccc23)cc1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
In a nitrogen purged sealed tube was dissolved N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)-4-(4-(2-(triethylsilyl)ethynyl)phenyl)phthalazin-1-amine (0.100 g, 0.164 mmol) in MeOH (2.00 mL). Potassium carbonate (0.068 g, 0.492 mmol) was added and the reaction was stirred at 20° C. for 24 h and then concentrated. The crude was extracted into DCM, washed 1× with water, 1× with brine, dried over Na2SO4, filtered through flitted funnel, concentrated. The resulting crude material was purified by silica gel chromatography eluting with 0-100% CH2Cl2:MeOH(90:10)/CH2Cl2. The product fractions were concentrated to afford 4-(4-ethynylphenyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine as light yellow solid. MS [M+H]=496; Calc'd 495.5 for C31H21N5O2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:31](=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: CCOC(=O)C(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(OC)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (52 mg, 0.13 mmol) and ethyl 2-chloro-2-oxoacetate (0.030 mL, 0.27 mmol). Yield 53 mg (81%).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][C:29]([F:30])([F:32])[F:31])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOCC(F)(F)F)C(=O)NC2C(=O)N3C(C(=O)O)=C(Cl)CS[C@H]23)cs1
Agent: Cl
Solvent: CO
Product: Nc1nc(C(=NOCC(F)(F)F)C(=O)NC2C(=O)N3C(C(=O)O)=C(Cl)CS[C@H]23)cs1
Yield: 98.2 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 0.7 g.), conc.hydrochloric acid (0.43 ml.) and methanol (16 ml.) were treated in a similar manner to that of Example 21-(3) to give 7-[2-(2-aminothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 0.65 g.)
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](N2C3C=CC=CC=3N=C2C(F)F)[CH:6]=[C:5]([N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]2[CH:30]([F:32])[F:31])[N:4]=1.[OH:33][CH2:34][C@H:35]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[F:31][CH:30]([F:32])[C:22]1[N:21]([C:5]2[N:4]=[C:3]([S:2][CH3:1])[N:8]=[C:7]([O:33][CH2:34][C@H:35]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]3)[CH:6]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1
Reactant: CSc1nc(-n2c(C(F)F)nc3ccccc32)cc(-n2c(C(F)F)nc3ccccc32)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CSc1nc(OC[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc(-n2c(C(F)F)nc3ccccc32)n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 93.7 %

Procedure:
To a solution of 1,1′-[2-(methylsulfanyl)pyrimidine-4,6-diyl]bis[2-(difluoromethyl)-1H-benzimidazole] (2 g) in N,N-dimethylacetamide (10 mL) were added tert-butyl (3S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (965 mg) and cesium carbonate (2.1 g), followed by stirring at 60° C. for 5 hours. After the completion of the reaction, to the reaction solution was added ice water and the precipitated solid was collected by filtration. After drying, the resultant was dissolved in dichloromethane and purified by silica gel column chromatography (hexane:ethyl acetate=90:10-65:35) to obtain tert-butyl (3S)-3-[({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(methylsulfanyl)pyrimidin-4-yl}oxy)methyl]pyrrolidine-1-carboxylate (2.01 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Br[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1.O>CO>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[N:15][CH:16]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: Brc1ccc(Br)nc1
Solvent: CO
Solvent: O
Product: Brc1ccc(N2CCN(c3ccncc3)CC2)nc1
Temperature: 200 °C
Yield: 50.3 %

