Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:16][C:17]1[CH:29]=[C:28]([O:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([NH:16][C:17]1[CH:29]=[C:28]([O:30][C:31]2[CH:32]=[C:33]([F:38])[CH:34]=[C:35]([F:37])[CH:36]=2)[CH:27]=[CH:26][C:18]=1[C:19]([OH:21])=[O:20])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2cc(F)cc(F)c2)cc1NC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(Oc2cc(F)cc(F)c2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
5.0 mL of trifluoroacetic acid solution containing 69 mg of tert-butyl 2-(benzamido)-4-(3,5-difluorophenoxy)benzoate was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 41 mg of 2-(benzamido)-4-(3,5-difluorophenoxy)benzoic acid as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[O:13])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[CH2:21][C:22]([C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=2[CH:34]=1)=[O:23].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:21][C:22]([C:24]4[CH:25]=[CH:26][C:27]5[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=5[CH:34]=4)=[O:23])[CH2:16][CH2:15]3)=[O:13])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2sc(C(=O)C3CCNCC3)nc12
Reactant: O=C1COc2ccc(C(=O)CCl)cc2N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2sc(C(=O)C3CCN(CC(=O)c4ccc5c(c4)NC(=O)CO5)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A mixture of (4-methoxy-benzothiazol-2-yl)-piperidin-4-yl-methanone (83 mg, 0.3 mmol) and 6-(2-chloro-acetyl)-4H-benzo[1,4]oxazin-3-one (68 mg, 0.3 mmol) in DMF (1 ml) was treated with DIPEA (50 μl, 0.3 mmol) and the mixture was stirred at RT overnight. The mixture was poured on water and extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated. Crystallisation from ether gave 113 mg (81%) of title compound as a beige solid.
Reaction SMILES: COC(=O)[CH2:4][NH:5][CH2:6][C@H:7]([NH:14][C:15]([O:17]CC1C=CC=CC=1)=O)[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.N#N>CO.C(Cl)Cl.[Pd]>[CH:8]1([C@H:7]2[NH:14][C:15](=[O:17])[CH2:4][NH:5][CH2:6]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)CNC[C@H](NC(=O)OCc1ccccc1)C1CCCCC1
Agent: [Pd]
Agent: N#N
Solvent: CO
Solvent: ClCCl
Product: O=C1CNC[C@@H](C2CCCCC2)N1
Reaction time: 18 h
Yield: 128.3 %

Procedure:
To a 2.0 L round bottom flask containing a solution of ((R)-2-Benzyloxycarbonylamino-2-cyclohexyl-ethylamino)-acetic acid methyl ester (27 g, 77 mmol) in MeOH (300 mL) under a stream of N2 was added Pd (10% on carbon, 4.1 g, 0.05 equiv). The mixture was stirred under 1.0 atm of H2 for 18 hours. The mixture was diluted with 100 mL of CH2Cl2 and filtered through Celite. The filtrate was concentrated to give crude product (R)-6-Cyclohexyl-piperazin-2-one 18 g (127%). The product, which contained impurity and solvent, was continued to the next step with no further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[C:12](Cl)(Cl)=[S:13].C(OCC)(=O)C>O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[N:5]=[C:12]=[S:13]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: S=C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)c1ccccc1N=C=S

Procedure:
2-trifluoromethylaniline (4.1 ml, 0.0325 mol) is added dropwise at a temperature close to 20° C. and under an argon atmosphere to a mixture containing thiophosgene (2.5 ml, 0.0326 mol) in 43 ml of water. Agitation is carried out for twelve hours then 30 ml of ethyl acetate is added. The organic phase is extracted with water then with a solution of 10% sodium bicarbonate and finally with a solution of salt water. The organic phase is dried over magnesium sulphate and the solvent is evaporated off with a rotary evaporator. The product obtained (6.85 g, 100%) is in the form of a brown oil which is used immediately for the following reaction.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C@@H:7]1[OH:15])=[O:4].[H-].[Na+]>C1COCC1>[O:15]1[CH2:2][C:3](=[O:4])[NH:5][C@@H:6]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH2:8][C@H:7]12
Reactant: O=C(CCl)N[C@@H]1c2ccccc2C[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CO[C@H]2Cc3ccccc3[C@H]2N1
Reaction time: 3 h

