Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]1[O:31][C:30]2[C:4](=[CH:5][C:6]3[O:11][CH2:10][C@H:9]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]4[CH:28]=[CH:27][C:21]5[CH:22]=[CH:23][C:24](=[O:26])[O:25][C:20]=5[CH:19]=4)[O:8][C:7]=3[CH:29]=2)[O:3]1.I[CH2:33][CH3:34].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:2]1[O:31][C:30]2[C:4](=[CH:5][C:6]3[O:11][CH2:10][C@H:9]([CH2:12][N:13]([CH2:33][CH3:34])[CH2:14][CH2:15][CH2:16][O:17][C:18]4[CH:28]=[CH:27][C:21]5[CH:22]=[CH:23][C:24](=[O:26])[O:25][C:20]=5[CH:19]=4)[O:8][C:7]=3[CH:29]=2)[O:3]1
Reactant: CCI
Reactant: O=c1ccc2ccc(OCCCNC[C@H]3COc4cc5c(cc4O3)OCO5)cc2o1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCCOc1ccc2ccc(=O)oc2c1)C[C@H]1COc2cc3c(cc2O1)OCO3
Temperature: 60 °C
Yield: 43.8 %

Procedure:
(S)-7-[3-[[(2,3-Dihydro-6,7-methylenedioxy-1,4-benzodioxin-2-yl)methyl]amino]propoxy]-2H-1-benzopyran-2-one hydrochloride (0.60 g, 1.3 mmole), iodoethane (0.16 ml, 2.0 mmole) and diisopropylethylamine (2.26 ml, 13.0 mmole) were combined in 50 ml of DMF and heated at 60° C. for 2 days under a nitrogen atmosphere. The solvent was then removed in vacuum and the residue was dissolved in dichloromethane and washed with an equal volume of aqueous saturated sodium bicarbonate. The aqueous portion was back-extracted with dichloromethane and the combined organic portions were washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using dichloromethane as eluant. The product-containing fractions were combined and concentrated in vacuum, and the residue redissolved in methanol and acidified with 4N HCl/isopropanol to pH<3 in an ice bath. The mixture was diluted with isopropanol to precipitate a white solid, which was recrystallized from methanol to give 0.25 g of the title compound as the monohydrochloride, m.p. 209° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[C:11](Cl)(=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14].[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:14][CH:13]([CH3:15])[CH2:12][C:11]([C:3]1[S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1])=[O:16]
Reactant: Cc1csc2ccccc12
Reactant: CC(C)CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: Cc1c(C(=O)CC(C)C)sc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a mixture of 3-methyl-1-benzothiophene (5.00 g), isovaleryl chloride (4.52 mL) and nitromethane (50 mL) was added aluminum (III) chloride (8.98 g) at 0° C., and the mixture was stirred at 0° C. for 30 min then at room temperature for 4 hr. The reaction mixture was poured into ice-cooled water, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19, volume ratio) to give the title object compound (7.72 g, 99%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2C(=O)[O:11][N:10]=[C:9]2[C:14]2[C:15]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:21])=[N:16][O:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[OH-:29].[Na+]>C(O)C.O>[NH:8]([C:9]([N:19]([C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21])[C:15]1[C:14]([C:9](=[N:10][OH:11])[NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:18][O:17][N:16]=1)=[O:29])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1.[NH:22]([C:20]([NH:19][C:15]1[C:14]([C:9](=[N:10][OH:11])[NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:18][O:17][N:16]=1)=[O:21])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: [OH-]
Reactant: O=C(Nc1ccccc1)Nc1nonc1-c1noc(=O)n1-c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccccc1)N(C(=O)Nc1ccccc1)c1nonc1C(=NO)Nc1cccc(Cl)c1
Product: O=C(Nc1ccccc1)Nc1nonc1C(=NO)Nc1cccc(Cl)c1
Reaction time: 0.5 h
Yield: 38 %

