Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[CH:5](=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C([BH3-])#N.[Na+].Cl>O.CO>[CH2:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:2]=[CH2:3]
Reactant: CCCCCCC=O
Reactant: C=CCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CCNCCCCCCC

Procedure:
To 100 mL of methanol is added 2-propenylamine (5.7 g, 0.1 mol), 11.4 g (0.1 mol) of heptaldehyde, and 12 g (0.2 mol) of sodium cyanoborohydride. The pH is adjusted to six with concentrated HCl. Monitor the reaction by thin-layer chromatography. Upon completion, add concentrated HCl until gas evolution ceases. Add 300 mL of H2O and extract once with 200 mL of ether. Add 1N NaOH to the aqueous solution until it is basic and extract twice with 200 mL of ether. Dry the organic phase over Na2SO4. Filter off the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [CH:1]1[N:9]2[C:4]([NH:5][NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][N:2]=1.[C:14](Cl)(=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[C:14]([N:5]1[C:4]2=[N:3][N:2]=[CH:1][N:9]2[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]1[C:14](=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: c1ccc2c(c1)NNc1nncn1-2
Solvent: CN(C)C=O
Product: O=C(C=Cc1ccccc1)N1c2ccccc2-n2cnnc2N1C(=O)C=Cc1ccccc1
Yield: 75 %

Procedure:
A mixture of 4.0 g (0.023 mole) of 4,5-dihydro-s-triazolo[3,4-c]benzo-as-triazine, 7.66 g (0.046 mole) of cinnamoyl chloride and 70 ml of dimethyl formamide is refluxed for 4 hours, and the mixture is processed in the usual way. 7.48 g (75%) of the title compound are obtained; m.p.: 220°-221° C.
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1[N:11]=[C:10](OS(C(F)(F)F)(=O)=O)[CH:9]=[C:8]([CH2:20][CH2:21][CH3:22])[C:7]=1[C:23]#[N:24])(=[O:3])[NH2:2].Cl.Cl.Cl.[NH:28]1[CH2:33][CH2:32][CH:31]([NH:34][CH2:35][CH:36]([OH:45])[CH2:37][O:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[CH2:30][CH2:29]1.C[O-].[Na+].CO>CN(C=O)C>[NH2:24][C:23]1[C:7]2[C:6](=[N:11][C:10]([N:28]3[CH2:33][CH2:32][CH:31]([NH:34][CH2:35][CH:36]([OH:45])[CH2:37][O:38][C:39]4[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=4)[CH2:30][CH2:29]3)=[CH:9][C:8]=2[CH2:20][CH2:21][CH3:22])[S:5][C:4]=1[C:1]([NH2:2])=[O:3]
Reactant: CCCc1cc(OS(=O)(=O)C(F)(F)F)nc(SCC(N)=O)c1C#N
Reactant: OC(CNC1CCNCC1)COc1ccncc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCc1cc(N2CCC(NCC(O)COc3ccncc3)CC2)nc2sc(C(N)=O)c(N)c12
Temperature: 70 °C
Reaction time: 2 h
Yield: 28.5 %

Procedure:
To a sealed tube was added trifluoro-methanesulfonic acid 6-carbamoylmethylsulfanyl-5-cyano-4-propyl-pyridin-2-yl ester (66.7 mg, 0.174 mmol) in 4 mL of dry DMF, followed by the addition of 1-(piperidin-4-ylamino)-3-(pyridin-4-yloxy)-propan-2-ol trihydrochloride salt (69 mg, 0.191 mmol) and N-N-diisopropylethylamine (180 mg, 1.39 mmol). The reaction mixture was stirred at 70° C. for 2 h. DMF was removed in vacuo. The residue was dissolved in 5 mL of MeOH, followed by the addition of sodium methoxide, 0.5 M solution in MeOH (1.74 mL, 0.86 mmol). The reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was concentrated in vacuo. The residue was loaded onto a flash chromatography column. The column was eluted with 0–5% 2M NH3 in MeOH/CH2Cl2. The product fractions were collected, concentrated and dried under high vacuum pump to afford 24 mg (28.5%) of the title compound as a light brown solid product. (TLC: Rf=0.4, 5% 2M NH3 in MeOH/CH2Cl2, UV). ES+ 485.29 m/z (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[C:20]([CH2:22][C:23]([NH:25][NH2:26])=O)#[N:21]>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:23]([CH2:22][C:20]#[N:21])=[N:25][N:26]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: N#CCC(=O)NN
