Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:14])([F:13])[O:7][C:8]2([F:12])[F:11])=[CH:4][C:3]=1[Cl:15].[N:16](OS(=O)(=O)O)=O.N([O-])=O.[Na+].S(=O)(=O)(O)O.Cl.[OH-].[Na+]>C(O)(=O)C>[Cl:15][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][NH2:16])[C:8]([F:11])([F:12])[O:7][C:6]2([F:14])[F:13]
Reactant: O=NOS(=O)(=O)O
Reactant: Nc1cc2c(cc1Cl)C(F)(F)OC2(F)F
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: NNc1cc2c(cc1Cl)C(F)(F)OC2(F)F
Temperature: 0 °C

Procedure:
To a solution wherein 6-amino-5-chloro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran (2.41 g, 10.0 mmol) is in acetic acid (30 ml), a nitrosylsulfuric acid solution prepared from sodium nitrite (760 mg, 11.0 mmol) and concentrated sulfuric acid (5.5 ml) was added dropwise at 10 to 15° C. over a period of about 10 minutes. The reaction solution was then added dropwise into a solution consisting of stannous chloride anhydride (9.5 g) and concentrated hydrochloric acid (8 ml) under vigorous stirring at 0° C. and further stirred for 30 minutes. After a sodium hydroxide solution was added to the reaction mixture to make the solution alkaline, the solution was extracted with diethyl ether, and the organic layer was then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to give 1.8 g of 5-chloro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-6-yl-hydrazine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][Cl:25])[N:19]=1>C1COCC1>[Cl:25][CH2:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(CNCc2ccccn2)nc1
Reactant: ClCc1cccc(CCl)n1
Solvent: C1CCOC1
Product: ClCc1cccc(CN(Cc2ccccn2)Cc2ccccn2)n1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
In a 250 ml three-necked flask 1 equivalent of bis(2-pyridylmethyl)amine was dissolved in 100 ml of THF and the solution was admixed with 1 equivalent of 2,6-bis(chloromethyl)pyridine and 4 equivalents of N,N-diisopropylethylamide. The solution was stirred at room temperature for 7 days. The solution was filtered and the filtrate was purified by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:14])[CH2:12]O)=[O:4].C(OC([N+](C(OCC)=O)=[N-])=O)C.C1(P([N:47]=[N+:48]=[N-:49])(C2C=CC=CC=2)=O)C=CC=CC=1.P>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:14])[CH2:12][N:47]=[N+:48]=[N-:49])=[O:4]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)CO
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: P
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(C)CN=[N+]=[N-]

Procedure:
A mixture of 3-(2-Hydroxy-1-methyl-ethylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (213 mg, 0.257 mmol), diethyldiazodicarboxylate (250 μL, 1.59 mmol, 2 eq), diphenylphosphoryl azide (343 μL, 1.59 mmol, 2 eq) and trphenyl phosphine (417 mg, 1.59 mmol, 2 eq) was stirred at 21° until all starting alcohol was consumed. The reaction was evaporated to dryness and the crude residue purified on biotage with 5% EtOAc/hexane followed by 100% toluene as eluent. 3-(2-Azido-1-methyl-ethylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester was isolated as a solid (181 mg, 78%); 1H NMR (300 MHz, CDCl3) 1.33 (d, J=6.6 Hz, 3H), 3.38-3.46 (m, 2H), 3.78-3.81 (m, 1H), 6.82 (s, 1H), 7.36-7.41 (m, 3H), 7.60-7.62 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH:15]([C:17](O)=[O:18])[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]2=[O:26])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH:15]([C:17]([N:38]3[CH2:39][CH2:40][CH:35]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][CH3:27])[CH2:36][CH2:37]3)=[O:18])[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]2=[O:26])(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccccc1C1CCNCC1
Reactant: COc1cccc(S(=O)(=O)N2CC(C(=O)O)N(c3ccccc3)C2=O)c1
Product: COc1cccc(S(=O)(=O)N2CC(C(=O)N3CCC(c4ccccc4OC)CC3)N(c3ccccc3)C2=O)c1