Procedure:
A solution of N-{4-[4-(3-chlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-N′-phenylurea (17 mg, 43 μmol) in ethanol (1.5 mL) was treated with 2.0 M sodium hydroxide in water (0.3 mL) and stirred for 30 min. Purification of the crude reaction mixture by preparative HPLC gave the desired product 4-[(anilinocarbonyl)amino]-N-(3-chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (6 mg, 38%). LCMS for C16H14ClN6O3 (M+H)+: m/z=373.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl.O>[CH3:1][C:2]1([CH3:9])[O:6][C@@H:5]([CH2:7][O:8][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@H](CO)O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)OC[C@H](COS(C)(=O)=O)O1
Reaction time: 8 h
Yield: 100.6 %

Procedure:
((S)-2,2-Dimethyl-[1,3]dioxolan-4-yl)-methanol (2.0 g, 15.13 mmol) and triethylamine (2.53 ml, 18.16 mmol) were dissolved in dichloromethane (60 mL) followed by the addition of methanesulfonyl chloride (1.35 ml, 17.40 mmol) at 0° C. The reaction was warmed to ambinet temperature, stirred overnight, and then diluted with water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine and dried over sodium sulfate. Removal of solvents gave methanesulfonic acid (R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester as an oil (3.2 g, 100%).
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.C[O:9][C:10]1[C:11](=[O:26])[CH:12]=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:15]=1>C(#N)C.O>[OH:9][C:10]1[C:11](=[O:26])[CH:12]=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)[CH:15]=1
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)ncc1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=c1cnn(-c2cccc(C(F)(F)F)c2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 180.7 %

Procedure:
To a solution of sodium iodide (0.513 g) in acetonitrile (4 mL) was added chlorotrimethylsilane (0.434 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 min, a solution of 5-methoxy-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.185 g) in acetonitrile (6 mL) was added at room temperature. The reaction mixture was heated under reflux for 3 hr, cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate/hexane-methanol/ethyl acetate) to give the title compound (0.317 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6](O)[CH2:7][O:8][C:4]=2[CH:3]=1.C1(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:26]([CH:6]1[C:5]2[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=2[O:8][CH2:7]1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OC1COc2cc(Br)ccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC1COc2cc(Br)ccc21

Procedure:
In analogy to the procedures described for the preparation of intermediates A-2 [B] and A-2 [C], (rac)-6-bromo-2,3-dihydro-benzofuran-3-ol was treated with diphenylphosphoryl azide, DBU in toluene to give (rac)-3-azido-6-bromo-2,3-dihydro-benzofuran, which was subsequently reduced with triphenylphosphine in THF/water to yield the title compound as light yellow oil. MS: 213 (M+, 1Br).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[N:6]([CH3:12])[N:5]=1)([CH3:3])[CH3:2].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][C:46]=1[F:47])[O:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([CH:35]=[C:36]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])[N:37]=2)[N:34]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C(=O)C>[CH:41]1([C:39]([NH:38][C:36]2[N:37]=[C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:44]=[CH:45][C:46]([F:47])=[C:25]([NH:24][C:9]([C:7]5[N:6]([CH3:12])[N:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:8]=5)=[O:11])[CH:26]=4)=[N:34][N:33]3[CH:35]=2)=[O:40])[CH2:42][CH2:43]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: CC(C)c1cc(C(=O)O)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of 3-isopropyl-1-methyl-1H-pyrazole-5-carboxylic acid (144 mg, 0.86 mmol) in tetrahydrofuran (3.0 mL) were added N,N-dimethylformamide (30 μL, 0.39 mmol) and oxalyl chloride (75 μL, 0.86 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was added to a solution of N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) in N,N-dimethylacetamide (4.0 mL), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (216 mg, 74%) as a white powder.
Reaction SMILES: [CH2:1]1[C:11]2[N:10]3[C:12]4[CH:21]=[CH:20][N:19]=[CH:18][C:13]=4[C:14]4[CH2:15][CH2:16][CH:17]=[C:8]([C:9]=43)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH2:2]1.Br[CH2:23][CH:24]=[CH2:25].C(=O)(O)[O-].[Na+].CN(C)C=O>O>[CH2:25]([CH:3]1[CH2:4][C:5]2[CH:6]=[CH:7][C:8]3[C:9]4[N:10]([C:12]5[CH:21]=[CH:20][N:19]=[CH:18][C:13]=5[C:14]=4[CH2:15][CH2:16][CH:17]=3)[C:11]=2[CH2:1][CH2:2]1)[CH:24]=[CH2:23]
Reactant: C1=CC2=C(CCCC2)n2c3c(c4cnccc42)CCC=C13
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC1CCC2=C(C=CC3=CCCc4c3n2c2ccncc42)C1

