Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([CH2:16][CH2:17][O:18]C(=O)C)[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)(=O)C.[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31]C(O)=O)=[CH:27][CH:26]=1)([O-:24])=[O:23].N1CCCCC1>CN(C)C=O>[OH:18][CH2:17][CH2:16][N:7]([CH2:6][CH2:5][OH:4])[C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[CH:31][C:28]2[CH:29]=[CH:30][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)=[CH:14][CH:15]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OCCN(CCOC(C)=O)c1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(N(CCO)CCO)cc2)cc1
Temperature: 0 °C

Procedure:
A mixture of the crude reaction product of the previous step, viz. 4-di(2-acetyloxyethyl)aminobenzaldehyde, 270 g of 4-nitrophenyl acetic acid, 2 l of dimethyl formamide, and 100 ml of piperdine was stirred for 4 days at 20°-25° C. Next, the reaction mixture was concentrated by evaporation at 70° C. to a thick red oil, which was titrated three times, each time with 1 l of n-hexane. The residue was dissolved in 2.5 l of dimethyl formamide. Then there was added a solution of 320 g of sodium hydroxide in 800 ml of water. The resulting reaction mixture was then heated for 16 hours to 100° C. and subsequently poured into 10 l of ice water. The precipitated product was filtered off and thoroughly after-washed three times, each time with 1 l of water. After drying the crude reaction product was crystallized from 250 ml of dimethyl formamide and 500 ml of dichloromethane. The resulting yield of 4-di(2-hydroxy-ethyl) amino-4'-nitrostilbene was 190 g with a melting point of 184°-185° C. Calculated on N,N-di(2-hydroxyethyl)aniline this is 58% of theory.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9](Cl)=[O:10])=[CH:4][N:3]=1.[NH:12]([CH3:14])[CH3:13].CCN(CC)CC.O>C(Cl)Cl>[CH3:13][N:12]([CH3:14])[C:9]([C:5]1[C:6]([Cl:8])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)=[O:10]
Reactant: CNC
Reactant: O=C(Cl)c1cnc(Cl)nc1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cnc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 158.8 %

Procedure:
To a solution of 2,4-dichloro-pyrimidine-5-carbonyl chloride (197.7 mg, 0.94 mmol) in CH2Cl2 (9.4 mL) at RT is added Me2NH (2.0 M THF solution, 390 μL, 0.78 mmol) and Et3N (108.6 μL, 0.78 mmol) at 0° C. The reaction mixture is stirred overnight at RT. After adding water, the mixture is extracted with CH2Cl2. The organic layer is dried and concentration under reduce pressure give 2,4-dichloro-pyrimidine-5-carboxylic acid dimethylamide (272.5 mg, quant). ESI-MS m/z: 221 [M+1]+, Retention time 1.94 min (condition B).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[C:8](Cl)(=[O:11])[CH2:9][CH3:10].O>N1C=CC=CC=1>[C:8]([NH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1)(=[O:11])[CH2:9][CH3:10]
Reactant: CCC(=O)Cl
Reactant: Nc1nnc(S)s1
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)Nc1nnc(S)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
To a suspension of 20 g of 2-amino-5-mercapto-1,3,4 -thiadiazole in 200 ml of pyridine was added 14.6 g of propionyl chloride with cooling over a 5 minute period. After stirring the reaction mixture for 4 hours at room temperature, water was added and the resulting solid collected by filtration to give 20.2 g of 2-propionamido-5-mercapto-1,3,4-thiadiazole, m.p. 234°-237° C.
Reaction SMILES: [NH3:1].C(O)(=O)C.Cl[C:7]1[C:27](=[O:28])[CH2:26][CH2:25][C@@:24]2([CH3:29])[C:8]=1[CH2:9][CH2:10][C@@H:11]1[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:30])[C@H:12]1[CH2:13][CH2:14][C@@H:15]2[C@H:16]([CH3:19])[CH2:17][OH:18].CCOCC>O>[NH2:1][C:7]1[C:27](=[O:28])[CH2:26][CH2:25][C@@:24]2([CH3:29])[C:8]=1[CH2:9][CH2:10][C@@H:11]1[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:30])[C@H:12]1[CH2:13][CH2:14][C@@H:15]2[C@H:16]([CH3:19])[CH2:17][OH:18]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(Cl)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: N
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -78 °C
Reaction time: 8 h
Yield: 4 %