Procedure:
In analogy to example 1, (RS)-1-(3-methoxy-benzenesulfonyl)-2-oxo-3-phenyl-imidazolidine-4-carboxylic acid (step 4 of example 1) was reacted with 4-(2-methoxyphenyl)piperidine to give the title compound as a colorless solid. MS: 550.0 ([M+H]t)
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][NH2:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([S:20][C:21](Cl)=[O:22])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:18]([S:20][C:21](=[O:22])[NH:15][CH2:14][CH2:13][O:12][C:11]1[CH:16]=[CH:17][C:8]([S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1)[CH3:19]
Reactant: NCCOc1ccc(Sc2ccccc2)cc1
Reactant: CCSC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCSC(=O)NCCOc1ccc(Sc2ccccc2)cc1
Yield: 66.2 %

Procedure:
7 g of 2-[p-(phenylthio)phenoxy]ethylamine and 18.6 g of chlorothioformic acid S-ethyl ester are dissolved in 250 ml of acetone. 24 g of potassium carbonate are added to the solution and the mixture is heated under reflux for 6 hours. The mixture is then filtered, the residue is washed with acetone and the filtrate is evaporated in vacuo. The 13 g of residue are filtered through a 10-fold amount of silica gel with ether/cyclohexane (7:3). The first fractions yielded 10.2 g which, after recrystallization from ether/low boiling petroleum ether yields 6.3 g (76%) of 2-[p-(phenylthio)phenoxy]ethylthiocarbamic acid S-ethyl ester, m.p.--77°-79° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([CH2:38][S:39][C:40]5[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([CH2:38][S:39]([C:40]5[CH:45]=[CH:44][C:43]([C:46]([F:48])([F:49])[F:47])=[CH:42][N:41]=5)=[O:59])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4ccc(C(F)(F)F)cn4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)c4ccc(C(F)(F)F)cn4)cc2)CCN3CC(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 26.1 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[5-(trifluoromethyl)-2-pyridinyl]sulfanyl]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.51 g) was dissolved in methylene chloride (20.4 ml), m-chloroperbenzoic acid (125 mg) was added to the mixture at 0° C., and the mixture was stirred at 0° C. for 15 minutes. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[5-(trifluoromethyl)-2-pyridinyl]sulfinyl]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 191) (136 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:5]=[C:6]([F:8])[CH:7]=1.CN(C)CCN(C)C.C([Li])CCC.[S:30]1[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]1>C1COCC1>[OH:36][C:33]1([C:7]2[C:2]([F:1])=[CH:3][C:4]([NH:9][C:10](=[O:16])[O:11][CH2:12][CH:13]([CH3:14])[CH3:15])=[CH:5][C:6]=2[F:8])[CH2:34][CH2:35][S:30][CH2:31][CH2:32]1
Reactant: O=C1CCSCC1
Reactant: CC(C)COC(=O)Nc1cc(F)cc(F)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)COC(=O)Nc1cc(F)c(C2(O)CCSCC2)c(F)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A stirred solution of isobutyl 3,5-difluorophenylcarbamate (Step A, 10.0 g, 43.6 mmol) and N,N,N′,N′-tetramethylethylenediamine (13.7 mL, 87.3 mmol) in anhydrous THF (87 mL) at −78° C. under N2 is treated n-butyllithium (1.6M in hexanes, 35.8 mL, 89.4 mmol) dropwise over 35 mins. The mixture is stirred at −78° C. for 20 mins and is then treated with a solution of tetrahydro-2H-thiopyran-4-one (5.32 g, 45.8 mmol) in anhydrous THF (15 mL) dropwise over 10 mins. After 45 mins at −78° C., the cooling bath is removed and the mixture is allowed to warm to ambient temperature and is then quenched by the slow addition of saturated aqueous ammonium chloride (50 mL). Water (50 mL) and EtOAc (100 mL) are added, the layers are separated, and the organic phase is washed with water (100 mL) and saline (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product is triturated and filtered from EtOAc (approx. 25 mL) to remove an insoluble impurity, and the filtrate is chromatographed on two Flash 40M 90 g silica gel cartridges, eluting with EtOAc/heptane (20/80). Pooling and concentration of those fractions with an Rf=0.26 by TLC (EtOAc/hexanes, 25/75) gives the title compound, mp 103-104° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](O)=[O:12])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.N=C=N.[CH2:35]([N:38]1[CH2:43][CH2:42][N:41]([CH:44]2[CH2:48][CH2:47][NH:46][CH2:45]2)[CH2:40][CH2:39]1)[CH2:36][CH3:37].C(=O)([O-])[O-]>ClCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH:10]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:11](=[O:12])[N:46]3[CH2:47][CH2:48][CH:44]([N:41]4[CH2:42][CH2:43][N:38]([CH2:35][CH2:36][CH3:37])[CH2:39][CH2:40]4)[CH2:45]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: CCCN1CCN(C2CCNC2)CC1
Reactant: O=C(O)C(c1ccccc1)n1c(=O)[nH]c2cc(Cl)ccc21
Agent: N=C=N
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCN1CCN(C2CCN(C(=O)C(c3ccccc3)n3c(=O)[nH]c4cc(Cl)ccc43)C2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
110 mg (0.36 mmol) of (5-chloro-2-oxo-2,3-dihydrobenzimidazol-1-yl)phenyl-acetic acid (VIIIe), 69.1 mg (0.51 mmol) of HOBt and 335 mg (0.44 mmol, 1.3 mmol/g) of solid phase-bound PS-carbodiimide were dissolved in 6 ml of dry dichloromethane in a screw-cap tube and shaken mechanically at room temperature for 10 min. 78.9 mg (0.40 mmol) of 1-propyl-4-pyrrolidin-3-ylpiperazine were added, and the mixture was then shaken mechanically overnight. Three equivalents of solid phase-bound MP-carbonate were then added to the reaction mixture, and shaking was continued for 2 h. The solid phase-bound reagents were filtered off and washed with dichloromethane. The filtrate was concentrated in vacuo and the residue was dried in vacuo. The reaction product was used without further purification for the next reaction step.
Reaction SMILES: [CH:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21](=O)[CH:22]([CH3:24])[CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CC(C)C=O
Reactant: c1ccc(N2CCNCC2)c(C2CCCCCCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)CN1CCN(c2ccccc2C2CCCCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.9 %