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Solvent: CCCCO
Product: N#CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
A mixture of 1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepine-2-thione (5.72 g., 0.02 mole), cyanoacetic acid hydrazide (5.95 g., 0.06 mole) and n-butylalcohol (275 ml.) is refluxed for 7.5 hours with a slow stream of nitrogen bubbling through the mixture. The mixture is then concentrated in vacuo. The resulting residue is suspended in water and extracted with methylene chloride. The extract was dried and concentrated. The residue is chromatographed on silica gel (400 g.) with 2% methanol- 98% CHCl3. The product eluted from the column is crystallized from ethyl acetate-Skellysolve B hexanes to give 2.62 g. of 8-chloro-6-phenyl-4H-s-triazolo[4,3a][1,4]benzodiazepine-1-acetonitrile of melting point 198°-201° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[C:5]([C:11]([O:13][CH3:14])=[O:12])=[C:6]([CH3:10])[NH:7][C:8]=1[CH3:9])#[N:2].[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1N1C=CCC=C1)([O-:24])=[O:23].[CH3:37][OH:38]>[Pd]>[CH3:10][C:6]1[NH:7][C:8]([CH3:9])=[C:3]([C:1]#[N:2])[CH:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:37](=[O:38])[C:28]2[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:30][CH:29]=2)[C:5]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=[N+]([O-])c1ccccc1N1C=CCC=C1
Reactant: CO
Reactant: COC(=O)C1=C(C)NC(C)=C(C#N)C1c1ccccc1N
Agent: [Pd]
Product: COC(=O)C1=C(C)NC(C)=C(C#N)C1c1ccccc1NC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
5-Cyano-2,6dimethyl-3-methoxycarbonyl-4-(2-aminophenyl)-1,4-dihydropyridine used as starting material is prepared by the following method: The solution of 0.8 g (2.5 mmoles) of 5cyano-2,6-dimethyl-3-methoxycarbonyl-4-(2-nitrophenyl)-1,4- (2-nitrophenyl-1,4-dihydropyridine (published German patent application No. 2,658,804) in 80 ml of methanol is submitted to hydrogenolysis in the presence of Pd-C at atmospheric pressure. After completed reduction the catalyst is filtered and washed with hot methanol. The solvent is evaporated and the residue is recrystallized from ethanol.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15]I)=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH:17]([C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][N:20]2[CH:21]=[CH:22][N:23]=[C:19]2[CH:17]=[O:18])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Oc1ccc(CCCCI)cc1
Reactant: O=Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Oc1ccc(CCCCn2ccnc2C=O)cc1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A suspension of 1-tert-butoxy-4-(4-iodobutyl)benzene (10.0 g), 2-formyl-1H-imidazole (3.47 g) and potassium carbonate (4.16 g) in DMF (100 ml) was stirred at 70° C. for 17 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was successively washed with water (3 times) and saturated brine, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crude 1-[4-(4-tert-butoxyphenyl)butyl]-1H-imidazole-2-carbaldehyde as a pale brown oil. Sodium borohydride (1.25 g) was added to a solution of the compound in methanol (200 ml) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was combined with water, concentrated and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Chromatorex, 100-200 mesh, Fuji silicia chemical) (eluent; hexane:ethyl acetate=1:3 to ethyl acetate) to give the titled compound (8.29 g) as a colorless amorphous form.