Procedure:
Ammonia (about 8 mL) was condensed into a Carius tube which contained (20S)-4-chloro-21-hydroxy-20-methylpregn-4-en-3-one acetate (1.5 g, 3.69 mmol) and which was cooled to -78° C. The tube was sealed, heated to 70° C. for one hour, and then allowed to stand at room temperature overnight. The contents of the tube were poured into a mixture of ether and water and the two layers were separated. The organic layer was extracted with 0.5N hydrochloric acid and the resulting acidic, aqueous solution was washed with ether and then made alkaline with 1N aqueous sodium hydroxide. The resulting alkaline, aqueous mixture was extracted with ether and the ether extracts were dried over magnesium sulfate and concentrated to a yellow, foamy solid. This residue was dissolved in methanol (25 mL) and 2N hydrochloric acid (2 mL) and the resulting mixture was heated to reflux for 15 minutes and then allowed to cool to room temperature. The mixture was extracted with ether, then made alkaline with solid sodium carbonate, and extracted with ether. The organic extracts of the alkaline, aqueous solution were dried over magnesium sulfate and concentrated to give (20S)-4-amino-21-hydroxy-20-methylpregn-4-en-3-one as an off-white solid (50 mg, 4%). This compound has the following structure: ##STR7##
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:16][CH:17]([C:19]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)=[O:20])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)N2CCCC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C1CNC1)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Pyrrolidine (271 μL, 5.50 mmol) was added to a solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.0 g, 4.97 mmol), HATU (2.09 g, 5.50 mmol) and DIPEA (2.18 mL, 12.52 mmol) in DMF (100 mL) and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give 3-(pyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of 3-(pyrrolidine-1-carbonyl)-azetidine-1-carboxylic acid tert-butyl ester in DCM (15 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a colourless oil (550 mg, 72%). 1H NMR (CD3OD, 400 MHz) δ 3.93-3.65 (m, 5H); 3.43-3.28 (m, 4H) and 2.00-1.81 (m, 4H).
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.C(N(C(C)C)C(C)C)C.[OH:37][C:38]1([CH3:44])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>ClC(Cl)Cl.O1CCCC1>[CH3:26][O:25][C:15]1[C:13]2[N:14]=[C:10]([NH:9][C:8]([N:41]3[CH2:42][CH2:43][C:38]([OH:37])([CH3:44])[CH2:39][CH2:40]3)=[O:27])[S:11][C:12]=2[C:18]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[CH:17][CH:16]=1
Reactant: CC1(O)CCNCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)N3CCC(C)(O)CC3)nc12
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-carbamic acid phenyl ester (3.2 g, 8.3 mmol) and N-ethyl-diisopropyl-amine (4.4 ml, 25 mmol) in trichloromethane (50 ml) is added a solution of 4-hydroxy-4-methyl-piperidine in trichloromethane (3 ml) and tetrahydrofurane (3 ml) and the resulting mixture heated to reflux for 1 h. The reaction mixture is then cooled to ambient temperature and extracted with saturated aqueous sodium carbonate (15 ml) and water (2×5 ml). Final drying with magnesium sulphate and evaporation of the solvent and recrystallization from ethanol afforded the title compound as white crystals (78% yield), mp 236° C. MS: m/e=407(M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[NH2:8]
Reactant: Cc1cc([N+](=O)[O-])ccc1N1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(N)ccc1N1CCCCC1
Yield: 94.5 %

