Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].[K+].CN1C(=O)CCC1.[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[N:17]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:18]=[C:19](I)[C:12]=12.C[Si](C)(C)[C:33]([F:36])([F:35])[F:34]>[Cu]I.C(OC)(C)(C)C.CN(C=O)C>[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[N:17]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:18]=[C:19]([C:33]([F:36])([F:35])[F:34])[C:12]=12
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)ccnc32)cc1
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(C(F)(F)F)c3c(Cl)ccnc32)cc1
Temperature: 220 °C
Yield: 67.3 %

Procedure:
Under protective gas atmosphere (argon), 23.1 g (0.398 mol) of dry potassium fluoride and 75.7 g (0.398 mol) of copper(I) iodide were titrated together and heated to 220° C. under high vacuum with agitation for 10 minutes until a slightly greenish colouration appeared. A reaction flask was initially charged under protective gas atmosphere (argon) with the calcined mixture of potassium fluoride and copper(I) iodide together with 170 ml of absolute NMP and 170 ml of absolute DMF, and 86 g (0.199 mol) of 4-chloro-1-(toluene-4-sulphonyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine were subsequently introduced in portions at 20° C. with stirring to form a light grey suspension. 62.1 g (0.437 mol) of trimethyltrifluoromethylsilane were added dropwise to the reaction mixture within 20 minutes and the mixture was left to stir at 20° C. for 18 h. On completion of conversion (GC monitoring of conversion), the reaction mixture was added to 2000 ml of methyl tert-butyl ether, the organic phase was decanted and the residue was dispersed once more with 1000 ml of methyl tert-butyl ether. The combined organic phases were washed three times with 2000 ml each time of water and subsequently dried over MgSO4. Filtration and removal of the volatile constituents in a water-jet vacuum resulted in 50.1 g (0.134 mol; 67%) of 4-chloro-1-(toluene-4-sulphonyl)-3-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine as a beige solid.
Reaction SMILES: [C:1](=[O:11])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:2].C([N:14]([CH2:17][CH3:18])CC)C.[CH3:19][CH2:20][O:21][C:22]([C@H](OS(C(F)(F)F)(=O)=O)C)=[O:23]>CC.ClCCl>[CH2:20]([O:21][C:22](=[O:23])[CH:17]([NH:14][NH:2][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:11])[CH3:18])[CH3:19]
Reactant: NC(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Agent: CC
Solvent: ClCCl
Product: CCOC(=O)C(C)NNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
To a solution of benzyl carbamate (665 mg, 4 mmol), triethylamine (1.11 mL) in ethane (4 ml) was added dropwise ethyl O-trifluoromethanesulfonyl-D-lactate at 0° C. The solution was stirred at 0° C. for 15 min then at room temperature for 16 hours. The mixture was diluted with dichloromethane (100 mL), washed with water (50 mL×2), 1% HCl (50 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to dryness in vacuo to give 570 mg (54% yield) of the title compound. 1H-NMR (500 MHz, CDCl3) δ 1.25-1.40 (m, 6H), 3.68-3.78 (m, 1H), 4.12-4.20 (m, 3H), 5.07-5.15 (m, 1H), 6.45-6.57 (m, 1H), 7.30-7.45 (m, 5H). Analytical HPLC: 5.56 min. LC-MS (ES+): m/e=267 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]=1[CH3:9])(=[O:3])[CH3:2].[F:17][C:18]1[CH:19]=[C:20]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:21]=[C:22]([F:24])[CH:23]=1.Cl.[CH2:32](O)C.C(=O)([O-])O.[Na+]>C(O)C>[Cl:16][C:15]1[C:10]([N:7]2[C:8]([CH3:9])=[C:4]([C:1](=[O:3])[CH2:2][CH2:32][N:28]3[CH2:29][CH2:30][N:25]([C:20]4[CH:19]=[C:18]([F:17])[CH:23]=[C:22]([F:24])[CH:21]=4)[CH2:26][CH2:27]3)[CH:5]=[N:6]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCO
Reactant: CC(=O)c1cnn(-c2ncccc2Cl)c1C
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1c(C(=O)CCN2CCN(c3cc(F)cc(F)c3)CC2)cnn1-c1ncccc1Cl
Reaction time: 21 h

Procedure:
