Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[N:3]=1.[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)=[CH2:18].C([N:29](CC)C(C)C)(C)C.N>O1CCCC1>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([CH3:16])=[C:9]([C:4]2[N:5]=[C:6]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([CH:17]=[CH2:18])=[CH:20][CH:21]=3)[N:7]=[C:2]([NH2:29])[N:3]=2)[CH:14]=1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)n1
Reactant: C=Cc1ccc(N)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: N
Solvent: C1CCOC1
Product: C=Cc1ccc(Nc2nc(N)nc(-c3cc(Cl)ccc3C)n2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
A mixture of 2,4-dichloro-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine (500 mg, 1.8 mmol), 4-vinylphenylamine (228 mg, 1.9 mmol), tetrahydrofuran (20 ml), and N,N-diisopropylethylamine (0.63 ml, 3.6 mmol) was stirred for 2 hours. The mixture was transferred to a pressure bottle and chilled to −78° C. A slow stream of ammonia gas was passed into the mixture for 2 minutes and the bottle was sealed. After stirring at room temperature for 60 hours, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3) to provide the title compound (260 mg, 41% yield). 1H NMR (acetone-d6) 8.78 (br s, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.88 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.6 Hz, 2H), 7.39 (dd, J=2.4 Hz, J=8.2 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H), 6.74 (dd, J=11.0 Hz, J=17.6 Hz, 1H), 6.64 (br s, 1H), 5.73 (dd, J=1.0 Hz, J=17.6 Hz, 1H), 5.15 (dd, J=1.0 Hz, J=11.0 Hz, 1H), 2.61 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([CH:8]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:9][C:10](OCC)=[O:11])=O)=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>C(O)C>[F:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]2[CH:8]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH2:9][C:10](=[O:11])[NH:24][N:25]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)CC(C(=O)c1ccc(F)cc1)c1ccncc1
Solvent: O
Solvent: CCO
Product: O=C1CC(c2ccncc2)C(c2ccc(F)cc2)=NN1

Procedure:
A solution of ethyl 3-(4-fluorobenzoyl)-3-(4-pyridyl)-propionate (1.0 g, 3.32 mmol) and hydrazine monohydrate (1 ml, 20.6 mmol) in ethanol (1 ml) was refluxed for 2.5 h. The solvent and hydrazine monohydrate were evaporated. The remainder was taken up in n-butanol and the mixture was heated at reflux for 45 min. Evaporation was followed by column chromatography on silica gel (3-7.5% methanol/dichloromethane) to provide the title compound. MS (m/z): 270.2 (M+H)+; C15H12FN3O requir. 269.3.
Reaction SMILES: C([C:3]1([C:10](=O)[CH2:11][CH3:12])[CH2:8][NH:7][C:6](=[O:9])[CH:5]=[CH:4]1)C.Cl.[CH3:15][O:16][NH2:17].N1C=CC=[CH:20][CH:19]=1>CCO>[CH2:19]([C:8]1[NH:7][C:6](=[O:9])[CH:5]=[CH:4][C:3]=1[C:10](=[N:17][O:16][CH3:15])[CH2:11][CH3:12])[CH3:20]
Reactant: c1ccncc1
Reactant: CON
Reactant: CCC(=O)C1(CC)C=CC(=O)NC1
Agent: Cl
Solvent: CCO
Product: CCC(=NOC)c1ccc(=O)[nH]c1CC
Temperature: 25 °C

Procedure:
A mixture of 5-ethyl-5-(1-oxopropyl)-2-(1H)-pyridinone (1.0 g, 0.0056 mol), methoxyamine hydrochloride (0.53 g, 0.0063 mol) and pyridine (3.0 ml) were heated and stirred at reflux for 48 hours in EtOH (30 ml). The reaction mixture was allowed to cool to room temperature and concentrated to a viscous liquid on the rotary evaporator at 60° C. The residue solidified on cooling. The solid was triturated with H2O (50 ml) and then collected by filtration to give 0.91 g, m.pt. 120°-125° C. One recrystallization (EtOH-H2O) gave 0.55 g (47%), m.pt. 129°-131° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[Cl:21][C:22]1[CH:23]=[N:24][C:25]2[C:30](=O)[CH2:29][CH2:28][C:26]=2[CH:27]=1.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:30]3[C:25]4=[N:24][CH:23]=[C:22]([Cl:21])[CH:27]=[C:26]4[CH2:28][CH2:29]3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: O=C1CCc2cc(Cl)cnc21
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3CCc4cc(Cl)cnc43)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 3-chloro-5H-cyclopentapyridin-7(6H)-one using decaborane yielded (6S)-2-amino-6-(5-(3-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylamino)-2-fluorophenyl)-3,5,5,6-tetramethyl-5,6-dihydropyrimidin-4(3H)-one as a white foam. MS (ESI): m/z=430.3 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:18]=[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:28])=[C:9]([CH2:12][CH2:13][C:14]([O:16]C)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[OH-].[K+].C(O)C.O>C(O)(=O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[NH:7][C:8]=1[CH:18]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][C:20]1=[O:28])([OH:16])=[O:15]
Reactant: CCOC(=O)c1[nH]c(C=C2C(=O)Nc3ccccc32)c(CCC(=O)OC)c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1c(C(=O)O)[nH]c(C=C2C(=O)Nc3ccccc32)c1CCC(=O)O
Temperature: 25 °C
Yield: 95 %