Procedure:
To a solution of 1-(2-methyl-4-nitrophenyl)piperidine (6.75 g, 30.6 mmol) in ethyl acetate (50 mL) was added 10% palladium on carbon (0.033 g, 0.306 mmol) and the mixture hydrogenated (hydrogen balloon) at room temperature for 20 hours. The mixture was then filtered through diatomaceous earth and washed with ethyl acetate; the filtrate was then concentrated to afford 5.5 g (94%) of the title compound. MS (ESI) m/z 191 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([CH2:19]C(O)=O)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC([O:27][CH2:28]C)=O.[N-:30]=[N+]=[N-].[Na+].[Na+].[Cl-]>C1COCC1.O>[O:27]=[C:28]1[NH:30][CH2:19][C@H:10]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:23])[N:11]1[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)O)C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C(=O)NC[C@@H]1C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of Boc-D-Aspartic acid-1-benzyl ester (0.250 g, 0.77 mmol) taken in THF (4 mL), cooled to −10° C., Ethyl chloroformate (0.11 ml, 1.1 mmol) and TEA (0.34 ml, (2.47 mmol) was added and stirred for 30 min. NaN3 (0.25 g, 0.386 mmol) was dissolved in water (4 ml) and added portion wise to the reaction mixture maintaining the temperature at −10° C. The reaction mixture was slowly warmed to room temperature and stirred for further 2 h. After completion of reaction (by TLC), the reaction mixture was poured into saturated NaCl solution and extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to half of the volume; PhMe (15 mL) was added and heated to 80° C. for 4 h. After completion (by TLC), the reaction mixture was poured into saturated NaCl solution and extracted with EtOAc (2×15 mL). The combined organic extracts were dried over Na2SO4 and purified by column chromatography to afford 25a (0.11 g, 44%) as a brown sold.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]2[O:14][C:15]3[C:16]([N:21]=2)=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:10]=[C:11]([C:13]2[O:14][C:15]3[C:16]([N:21]=2)=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc(-c2nc3ncccc3o2)cc([N+](=O)[O-])c1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(CO)cc(-c2nc3ncccc3o2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
In a typical run, 3-nitro-5-(oxazolo[4,5-b]pyridin-2-yl)benzoic acid (770 mg, 2.70 mmol) was suspended in 50 mL of anhydrous THF and cooled in an ice bath along with NMM (0.3 mL, 2.70 mmol). Isobutyl chloroformate (0.35 mL, 2.70 mmol) was added and the reaction mixture was stirred at 0° C. for 1 hour. A solution of NaBH4 (102 mg, 2.70 mmol) in 6 mL of water was then added at 0° C. and the reaction mixture was stirred at the same temperature for 45 min. It was then concentrated and the resulting residue was diluted with 10 mL of water. The aqueous layer was extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated to afford 500 mg of (3-nitro-5-oxazolo[4,5-b]pyridin-2-yl-phenyl)-methanol (68% yield, >95% pure by LC/MS).
Reaction SMILES: [CH2:1]([N:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH2:5])[CH:2]=[CH2:3].[CH2:12]([N:19]=[C:20]=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:5][C:20](=[O:21])[NH:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:2]=[CH2:3]
Reactant: O=C=NCc1ccccc1
Reactant: C=CCN(N)CC(=O)OCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCN(CC(=O)OCC)NC(=O)NCc1ccccc1
Yield: 73.6 %

Procedure:
To the solution of ethyl 2-(1-allylhydrazinyl)acetate (Compound XV-1) 6.9 g (44 mmol) in tetrahydrofuran 40 ml, benzyl isocyanate 6.1 g (46 mmol) was added at 0° C. and at room temperature for 3.5 hours. The reaction mixture was diluted with ethyl acetate 150 ml and washed with water 75 ml and brine 75 ml. The organic phase was dried with magnesium sulfate and filtered. The filtrate was concentrated in vacuo to obtain the title compound 9.43 g (75%).
Reaction SMILES: [CH3:1][S:2][CH2:3][C@@H:4]([C:6]([OH:8])=[O:7])[NH2:5].C(N(CC)CC)C.F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>O.CC(C)=O>[F:23][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([NH:5][C@H:4]([C:6]([OH:8])=[O:7])[CH2:3][S:2][CH3:1])[CH:22]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CSC[C@H](N)C(=O)O
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CSC[C@H](Nc1cc(F)ccc1[N+](=O)[O-])C(=O)O