In 40 ml of absolute ethanol was dissolved 0.72 g of 4-acetyl-1-(3-chloro-2-pyridyl)-5-methylpyrazole, and 1.38 g of 1-(3,5-difluorophenyl)piperazine, 7 ml of a 1N hydrochloric acid/ethanol solution, and 0.917 g of p-formaldehyde were added thereto, followed by refluxing for 20 hours. To the reaction mixture was further added 0.917 g of p-formaldehyde, followed by refluxing for 50 hours. After the reaction mixture was allowed to stand at room temperature for 21 hours, a saturated aqueous solution of sodium hydrogencarbonate was added thereto, and the mixture was extracted with chloroform three times. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was subjected to silica gel column chromatography using a mixture of chloroform-methanol (50:1 by volume) as a developing solvent. The fraction containing the desired compound was concentrated to yield 0.72 g of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][NH:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[OH-].[Na+].[C:18](Cl)(Cl)=[O:19].N1C=CC=CC=1>O.COCCOC>[N+:12]([C:9]1[CH:8]=[CH:7][C:6]([C:5]2[O:15][C:18](=[O:19])[N:2]([CH3:1])[CH2:3][N:4]=2)=[CH:11][CH:10]=1)([O-:14])=[O:13]
Reactant: CNCNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Solvent: c1ccncc1
Product: CN1CN=C(c2ccc([N+](=O)[O-])cc2)OC1=O
Reaction time: 2 h

Procedure:
A suspension of 24.6 g (0.1 mole) of N-(methylaminomethyl)-4-nitro-benzamide in 300 ml of water is neutralised at 0°-25°C with 50 ml of 2 normal sodium hydroxide solution (0.1 mole). The neutralised product is filtered off and dried in vacuo. It is then taken up in 150 ml of 1,2-dimethoxyethane and this solution is treated at 0°-25°C over the course of 1 hour with 9.9 g (0.1 mole) of phosgene in 150 ml of 1,2-dimethoxyethane. A solution of 15.8 g (0.2 mole) of pyridine in 150 ml of 1,2-dimethoxyethane is then added over the course of a further hour. Stirring of the reaction mixture is continued for 2 hours and then it is refluxed for 5 hours. After the reaction mixture has cooled, the precipitate which has formed is collected by filtration, the residue is dissolved in methylene chloride and washed first with sodium bicarbonate solution and then with water and dried. The solvent is evaporated and the residue is recrystallised from ethyl acetate to yield 6-(4-nitro-phenyl)-3-methyl-3,4-dihydro-2H-1,3,5-oxadiazin-2-one with a melting point of 153°-154°C (compound 2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25].C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:23][C:24](=[O:26])[CH3:25])=[C:8]2[CH:16]=[CH:15][N:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2-c2ccccc2)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1nc(C#N)c2c(ccn2-c2ccccc2)c1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 7-cyano-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (206 mg), acetic anhydride (0.127 mL), and triethyl amine (0.187 mL) in dichloromethane (2 mL) was stirred at room temperature for 1 h; then the mixture was concentrated, the residue was purified with column to give the title compound (201 mg). The title compound, ESI MS (m/z): 350 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([C:13]([OH:15])=O)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:39])[C@@H:28]([NH2:38])[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23][CH2:22]1)=[O:20])[CH3:17].C(Cl)CCl>CN(C=O)C.C(OCC)(=O)C>[CH2:16]([O:18][C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:39])[C@@H:28]([NH:38][C:13]([C:9]2[CH:10]=[C:11]([OH:12])[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[O:15])[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:25][CH2:26]1)=[O:20])[CH3:17]
Reactant: O=C(O)c1cc(=O)n(-c2ccccc2)[nH]1
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 7.2 g 1-phenyl-3-carboxy-5-pyrazolone and 12.1 g 4-((S)-2-amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 100 ml DMF 5.4 g HOBT and 6.7 g EDC were added and the reaction mixture was stirred for 12 h at RT. Then the reaction mixture was diluted with ethyl acetate and subsequently extracted with aqueous LiCl (4% w/w), 0.1 M HCl and aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was used in the subsequent reaction.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C(OC([N:15]1[CH2:18][CH:17]([C:19]([NH:21][CH2:22][CH2:23][N+:24]23[CH2:31][CH2:30][CH:27]([CH2:28][CH2:29]2)[C@@H:26]([O:32][C:33](=[O:48])[C:34]([OH:47])([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:25]3)=[O:20])[CH2:16]1)=O)(C)(C)C.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50].C(Cl)Cl>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:52][C:51]([F:54])([F:53])[C:49]([OH:55])=[O:50].