Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:27]=[C:28]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][O:5][C:30]1[CH:29]=[C:28]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:27]=[CH:26][C:31]=1[O:32][CH3:33]
Reactant: Cc1cccc(C)c1CO
Reactant: CCOC(=O)Cc1ccc(OC)c(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)Cc1ccc(OC)c(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2,6-Dimethylbenzyl alcohol (3.23 g, 23.7 mmol) and diisopropyl azodicarboxylate (DIAD, 5.23 g, 25.9 mmol) in THF (20 ml) was added drop wise to a solution of Ethyl 2-(3-Hydroxy-4-methoxyphenyl)acetate (Step A, 5.48 g, 26.12 mmol) and triphenylphosphine (6.79 g, 25.9 mmol) in THF (100 ml) at 0° C. The reaction mixture was stirred at room temperature for 4 hours, diluted with ether and washed with water and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([N:5](C)[C:6](=O)OCC)[CH3:4].C(O)C.[OH-].[K+].[ClH:19]>O>[ClH:19].[F:1][C:2]([F:13])([F:12])[CH:3]([NH:5][CH3:6])[CH3:4]
Reactant: CCOC(=O)N(C)C(C)C(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNC(C)C(F)(F)F
Temperature: 40 °C
Reaction time: 66 h

Procedure:
A mixture of 1000 mg of ethyl N-(2,2,2-trifluoro-1-methylethyl)-N-methylcarbamate, 20 ml of ethanol and 20 ml of water is admixed with 1070 mg of powdered potassium hydroxide and the mixture is stirred at 40° C. for 66 hours. The reaction mixture is then diluted with water and extracted with three times 20 ml of a mixture consisting of equal parts of methylene chloride and diethyl ether. The combined organic phases are dried over sodium sulphate and then concentrated under slightly reduced pressure at room temperature. The solution obtained is admixed with ethereal hydrochloric acid, with ice cooling, and is stirred at room temperature for 60 hours. Concentration under reduced pressure gives 280 mg of N-(2,2,2-trifluoro-1-methylethyl)-N-methylamine hydrochloride. The yield was calculated accordingly to be 34% of theory.
Reaction SMILES: [NH2:1][CH:2]1[C:16](=[O:17])[N:4]2[C:5]([C:13]([OH:15])=[O:14])=[C:6]([CH2:9][N:10]=[N+:11]=[N-:12])[CH2:7][S:8][C@H:3]12.[C:18](=[O:21])(O)[O-:19].[Na+]>O.C(O)(C)(C)C>[N:10]([CH2:9][C:6]1[CH2:7][S:8][C@@H:3]2[CH:2]([NH:1][C:18]([O:19][C:6]([CH3:9])([CH3:7])[CH3:5])=[O:21])[C:16](=[O:17])[N:4]2[C:5]=1[C:13]([OH:15])=[O:14])=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12
Temperature: 25 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
The cephalosporin starting material may be obtained as follows: 7-Amino-3-azidomethylceph-3-em-4-carboxylic acid (170 g.) was suspended by stirring in water (750 ml.) and sodium bicarbonate (60 g.) added carefully, followed by t-butanol (750 ml.). Bis(O-t-butyl)carbonic anhydride (170 ml.) dissolved in t-butanol (375 ml.) was added and the mixture left to stir at ambient temperature; further portions of reagent (20 ml.) in t-butanol (40 ml.) were added after 24 and 48 hours. After 72 hours, t-butanol was removed by evaporation and the aqueous residue, diluted with water to 21°, was cooled in ice. The pH was reduced to 3 with concentrated hydrochloric acid, and the precipitate filtered, and washed free of acid. After drying under vacuum, the crude product was extracted successively with 500 ml. and two 400 ml. portions of acetonitrile. The combined extracts were evaporated to a small volume and filtered to give 3-azidomethyl-7-t-butoxycarbonylaminoceph-3-em-4-carboxylic acid (84 g.), having the following n.m.r. in solvent A: 1.4(s, 9H); 3.5(d, 2H); 4.2(d, 2H); 5.0(d, 1H); 5.4(d, 1H).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]2([CH2:14][CH2:13][C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([N:15]([CH3:17])[CH3:16])[CH2:11][CH2:10]2)[CH2:6][CH2:5]1)C=C>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.C1(C)C=CC=CC=1>[CH3:16][N:15]([CH3:17])[C:12]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:11][CH2:10][C:7]2([CH2:6][CH2:5][NH:4][CH2:9][CH2:8]2)[CH2:14][CH2:13]1
Reactant: C=CCN1CCC2(CC1)CCC(c1ccccc1)(N(C)C)CC2
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CN(C)C1(c2ccccc2)CCC2(CCNCC2)CC1