Procedure:
16.2 g of (-)-S-Methyl-L-cysteine (0.1 mol) are suspended in a mixture of 120 ml of water and 120 ml of acetone in a four-necked flask under N2. 30.4 ml (22.2 g) of triethylamine (0.22 mol) are added rapidly while stirring. 15.9 g of 2,4-difluoronitrobenzene (0.1 mol) are added, with further stirring, to the resulting yellow solution. The mixture is heated to reflux for 7.5 hours while stirring (orange-colored solution) and the acetone is then stripped off under reduced pressure on a rotary evaporator; the aqueous residue is transferred to a separating funnel and extracted 2× with approximately 50 ml of methyl tert-butyl ether (MTB ether). This extract is composed, in the main, of 2,4-difluoronitrobenzene and is discarded. The aqueous phase is transferred to a four-necked flask and 150 ml of MTB ether are added to it, after which the mixture is adjusted, while being cooled (<25° C.), to pH 1 with approximately 25 ml of 38% sulfuric acid. The mixture is then stirred thoroughly until clear phases are formed. The ether phase is separated off and the aqueous phase is extracted once again with 50 ml of MTB ether. The extracts are dried over sodium sulfate and evaporated on a rotary evaporator. The yield comprises 27 g of a yellow oil which soon solidifies. M.p. 147° (from water/methanol).
Reaction SMILES: [NH2:1][C@@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:3]1=[O:24].C(N(CC)CC)C.[OH:32][CH2:33][C:34]1[NH:35][C:36](=[O:45])[N:37]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:38]=1.[O:46]1CCC[CH2:47]1>>[OH:32][CH2:33][C:34]1[NH:35][C:36](=[O:45])[N:37]([CH:39]2[CH2:44][CH2:43][N:42]([C:47]([NH:1][C@@H:2]3[N:8]=[C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:6]4[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=4[N:4]([CH2:19][C:20]([F:21])([F:23])[F:22])[C:3]3=[O:24])=[O:46])[CH2:41][CH2:40]2)[CH:38]=1
Reactant: N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Reactant: O=c1[nH]c(CO)cn1C1CCNCC1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O)N1CCC(n2cc(CO)[nH]c2=O)CC1
Reaction time: 1 h

Procedure:
(3R)-3-Amino-5-phenyl-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (338 mg, 1.014 mmol) (Y.-J. Shi et al., Tetrahedron, 1999, 55, 909-918) and triethylamine (0.141 mL, 1.014 mmol) were added to a solution of p-nitrophenylchloroformate (204 mg, 1.014 mmol) in tetrahydrofuran (15 mL) at 0° C. After 1 h, 4-(hydroxymethyl)-1-piperidin-4-yl-1,3-dihydro-2H-imidazol-2-one (200 mg, 1.014 mmol) was added and the reaction stirred at 0 oC for 10 min and was then heated to 50 oC. After 4 h, the reaction was partitioned between ethyl acetate and saturated sodium bicarbonate and the organics were washed with water, brine, and dried over magnesium sulfate. Purification by preparative reverse phase chromatography gave the title compound (18 mg). MS 557.21 (M+1).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:17]1[N:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:20]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:19][CH:18]=1>C(O)CC>[CH2:1]([NH:8][C:17]1[N:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:20]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1C(=O)OCC
Reactant: NCc1ccccc1
Solvent: CCCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NCc2ccccc2)nc1C(=O)OCC
Reaction time: 0.17 h

Procedure:
10.7 g (0.1 mol) of benzylamine and 10.1 g (0.1 mol) of triethylamine were added to a mixture of 25.8 g (0.1 mol) of diethyl 6-chloropyridine-2,3-dicarboxylate in 250 ml of propanol at 25° C. with stirring in the course of 10 minutes. After stirring under reflux for 12 hours, the reaction mixture was concentrated, the residue was taken up in methylene chloride and the solution was extracted with water. The organic phase was dried, filtered off with suction through neutral alumina and concentrated under reduced pressure. The residue was stirred in ether/pentane, filtered off with suction and dried, 23.3 g (71.1% of theory) of the title compound of m.p. 110°-114° C. being obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13](Cl)[N:12]=[C:11]([O:16][CH2:17][CH2:18][OH:19])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C1(C)C=C(C)C=C(C)C=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[N:12]=[C:11]([O:16][CH2:17][CH2:18][OH:19])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: C1CNCCN1
Reactant: OCCOc1nc(Cl)nc2c1[nH]c1cc(Br)ccc12
Solvent: Cc1cc(C)cc(C)c1
Product: OCCOc1nc(N2CCNCC2)nc2c1[nH]c1cc(Br)ccc12