Procedure:
To a solution of the 1-(2-cyclooctylphenyl)piperazine (7 mg, 0.0257 mmol) produced in Example (46d) in tetrahydrofuran (1 mL) were added isobutyraldehyde (2.4 mg, 0.0334 mmol), sodium triacetoxyborohydride (7.1 mg, 0.0334 mmol) and acetic acid (0.0028 mL, 0.0448 mmol), followed by stirring for 17 hours and 10 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed three times with ethyl acetate. The organic layers was concentrated to produce a residue, which was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 4.3 mg of 1-(2-cyclooctylphenyl)-4-isobutylpiperazine as a colorless oil.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([CH3:21])=[N:11][C:12]([O:16][CH2:17][C:18]([OH:20])=O)=[N:13][C:14]=1[CH3:15])=O)(C)(C)C.[CH:22]1([C:26]([N:28]2[CH2:33][CH2:32][CH:31]([NH:34][CH3:35])[CH2:30][CH2:29]2)=[O:27])[CH2:25][CH2:24][CH2:23]1>>[NH2:8][C:9]1[C:14]([CH3:15])=[N:13][C:12]([O:16][CH2:17][C:18]([N:34]([CH:31]2[CH2:32][CH2:33][N:28]([C:26]([CH:22]3[CH2:25][CH2:24][CH2:23]3)=[O:27])[CH2:29][CH2:30]2)[CH3:35])=[O:20])=[N:11][C:10]=1[CH3:21]
Reactant: Cc1nc(OCC(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Reactant: CNC1CCN(C(=O)C2CCC2)CC1
Product: Cc1nc(OCC(=O)N(C)C2CCN(C(=O)C3CCC3)CC2)nc(C)c1N

Procedure:
The title compound was synthesized from Compound 9 and cyclobutyl (4-(methylamino)piperidine-1-yl)methanone in the same manner as in Example 64.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[C:12](O)[CH:11]=[C:10]([CH:15]3[CH2:17][CH2:16]3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:20])=O.Cl.[OH-].[Na+]>O>[C:1]1([NH:7][C:8]2[N:13]=[C:12]([Cl:20])[CH:11]=[C:10]([CH:15]3[CH2:17][CH2:16]3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(C2CC2)nc(Nc2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1cc(C2CC2)nc(Nc2ccccc2)n1
Temperature: 25 °C