Procedure:
Grubb's catalyst (0.012 g, 0.013 mmol) was added to a solution of 3-allyl-N,N-dimethyl-9-phenyl-3-azaspiro[5.5]undecan-9-amine (0.09 g, 0.266 mmol) in dry toluene (5 ml) at room temperature and the mixture was refluxed for 2 h. The sediment was filtered off over celite and rewashed with ethyl acetate. The filtrate was concentrated to small volume under vacuum and the crude product used in the next stage without further purification. Yield: quantitative
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[CH:19](NC(C)C)(C)C.[Li].CO[C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>C1COCC1>[CH3:19][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][C:3]2([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:2]2)=[CH:31][CH:30]=1
Reactant: CC(C)NC(C)C
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Li]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccc(C)cc2)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of the product from STEP 1 (5.0 g, 19.5 mmol) in 20 ml THF was added to a solution of lithium diisopropylamine (11.7 ml, 23.4 mmol, 2M solution) in 25 ml THF dropwise at −20° C. The resulting mixture was stirred at 0° C. for 15 min and allowed to warm to room temperature. After 1 h, the reaction was cooled to −20° C. and treated, dropwise, with a solution of 4-methoxy-benzyl chloride (3.1 g, 19.5 mmol) in 20 ml THF. The resulting mixture was stirred at −10° C. for 1 h, and warmed to 35° C. After 1 h, the reaction was quenched with 25 ml saturated aqueous NH4Cl solution. The product was extracted with ethyl acetate (2×100 ml). The aqueous layer was extracted with ethyl acetate. The combined layers were were washed with H2O, brine, and then dried with Na2SO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=1/4) to yield a viscous oil in 5.2 g. The 1H NMR spectrum of the product was consistent for the proposed structure.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22]C)[CH:18]=2)[CH2:13]1)[CH3:2].Cl.[N:25]1([CH2:32][CH2:33][O:34][C:35]2[CH:43]=[CH:42][C:38]([C:39](Cl)=O)=[CH:37][CH:36]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:32][CH2:33][O:34][C:35]2[CH:43]=[CH:42][C:38]([CH2:39][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:37][CH:36]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCCC2)cc1
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Product: Oc1ccc2c(c1)CCC(c1ccc(O)cc1NCCCc1ccc(OCCN3CCCCCC3)cc1)C2
Yield: 59 %

Procedure:
Synthesized from ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (400 mg) and 4-(2-azepan-1-ylethoxy)benzoyl chloride hydrochloride (530 mg) according to an analogous synthetic method to Example 187, the title compound (390 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:26][C:27]([CH3:36])=[CH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1>C1(C)C=CC=CC=1.O>[CH3:12][C:4]1[C:3]([CH3:13])=[C:2]([O:1][CH2:26][C:27]([CH3:36])=[CH:28][C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[NH:9][CH:10]=[O:11]
Reactant: CC(=Cc1ccc(C)cc1)CCl
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=Cc1ccc(C)cc1)COc1cc(C)c(NC=O)c(C)c1C
Temperature: 50 °C
Reaction time: 14 h
Yield: 78.9 %