[F:52][C:51]([F:54])([F:53])[C:49]([O-:55])=[O:50].[NH:15]1[CH2:18][CH:17]([C:19]([NH:21][CH2:22][CH2:23][N+:24]23[CH2:31][CH2:30][CH:27]([CH2:28][CH2:29]2)[C@@H:26]([O:32][C:33](=[O:48])[C:34]([OH:47])([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:25]3)=[O:20])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)NCC[N+]23CCC(CC2)[C@@H](OC(=O)C(O)(c2ccccc2)c2ccccc2)C3)C1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2)C1CNC1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-1-(2-[(1-tert-butoxycarbonyl-azetidine-3-carbonyl)-amino]ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)1-azonia-bicyclo[2.2.2]octane hexafluorophosphate is dissolved in TFA:DCM (1:1) (2 ml) and stirred at room temperature for 1 hour. TFA:DCM (2 ml) is added to the reaction mixture to complete the reaction. The solvent is removed in vacuo and purification of the crude residue by mass directed preparative HPLC eluting with water:acetonitrile:trifluoroacetic acid yields the titled compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[C:13](SC)[N:12]=[C:11]([OH:17])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]>[Ni]>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([OH:17])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CSc1nc(O)cc(-c2cccc(C#N)c2)n1
Agent: [Ni]
Product: N#Cc1cccc(-c2cc(O)ncn2)c1

Procedure:
Starting from 6-(3-cyanophenyl)-4-hydroxy-2-methylthiopyrimidine [=4-(3-cyanophenyl)-6-hydroxy-2-methylthiopyrimidine, see Example 10a], the title compound is obtained by desulfurisation with Raney nickel in boiling ethanol.
Reaction SMILES: [OH:1][NH:2][CH2:3][CH2:4][CH2:5][P:6](=[O:9])([OH:8])[OH:7].[C:10](OC(=O)C)(=[O:12])C.C(O)=O.[OH-].[Mg+2].[OH-]>O>[CH:10]([N:2]([CH2:3][CH2:4][CH2:5][P:6](=[O:8])([OH:7])[OH:9])[OH:1])=[O:12]
Reactant: CC(=O)OC(C)=O
Reactant: O=P(O)(O)CCCNO
Agent: [Mg+2]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: O=CN(O)CCCP(=O)(O)O
Yield: 65.8 %

Procedure:
An oily 3-(N-formyl-N-hydroxyamino)propylphosphonic acid (12.05 g.), which was prepared by the reaction of 3-(N-hydroxyamino)propylphosphonic acid (15.5 g.), acetic anhydride (12.3 g.) and formic acid (9.8 ml.) conducted in substantially the same manner as that of Example (31), was dissolved in water (80 ml.) and treated with magnesium hydroxide (5.83 g.) for 15 minutes under ice-cooling with stirring.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5](O)[CH:6]=[CH:7][CH:8]=1.[OH-:11].[Na+].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:10])[CH3:1])[CH:4]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCCCCBr
Reactant: [OH-]
Reactant: CN(C)c1cccc(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)c1cccc(CCCCCCCCOCCCCCCCCc2cccc(N(C)C)c2)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
200 ml of toluene, 54.8 g (0.4 mol) of 3-dimethylaminophenol and 13.58 g (0.04 mol) of tetrabutylammonium hydrogen sulfate are placed in a 750 ml sulfonating flask having an anchor mixer, thermometer, reflux condenser and dropping funnel and at RT 80 g (1.0 mol) of a 50% aqueous NaOH solution are added dropwise in the course of 30 minutes. The suspension is then stirred for 30 minutes at 80° C. and then at the same temperature 154 g (0.8 mol) of octyl bromide are added in the course 45 minutes. After a subsequent reaction period of 2.5 hours the mixture is cooled and filtered, and the filtrate is washed with 1×70 ml of H2O, dried over MgSO4, filtered and concentrated by evaporation. The crude product is distilled under a high vacuum, yielding 65.5 g of 3-dimethylaminophenyloctyl ether in the form of a colourless liquid having a boiling point of 150°-152 ° C. (0.1 mbar) which no longer has an OH band in the IR spectrum and of which the NMR analysis is in agreement with the sand structure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([O:23][C:24](=[O:26])[NH2:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>O1CCCC1.O>[C:24]([O:23][CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:34](=[O:36])[CH3:35])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)(=[O:26])[NH2:25]
