Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=[CH:6][C:5]=1[NH:22][CH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1)([O-])=O.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(O)C>[NH2:1][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=[CH:6][C:5]=1[NH:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=1
Reactant: N#Cc1ccc(CNc2ccc(OCc3ccc4ccccc4n3)cc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(CNc2ccc(OCc3ccc4ccccc4n3)cc2N)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 2-((4-fluoro-3-nitrophenoxy)methyl)quinoline (298 mg, 1 mmol) and 4-(aminomethyl)benzonitrile (132 mg, 1 mmol) in acetonitrile (1 mL) was added DIPEA (2 mL, 12 mmol). The mixture was stirred at 80° C. overnight. The mixture was cooled to RT, water (20 mL) was added, and the mixture was extracted with DCM (3×20 mL). The organics were combined, washed with brine (20 mL), dried (Na2SO4), filtered and concentrated to dryness. The residue was recrystallized from ethanol to give 4-((2-nitro-4-(quinolin-2-ylmethoxy)phenylamino)methyl)benzonitrile. The recrystallized 4-((2-nitro-4-(quinolin-2-ylmethoxy)phenylamino)methyl)benzonitrile (307 mg, 0.75 mmol) was then dissolved in ethanol (20 mL) and SnCl2.2H2O (1 g, 4.5 mmol) was added. The resulting mixture was stirred at 90° C. overnight. The mixture was cooled to RT and the pH adjusted to ˜pH 8-9 by the addition of sat. aq. NaHCO3. The aqueous mixture was stirred at RT for 30 min. and then extracted with DCM (3×20 mL). The organics were combined, washed with brine (20 mL), dried (Na2SO4), filtered and concentrated to dryness to afford the title compound, which was used without further purification. MS (ESI): mass calcd. for C24H20N4O, 380.16; m/z found, 381.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[Cl:27])[N:23]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:22]=[C:21]2[NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40]>O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][C:26]=2[Cl:27])[N:23]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:35])[CH3:33])[N:22]=[C:21]3[NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccc(F)cc3)cc12

Procedure:
470 mg of 4-fluorophenylboronic acid, 593 mg of sodium carbonate in 40 cm3 of water and 155 mg of tetrakis(triphenylphosphine)palladium are added to 1 g of N-[5-bromo-6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 58, in 40 cm3 of dioxane. The mixture is refluxed for 18 hours and the reaction medium is filtered through a sinter funnel packed with Celite. 60 cm3 of ethyl acetate and 50 cm3 of distilled water are added to the filtrate. The organic phase is washed with 2×20 cm3 of saturated aqueous sodium chloride solution and then separated out after settling of the phases has taken place and dried over magnesium sulphate. After filtration, the filtrate is concentrated to dryness under reduced pressure (2 kPa; 50° C.) and the residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4.5 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 0.75 g of N-[5-(4-fluorophenyl)-6-chloro-1-[(2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide is thus obtained in the form of a yellow wax.
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].N1C=CC=CC=1.[Cl:17][CH2:18][C:19](Cl)=[O:20].Cl>ClCCl>[O:9]=[C:4]1[CH:5]2[CH2:8][CH:1]([CH2:7][CH2:6]2)[C:2]([O:10][C:19](=[O:20])[CH2:18][Cl:17])=[CH:3]1
Reactant: O=C(Cl)CCl
Reactant: O=C1CC(=O)C2CCC1C2
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCl)OC1=CC(=O)C2CCC1C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
Into a 250 ml round bottom flask containing the bicyclo[3.2.1]octane-2,4-dione (10 g, 72 mmol) is added dry dichloromethane (100 ml) and pyridine (6.28 g, 87 mmol). To the stirred mixture is added dropwise over a period of 15 minutes the chloroacetyl chloride (9.82 g, 72 mmol) diluted in dichloromethane (100 ml). The reaction mixture is therefore stirred for 2 hours at room temperature. The reaction mixture is therefore poured into 100 ml of aqueous 2N HCl and extracted with ethyl acetate (2×100 ml). The combined organic extracts are dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an orange oil. The crude product is distilled under reduced pressure to give chloro-acetic acid 4-oxo-bicyclo[3.2.1]oct-2-en-2-yl ester (13.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Cl[CH2:45][C:46]1[CH:50]=[CH:49][O:48][CH:47]=1>>[CH3:43][O:42][C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:29]([CH2:45][C:46]4[CH:50]=[CH:49][O:48][CH:47]=4)[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: ClCc1ccoc1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4Cc4ccoc4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 35.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and 3-(chloromethyl)furan (J. Am. Chem. Soc. 72, 2195-2199 (1950)) to give the title compound.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:11]1([CH2:18][C:19]2[S:20][C:21]([C:24]([NH:26][NH2:27])=O)=[CH:22][CH:23]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.BrC(Cl)(Cl)C(Br)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C(#N)C>[CH2:1]([NH:8][C:9]1[O:10][C:24]([C:21]2[S:20][C:19]([CH2:18][N:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:23][CH:22]=2)=[N:26][N:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: NNC(=O)c1ccc(CN2CCCCCC2)s1
Agent: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: c1ccc(CNc2nnc(-c3ccc(CN4CCCCCC4)s3)o2)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 33.1 %