Procedure:
To a mixture of N-(4-hydroxy-2,3,6-trimethylphenyl) formamide (660.4 g), potassium carbonate (1019 g) and dimethylformamide (3302 ml) was added a solution of 1-(3-chloro-2-methyl-1-propenyl)-4-methylbenzene (755 g) in toluene (675 ml), and the mixture was stirred at 50° C. for 14 hr. Water (5944 ml) was then added thereto and the mixture was stirred at 30° C. for 1 hr. The precipitated crystals were collected by filtration and washed with water and isopropylether to give the title compound (940 g, yield 74.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]#[C-:18])=[CH:13][CH:12]=1)([O-:10])=[O:9].[CH:19]([C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[C:23]([O:25]C)=O)=O.Cl(O)(=O)(=O)=O.CC(C)([O-])C.[K+]>CO>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:18]3[N:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]4=[N:1][C:19]=3[C:21]3[C:22](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:23]2=[O:25])=[CH:15][CH:16]=1)([O-:10])=[O:9]
Reactant: COC(=O)c1ccccc1C=O
Reactant: Nc1ccccn1
Reactant: [C-]#[N+]c1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Product: O=c1c2ccccc2c2nc3ccccn3c2n1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A mixture of 2-aminopyridine (I1) (1.0 equiv., 5.30 mmol, 0.500 g), 4-nitrophenyl isocyanide (I2) (1.1 equiv., 5.80 mmol, 0.870 g), methyl 2-formylbenzoate (13) (1.1 equiv., 5.80 mmol, 0.960 g) and perchloric acid (0.1 equiv., 0.53 mmol, 0.053 g) in methanol (25 ml) was stirred at room temperature until no starting material was left. The progress of the reaction was monitored by LCMS. Potassium tert-butoxide (1.1 equiv., 5.80 mmol, 0.660 g) was added and the reaction mixture was further stirred at room temperature for 2 h. The resulting precipitate was filtered off and washed with isopropanol and isopropyl ether to give 6-(4-nitrophenyl)-pyrido[2′,1′:2,3]imidazo-[4,5-c]isoquinolin-5(6H)-one (1) (1.20 g, yield=63%, purity (LC)=95%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([Cl:62])[C:57]=2[F:63])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([Cl:62])[C:57]=2[F:63])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(Cl)c2F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(Cl)c2F)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.2 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 96 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(3-chloro-2-fluoro-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 4 h at rt, the reaction mixture was diluted with 50 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 103 mg white solid (73%). MS (EI) 464.1 (M)+.
Reaction SMILES: [N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:15](=[O:25])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH:23]=C)[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.I([O-])(=O)(=O)=[O:33].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:15](=[O:25])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH:23]=[O:33])[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cccc2cc([C@H](C)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(C=O)c2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of ethyl 2-(4-methyl-N-phenyl-2-vinylnicotinamido)acetate (8) (767 mg, 1.88 mmol) in 1,4-dioxane-H2O (3:1, 20 mL) at RT, osmium tetraoxide (2.5% wt in H2O, 0.5 mL, 0.05 mmol) was added and the resulting mixture was stirred at RT for 30 min. To this mixture, sodium periodate (1.21 g, 5.53 mmol) was added and the resulting mixture was stirred at RT for 30 h. The mixture was filtered through celite and the filtrate was extracted with ethyl acetate (100 mL×2). The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the product, (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-1-oxo-2-phenyl-1,2-dihydroisoquinoline-8-carbaldehyde (15) (730 mg, 95% yield) as a yellowish solid. ESI-MS m/z: 411.2 [M+H]+.
Reaction SMILES: Cl.C([N:9]1[CH2:18][CH2:17][C:16]2[N:15]=[C:14]([Cl:19])[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:12][C:11]=2[CH2:10]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCl.CO>[ClH:19].[Cl:19][C:14]1[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:12][C:11]2[CH2:10][NH:9][CH2:18][CH2:17][C:16]=2[N:15]=1
Reactant: CCOC(=O)c1cc2c(nc1Cl)CCN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1cc2c(nc1Cl)CCNC2
Temperature: 40 °C