Procedure:
To a stirred mixture of 2-chloro-N-[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]acetamide from Step A (780 mg, 3.46 mmol) in anhydrous THF (75 mL) at 0° C. was added NaH (498 mg of a 60% dispersion in oil, 12.4 mmol). The resulting mixture was stirred for 3 h, quenched with saturated aqueous NaHCO3 (20 mL) and then extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=190 (M+1).
Reaction SMILES: Cl.Cl.[CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:16]3)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].Cl[C:31]([O:33][CH3:34])=[O:32]>>[CH3:34][O:33][C:31]([N:27]1[CH2:28][CH2:29][N:24]([C:22]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:12][CH:9]2[CH2:8][CH2:7][N:6]([CH:3]([CH3:5])[CH3:4])[CH2:11][CH2:10]2)=[CH:21][CH:20]=3)=[O:23])[CH2:25][CH2:26]1)=[O:32]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCNCC4)cc3c2)CC1
Reactant: COC(=O)Cl
Agent: Cl
Product: COC(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone dihydrochloride and methyl chloroformate. Light-yellow solid. MS (m/z): 429.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:26]3[CH:25]=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][C:21]=3[O:20][CH2:19][CH:16]3[CH2:18][CH2:17]3)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c[nH]c2c(-c3cc(OC)ccc3OCC3CC3)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 2-(2-Cyclopropylmethoxy-5-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example A37) the title compound is obtained as colorless solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:15]([CH2:22][CH3:23])[C:16](=[O:21])[CH2:17][C:18]([CH3:20])=[O:19])[CH3:14].[CH:24](=[O:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>CCCCCC.O>[CH2:22]([N:15]([CH2:13][CH3:14])[C:16](=[O:21])[CH2:17][C:18](=[O:19])[CH2:20][CH:24]([OH:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:23]
Reactant: O=CC=Cc1ccccc1
Reactant: CCN(CC)C(=O)CC(C)=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CCCCCC
Product: CCN(CC)C(=O)CC(=O)CC(O)C=Cc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 84.9 %

Procedure:
2.65 cm3 of diisopropylamine are introduced into a three-necked, round-bottomed flask equipped with a septum and a dropping funnel and are then cooled to -10° C. 10.4 cm3 of n-butyllithium in solution in hexane at 1.6 mol/liter (16.6 mmol) are then slowly added and the mixture is then stirred for 15 minutes. 1.40 g of N,N-diethylacetoacetamide (8.65 mmol) are then slowly added and the mixture is then stirred for 15 minutes. 1.0 g of cinnamaldehyde (7.57 mmol) is added. The mixture is stirred for 25 minutes and then 2 cm3 of concentrated hydrochloric acid and 25 cm3 of water are added. Extraction is carried out with 2 times 25 cm3 of dichloromethane. The combined organic phases are washed with 4 times 50 cm3 of water and dried over sodium sulphate. After filtration and concentration to dryness, there is obtained, with a yield of 85%, 1.86 g of N,N-diethyl-7-phenyl-5-hydroxy-3-oxo-6-heptenamide, the structure of which is confirmed by the proton nuclear magnetic resonance spectrum.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]3[CH2:18][C:17]4([CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]4)[O:16][N:15]=3)=[CH:12][N:11]=[C:10]3[N:25]([CH2:29][CH3:30])[N:26]=[C:27]([CH3:28])[C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1.O>ClCCl>[CH3:48][C:38]1[CH:43]=[CH:42][C:41]([S:44]([O:24][CH:21]2[CH2:22][CH2:23][C:17]3([O:16][N:15]=[C:14]([C:13]4[C:8]([NH:7][CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[C:9]5[C:27]([CH3:28])=[N:26][N:25]([CH2:29][CH3:30])[C:10]5=[N:11][CH:12]=4)[CH2:18]3)[CH2:19][CH2:20]2)(=[O:46])=[O:45])=[CH:40][CH:39]=1
Reactant: CCn1nc(C)c2c(NC3CCCCC3)c(C3=NOC4(CCC(O)CC4)C3)cnc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1nc(C)c2c(NC3CCCCC3)c(C3=NOC4(CCC(OS(=O)(=O)c5ccc(C)cc5)CC4)C3)cnc21
Reaction time: 5 h