Procedure:
0.13 ml (1.05 mmol) of benzyl isocyanate was added to 25 ml of acetonitrile solution containing 253 mg (1.0 mmol) of 2-(hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxylic acid hydrazide, and the mixture was stirred at room temperature for 40 hours, 718 mg (2.2 mmol) of 1,2-dibromo-1,1,2,2-tetrachloroethane, 1.22 ml of triethylamine and 1.16 g of triphenylphosphine were added, and then the mixture was stirred at room temperature for 9 hours. The reaction solution was concentrated, chloroform was added to the resulting residue, followed by washing with water and drying over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by a silica gel column chromatography to give 122 mg of the title compound in its free form. By subjecting 117 mg of this compound to salt formation using 27 mg of oxalic acid, 122 mg of the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:13][CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[H-].[Na+].[CH3:17][O:18][CH:19]([O:22][CH3:23])[CH2:20]Br>CN(C)C=O>[CH3:1][O:2][C:3]1([O:13][CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:20][CH:19]([O:22][CH3:23])[O:18][CH3:17])[C:4]1=[O:12]
Reactant: COC(CBr)OC
Reactant: COC1(OC)C(=O)Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(CN1C(=O)C(OC)(OC)c2ccccc21)OC
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
A solution of 34.3 g of 3,3-dimethoxyindolin-2-one in 400 ml of N,N-dimethylformamide was added dropwise to a suspension of 8.56 g of sodium hydride (60%) in 100 ml of N,N-dimethylformamide at 0° C. in a nitrogen stream. After the mixture was stirred at that temperature for 30 minutes, 36.2 g of bromoacetaldehyde dimethyl acetal was added thereto. The resulting mixture was stirred at 80° C. for 1 day and then concentrated. Ethyl acetate was added to the residue, and the mixture was washed with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was recrystallized from isopropyl alcohol/hexane to give 25.1 g (50%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[C:4]([CH3:6])=O.S([O-])([O-])(=O)=O.[Mg+2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:22]=[C:4]([CH3:6])[CH:3]([O:7][CH3:8])[O:2][CH3:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(OC)C(C)=O
Reactant: NCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: COC(OC)C(C)=NCc1ccccc1
Temperature: 25 °C

Procedure:
12.9 mL 1,1-dimethoxyacetone was added to 10 mL benzylamine in 100 mL petrolether. Magnesiumsulfate was added and the reaction was stirred over night at RT. The mixture was filtered and evaporated to give 18.9 g of the desired product. (M+H)+: 209
Reaction SMILES: Cl.[CH3:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28].O>CN(C=O)C>[CH3:28][O:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24][N:13]1[CH:14]=[C:9]([C:6]2[CH:7]=[N:8][C:3]([CH3:2])=[CH:4][CH:5]=2)[C:10](=[O:16])[NH:11][C:12]1=[O:15]
Reactant: Cc1ccc(-c2c[nH]c(=O)[nH]c2=O)cn1
Reactant: COC(CCBr)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCn1cc(-c2ccc(C)nc2)c(=O)[nH]c1=O)OC
Yield: 48 %