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12]CC)=[O:11])[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.CCO.O.O[Li].O>Cl>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1-c1cccc(F)c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(C(=O)O)n(-c2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a stirring solution of ethyl 3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazole-5-carboxylate (0.786 g, 2.71 mmol) in 1:1:1 THF/EtOH/H2O (36 ml) at RT was added LiOH.H2O (0.568 g, 13.5 mmol). After stirring at RT overnight, the reaction mixture was diluted with 3M HCl (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×30 mL), dried (MgSO4) and concentrated to afford 3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazole-5-carboxylic acid (0.602 g, 85% yield) as white solid. MS (ESI) m/z: 263 (M+H+).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7](/[N:8]=C/C2C=CC(OC)=CC=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][CH3:21])=[O:19])[CH2:3]1.O.C(O)(C(F)(F)F)=O>CO>[NH2:8][C@@H:7]1[CH2:6][CH2:5][N:4]([C:18]([O:20][CH3:21])=[O:19])[CH2:3][C@H:2]1[OH:1]
Reactant: COC(=O)N1CC[C@@H](/N=C/c2ccc(OC)cc2)[C@H](O)C1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)N1CC[C@@H](N)[C@H](O)C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of (3R,4R)-methyl 3-hydroxy-4-((E)-(4-methoxybenzylidene)amino)piperidine-1-carboxylate (499 mg, 1.707 mmol) in MeOH (17 ml) was added water (1 ml, 55.5 mmol) and TFA (2 ml, 26.0 mmol). The reaction was stirred at 50° C. overnight. The reaction mixture was applied on a SCX column (Phenomenex, Strata XC) and eluted with 2N ammonia in methanol. The solvents removed to afford (3R,4R)-methyl 4-amino-3-hydroxypiperidine-1-carboxylate (290 mg).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:25][CH2:24][C:13]2([CH:15]([NH:16]C(OC(C)(C)C)=O)[CH2:14]2)[CH2:12]1)=O)C1C=CC=CC=1.[NH2:26][C:27]1[C:36]([F:37])=[C:35](F)[C:34](C)=[C:33]2[C:28]=1[C:29](=[O:47])[C:30]([C:44]([OH:46])=[O:45])=[CH:31][N:32]2[C@@H:40]1[CH2:42][C@@H:41]1[F:43].C(N(CC)CC)C>C(O)C.[C].[Pd]>[NH2:26][C:27]1[C:36]([F:37])=[C:9]([N:11]2[CH2:25][CH2:24][C:13]3([CH:15]([NH2:16])[CH2:14]3)[CH2:12]2)[C:34]([CH3:35])=[C:33]2[C:28]=1[C:29](=[O:47])[C:30]([C:44]([OH:46])=[O:45])=[CH:31][N:32]2[C@@H:40]1[CH2:42][C@@H:41]1[F:43]
Reactant: CC(C)(C)OC(=O)NC1CC12CCN(C(=O)OCc1ccccc1)C2
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1c(N2CCC3(CC3N)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 155 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A 693 mg (2.00 mmol) portion of 5-benzyloxycarbonyl-1-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane (1-a) was dissolved in 60 ml of ethanol, and the solution was mixed with 600 mg of 10% palladium-carbon and subjected to 2 hours of hydrogenation under atmospheric pressure. After completion of the reaction, 10% palladium-carbon was removed by filtration and ethanol was evaporated. The thus obtained residue was suspended in 6 ml of dimethyl sulfoxide, and the suspension was mixed with 312 mg (1.00 mmol) of 5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2.00 ml (14.35 mmol) of triethylamine, and heated at 150 to 160° C. for 19 hours in a stream of nitrogen. After evaporation of the solvent, the thus obtained residue was mixed with chloroform, washed with water, 10% citric acid aqueous solution and saturated brine in that order, and then dried over anhydrous sodium sulfate, subsequently evaporating the solvent. The thus obtained tert-butylcarbamate compound was mixed with 5 ml of concentrated hydrochloric acid, stirred at room temperature for 20 minutes, washed with chloroform (50 ml×3), adjusted to pH 7.4 with sodium hydroxide aqueous solution and then extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. After evaporation of the solvent, the resulting residue was purified by a preparative TLC (developed by the lower layer of chloroform:methanol:water 7:3:1) and recrystallized from ethanol-ether to yield 142 mg (35%) of the title compound.