Procedure:
A mixture of 1-(4-pyridyl)piperazine (3.26 g, 20 mmol) and 2,5-dibromopyridine (2.36 g) was heated gradually on an oil bath up to 200° C. At approximately 150° C. a clear, slightly coloured melt was obtained and at approximately 180° C. a vigorous reaction set in which caused the melt to darken markedly. The now-dark melt was heated at 200° C. for 10 minutes then allowed to cool to room temperature. The solid reaction mixture was dissolved in methanol (100 mL) and poured into water (100-150 mL). The resultant precipitate was collected, washed with water, dried, then recrystallised from hot aqueous methanol to give the product (1.6 g, 25% yield) as a buff-coloured solid: m.p. 176-180° C.; NMR (DMSO-d6), 3.32 (4H, m), 3.50 (4H, m), 6.72 (2H, m), 6.75 (1H, d), 7.59 (1H, dd), 8.05 (3H, m); Found: MH+, 319/321; C14H15BrN4 requires MH+, 319/321.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[Li+].[CH2:11](Br)[CH2:12][C@H:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH3:14]>C(OCC)C.C1COCC1.[Cu](Cl)Cl>[CH3:14][C@@H:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH2:12][CH2:11][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: CC(C)=CCC[C@H](C)CCBr
Agent: Cl[Cu]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)=CCC[C@H](C)CCC1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
A flask was charged with 100 mL of dry THF and cooled to 0° C. To this flask was added 103 mL (205 mmol) of 2 M cyclohexylmagnesium chloride in diethylether. Then 2.30 g (17 mmol) copper (II) chloride was taken up in 60 mL of THF and added as a slurry to the Grignard reagent. To this mixture was added 0.73 g (17.1 mmol) lithium chloride, and the mixture was stirred at 0° C. for 30 minutes. Then 13.5 mL (68.4 mmol) of (S)-citronellyl bromide was added, and the mixture was stirred 2 hours at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by the addition of sat. aq. NH4Cl until bubbling ceased. The THF was removed under reduced pressure. The residue was taken up in water and extracted with diethyl ether. The combined ether layers were dried over MgSO4. The drying agent was removed by filtration. The solvent was removed under reduced pressure to yield 11.48 g (76% yield) of a clear oil. The crude long-chain alkyl was not readily characterized, and was carried on without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[N:18]=[N:19][C:20]([NH:23][NH2:24])=[CH:21][CH:22]=1)[CH:14]=[CH:13][O:12]2.C([O-])([O-])=O.[Na+].[Na+].[N:31]#[C:32]Br>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:22]=[CH:21][C:20]3[N:19]([C:32]([NH2:31])=[N:24][N:23]=3)[N:18]=1)[CH:14]=[CH:13][O:12]2
Reactant: N#CBr
Reactant: NNc1ccc(-c2c(-c3ccc(F)cc3F)nc3occn23)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Reaction time: 1 h
Yield: 57 %

Procedure:
The 6-(2,4-difluorophenyl)-5-(6-hydrazinylpyridazin-3-yl)imidazo[2,1-b]oxazole (0.300 g, 0.914 mmol, Example #40, Step B, was dissolved in MeOH (15 mL) at about ambient temperature before addition of Na2CO3 (0.112 g, 1.371 mmol). Cyanogen bromide (3M in DCM, 0.305 mL, 0.914 mmol) was added and the resulting mixture was stirred at about ambient temperature for about 1 h. The crude mixture was partitioned between water and DCM. The organics were dried over MgSO4, filtered, concentrated under reduced pressure to give a yellow solid that was triturated with Et2O and filtered to give the title compound (0.185 g, 57%): LC/MS (Table 1, Method g) Rt=1.65 min.; MS m/z: 354.07 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH-:9].[O:10]=[C:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:24](O)=O)[C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2.C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[CH3:8][C:4]1[C:3]2[N:9]=[C:24]([C:19]3[C:18]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[C:11](=[O:10])[C:23]=4[CH:22]=[CH:21][CH:20]=3)[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1cccc2c1-c1ccccc1C2=O
Reactant: Cc1cccc(N)c1[NH-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc2[nH]c(-c3cccc4c3-c3ccccc3C4=O)nc12