Procedure:
5-(6-methyl-pyridin-3-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep57, 385 mg, 1.62 mmol), K2CO3 (224 mg, 1.62 mmol) and 3-bromo-1,1dimethoxy-propane (commercially available from Aldrich, 183 mg, 1.0 mmol) were suspended in dry DMF (8 mL). After stirring the reaction at room temperature for 24 hours, additional 3-bromo-1,1dimethoxy-propane (180 mg, 0.98 mmol) was added portionwise over a period of 96 h. Water was added and the mixture washed with diethyl ether. The aqueous layer was then extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated to give 320 mg of the final compound that was used without further purification in the next step (48% yield).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([N:18]=2)[C:16]2[CH:19]=[C:20]([C:23]([OH:25])=O)[CH:21]=[CH:22][C:15]=2[O:14][CH2:13][CH2:12]3)=[N:7][CH:6]=[N:5]1.C(OC([N:35]1[CH:39]=[C:38]([NH2:40])[CH:37]=[N:36]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:35]1[CH:39]=[C:38]([NH:40][C:23]([C:20]2[CH:21]=[CH:22][C:15]3[O:14][CH2:13][CH2:12][C:11]4[N:17]([N:18]=[C:9]([C:8]5[N:4]([CH2:3][C:2]([F:1])([F:27])[F:26])[N:5]=[CH:6][N:7]=5)[CH:10]=4)[C:16]=3[CH:19]=2)=[O:25])[CH:37]=[N:36]1
Reactant: O=C(O)c1ccc2c(c1)-n1nc(-c3ncnn3CC(F)(F)F)cc1CCO2
Reactant: CC(C)(C)OC(=O)n1cc(N)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cn[nH]c1)c1ccc2c(c1)-n1nc(-c3ncnn3CC(F)(F)F)cc1CCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Following the procedure for 126, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylic acid was reacted with 4-amino-pyrazole-1-carboxylic acid tert-butyl ester. The intermediate carboxylic acid tert-butyl ester was dissolved in DCM (5 mL) and treated with TFA (2 mL) before the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the resultant residue triturated in water to give 127 as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 10.53 (s, 1H); 8.51 (d, J=2.2 Hz, 1H); 8.23 (s, 1H); 7.96 (dd, J=8.5, 2.2 Hz, 1H); 7.84 (s, 2H); 7.39 (d, J=8.5 Hz, 1H); 7.02 (s, 1H); 5.77 (q, J=8.7 Hz, 2H); 4.59 (t, J=5.8 Hz, 2H). 3 Protons obscured by water peak. LCMS: RT=9.11 min, M+H+=445
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([NH2:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.[CH:15]([NH:18][C:19]([NH:21][C:22]#[N:23])=[NH:20])([CH3:17])[CH3:16].[OH-].[Na+]>O>[ClH:1].[ClH:1].[CH3:2][CH:3]([NH:14][C:22]([NH:21][C:19]([NH:18][CH:15]([CH3:17])[CH3:16])=[NH:20])=[NH:23])[C:4]1[CH:5]=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:9]=1
Reactant: CC(C)NC(=N)NC#N
Reactant: CC(N)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)NC(=N)NC(=N)NC(C)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A stirred mixture of 15.5 g (0.0687 mole) of α-methyl-p-trifluoromethylbenzylamine hydrochloride and 9.55 g (0.0756 mole) of 1-i-propyl-3-cyanoguanidine is immersed in a 190° C oil bath for ten minutes. The melt is cooled to room temperature, dissolved in 100 ml of water, made alkaline with 40% sodium hydroxide solution and extracted twice with 200 ml of ether. The combined ether extracts are dried over potassium carbonate, filtered, and the ether solution made strongly acidic with a saturated ethereal hydrochloric acid ether solution. The precipitate is collected on a filter, washed twice with 50 ml of anhydrous ether, and dried at 40°C/125 mm. for 5 hours. The dihydrochloride is dissolved in 50 ml of water, made strongly alkaline with 40% sodium hydroxide solution, and extracted twice with 100 ml of ether. The combined ether extracts are dried over potassium carbonate, filtered, and the ether solution made strongly acidic with a saturated ethereal hydrochloric acid solution. The precipitate is collected on a filter, washed twice with 50 ml of anhydrous ether, and dried at 40° C/125 mm. to obtain 1-(α-methyl-p-trifluoromethylbenzyl)-5-i-propylbiguanide dihydrochloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(C(F)(F)F)=O>CCN(CC)CC>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][CH:9]=[CH:10][C:3]=23)=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: Oc1ccc(OCc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: c1ccc(COc2ccc(Oc3ccnc4[nH]ccc34)cc2)cc1