Reaction SMILES: Cl[S:2]([C:5]1[C:6]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([S:14][CH2:15][CH3:16])[CH:8]=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[NH3:24]>>[CH2:15]([S:14][C:7]1[CH:8]=[C:9]([CH:13]=[C:5]([S:2](=[O:4])(=[O:3])[NH2:24])[C:6]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]([OH:12])=[O:11])[CH3:16]
Reactant: N
Reactant: CCSc1cc(C(=O)O)cc(S(=O)(=O)Cl)c1Oc1ccccc1
Product: CCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
5-Chlorosulfonyl-3-ethylthio-4-phenoxybenzoic acid (1 g) is added to concentrated aqueous ammonia (20 ml) at 5°-10° C. After 30 minutes the reaction mixture is heated on a steam-bath for 1 hour while most of the excess of ammonia was allowed to distill off. After cooling, the precipitated ammonium salt of 3-ethylthio-4-phenoxy-5-sulfamylbenzoic acid is collected by filtration. The salt is dissolved in hot water (75 ml) and the solution acidified by addition of hydrochloric acid. After cooling, the precipitated 3-ethylthio-4-phenoxy-5-sulfamylbenzoic acid is collected by filtration and recrystallized from aqueous ethanol to yield the compound with a melting point of 225°-227° C after drying in vacuo at 80° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[Br:13]Br>CO>[Br:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Solvent: CO
Product: O=[N+]([O-])c1ccc2[nH]nc(Br)c2c1
Reaction time: 48 h
Yield: 83.6 %

Procedure:
5-Nitroindazole (20.0 g, 123 mmol, 1 equiv) was suspended in 500 mL MeOH. The mixture was refluxed and bromine (6.3 mL, 123 mmol, 1 equiv) was added dropwise. The reaction was stirred at reflux for 3 hours, then at room temperature for 2 days. The reaction mixture was filtered and the solid was washed with diisopropyl either to afford 24.9 g (84%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH2:15][OH:16])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C(N(CC)CC)C.ClCCl.[C:27](Cl)(=[O:31])[C:28]([CH3:30])=[CH2:29]>C(OCC)C>[CH2:1]([N:4]([CH2:14][CH2:15][O:16][C:27](=[O:31])[C:28]([CH3:30])=[CH2:29])[C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: C=CCN(CCO)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCN(CCOC(=O)C(=C)C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-allyl-N-(2-hydroxyethyl)-4-nitrobenzenamine (2.22 g, 0.01 mol), triethylamine (1.2 ml) and dichloromethane (20 ml) is added methacryloyl chloride (1.14 g, 11 mmol) with stirring at room temperature. After 3 hours, an additional amount of triethylamine (0.6 ml) and methacryloyl chloride (0.5 g) is added and stirring continued for 3 hours. The mixture is diluted with ethyl ether (100 ml) and washed with water two times, washed with brine, and dried over sodium sulfate. The mixture is concentrated and chromatographed on silica with hexane-ethyl acetate to provide N-allyl-N-(2-methacryloyloxyethyl)-4-nitrobenzenamine.