Procedure:
4-(2-Methoxycarbonylethyl)-3-methyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid ethyl ester (81.7 g) ), 56.5 g of potassium hydroxide, 200 mL of ethanol and 200 mL of water were charged to a 1 L, 3 neck round bottom flask equipped with mechanical stirring and a thermometer. The mixture was stirred at 90° C. for 90 minutes, cooled to room temperature, and acidified with acetic acid until a precipitate formed. The precipitate was collected by vacuum filtration, washed with 50 mL of water and vacuum dried to give 69.1 g (85 %) of 4-(2-carboxyethyl)-3-methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid as a red solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.[CH2:14]([NH2:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:16]([CH2:14][CH3:15])[CH2:12]2
Reactant: CCN
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCN1Cc2cc(Br)ccc2C1=O

Procedure:
A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (0.5 g, 2 mmol) (AstaTech Cat. No. 27012), ethylamine in THF (1.0 mL, 2.0 M) (Aldrich Cat. No. 395072), and potassium carbonate (0.34 g, 2.4 mmol) in ethanol (5 mL) in a sealed vial was stirred at 40° C. overnight. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.28 g). LCMS (M+H)+=240.0/242.0.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.Cl[S:22]([C:25]1[N:26]=[CH:27][N:28]2[CH:32]=[CH:31][S:30][C:29]=12)(=[O:24])=[O:23].C(OCC)(=O)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][S:22]([C:25]2[N:26]=[CH:27][N:28]3[CH:32]=[CH:31][S:30][C:29]=23)(=[O:23])=[O:24])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(Cl)c1ncn2ccsc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(CNS(=O)(=O)c2ncn3ccsc23)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.1 %

Procedure:
4-Nitrobenzylamine (1.24 g) and 2 ml of diisopropylethylamine were added to a solution of 0.95 g of 7-chlorosulfonylimidazo[5,1-b]thiazole in 20 ml of DMF. The mixture was stirred at room temperature for 12 hr. Ethyl acetate was added to the reaction mixture. The mixture was washed with water and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resultant powder was collected by filtration to gives 1.07 g of 7-(4-nitrobenzylsulfamoyl)imidazo[5,1-b]thiazole.
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C([Li])CCC.CCCCCC.[Cl:22][C:23]1[CH:32]=[CH:31][C:26]([CH:27]=[CH:28][CH:29]=[O:30])=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>CCOCC>[Cl:8][C:6]1[CH:7]=[C:2]([CH:29](/[CH:28]=[CH:27]/[C:26]2[CH:25]=[CH:24][C:23]([Cl:22])=[CH:32][CH:31]=2)[OH:30])[C:3]([O:9][CH3:10])=[N:4][CH:5]=1
Reactant: COc1ncc(Cl)cc1Br
Reactant: O=CC=Cc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ncc(Cl)cc1C(O)/C=C/c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
A solution of 4.0 g of 3-bromo-5-chloro-2-methoxypyridine in 75 ml of anhydrous ether was cooled to -70° C. under nitrogen. The resulting slurry was stirred rapidly and there was added 12.0 ml of 1.65M n-butyllithium/hexane dropwise over a period of about 5 minutes while keeping the temperature below -70° C. The reaction mixture became homogeneous and, after 15 minutes, a solution of 3.0 g of 4-chlorocinnamaldehyde in 35 ml of ether was added dropwise while keeping the temperature below -60° C. The cold mixture was then poured into aqueous saturated sodium bicarbonate solution and the resulting mixture was extracted with ether. The ether layer was washed with aqueous saturated sodium chloride solution, dried over potassium carbonate and concentrated under reduced pressure to give a white solid. This solid was recrystallized from a mixture of ethyl acetate/hexane to give (E)-5-chloro-α-[2-(4-chlorophenyl)ethenyl]-2-methoxy-3-pyridinemethanol as white needles melting at about 135°-139.5° C.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[S:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].C(O)C>O>[OH:12][CH2:11][C:9]1[S:10][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(CO)s1
Reaction time: 0.67 h
Yield: 49.4 %