Procedure:
A solution of the product from Step A above (0.095 mg, 0.287 mmol) in 10 mL of dichloromethane was treated with 1-chloroethyl chloroformate (0.050 g; 0.344 mmol), and the mixture was warmed at reflux temperature overnight. The reaction was concentrated under reduced pressure to afford a yellow oil, which was dissolved in 10 mL of methanol. The solution was heated at 40° C. for 2 h, cooled to room temperature and concentrated in vacuo. To the yellow solid was added diisopropyl ether. The pale yellow crystals were collected by filtration and recrystallized from ethanol to afford the title compound. LC/MS: 240.0 (M+1)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=C)[N:16]=3)=[C:9]([F:30])[CH:8]=1.[O:31]=[O+][O-]>C(Cl)Cl.CO>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:31])[N:16]=3)=[C:9]([F:30])[CH:8]=1
Reactant: C=C(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylvinyl)thiazolo[5,4-b]pyridine (2.66 g, 6.4 mmol) in 3:1 CH2Cl2/MeOH (128 mL) at −78° C. was treated with ozone for 15 min. The solution was then sparged with O2, dimethyl sulfide (18 mL) was added, and the bath was allowed to expire. The resulting solution was stirred at 25° C. for 3 d and then concentrated in vacuo. This residue was taken up in CH2Cl2 (400 mL) and sequentially washed with water and brine, then concentrated in vacuo to provide (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)thiazolo[5,4-b]pyridine-5-yl)(phenyl)methanone as a yellow solid. MS (ESI) m/z: Calculated: 420.1; Observed: 421.1 (M++1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5]Br.[Mg].[Br:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]#N)[CH:10]=1.Cl.[OH-:18].[NH4+]>CCOCC>[Br:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15](=[O:18])[CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:10]=1
Reactant: [OH-]
Reactant: N#Cc1cc(Br)ccn1
Reactant: COCCCBr
Agent: Cl
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COCCCC(=O)c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The Grignard reagent prepared from 20 mmol of 3-methoxypropylbromide and 22 mmol of magnesium in dry ether (100 ml) is added slowly to 30 mmol of 4-bromo-2-cyanopyridine in 80 ml of dry ether under argon. The reactions mixture is stirred for 12 hours at room temperature and 5M HCl is added. The mixture is made alkaline with 25% aqueous ammonium hydroxide solution and the layers are separated. The organic layer is dried over sodium sulphate and evaporated. Flash chromatography (SiO2 60 F) of the residue provides the title compound which is identified on the basis of the Rf value.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:7])[CH2:4][C:5]#[N:6].C([O:10][C:11](=O)[CH2:12][C:13]([CH3:15])=O)C.CN>O.S(=O)(=O)(O)O>[CH3:1][N:2]1[C:11]([OH:10])=[CH:12][C:13]([CH3:15])=[C:4]([C:5]#[N:6])[C:3]1=[O:7]
Reactant: CCOC(=O)CC(C)=O
Reactant: CNC(=O)CC#N
Agent: CN
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(O)n(C)c(=O)c1C#N
Temperature: 90 °C
Yield: 95 %

Procedure:
250 parts of water, 98 parts of N-methylcyanoacetamide and 169 parts of acetoacetic acid ethyl ester are initially placed in an autoclave, 40 parts of gaseous monomethylamine are injected, while stirring, and the reaction mixture is then heated at 90° C. for 3 hours, a pressure of 2.9 bars being generated. The batch is diluted with 400 parts of water, 80 parts of 61% strength sulphuric acid are added at 30°-35° C., the batch is cooled to 20° C. and the precipitate which has been formed is filtered off. 155.8 parts (95% of theory) of 1,4-dimethyl-3-cyano-6-hydroxypyrid-2-one with a melting point of 285° C. are obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:3][CH2:4][CH2:5][NH2:6].[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23].[NH:34]([C:38]1[S:39][CH:40]=[C:41]([CH2:43][S:44][CH2:45][CH2:46][NH2:47])[N:42]=1)[C:35]([NH2:37])=[NH:36]>C(OCC)(=O)C.CO>[NH:34]([C:38]1[S:39][CH:40]=[C:41]([CH2:43][S:44][CH2:45][CH2:46][NH:47][C:22]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH2:7][CH2:8][CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH3:1])=[O:23])[N:42]=1)[C:35]([NH2:37])=[NH:36]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(CCCN)CCC(c1ccccc1)c1ccccn1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(CCCNC(=O)NCCSCc1csc(NC(=N)N)n1)CCC(c1ccccc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.85 g (3 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,3-propanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.75 g (3.2 mmol) of 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as starting materials. Working up by chromatography (eluant: chloroform/methanol 9+1) analogously to Example 63 yields the purified title compound in the form of an oil; MS (+FAB method): m/z (rel. int. [%])=541 ([M+H]+, 2), 196 (100); IR (KBr): 1650 cm-1 (C=O). For analytical purposes a sample is converted into the maleic acid salt and recrystallised from ether/ethanol; m.p.: 95°-98° C.
Reaction SMILES: C(O[C:4]([C:6]1[N:10]=[CH:9][N:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[C:21]([F:24])([F:23])[F:22])[NH:17][C:16](=[O:25])[N:15]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:14]3=[O:31])[N:7]=1)=[O:5])C.[CH3:32][NH2:33]>CO.C(O)C>[CH3:32][NH:33][C:4]([C:6]1[N:10]=[CH:9][N:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[C:21]([F:22])([F:24])[F:23])[NH:17][C:16](=[O:25])[N:15]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[C:14]3=[O:31])[N:7]=1)=[O:5]
Reactant: CN
Reactant: CCOC(=O)c1ncn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)n1
Solvent: CO
Solvent: CCO
Product: CNC(=O)c1ncn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 22 h
Yield: 86 %