Reaction SMILES: [CH3:1][Si:2]([CH2:5][NH:6][CH2:7][CH2:8][CH2:9][CH3:10])([CH3:4])[CH3:3].[CH2:11]=O.CO.[C:15]([O-:18])([O-])=O.[K+].[K+]>CC(OC)(C)C>[CH3:11][O:18][CH2:15][N:6]([CH2:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C=O
Reactant: O=C([O-])[O-]
Reactant: CCCCNC[Si](C)(C)C
Agent: [K+]
Solvent: CO
Solvent: COC(C)(C)C
Product: CCCCN(COC)C[Si](C)(C)C
Temperature: 0 °C
Yield: 152.9 %

Procedure:
N-(trimethylsilyl)methyl-1-butanamine (12.5 g; max. 66.0 mmol) was added dropwise to a mixture of 37% aqueous formaldehyde (5.4 g) and methanol (2.2 g) while stirring at 0° C. After the addition was complete the reaction mixture was stirred for 90 minutes at 0° C. K2CO3 (6 g) was added and the mixture was stirred for an additional 2 hours. Then, tBME (100 ml) was added and the organic layer was separated. The aqueous layer was washed with tBME (50 ml). The combined organic layers were dried with Na2SO4. Evaporation at 75° C. under vacuum at 450 mbar gave the crude product N-(methoxymethyl)-N-((trimethylsilyl)methyl)butan-1-amine (13.5 g) as an oil in quantitative yield. The product was used without further purification.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]1[NH:17][C:18]([CH2:20][CH3:21])=[N:19][C:11]1=[N:10]2.C(N(CC)CC)C.[CH:29]([NH:31][CH:32](Cl)[C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30]>O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]1[N:17]([CH:32]([NH:31][CH:29]=[O:30])[C:33]([Cl:36])([Cl:35])[Cl:34])[C:18]([CH2:20][CH3:21])=[N:19][C:11]1=[N:10]2
Reactant: O=CNC(Cl)C(Cl)(Cl)Cl
Reactant: CCc1nc2nc3cc(Cl)ccc3nc2[nH]1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1nc2nc3cc(Cl)ccc3nc2n1C(NC=O)C(Cl)(Cl)Cl
Reaction time: 1.25 h

Procedure:
To 240 ml of dry dimethylformamide warmed to 50° was added 3.5 parts of 6-chloro-2-ethyl-1H-imidazo[4,5-b]quinoxaline and 1.75 parts of triethylamine. The resulting solution was added, with stirring, to a 500 ml round-bottomed flask containing 3.3 parts of 1-formamido-1,2,2,2-tetrachloroethane and 45 parts of dry dimethylformamide at room temperature. After standing for 75 minutes, the clear solution was poured onto a mixture of 1500 parts of ice and water. The resulting solids were collected, washed with water and dried to give 4.6 parts of 6-chloro-2-ethyl-1-(1-formamido-2,2,2-trichloroethyl)-1H-imidazo[ 4,5-b]quinoxaline, decomposing at 109°.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][NH:11][C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[F:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1.O>CN(C=O)C>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][N:11]3[C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:7](=[O:8])[C:6]=4[CH:9]=[CH:10]3)=[CH:23][CH:22]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Reactant: Cn1ncc2[nH]ccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc2c(ccn2Cc2ccc(C(=O)c3ccc(F)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
A solution of 5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (373 mg) in DMF (10 ml) was dripped into a suspension of 60% sodium hydride-oil (120 mg) in DMF (10 ml) on an ice-water bath. The mixture was stirred at room temperature for 1 hour, after which a solution of 4-(4-fluorobenzoyl)benzyl bromide (806 mg) in DMF (20 ml) was added and the mixture was further stirred at room temperature for 13 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; dichloromethane: methanol=99:1) to provide the title compound as white powder (615 mg, yield 68%).