Procedure:
3-[4-(Cyclohexylamino)-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-1-oxa-2-azaspiro[4.5]dec-2-en-8-ol (0.0025 mole) (example 26) is dissolved in dichloromethane. Triethyl amine (0.0050 mol) is added at 0° and p-toluene sulphonyl chloride (0.0050 mole) is added. The reaction mixture is stirred for about 5 hrs. Water is added and extraction is done with dichloromethane. The organic layer is washed with brine, dried and concentrated under reduced pressure to give crude product, which is purified by column chromatography.
Reaction SMILES: Cl[CH:2]([CH2:12][C:13]([Cl:16])([Cl:15])Cl)[C:3]([CH3:11])([CH3:10])[CH:4]([C:8]#[N:9])C(O)=O.C1(C)C=CC=CC=1>CN(C)C=O>[Cl:16][C:13]([Cl:15])=[CH:12][CH:2]1[C:3]([CH3:10])([CH3:11])[CH:4]1[C:8]#[N:9]
Reactant: CC(C)(C(Cl)CC(Cl)(Cl)Cl)C(C#N)C(=O)O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1(C)C(C#N)C1C=C(Cl)Cl
Temperature: 145 °C
Reaction time: 6 h
Yield: 86.8 %

Procedure:
A solution of 4-chloro-2-cyano-3,3-dimethyl-6,6,6-trichlorohexanoic acid (6.14 g) in dimethyl formamide (12 ml) was stirred at 145° C. for 4 hours under an ammonia atmosphere at initially 5 bar pressure. After release of the pressure the mixture was stirred for another 6 hours at 145° C. After cooling, over 90% of the solvent was flashed off (bath temperature max. 60° C., pressure 12 mmHg). The residue was mixed with toluene and subsequently washed with aqueous hydrochloric acid and aqueous sodium bicarbonate. After drying of the organic phase the solvent was removed under reduced pressure to yield 3.3 g of the required 2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropane nitrile (97% pure, 89% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[F:17][C:18]([F:28])([F:27])[O:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1>>[F:17][C:18]([F:27])([F:28])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][N:9]=3)=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: CCCc1cnc(-c2ccc(Br)cc2)nc1
Product: CCCc1cnc(-c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)nc1

Procedure:
Analogously to Example 9 , by reacting 14.0 g of 2-(4-bromophenyl)-5-propylpyrimidine and 12.1 g of trifluoromethoxy-4-bromobenzene, the corresponding 2-(4'-trifluoromethoxybiphenyl-4-yl )-5-propylpyrimidine having C 125° SG 1110 SA 218° I is obtained.
Reaction SMILES: [CH2:1]([N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]CC=C.[Mn]([O-])(=O)(=O)=O.[K+].S(=O)(O)[O-].[Na+].[C:34]([OH:37])(=[O:36])[CH3:35]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].CCCCCC.O>[O:22]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[N:12]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:35][C:34]([OH:37])=[O:36]
Reactant: CC(=O)O
Reactant: C=CCCCCCCCCCN1C(=O)c2ccccc2C1=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=S([O-])O
Solvent: CCCCCC
Solvent: O
Product: O=C(O)CCCCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 7 h
Yield: 61 %

Procedure:
A solution of 2-undec-10-enyl-1,3-dioxo-1,3-dihydroisoindole (2 g, 6.68 mmol) of Step 1 and Aliquat® 336 (0.2 g) in a mixture of hexane (20 ml) and acetic acid (6 ml) was added dropwise to a solution of potassium permanganate (2.76 g, 20 mmol) in water (28 ml) while cooling at 0° C. The reaction mixture was stirred at room temperature for 7 hours, then an aqueous solution of sodium bisulfite was added until disappearance of the purple colour. The mixture was then extracted with ethyl acetate and the organic phase was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography eluting with 2:1 hexane:ethyl acetate mixture. The product was obtained as a white solid (1.29 g, 61% yield). M.p. 58–60° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([O-])(=O)C.[Na+].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=1Cl)([O-:16])=[O:15]>C(O)C>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: Nc1ccccc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Nc1ccccc1O
Temperature: 25 °C

Procedure:
17.30 g (157 mmol) of 99% strength 2-aminophenol and 17.15 g (209 mmol) of anhydrous sodium acetate are added to a solution of 25.0 g (121 mmol) of 98% strength 2,6-dinitrochlorobenzene in 185 ml of anhydrous ethanol under nitrogen while stirring. The reaction solution is refluxed for 2 hours and subsequently cooled to room temperature. The red-violet crystalline needles are separated off on a “black band” filter, washed with water until the washings are colorless and dried at 50° C. under reduced pressure. This gives 27.90 g (84% of theory) of shiny black needles which melt at 189-192° C. (lit.: 191° C.).
Reaction SMILES: [ClH:1].O1CCOCC1.[F:8][C@H:9]1[C@:14]([CH2:17][OH:18])([O:15][CH3:16])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1>>[ClH:1].[F:8][C@H:9]1[C@:14]([CH2:17][OH:18])([O:15][CH3:16])[CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: CO[C@]1(CO)CCN(C(=O)OC(C)(C)C)C[C@H]1F
Agent: Cl
Solvent: C1COCCO1
Product: CO[C@]1(CO)CCNC[C@H]1F
Reaction time: 1 h