Procedure:
Sodium borohydride (0.24 g) was added to a mixture of 5-nitro-2-thiophenecarboxaldehyde (1.0 g) and ethanol (30 ml) at 0° C. and then this mixture was stirred at the same temperature for 40 minutes. The reaction mixture was poured into water and extracted with dichloromethane. The dichloromethane layer was washed with water and dried (MgSO4), after which the solvent was evaporated off, to yield 2-hydroxymethyl-5-nitrothiophene (0.5 g, 49%).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C[Si](C#N)(C)C.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([S:24](Cl)(=[O:26])=[O:25])=[C:19]([CH3:28])[C:18]=1[CH3:29].CO>C(#N)C>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([S:24]([NH:1][C@H:2]([C@@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])(=[O:25])=[O:26])=[C:19]([CH3:28])[C:18]=1[CH3:29]
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CO
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](C(=O)O)[C@H](C)O)c(C)c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a suspension of D-threonine (7.87 g, 66.1 mmol) in acetonitrile (100 mL) was added trimethylsilyl cyanide (40 mL, 298 mmol) and the resulting solution was heated to 80° C. After 1 h, 4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride (17.3 g, 69.4 mmol) was added and the heating was continued. After 12 h, the reaction mixture was cooled to room temperature. Methanol (15 mL) was added, and the organics were removed in vacuo. The residue was diluted with diethyl ether (300 mL) and after cooling the reaction mixture to 0° C., the pH was adjusted to 8 with 6 N aqueous sodium hydroxide solution. The organic layer was collected and the aqueous layer was extracted with diethyl ether. The aqueous layer was adjusted to pH 4 and again extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated to afford 2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3(S)-hydroxybutyric acid (22 g) as a brown foam which was used without further purification.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=O)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([CH:16]=[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1)[CH3:18])([O:14][CH3:15])=[O:13]>CO.C(Cl)(Cl)Cl>[C:12]([CH:16]=[C:17]([C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][NH:27][CH2:10][CH:8]([OH:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:23][CH:24]=1)[CH3:18])([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C=C(C)c1ccc(CCN)cc1
Reactant: O=CC(=O)c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C=C(C)c1ccc(CCNCC(O)c2ccccc2)cc1
Yield: 35.3 %

Procedure:
This was prepared in an identical manner to the compound described in Example 13 using phenylglyoxal monohydrate (1.50 g) and 2-{4-(2-carbomethoxy-1-methylethenyl) phenyl} ethanamine (2.19 g). The title compound (1.18 g) m.p. 120°-125° C. (benzene-hexane) was obtained after chromatography on Kieselgel 60 eluting with 1% methanol-chloroform. τ (CDCl3) 7.5 (3H, d, J=1.5 Hz), 7.5 (2H, m), 7.2 (6H, m), 6.3 (3H, s), 5.29 (1H, dd), 3.87 (1H, q, J=1.5 Hz), 2.85 (2H, d, J=9 Hz), 2.7 (5H, s), 2.6 (2H, d, J=9 Hz).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]1[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:22]=2[F:21])[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2ccccn2)c1F
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2ccccn2)c1F

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 2-fluoro-3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.68 min.; [M+H]+: 421.11 g/mol.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][Br:18]>CN(C)C=O.C(OCC)(=O)C>[BrH:18].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:10]1[CH:9]=[C:8]([C:11]#[N:12])[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2]1=[NH:1]
Reactant: Clc1cccc(CBr)c1
Reactant: N#Cc1cnc(N)c(C(N)=O)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Br
Product: N#Cc1cc(C(N)=O)c(=N)n(Cc2cccc(Cl)c2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a solution of 2-amino-5-cyanonicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 3-chlorobenzylbromide (0.29 g), and the mixture was stirred at 100° C. for 8 hr. The reaction mixture was diluted with ethyl acetate. The precipitate was filtered and washed with ethyl acetate. The obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (0.09 g).
Reaction SMILES: [C:1]1([N:7]=[CH:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23].[C:26]([O:30][CH3:31])(=[O:29])[CH:27]=[CH2:28]>C1(C)C(C)=CC=CC=1.O>[CH3:31][O:30][C:26]([CH:27]1[CH:8]([N:7]([C:22](=[O:24])[CH3:23])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH2:14][CH2:28]1)=[O:29]
Reactant: C=CC(=O)OC
Reactant: Cc1ccsc1C=Nc1ccccc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: COC(=O)C1CCc2ccsc2C1N(C(C)=O)c1ccccc1
Yield: 69.6 %