Reaction SMILES: C(O)=O.[CH2:4]([N:11]1[CH2:25][CH2:24][N:14]2[C:15]3[N:23]=[CH:22][CH:21]=[CH:20][C:16]=3[NH:17][CH2:18][CH2:19][CH:13]2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:26]=O>C(Cl)Cl>[CH2:4]([N:11]1[CH2:25][CH2:24][N:14]2[C:15]3[N:23]=[CH:22][CH:21]=[CH:20][C:16]=3[N:17]([CH3:26])[CH2:18][CH2:19][CH:13]2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=O
Reactant: c1ccc(CN2CCN3c4ncccc4NCCC3C2)cc1
Solvent: ClCCl
Solvent: O=CO
Product: CN1CCC2CN(Cc3ccccc3)CCN2c2ncccc21
Temperature: 110 °C

Procedure:
Formic acid (88%, 3 mL) was added to a solution of the product of Example 52 (97 mg, 0.231 mmol) in CH2Cl2 (2 mL). Aqueous formalin (0.5 mL, 6.5 mmol) was added, and the mixture was heated at 110° C. for 45 minutes, then cooled to room temperature and concentrated under vacuum. The residue was purified by HPLC (30×100 mm XBridge™ column cluting with aqueous 0.1 M (NH4)2CO3-methanol, 80:20-0:100 over 15 minutes) to provide the title compound: 1H NMR (300 MHz, CD3OD) δ ppm 1.62-1.74 (m, 1H), 1.77-1.91 (m, 1H), 2.23 (t, J=10.5 Hz, 1H), 2.39 (td, J=11.0, 3.1 Hz, 1H), 2.70 (ddd, J=10.8, 2.4, 1.9 Hz, 1H), 2.79 (s, 3H), 2.80-2.88 (m, 1H), 2.96 (ddd, J=11.1, 6.5, 4.4 Hz, 1H), 3.23-3.29 (m, 1H), 3.32-3.40 (m, 2H), 3.50 (dt, J=12.9, 3.1 Hz, 1H), 3.59 (s, 2H), 6.87 (dd, J=7.8, 4.7 Hz, 1H), 7.08 (dd, J=7.8, 1.4 Hz, 1H), 7.22-7.39 (m, 5H), 7.71 (dd, J=4.9, 1.5 Hz, 1H); MS (ESI) m/z 309 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14]CC)=O)[N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[CH:22][C:23]=1[F:24].C1COCC1>C1COCC1>[Cl:17][C:18]1[CH:19]=[C:20]([C:12]([C:4]2[N:3]=[C:2]([Cl:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:14])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: Fc1ccc([Mg]Br)cc1Cl
Reactant: CCOC(=O)c1nc(Cl)c2ccccc2n1
Solvent: C1CCOC1
Product: O=C(c1ccc(F)c(Cl)c1)c1nc(Cl)c2ccccc2n1
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 36.7 %

Procedure:
A mixture of ethyl 4-chloroquinazoline-2-carboxylate (1 g, 4.2 mmol) in THF (50 mL) was filtered, and to the filtrate at −30° C. under Ar was added 0.5 M (3-chloro-4-fluorophenyl)magnesium bromide/THF (10.4 mL, 5.2 mmol). After stirring at −30° C. for 0.75 h, additional 0.5 M (3-chloro-4-fluorophenyl)magnesium bromide/THF (4.2 mL). After 1 h, the reaction was quenched by addition of saturated aq ammonium chloride and allowed to warm to rt. The mixture was extracted with EtOAc, and the extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford (3-chloro-4-fluorophenyl)(4-chloroquinazolin-2-yl)methanone (495 mg, 37%) which was used directly in the next step. LC-MS (ESI) m/z 321 (M+H)+.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[N:9]=1.[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>CCCCC.C1COCC1>[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][N:19]=3)[CH:14]=2)[N:9]=1
Reactant: c1cnccn1
Reactant: COc1ccc2cc(Br)ccc2n1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc2cc(-c3cnccn3)ccc2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
t-Butyl lithium (4.6 cm3 of a 2.6M solution in pentane) was added dropwise to a stirred solution of 2-methoxy-6-bromoquinoline (1.43 g) in THF (10 cm3) at -70° under nitrogen. After 20 minutes a solution of pyrazine (0.48 g) in THF (5 cm3) was added and after stirring for a further 20 minutes a stream of dry air was bubbled through the solution for 0.5 hour at -70° and then for a further 1 hour as the mixture warmed to room temperature. Chloroform (50 cm3) was added and the solution was washed with water (10 cm3), dried (MgSO4) and concentrated in vacuo to afford a residue which was chromatographed on silica (Merck "MK 60.9385") eluting with ethyl acetate:hexane, 1:1, to give a solid. Recrystallisation from ethyl acetate gave 2-methoxy-6-(2-pyrazinyl)quinoline. 1/4H2O, m.p. 130°-132°, (0.22 g).