Procedure:
4M hydrochloric acid/dioxane solution (11.4 ml) was added to tert-butyl rel-(3R,4S)-3-fluoro-4-(hydroxymethyl)-4-methoxypiperidine-1-carboxylate (800 mg) and stirring was performed at room temperature for 1 hour. Concentration under reduced pressure gave rel-[(3R,4S)-3-fluoro-4-methoxypiperidin-4-yl]methanol hydrochloride (606 mg).
Reaction SMILES: [C:1]([NH:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([NH:9][NH2:10])=[O:8])(=O)[CH3:2]>C(O)C>[NH2:10][N:9]1[C:7](=[O:8])[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:5][N:4]=[C:1]1[CH3:2]
Reactant: CC(=O)NN=C(C(=O)NN)c1ccccc1
Solvent: CCO
Product: Cc1nnc(-c2ccccc2)c(=O)n1N
Yield: 76 %

Procedure:
175 g (0.8 mol) of phenylglyoxylic acid hydrazide-2-acetylhydrazone were dissolved in 2 liters of ethanol and the solution was heated to boil under reflux for 12 hours. After cooling, the product which had precipitated was filtered off. The mother liquor was partially freed from the solvent; on cooling, a further precipitate was obtained, which was also filtered off and well washed with water. The combined precipitates were dried. 123 g (76% of theory) of 4-amino-3-methyl-6-phenyl-1,2,4-triazin-5-(4H)-one of melting point 160°-163° C. were obtained.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[CH:9]1([C:12]([NH2:14])=[O:13])[CH2:11][CH2:10]1.N1C=CC=CC=1>COCCOC>[CH:9]1([C:12]([NH:14][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[O:13])[CH2:11][CH2:10]1
Reactant: O=C(Cl)CCCCBr
Reactant: NC(=O)C1CC1
Solvent: c1ccncc1
Solvent: COCCOC
Product: O=C(CCCCBr)NC(=O)C1CC1
Yield: 40 %

Procedure:
A solution of 7.96 g. of 5-bromovaleric acid chloride, 3.40 g. of cyclopropanecarboxamide, 3.16 g. of pyridine, and 20 ml. of 1,2-dimethoxyethane was heated to reflux under nitrogen for 1.5 hours, then was concentrated by rotary evaporation. The resultant semi-solid was triturated with methylene chloride (2X). The combined methylene chloride layers were washed with saturated brine, were dried (anhydrous magnesium sulfate), were treated with activated charcoal, and were filtered. The filtrate was concentrated on a steam-bath with addition of hexane until crystallization started. Thus, 3.98 g. (40% yield) of white, crystalline N-cyclopropanecarbonyl-5-bromovaleramide was obtained melting at 114°-115°C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][NH:6][C:7](=[O:10])[CH2:8][NH2:9].C(N1CCCCC1)C.ClC1C([O:27][C:28](=O)[C@H:29]([CH2:41][CH2:42][C:43](=[O:45])[NH2:44])[NH:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])=C(Cl)C(Cl)=C(Cl)C=1Cl>CN(C)C=O.ClCCl>[CH3:2][O:3][C:4](=[O:11])[CH2:5][NH:6][C:7](=[O:10])[CH2:8][NH:9][C:28](=[O:27])[C@H:29]([CH2:41][CH2:42][C:43](=[O:45])[NH2:44])[NH:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32]
Reactant: COC(=O)CNC(=O)CN
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: CCN1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of glycyl-glycine methyl ester hydrochloride (1.9 g; 10 mmoles) in a dimethylformamide-dichloromethane (1:2) mixture (30 ml) is admixed with N-ethylpiperidine (1.4 ml) and stirred for 2 hours at room temperature. After that benzyloxycarbonylglutamine pentachlorphenyl ester (5.3 g; 10 mmoles) is added and the reaction mixture is stirred at room temperature a further 4 hours. After 8 hours of standing, the precipitated crystalline product is separated and crystallized from methanol - dichloromethane. Yield 2.5 g (61%), m.p. 129°-134° C., after additional crystallization from methanol 132°-134° C. Rf 0.57/S1, 0.78/S2⟦alpha⟧sub.D20 -8.5° (c 0.2; 50% acetic acid). Composition: C18H24N4O7.1/2H2O.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5](O)=[N:6][C:7]=1[CH3:8].P(Cl)(Cl)([Cl:15])=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[Cl:15][C:5]1[C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=1
Reactant: Cc1cc([N+](=O)[O-])c(O)nc1C
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Product: Cc1cc([N+](=O)[O-])c(Cl)nc1C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
A mixture of 5,6-dimethyl-3-nitropyridin-2-ol (7.09 g, 42.2 mmol), benzyltriethylammonium chloride (4.82 g, 21.1 mmol) and acetonitrile (90 mL) at room temperature was slowly treated with phosphorus oxychloride (11.8 mL, 125 mmol) then heated to reflux and stirred overnight. The mixture was concentrated under reduced pressure and treated with ice-water (220 mL) and basified with concentrated ammonium hydroxide (100 mL). The mixture was extracted with dichloromethane (3×100 mL) and the combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 2-chloro-5,6-dimethyl-3-nitropyridine (7.28 g, 92%). Mp. 72-76° C.; 400 M Hz 1H NMR (CDCl3) δ: 8.01 (s, 1H), 2.58 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18]>CO>[C:1]1([C:7]2[N:8]([CH2:18][CH2:17][C:16]([O:20][CH3:21])=[O:19])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCn1c(-c2ccccc2)nc2ccccc21
Temperature: 60 °C
Reaction time: 100 h
Yield: 60 %