Reactant: NC(=O)OC(CCN1CCN(c2ccc(O)cc2)CC1)c1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(N2CCN(CCC(OC(N)=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The compound ‘carbamic acid 3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-1-phenyl-propyl ester (2 mmol) prepared in Example 84 was dissolved in tetrahydrofuran (25 mL), and triethylamine (2.4 mmol) and acetylchloride (2.4 mmol) were added thereto, and the resulting mixture was stirred at a room temperature for 5 hours. The reaction mixture was diluted with water, and extracted several times with ethyl acetate to obtain an organic phase. The prepared organic phase was dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting pellet was purified with column chromatography (hexane:ethyl acetate=1:1) to obtain a title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14]C)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[Mg].[Cl-].[NH4+].C(OCC)(=O)C>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([C:11]([O:13][CH3:14])=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C1Cc2ccc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.4 %

Procedure:
To a stirred suspension-solution of ethyl 6-chloroindole-2-carboxylate (20.0 g, 89.4 mmol) in methanol (350 mL) under Ar was added magnesium turnings (21.7 g, 0.89 mol). After 10 min, the internal temperature had risen to 24° C. and effervescence was apparent. The mixture was to 10-15° C. and was maintained for 1.5 h. After this time, the reaction mixture was allowed to warm to ambient temperature, and was stirred for 1 h. The mixture was poured onto saturated aqueous ammonium chloride solution (1 L), and ethyl acetate (300 mL) was added. After 1.5 h sting, the layers were separated, and the aqueous layer was extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with brine (200 mL), dried (magnesium sulfate) and concentrated in vacuo to give a brown oil. Purification by flash column chromatography [SiO2; ethyl acetate-heptane (1:3)] afforded the title compound (12.0 g, 63%) as an orange oil which crystallised on standing: IR νmax (film)/cm−1 3375, 2953, 2851, 1737, 1610, 1486, 1438, 1321, 1287, 1204, 1161, 1069, 1011, 948, 906, 846, 796, 794, 594 and 548; NMR δH (400 MHz; CDCl3) 3.27 (1H, dd, J 16.0, 5.0 Hz), 3.34 (1H, ddd, J 16.0, 10.5, 1.0 Hz), 3.76 (3H, s), 4.40 (1H, dd, J 10.5, 5.0 Hz), 4.47 (1H, br s), 6.68 (1H, br d, J 2 Hz), 6.69 (1H, dd, J 7.5, 2.0 Hz) and 6.96 (1H, d, J 7.5 Hz); hplc [Chiralcel OD; hexane-isopropanol (90:10); 1 mL/min; 260 nm] 50% (10.04 min) and 5% (11.61 min).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[O:5][N:4]=1.C(N(C(C)C)[CH:28]([CH3:30])[CH3:29])C.[CH2:34](Br)[CH:35]=[CH2:36]>C(Cl)Cl>[CH2:30]([N:1]([CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[O:5][N:4]=1)[CH2:36][CH:35]=[CH2:34])[CH:28]=[CH2:29]
Reactant: CCN(C(C)C)C(C)C
Reactant: C=CCBr
Reactant: NCc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2ccccc2-3)n1
Solvent: ClCCl
Product: C=CCN(CC=C)Cc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2ccccc2-3)n1

Procedure:
4.72 g (14.6 mmol) of crude (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, 70 ml of methylene chloride, 6 ml (35 mmol) of N-ethyldiisopropylamine and 3.53 g (29.2 mmol) of allyl bromide were stirred at room temperature for 60 hours. The reaction mixture was evaporated and the residue was chromatographed on 180 g of silica gel while eluting with ethyl acetate. By concentrating the uniform fractions there was obtained (S)-1-(3-diallylaminomethyl-1,2,4-oxadiazol-5-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 147°-150°.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)C(C)C)(C)C.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[S:27][CH:28]=[C:29]([C:31](Cl)=[O:32])[N:30]=2)[CH:21]=1>ClCCl.O>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[S:27][CH:28]=[C:29]([C:31]([C:2]3[S:1][C:10]4[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=4[CH:3]=3)=[O:32])[N:30]=2)[CH:21]=1
Reactant: c1cc2c(s1)CCCCN2