Procedure:
3-methylthiophene-2-aldehyde phenylimine (100 mg, 0.497 mmol) and triethylamine (0.21 ml, 1.49 mmol) were mixed in xylene, to which acetyl chloride (0.14 ml, 1.99 mmol) was added under ice cooling. Methyl acrylate (0.22 ml, 2.48 mmol) was added to the resultant mixture and stirred under reflux for 7 hours. After allowing the reaction mixture to cool, water was added and the mixture was extracted with ethyl acetate. After washing the liquid extract with an aqueous solution of sodium chloride and drying over sodium sulfate, the solvent was distilled off to obtain 300 mg of crude products. Purification by silica gel column chromatography gave 114 mg (yield: 83%) of N-acetyl-N-phenyl-7-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-6-carboxylic acid methyl ester. 1H-NMR spectra (chemical shift, ppm: in CDCl3): 1.00-1.50 (1H, m), 1.73, 1.86 (joined 3H, s×2), 1.85-2.20 (1H, m), 230-2.85 (2.5H), 2.95-3.20 (0.5H, m), 3.74, 3.82 (joined 3H, s×2), 6.63-6.85 (2H), 7.15-7.70 (5H).
Reaction SMILES: [SH:1][CH2:2][C:3]([CH2:5][SH:6])=[CH2:4].[CH3:7][C:8]([CH3:10])=O.[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[CH3:7][C:8]1([CH3:10])[S:6][CH2:5][C:3](=[CH2:4])[CH2:2][S:1]1
Reactant: CC(C)=O
Reactant: C=C(CS)CS
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: C=C1CSC(C)(C)SC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(Mercaptomethyl)-3-mercapto-1-propene (Z. Chem. 1975, 15, 302)(0.83 g, 6.9 mmoles) and acetone (0.51 mL) were placed in about 15 mL of dichloromethane. Then anhydrous aluminum chloride (0.32 g) was added portionwise over one minute at room temperature. The solution was stirred at room temperature for 30 minutes. The reaction was worked up by addition of 20 mL of water followed by extraction with dichloromethane. The extracts were dried and evaporated to give 0.89 g clear oil with a penetrating smell. The oil was chromatographed to give 400 mg (40%) of clear oil.
Reaction SMILES: [H-].[Na+].[Br-].[C:4]([O:8]C(C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)(C)(C)C.C([C:33]1[NH:37][C:36]([C:38]([O:40][CH3:41])=[O:39])=[CH:35][CH:34]=1)=O>C1COCC1>[CH:4]([C:34]1[CH:35]=[C:36]([C:38]([O:40][CH3:41])=[O:39])[NH:37][CH:33]=1)=[O:8]
Reactant: CC(C)(C)OC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C=O)[nH]1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C=O)c[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (5.74 g, 143.5 mmol; 60% in oil) in THF (200 mL) at 0° C. was added (tert-butoxycarbonylmethyl)triphenylphosphonium bromide (66 g, 143.5 mmol) as a solid in three portions. Cooling was removed and the mixture was stirred at rt for 30 min. It was then cooled to 0° C. and methyl 5-formyl-1H-pyrrole-2-carboxylate (16.9 g, 110.4 mmol) in THF (60 mL) was added dropwise over 40 min. The reaction mixture was allowed to warm to rt and was stirred overnight. Silica was added and the solvent was removed. The crude product was purified by flash chromatography (0-20% EtOAc/Heptane) to afford two isomeric compounds:
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[CH3:23][C:24]1([CH3:32])[CH:29]([NH:30][CH3:31])[CH2:28][CH2:27][NH:26][CH2:25]1.C(N(CC)CC)C>CS(C)=O.C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:27][CH2:28][CH:29]([NH:30][CH3:31])[C:24]([CH3:32])([CH3:23])[CH2:25]2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CNC1CCNCC1(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CNC1CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)CC1(C)C
Temperature: 70 °C