Procedure:
400 mg (1.17 mmol) 2-(7-bromo-2-chloro-5H-pyrimido[5,4-b]indol-4-yloxy)ethanol and 1.0 g (11.7 mmol) piperazine in 50 ml mesitylene were heated to 150° C. for 5 h. Then, the solvent was removed and the residue was taken up in EtOH and filtrated. Having removed the solvent, 250 mg (55%) of the title substance was obtained. ESI-MS [m/z]: 392, 394[M+H]+
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10].Br[C:20]1[C:21](=[O:35])[N:22]([CH3:34])[C:23](=[O:33])[N:24]([CH2:26][CH2:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:25]=1.C(N(CC)CC)C>C(O)CCC.O>[CH3:14][C:8]([O:7][C:6]1[CH:16]=[CH:17][CH:18]=[C:4]([CH2:3][CH2:2][NH:1][C:20]2[C:21](=[O:35])[N:22]([CH3:34])[C:23](=[O:33])[N:24]([CH2:26][CH2:27][CH2:28][C:29]([F:30])([F:31])[F:32])[N:25]=2)[CH:5]=1)([CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CCN)c1
Reactant: Cn1c(=O)c(Br)nn(CCCC(F)(F)F)c1=O
Solvent: CCN(CC)CC
Solvent: CCCCO
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1cccc(CCNc2nn(CCCC(F)(F)F)c(=O)n(C)c2=O)c1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
Compound 56 is prepared according to synthesis method 1: 1.1 g (4.4 mmol) of derivative 13b and 1 g (3.7 mmol) of triazine 4a are placed in 10 ml of nBuOH in the presence of 1.3 ml (9.3 mmol) of triethylamine. This mixture is stirred at 120° C. for 24 h. After dry concentration of the reaction medium, the residue obtained is taken up in H2O and extracted with AcOEt. The organic phases are dried on MgSO4, then dry concentrated. The oil obtained is purified by flash chromatography on silica (petroleum ether:AcOEt 90:10). 0.4 g of compound 56 is isolated in the form of an oil (yield=27%).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[I:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=1>CN(C=O)C.O>[CH2:7]([O:6][C:4]([C:3]1[N:17]=[C:14]2[CH:13]=[CH:12][C:11]([I:10])=[CH:16][N:15]2[CH:2]=1)=[O:5])[CH3:8]
Reactant: Nc1ccc(I)cn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2cc(I)ccc2n1
Reaction time: 2 h
Yield: 58.2 %

Procedure:
A mixture of sulfuric acid (0.5 mL), acetic acid (12 mL) and water (2 mL) was added to a reaction flask containing 2-aminopyridine (2.0 g, 21.26 mmol) and the solution was stirred for 5 minutes. NaIO4 (1.81 g, 8.5 mmol) followed by 12 (2.16 g, 8.5 mmol) was added into the reaction flask and stirred at 80° C. for 4 hrs. The reaction mixture was cooled to ambient temperature, diluted with cold water, basified with 20% aqueous KOH solution and extracted with DCM. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude residue. Purification by column chromatography (using silica gel 60-120 and 8% EtOAc in hexane as eluent) and subsequent recrystallisation from ethanol afforded 53 g (58.6% Yield) of 5-iodo-pyridin-2-ylamine. Ethyl bromopyruvate (4.89 g, 25.11 mmol) was added to solution of 5-iodo-pyridin-2-ylamine (5.0 g, 22.83 mmol) in DMF (25 mL) and stirring was continued at 80° C. for 2 hrs. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude residue. The residue obtained was purified by recrystallisation from methanol to afford 4.2 g (57.8% Yield) of 6-iodo-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester. A mixture of imidazole (513 mg, 7.5 mmol), cuprous oxide (71 mg, 0.5 mmol), 6-iodo-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (1.6 g, 5.02 mmol), salox (137 mg, 1.0 mmol) and cesium carbonate (3.27 g, 10.05 mmol) in ACN (2 mL) in a seal tube were subjected to reaction in a microwave reactor (time: 15 min, temp: 85° C., power: zero, pressure: zero). The reaction mixture was filtered through celite and the filtrate collected was concentrated under reduced pressure. The residue was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (using neutral alumina and 0.2% MeOH in DCM as eluent) to afford 400 mg (31% Yield) of 6-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester. A mixture of 6-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (250 mg, 0.97 mmol) in 8N aqueous HCl (3 mL) was stirred at 100° C. for 2 hrs. The reaction mixture was concentrated under reduced pressure to afford 130 mg (58.5% Yield) of 6-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylic acid.