Reactant: O=C(Cl)c1csc(-c2cccnc2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(c1csc(-c2cccnc2)n1)c1cc2c(s1)CCCCN2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled (0° C.) solution of 2 mmol of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine, 6 mmol of N,N-diisopropylethylamine in 8 ml of dichloromethane added 2.2 mmol of 2-(3-pyridinyl)thiazole-4-carbonyl chloride. The mixture is stirred at room temperature for 16 hours and diluted with 50 ml of dichloromethane and 25 ml of water. The organic layer is separated, washed with H2O, 1N NaHCO3, brine and dried (Na2SO4). The solvent is removed under vacuum and the residue chromatographed on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:17]=[C:18]([C:19]([O:21]C)=[O:20])[C:13]=3[N:12]=[C:11]2[CH3:29])[CH:5]=[CH:6][C:7]=1[CH3:8].[OH-].[Li+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15]=[C:16]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:13]=3[N:12]=[C:11]2[CH3:29])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1ccc(C)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(Cn2c(C)nc3c(C(=O)O)cc(N4CCOCC4)cc32)cc1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
To a mixture of methyl 1-[(3,4-dimethylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylate(0.24 g, 0.61 mmol) in Tetrahydrofuran (THF) (10 mL) was added in lithium hydroxide (5.99 mL, 11.99 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature. The organic solvent was removed in-vacuo. The precipitate was collected by filtration. Water (20 mL) was added in. The mixture was acidified with 1 N HCl. The resulting solid was filtered and washed with water and dried to give the product (0.16 g, 66%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.18 (s, 6H), 2.58-2.75 (s, 3H), 3.06-3.22 (m, 4H), 3.71-3.82 (m, 4H), 5.55 (s, 2H), 6.94 (m, 1H), 7.04 (s, 1H), 7.11 (d, 1H, J=7.83 Hz), 7.52 (m, 2H). MS(ES+) m/e 380.2[M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[N:27]=[C:26]([NH:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[C:25]([O:35][CH3:36])=[CH:24][N:23]=2)=[N:14]1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].C(O)(=O)C>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[N:27]=[C:26]([NH:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[C:25]([O:35][CH3:36])=[CH:24][N:23]=2)=[N:14]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c3ccccc32)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cnc(-c2nn(Cc3ccc(C(=O)O)cc3Cl)c3ccccc23)nc1Nc1ccncc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
150 mg of methyl 3-chloro-4-({3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazol-1-yl}methyl)benzoate (2-11-1, 0.299 mmol, 1. eq.) were dissolved in 0.364 ml of methanol. 60 mg of sodium hydroxid (1.50 mmol, 5 eq.) were added. The reaction mixture was stirred at room temperature for 3 hours. The resulting suspension was neutralised with acetic acid. The solution was diluted with ethyl acetate. The occurred precipitate was filtered off and washed with ethyl acetate and was dried in vacuo at 50° C. to yield 138 mg (0.28 mmol, 92.8%) of the analytically pure target compound.
Reaction SMILES: [Mg].Br[CH2:3][CH:4]1[CH2:9][CH:8]2[CH2:10][CH:5]1[CH:6]=[CH:7]2.[Br:11][CH2:12][CH2:13][CH2:14]Br.C(O)(=O)C>O1CCCC1.C(OCC)C>[Br:11][CH2:12][CH2:13][CH2:14][CH2:3][CH:4]1[CH2:9][CH:8]2[CH2:10][CH:5]1[CH:6]=[CH:7]2
Reactant: BrCCCBr
Reactant: BrCC1CC2C=CC1C2
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: BrCCCCC1CC2C=CC1C2
Reaction time: 1 h

Procedure:
In a 250 mL three neck bottle magnesium turnings (5.2 g, 214 mmol, 2.35 eq.) are mixed with tetrahydrofuran (10 ml). Whilst stirring 5-(brommethyl)-bicyclo[2.2.1]hept-2-ene (17 g, 90.8 mmol, 1.03 eq.) that is dissolved in tetrahydrofuran (25 ml) is added dropwise. After stirring for one hour the excess of magnesium turnings is filtered off. The solution is added dropwise to a mixture of 1,3-dibromopropan (17.9 g, 88 mmol, 1 eq.), Li2CuCl4 (0.1 M in THF) (9 ml, 0.9 mmol, 0.01 eq.) and tetrahydrofuran (35 ml). After complete addition of the Grignard reagent, the black solution is stirred for one hour more. The reaction mixture is hydrolyzed with acetic acid (20%). Diethylether (40 ml) is added and the organic phase is washed with saturated sodium hydrogencarbonate solution (30 ml) and distilled water (30 ml). The organic layer is dried over magnesium sulfate and the solvent evaporated in vacuo at room temperature. The product is distilled at 20 mbar and 140° C. A colourless oil is obtained (Yield: 10.31 g, 45 mmol, 51%).