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (1 g, 6.5 mmol), 4-benzyloxyphenol (1.5 g, 7.5 mmol) and Et3N:TFA (1.2 mL) was heated to 150° C. for 96 h. Formation of the compound was monitored by HPLC-mass spec. The crude was directly purified on silica gel without work-up using a Hexanes/EtOAc gradient (100/0 to 0/100) to afford 4-(4-benzyloxy-phenoxy)-1H-pyrrolo[2,3-b]pyridine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:9]=[N:8][C:5]2=[N:6][CH:7]=1.[CH3:30][C:31]1([CH3:55])[CH2:40][CH2:39][C:38]2[N:37]=[CH:36][N:35]=[C:34]([N:41]3[CH2:47][C:46]4[CH:48]=[C:49](B(O)O)[CH:50]=[CH:51][C:45]=4[O:44][CH2:43][CH2:42]3)[C:33]=2[CH2:32]1>>[CH3:30][C:31]1([CH3:55])[CH2:40][CH2:39][C:38]2[N:37]=[CH:36][N:35]=[C:34]([N:41]3[CH2:47][C:46]4[CH:48]=[C:49]([C:2]5[CH:3]=[C:4]6[NH:10][CH:9]=[N:8][C:5]6=[N:6][CH:7]=5)[CH:50]=[CH:51][C:45]=4[O:44][CH2:43][CH2:42]3)[C:33]=2[CH2:32]1
Reactant: Brc1cnc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2c1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc6nc[nH]c6c5)cc4C3)c2C1

Procedure:
Prepared according to the method of example 5 by using 6-bromo-1-(triphenylmethyl)-1H-imidazo[4,5-b]pyridine (reagent preparation 15) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, d6-DMSO): 8.64 (s, 1H), 8.48 (s, 1H), 8.39 (s, 1H), 8.22 (brs, 1H), 7.75 (d, 1H), 7.58 (dd, 1H), 7.06 (d, 1H), 4.67 (s, 2H), 4.35 (m, 2H), 3.85 (m, 2H), 2.72 (m, 2H), 2.46 (s, 2H), 1.61 (m, 2H), 0.85 (s, 6H); MS (EI) for C25H26N6O: 427 (MH+).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[C:18](=[O:19])[N:9]2[CH:10]=[CH:11][C:12]3[C:17]([C:8]2=[N:7][CH:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[CH2:20]([N:22]([CH2:25][CH2:26][Cl:27])[CH2:23][CH3:24])[CH3:21].[ClH:28]>CN(C)C=O.C(OCC)C>[ClH:27].[ClH:28].[CH2:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH2:24][O:3][CH2:4][C:5]1[C:18](=[O:19])[N:9]2[CH:10]=[CH:11][C:12]3[C:17]([C:8]2=[N:7][CH:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:21]
Reactant: O=c1c(CO)cnc2c3ccccc3ccn12
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCN(CC)CCOCc1cnc2c3ccccc3ccn2c1=O
Reaction time: 1 h
Yield: 28 %

Procedure:
To 0.7 g of sodium hydride (14.5 mmol) stirred in 40 ml of dry dimethylformamide under nitrogen was added dropwise over a 15 minute period a solution of 2.0 g of 3-(hydroxymethyl)-4H-pyrimido[2,1-a]isoquinolin-4-one (8.3 mmol) in 40 ml of warm dimethylformamide. After stirring for 1 hour, 1.58 g of diethylaminoethyl chloride (11.6 mmol) was added dropwise over a 15 minute period. The reaction mixture was stirred for 3 hours, then poured onto ice-water and extracted 3 times with 500 ml of methylene chloride. The extracts were dried and concentrated in vacuo to yield a semi-solid, to which 15 ml of isopropanolic hydrochloric acid solution and diethyl ether were added. The crystalline solid which formed was collected and washed with ether to yield 3-[[2-(diethylamino)ethoxy]methyl]-4H-pyrimido[2,1-a]isoquinolin-4-one dihydrochloride (0.973 g; 28% yield) of the formula: ##STR24## having a melting point of 128.7° C. and the following elemental analysis:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][NH:8][C:9]1[S:10][CH2:11][C:12](=[O:14])[N:13]=1.[CH2:15]([O:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([CH:28]=O)[CH:26]=2)[N:21]=[C:20]([NH:30][CH3:31])[N:19]=1)[CH3:16].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH2:15]([O:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([CH:28]=[C:11]3[S:10][C:9]([NH:8][CH2:7][C:3]4[S:4][CH:5]=[CH:6][C:2]=4[CH3:1])=[N:13][C:12]3=[O:14])[CH:26]=2)[N:21]=[C:20]([NH:30][CH3:31])[N:19]=1)[CH3:16]
Reactant: CCOc1nc(NC)nc2ccc(C=O)cc12
Reactant: Cc1ccsc1CNC1=NC(=O)CS1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOc1nc(NC)nc2ccc(C=C3SC(NCc4sccc4C)=NC3=O)cc12
Temperature: 150 °C