Procedure:
The procedure used in Example 68 is followed. In a 250 ml round-bottomed flask under an argon atmosphere, reflux, for 6 hours, a suspension of 5 g of (2-amino-6-methylphenyl)amide of 9-oxo-9H-fluorene-4-carboxylic acid, obtained in the previous stage, in 100 ml of acetic acid. After cooling, bring to dryness under reduced pressure. Take the residue up in 25 ml of water then bring to pH=8 by addition of a saturated aqueous solution of sodium hydrogen carbonate. The precipitate that formed is filtered off, washed with water, and made into a paste with diisopropyl ether, and in this way, we obtain 4.7 g of 4-(4-methyl-1H-benzimidazol-2-yl)-9H-fluoren-9-one, in the form of an orange powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:25])=[O:24])=[CH:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:38]1[C:42]([NH2:43])=[N:41][CH:40]=[N:39]1.C1COCC1.CC([O-])(C)C.[Li+]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23]([NH:43][C:42]1[S:38][N:39]=[CH:40][N:41]=1)(=[O:25])=[O:24])=[CH:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(C3CCCN3Cc3ccccc3)cccc2c1
Reactant: Nc1ncns1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=S(=O)(Nc1ncns1)c1ccc2c(C3CCCN3Cc3ccccc3)cccc2c1
Reaction time: 1 h
Yield: 60.9 %

Procedure:
A flask was charged with perfluorophenyl 5-(1-benzylpyrrolidin-2-yl)naphthalene-2-sulfonate (INTERMEDIATE LL) (24.8 mg, 0.046 mmol), 1,2,4-thiadiazol-5-amine (5.64 mg, 0.056 mmol), and THF (465 μl) to give a clear, colorless solution. The flask was cooled in an ice-bath for 5 min, then lithium 2-methylpropan-2-olate (1M in hexane) (102 μl, 0.102 mmol) was added dropwise. After 1 h, the mixture was loaded directly onto a 5-g silica gel loading column with the aid of DCM. The column was dried under vacuum, then eluted onto a prequilibrated 12-g silica gel column with 0 to 10% MeOH/DCM to give 5-(1-benzylpyrrolidin-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (12.69 mg, 0.028 mmol, 60.6% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=8.46-8.33 (m, 2H), 8.07 (d, J=8.0 Hz, 1H), 8.02 (s, 1H), 7.97 (d, J=7.1 Hz, 1H), 7.83 (dd, J=1.9, 8.9 Hz, 1H), 7.65 (t, J=7.7 Hz, 1H), 7.34-7.21 (m, 5H), 4.62 (br. s., 1H), 3.91 (d, J=13.0 Hz, 1H), 3.24 (br. s., 4H), 1.97 (d, J=14.1 Hz, 2H), 1.86-1.72 (m, 1H); m/z (ESI) 451.4 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[O:11]=[CH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:16]([O:17][CH3:18])[C:14]=1[OH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:18][O:17][C:16]1[C:14]([O:15][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[C:13]([CH:21]=[CH:20][CH:19]=1)[CH:12]=[O:11]
Reactant: COc1cccc(C=O)c1O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(C=O)c1Oc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 71 %

Procedure:
A mixture of 14.10 g (0.10 mole) of 4-fluoronitrobenzene, 16.40 g (0.10 mole) of o-vanillin, 30 g of powdered potassium carbonate, and 40 mL of DMF is heated with stirring to the boiling point. After 10 minutes the mixture is cooled to 100° C. and 300 mL of ice water is added. Petroleum ether (200 mL) is added and the entire mixture is filtered and the cake is washed with 200 mL of water and then 200 mL of petroleum ether. The damp cake is slurried in 100 mL of methanol and filtered; wt 19.50 g (71% yield); mp 130°-131° C.; mass spectrum (DEI), 273 (M+).
Reaction SMILES: [C:1]([CH2:6][C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH2:2][CH2:3][CH3:4].[F:14]F>C(#N)C>[C:1]([CH:6]([F:14])[C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: FF
Reactant: CCCC(=O)CC(=O)C(=O)OCC
Solvent: CC#N
Product: CCCC(=O)C(F)C(=O)C(=O)OCC