Procedure:
A suspension of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-quinoline-3-carboxylic acid (0.17 g, 0.55 mmol), 3,3-dimethyl-4-methylamino piperidine (0.15 g, 1.06 mmol) and triethylamine (1 g, 10 mmol) in a mixture of dimethylsulfoxide (10 ml) and acetonitrile (10 ml) was heated at 70° C. for 18 hr. Acetonitrile was distilled off, filtered to remove suspended impurities, diluted with water (5 ml). The precipitate thus separated was filtered, washed with water, dried and purified by silicagel column chromatography. Elute from a mixture of ethyl acetate and methanol furnished the required product. Yield 0.12 g (50%), m.p. 250° C. (decomp.), C22H29FN4O4, m/z 433 (M+1), PMR (DMSO-d6): 0.9 (m, 2H), 1.0 (m, 2H), 1.0 (s, 3H), 1.1 (s, 3H), 1.8-2.0 (m, 2H), 2.6 (s, 3H), 2.8-3.2 (m, 4H), 3.5 (s, 3H), 3.6 (s, 3H), 3.65 (m, 1H), 4.0 (m, 1H), 7.2 (bs, 2H, D2O exchangeable), 8.6 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16].[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:39])[CH2:35][C:36](=O)[CH3:37])=[CH:30][CH:29]=1)([O-:27])=[O:26]>O1CCCC1>[N+:25]([C:28]1[CH:29]=[CH:30][C:31]([C:34]([C:35]2[CH:21]([C:20]3[CH:23]=[CH:24][C:17]([C:15]#[N:16])=[CH:18][CH:19]=3)[NH:12][C:10](=[O:11])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=3)[C:36]=2[CH3:37])=[O:39])=[CH:32][CH:33]=1)([O-:27])=[O:26]
Reactant: CC(=O)CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: C1CCOC1
Product: CC1=C(C(=O)c2ccc([N+](=O)[O-])cc2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
9.85 g (48.27 mmol) N-[3-(trifluoromethyl)phenyl]urea, 6.33 g (48.27 mmol) 4-cyanobenzaldehyde, 10.00 g (48.27 mmol) 1-(4-nitrophenyl)butane-1,3-dione and 15 g polyphosphoric acid ethyl ester are suspended in 100 ml of tetrahydrofuran. The mixture is stirred at reflux for 20 hours. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][O:12][C:13]2[N:17]([CH3:18])[N:16]=[CH:15][CH:14]=2)=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:23][C:24]1([CH3:32])[CH2:31][C:29](=[O:30])[CH2:28][C:26](=[O:27])[CH2:25]1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:10]([CH2:11][O:12][C:13]2[N:17]([CH3:18])[N:16]=[CH:15][CH:14]=2)=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([CH:28]1[C:26](=[O:27])[CH2:25][C:24]([CH3:32])([CH3:23])[CH2:31][C:29]1=[O:30])=[O:6]
Reactant: Cn1nccc1OCc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1nccc1OCc1c(S(C)(=O)=O)ccc(C(=O)C2C(=O)CC(C)(C)CC2=O)c1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.0 g (2.9 mmol) of 2-chloro-3-[(1-methylpyrazol-5-yl)oxymethyl]-4-methylsulfonyl benzoic acid, 0.4 g (2.9 mmol) of dimedone and 0.72 g of N,N-dicyclohexylcarbodiimide in 50 ml of acetonitrile are heated at 40° C. for 4 h. After the reaction mixture has been stirred for 12 h at room temperature, 0.87 g of triethylamine and 0.57 g of trimethylsilylnitrile are added. Afterwards the reaction mixture is heated at 40° C. for 6 h, filtered, freed from the solvent under reduced pressure and the residue is purified over silica gel (eluent: toluene/tetrahydrofurane/acetic acid: 100/0/0→4/1/0.1). Yield: 0.25 g; m.p.82° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>C1COCC1>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][N:15]=[C:14]2[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2ncnc(C3C(=O)Nc4ccccc43)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12 %

Procedure:
A solution of oxindole (266 mg, 2.0 mmol) in THF (2 ml) was added dropwise under nitrogen to a stirred suspension of sodium hydride (80 mg, of a 60% dispersion in mineral oil, 2.0 mmol) in THF (1 ml). After stirring the resulting mixture for 15 minutes at ambient temperature, a solution of 4-chloro-6,7-dimethoxyquinazoline (449 mg, 2.0 mmol), (prepared as described for the starting material in Example 1), in THF (20 ml) was added. The mixture was stirred at ambient temperature for 2 hours, quenched with water and the volatiles removed by evaporation. The resulting solid was purified by flash chromatography eluting with methylene chloride/methanol (19/1). The purified product was triturated with methanol, collected by filtration, washed with ether and dried under vacuum to give 6,7-dimethoxy-4-(oxindol-3-yl)quinazoline (77 mg, 12%).