Procedure:
19.6 g (86.3 mmol) of 2-phenylamino-4-hydroxy-6-cyclopropyl-pyrimidine are added to 50 ml (0.55 mol) of phosphorus oxychloride at 75° C. in the course of one hour, while stirring, and the mixture is then refluxed for one hour. When the evolution of hydrogen chloride has ended, the reaction mixture is cooled to room temperature and poured into 200 ml of water, while stirring vigorously, the temperature being kept at about 50° C. by addition of ice. The approximately 400 ml of the pale brown suspension is brought to pH 7 by slow dropwise addition of 220 ml of 30% aqueous sodium hydroxide solution and is extracted three times with 150 ml of ethyl acetate each time. The combined extracts are washed twice with 100 ml of water each time, dried over sodium sulfate and filtered and the solvent is evaporated. The 20.7 of pale brown powder are treated with 400 ml of diethyl ether and the undissolved material is filtered off. After evaporation of the diethyl ether, the residue is recrystallized from diisopropyl ether. The yellowish crystals melt at 127°-128° C. Yield 17.7 g (72.1 mmol; 83.5% of theory).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:17][CH3:18])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[NH:8][C:7]1=[O:16].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[CH2:17]([C:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:28][CH2:27][N:26]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=3)[CH2:31][CH2:30]2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[NH:8][C:7]1=[O:16])[CH3:18]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccc(C)cc21
Product: CCC1(CCCCN2CCN(c3ccc(F)cc3)CC2)C(=O)Nc2ccc(C)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 from 3-(4-chlorobutyl)-3-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one and 1-(4-fluorophenyl-)-piperazine.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH:4]([OH:12])[CH:5]=[CH:6][CH2:7][CH2:8][CH2:9]CC.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:12][CH:4]([CH:5]=[CH:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH:2]=[CH2:1])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCC(O)C=CCCCCC
Product: C=CCC(C=CCCC)OC(C)=O
Yield: 75 %

Procedure:
36 g of 1,5-undecadien-4-ol is stirred and heated to reflux with 32.6 g of acetic acid anhydride for 1 hour. The excess anhydride and the resulting acetic acid are removed by distillation under reduced pressure. The residue is fractionated. Yield: 33.8 g (76%) 1,5-undecadien-4-yl acetate; b.p. 70°-80° C/2 Torr; n20D = 1.4468. 1,5-Nonadien-4-yl acetate was prepared in a similar way; yield: 75%; b.p. 85° C/10 Torr; n22D = 1.4403.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]4[N:40]([CH:41]=3)[CH:39]=[CH:38][S:37]4)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]4[N:40]([CH:41]=3)[CH:39]=[CH:38][S:37]4)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn4ccsc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3cn4ccsc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:21])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:8]=1.[Br:22]N1C(=O)CCC1=O>C1COCC1>[Br:22][C:4]1[NH:3][C:2]([CH3:1])=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:8]=2)[C:5]=1[CH3:21]
Reactant: Cc1c[nH]c(C)c1-c1ccnc(Nc2ccc(F)cc2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Cc1[nH]c(Br)c(C)c1-c1ccnc(Nc2ccc(F)cc2)n1
Temperature: -50 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine (80 mg, 0.28 mmol) was dissolved in THF (4 mL) and cooled to −50° C. N-Bromosuccinimide (55 mg, 0.31 mmol) was dissolved in THF (2 mL) and added dropwise, keeping the internal temperature ≦−40° C. The mixture was stirred for 1 h with cooling then evaporated in vacuo. The residue was treated with H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extractss were washed (brine), dried (MgSO4), filtered, and evaporated in vacuo. The crude product was purified by SiO2 chromatography heptane/EtOAc gradient elution) to afford the title compound (19 mg) as an orange solid after recrystallisation from iPr2O. M.p. 181.4–183.3° C. MS: [M+H]+=362.9 (C16H14BrFN4 requires 361.2). 1H-NMR (CDCl3) δ: 2.10 (s, 3H, CH3), 2.36 (s, 3H, CH3) 6.56 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 6.97 (t, 2H, J=8.3 Hz, Ph-H), 7.00 (br. s, 1H, NH), 7.79–7.52 (m, 2H, Ph-H), 8.85 (br. s, 1H, NH), 8.26 (d, 1H, J=5.1 Hz, pyrimidinyl-H).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH2:12][CH2:13][CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:16][C:17]([NH2:19])=[S:18].O>C(O)C>[NH2:19][C:17]1[S:18][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][CH2:13][CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:16]=1
Reactant: NC(N)=S
Reactant: CCCON=C(C(=O)CBr)C(=O)OCC
Solvent: CCO
Solvent: O
Product: CCCON=C(C(=O)OCC)c1csc(N)n1
Reaction time: 1 h
Yield: 58.3 %