Procedure:
In the same manner as in Example 1, ethyl 3-butyrylpyruvate (9.53 g; 0.0512 mol) is dissolved in acetonitrile (94 g) and reacted with fluorine at -5° C. By distilling off the solvent under reduced pressure, there is obtained a crude product (5.5 g), which is rectified to give ethyl 3-butyryl-3-fluoropyruvate. Boiling point, 72°-78° C./2 mmHg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23]2[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=2[C:25](OCC)=[O:26])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:10]=2)=[N:6][CH:7]=1.[NH2:34][C@@H:35]([CH3:38])[CH2:36][OH:37]>>[Cl:1][C:2]1[C:3]([NH:22][C:23]2[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=2[C:25]([NH:34][C@@H:35]([CH3:38])[CH2:36][OH:37])=[O:26])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[CH:10]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2cccc(N3CCN(C)CC3)c2)ncc1Cl
Reactant: C[C@H](N)CO
Product: C[C@@H](CO)NC(=O)c1ccccc1Nc1nc(Nc2cccc(N3CCN(C)CC3)c2)ncc1Cl
Temperature: 95 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
Ethyl 2-[(5-chloro-2-{[3-(4-methyl-1-piperazinyl)phenyl]amino}-4-pyrimidinyl)amino]benzoate (150 mg, 0.32 mmol) and (2S)-2-amino-1-propanol (0.5 mL) were combined in a vessel, which was sealed and heated with stirring at 95° C. for 18 h. The reaction was cooled to room temperature and the solid was filtered off and washed with ethanol/water (1:1 ratio) and ethyl ether to afford the product (82 mg, 52% yield) as a white solid. MS: M(C25H30ClN7O2)=496.01, (M+H)+=496.2 and 498.2.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:30])[CH2:17][S:18][CH2:19][CH2:20][N:21]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[C:22]([CH3:24])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:34]O>C(O)(=O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:30])[CH2:17][S:18]([CH2:19][CH2:20][N:21]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[C:22]([CH3:24])=[O:23])=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OO
Reactant: CC(=O)N(CCSCC(=O)NCCCOc1cccc(CN2CCCCC2)c1)c1cccs1
Solvent: CC(=O)O
Product: CC(=O)N(CCS(=O)CC(=O)NCCCOc1cccc(CN2CCCCC2)c1)c1cccs1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
There was dissolved 1.0 g (0.002 mol) of N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-[2-(2-thienylacetamino)ethylthio]acetamide in 30 ml, of acetic acid and added 0.24 ml, (0.0022 mol) of 30% aqueous solution of hydrogen peroxide under cooling with ice, and the mixture was stirred for 12 hours at room temperature. The solvent was removed under reduced pressure, and then the residue was purified by silica gel column chromatography (chloroform:ethanol=5:1) to give 0.72 g of the titled compound as crystals.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[CH:8]([O:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH:27]([NH2:29])[CH3:28])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)([CH3:10])[CH3:9].C(OC(=O)C)(=O)C>>[CH:8]([O:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH:27]([NH:29][C:3](=[O:5])[CH3:2])[CH3:28])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)([CH3:10])[CH3:9]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(N)/C=C/c1ccc(Oc2ccc(OC(C)C)nc2)cc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC(C)/C=C/c1ccc(Oc2ccc(OC(C)C)nc2)cc1

Procedure:
(E)-3-[4-(6-Isopropoxy-pyridin-3-yloxy)-phenyl]-1-methyl-allylamine trifluoroacetate (63 mg, 0.154 mmol) was reacted with acetic anhydride in analogy to example 2a. M+H+: 341.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16](=[O:20])[NH:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2.F[B-](F)(F)F.[CH2:26]([O+](CC)CC)[CH3:27]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16]([O:20][CH2:26][CH3:27])=[N:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)-c1cc(=O)[nH]c(=O)n1CC2
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOc1cc2n(c(=O)n1)CCc1cc(OC)c(OC)cc1-2
Reaction time: 8 h

Procedure:
A mixture of 3.0 g of 9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido(6,1-a)isoquinolin-2,4-dione and 15.0 g of triethyloxonium fluoroborate in 100 ml of dichloromethane is stirred overnight. The reaction mixture is washed with a solution of sodium carbonate. The organic layer is separated and dried over anhydrous sodium sulfate. Evaporation of the solvent gives the title compound, yield 1.8 g.