Procedure:
A mixture of 194 g of 2-phenylbenzimidazole, 103 g of methyl acrylate and 500 g of methanol was heated and stirred at 60° C. for 100 hours. The solvent was distilled off in vacuo, followed by purification by column chromatography. There was obtained methyl 3-(2-phenyl-1H-benzimidazol-1-yl)-propionate (yield 60%).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)[CH:2]=[CH2:3].[H][H]>[Pd]>[CH2:1]([C:4]1[CH:5]=[C:6]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCc1cc(CC(=O)OC)ccc1OCc1ccc2ccccc2n1
Agent: [Pd]
Product: CCCc1cc(CC(=O)OC)ccc1OCc1ccc2ccccc2n1

Procedure:
In analogy to the procedure of Example XXXIV, the title compound is prepared from 7.5 g (0.0225 mol) of the compound from Example XXXVII and 0.8 g of Pd/C (5%) using hydrogen.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[C:15]2[C:10]=1[C:11](=[O:41])[CH:12]=[C:13]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29][CH:28]=1)[O:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)O[O:44]1>C(Cl)Cl.CC(C)=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[C:15]2[C:10]=1[C:11](=[O:41])[C:12]([OH:44])=[C:13]([C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:31][CH:32]=1)[O:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OO1
Reactant: O=c1cc(-c2ccc(OCc3ccccc3)cc2)oc2cc(OCc3ccccc3)cc(OCc3ccccc3)c12
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=c1c(O)c(-c2ccc(OCc3ccccc3)cc2)oc2cc(OCc3ccccc3)cc(OCc3ccccc3)c12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution containing 1.00 g (1.85 mmol) of 3 in 30 mL of CH2Cl2 at 0° C. was added 30 mL of a 0.9-0.11 M solution of DMDO in acetone. The reaction mixture was stirred at 0° C. overnight under N2.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:3]1[CH2:14][N:15]=[N+:16]=[N-:17].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:22]=[CH:21][N:20]=1.COC(C)(C)C>C1(O)CCCCC1>[N:25]1([C:23]2[CH:22]=[CH:21][N:20]=[C:19]([NH:1][C@H:2]3[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])[C@@H:3]3[CH2:14][N:15]=[N+:16]=[N-:17])[N:24]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: Clc1nccc(N2CCCCCC2)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H]1CN=[N+]=[N-]
Solvent: OC1CCCCC1
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nccc(N3CCCCCC3)n2)[C@H]1CN=[N+]=[N-]
Temperature: 120 °C
Reaction time: 3.5 h
Yield: 46 %

Procedure:
To a solution of the compound 7 (240 mg) in cyclohexanol (0.4 mL), 1-(2-chloro-4-pyrimidinyl)azepane (210 mg) was added. The reaction mixture was stirred at 120° C. for 3.5 hours. After cooling to room temperature, the reaction mixture was added tert-butyl methyl ether, washed with aqueous 2N sodium hydroxide solution, dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol:27% aqueous ammonia=100:0:0→90:10:0→90:10:1) to obtain the title compound (190 mg) having the following physical properties.