Procedure:
85 g of ethyl 4-bromo-2-propoxyimino-acetoacetate are added dropwise to 23 g (0.3 mole) of thiourea in 155 ccs of water and 75 ccs of ethanol at 25°, while stirring. After one hour, the hydrobromide which has precipitated in the meantime is decomposed by adding concentrated ammonia up to pH 6. After filtering off the product, washing with water and diisopropyl ether and drying, 45 g of ethyl 2-(2-aminothiazol-4-yl)-2-propoxyimino-acetate are obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:22]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:23]C([O-])=O.Cl>O1CCCC1.O.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:8])[CH2:23][C:22]([O:28][CH2:29][CH3:30])=[O:27])=[CH:2]1
Reactant: O=C(O)c1ccoc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccoc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 184.4 %

Procedure:
To a solution of 3-furancarboxylic acid (25.5 g, 227 mmol) in tetrahydrofuran (200 ml) was added 1,1′-carbonylbis-1H-imidazole (40.5 g, 250 mmol) and the mixture was stirred at 60° C. for 2 hrs. To the reaction solution was added monoethyl malonate magnesium salt (35.8 g, 125 mmol) and the mixture was heated under reflux for 30 min. Ethyl acetate (50 ml) and water (50 ml) were added the reaction solution, and conc. hydrochloric acid was added until the aqueous layer showed acidic pH. The reaction solution was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(3-furanyl)-3-oxopropionate (42 g, 100%) as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(O[C:7](=[O:19])[CH2:8][NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])C.[O-][Si]([O-])=O.[Mg+2]>C(O)C.C(Cl)Cl>[CH3:1][N:2]([CH3:3])[C:7](=[O:19])[CH2:8][NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17]
Reactant: CNC
Reactant: CCOC(=O)CNc1ccncc1[N+](=O)[O-]
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCO
Product: CN(C)C(=O)CNc1ccncc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Condensed dimethylamine (20 ml) was added in portions to a solution of crude N-(3-nitro-4-pyridinyl)glycine ethyl ester (4.0 g, 0.018 mole) in absolute ethanol (10 ml). The reaction was allowed to stir at ambient temperature over the weekend. The mixture was diluted with petroleum ether and the solid was collected by filtration. The solid 3-g was dissolved in tetrahydrofuran, filtered and diluted with isopropyl ether to produce a dark amorphous solid which was filtered off. The filtrate was further diluted with petroleum ether and placed in the freezer to produce a dark orange crystalline solid. The solid (2.5 g) was dissolved in methylene chloride, treated with Florisil.COPYRGT., and the filtrate was evaporated to a yellow solid. which was dried under high vacuum at 70° C. to give 1.8 g (45%), mp 142°-143° C.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:9]([O:16][NH2:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH2:9]([O:16][N:17]=[CH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NOCc1ccccc1
Reactant: CCCCCCC=O
Solvent: C1CCOC1
Product: CCCCCCC=NOCc1ccccc1
Reaction time: 0.33 h
Yield: 91 %

Procedure:
To a 10 mL round bottom flask equipped with a stifling bar and purged with N2 was added heptanal (343 mg, 420 μL, 3.0 mmol) followed by O-benzylhydroxylamine (369 mg, 349 μL, 3.0 mmol). An immediate evolution of heat occurred with formation of a cloudy solution. The solution was stirred at room temperature during four minutes before 3 mL of dry THF was added. Stirring continued for 20 min, at which time the TLC (hexanes/ethyl acetate, 85:15) indicated completion of reaction. The volatiles were removed under reduced pressure, and the crude material was purified by column chromatography on silica gel using hexanes/ethyl acetate (95:5) as eluent to give 599 mg (91%) of clear oil: Rf=0.48 and 0.51 (two isomers) (hexanes/ethyl acetate, 95:5, v/v); 1H NMR (CDCl3) δ 7.43 (t, 3J=6.3 Hz, 0.6H), 7.36-7.31 (m, 4H), 7.30-7.26 (m, 1H), 6.66 (t, 3J=5.3 Hz, 0.4H), 5.09 (s, 0.8H), 5.04 (s, 1.2H), 2.37-2.33 (m, 0.8H), 2.19-2.15 (m, 1.2H), 1.48-1.42 (m, 2H), 1.34-1.23 (m, 6H), and 0.86 (t, 3J=7.0 Hz, 3H).