Procedure:
To a suspension of 2-[(3-methyl-thiophen-2-ylmethyl)-amino]-thiazol-4-one (36.2. mg, 0.16 mmole), and 4-ethoxy-2-methylamino-quinazoline-6-carbaldehyde (example 12f, 45.5 mg, 0.20 mmole) in 2 mL of toluene in a microwave tube were added benzoic acid (2.0 mg, 0.016 mmole) and piperidine (1.5 mg, 0.02 mmole). The reaction mixture was heated to 150° C. with microwave for 45 min. The reaction mixture was then cooled to r.t. and the solid was filtered off, washed with toluene, MeOH and ether to give 5-(4-ethoxy-2-methylamino-quinazolin-6-ylmethylene)-2-[(3-methyl-thiophen-2-ylmethyl)-amino]-thiazol-4-one as a brown solid: 56.5 mg (80.4%), MS: m/e 440 (MH+).
Reaction SMILES: [O:1]=[O+][O-].CSC.[CH3:7][C:8]12[O:22][C@H:9]1[CH2:10][C@@H:11](/[C:14](/C)=[CH:15]\CC=C(C)C)[CH2:12][CH2:13]2>C(Cl)Cl>[CH3:7][C:8]12[O:22][CH:9]1[CH2:10][CH:11]([C:14](=[O:1])[CH3:15])[CH2:12][CH2:13]2
Reactant: O=[O+][O-]
Reactant: CC(C)=CC/C=C(/C)[C@H]1CCC2(C)O[C@H]2C1
Solvent: CSC
Solvent: ClCCl
Product: CC(=O)C1CCC2(C)OC2C1

Procedure:
Compounds 8 and 9 were deoxygenated after the procedure of Delay and Ohloff, supra. These compounds dexoygenated (FIG. 1) individually or as a mixture, produced a single new compound that coeluted with 6 and matched the MS of synthetic 6. Isolated components in ca. 100 μl of CH2Cl2 were ozonized by addition of 100 μl of O3 -saturated CH2Cl2 at -78° C. (8341 Matheson Laboratory Ozonator), and ozonides were cleaved with methyl sulfide (30 μl; 40 μl/μl CH2Cl2). Compounds 12 and 13 (1-methyl-4-acetyl-1,2-epoxycyclohexane) were synthesized by standard methods and structurally verified by spectral comparisons to published values for these isomers. Ozonolysis of compounds 8 and 9 together produced ozonides 12 and 13 (FIG. 1) in approximately the same ratio as the ratio of 8:9 in airborne-trapped samples. Thus, compound 8 is trans-(Z)-1-methyl-4-(1,5-dimethyl-1,4-hexadienyl)-1,2-epoxycyclohexane. Deoxygenation of isolated 9 (>80% purity) produced a single compound having a GC-retention time and MS identical to synthetic 6 (FIG. 1). Ozonolysis of isolated 9 produced 13, but did not produce 12. Thus, component 9 is cis-(Z)-1-methyl-4-(1,5-dimethyl-1,4-hexadienyl)-1,2-epoxycyclohexane.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=O)[C:4]1=[O:14])[CH3:2].[N+:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[C-:16]>>[CH2:1]([N:3]1[C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:16]=[N:15][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]2[C:4]1=[O:14])[CH3:2]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CCn1c(=O)c(=O)[nH]c2cccnc21
Product: CCOC(=O)c1ncn2c1c(=O)n(CC)c1ncccc12

Procedure:
Ethyl 5-ethyl-4,5-dihydro-4-oxo-imidazo(1,5-a)pyrido(2,3-e)pyrazine-3-carboxylate was prepared from 4-ethyl-1,2,3,4-tetrahydro-2,3-dioxo-pyrido(2,3-e)pyrazine and ethyl isocyanoacetate. M.p. 215.5°-216.8° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f19) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.