Procedure:
A solution of 150 mg (0.324 mmol) of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-[1,2,4]triazole-3-carboxylic acid ethyl ester in 0.8 ml of methanol is treated with 0.40 ml (3.24 mmol) of a ˜8M methylamine solution in ethanol. The mixture is stirred for 22 hours at room temperature and then concentrated in vacuo. The crude product is taken up in water and the pH of the solution is adjusted to 3 with 1 M aqueous HCl solution and the mixture is stirred for 3 hours at 0° C. The crystals are filtered, washed with cold water and dried in vacuo to give 124 mg (86%) of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-[1,2,4]triazole-3-carboxylic acid methylamide as white crystals, m.p. 257-260° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl-:1].[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][P+:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Product: Cc1oc(-c2ccccc2)nc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]

Procedure:
4-Chloromethyl-5-methyl-2-phenyloxazole and triphenylphosphine were reacted in the same manner as in Reference Example 7 to yield (5-methyl-2-phenyl-4-oxazolylmethyl)triphenylphosphonium chloride. Melting point 277°-278° C.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13]3[NH:21][C:20]4[CH2:19][CH2:18][NH:17][C:16](=[O:22])[C:15]=4[CH:14]=3)[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1SC.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CCOCC>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13]3[NH:21][C:20]4[CH2:19][CH2:18][NH:17][C:16](=[O:22])[C:15]=4[CH:14]=3)[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CSc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2c(=O)n1C
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: Cn1c(Nc2ccccc2)nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2c1=O
Temperature: 150 °C
Yield: 4.2 %

Procedure:
A suspension of 3-methyl-2-(methylthio)-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinazolin-4(3H)-one (34.0 mg, 0.100 mmol), aniline (0.5 mL, 5.49 mmol), and HCl (conc.) (20 μl, 0.240 mmol) was heated by microwave in a sealed flask at 150° C. for 10 min. The mixture was diluted with Et2O (5 mL) and the precipitated solid was collected by vacuum filtration, washed with Et2O (5 mL), and dried in vacuo. Purification of the residue by revered-phase HPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm), 35 mL/min, 5-100% ACN/H2O+0.1% TFA) followed by supercritical-fluid chromatography (Chiralcel OD-H (250×21 mm, 5 μm), 50% liquid CO2/50% MeOH, 55 mL/min) afforded 3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-2-(phenylamino)quinazolin-4(3H)-one (1.6 mg, 4.15 μmol) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.98-9.15 (1H, m), 7.95-8.04 (1H, m), 7.81 (1H, d, J=7.6 Hz), 7.41-7.53 (5H, m), 7.23-7.33 (1H, m), 7.08-7.18 (1H, m), 6.89 (1H, s), 6.82 (1H, s), 3.61 (3H, s), 3.28 (2H, obsc. m), 2.33 (2H, m). m/z (ESI, +ve) 386.1 (M+H)+.