Procedure:
A mixture of 3.3 g. of the product of Example 1, 1.45 g. of freshly distilled 3-bromopropene and 1.7 g. of sodium bicarbonate is stirred at room temperature, for 24 hours, in 50 ml. dimethylformamide. At the end of this period, the mixture is poured into water, extracted with ether, and the combined extracts are dried and stripped down. The residue is dissolved in benzene, and the resulting solution chromatographed through a column of neutral alumina. The oily residue obtained on stripping down the eluate is recrystallized from isopropyl alcohol to yield 3-allyl-1,2,3,4,8,9-hexahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine m.p. 112°-113°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[NH:17][CH3:18].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24](Cl)=[O:25]>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[N:17]([CH3:18])[C:24](=[O:25])[C:23]1[CH:22]=[C:21]([C:20]([F:35])([F:34])[F:19])[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=1
Reactant: CNc1cnccc1-c1cccc(OC)c1OC
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1cccc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1OC

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2,3-dimethoxy-phenyl)-pyridin-3-yl]-methyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 40:60) for the chromatographic purification. Light yellow solid (72%). MS (ESI): m/z=485.127 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].S(=O)(=O)(O)O.[I:18]I>O>[I:18][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[CH:1]([CH3:3])[CH3:2])[C:8]([OH:10])=[O:9]
Reactant: CC(C)c1ccc(C(=O)O)cc1
Reactant: II
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)c1ccc(C(=O)O)cc1I
Yield: 0.8 %

Procedure:
4-Isopropylbenzoic acid (4.26 g, 25.9 mmol), sulfuric acid (25 mL), and water (2 mL) was heated to 95° C. and iodine (14.42 g, 56.8 mmol) was slowly added portionwise. The reaction was maintained at this temperature for 48 h. The reaction was cooled, poured into ice and extracted with methylene chloride. The organic extracts were dried over sodium sulfate, filtered, concentrated and then purified by reverse phase HPLC (MeOH/water/TFA) to yield 3-iodo-4-isopropylbenzoic acid (60 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[F:46][C:47]([F:60])([F:59])[CH2:48][CH2:49][O:50][C:51]([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)=[O:52]>C(OCC)(=O)C>[F:60][C:47]([F:46])([F:59])[CH2:48][CH2:49][O:50][C:51]([N:53]1[CH2:54][CH2:55][N:56]([C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:57][CH2:58]1)=[O:52]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: O=C(OCCC(F)(F)F)N1CCNCC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: O=C(NCC(=O)N1CCN(C(=O)OCCC(F)(F)F)CC1)OCc1ccccc1
Reaction time: 48 h

Procedure:
To a solution of 842 mg N-Benzyloxycarbonyl glycine were added 2.0 ml N-ethylmorpholine, 1.32 g TOTU and 910 mg Piperazine-1-carboxylic acid 3,3,3-trifluoro-propyl ester. After stirring for 48 h the reaction mixture was diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl, saturated aqueous NaHCO3 and brine. The crude product obtained was used without further purification. Yield: 1.63 g.
Reaction SMILES: ClC(OCC)=O.[CH2:7]([O:9][C:10]([NH:12][CH2:13][C:14]([OH:16])=O)=[O:11])[CH3:8].C(N(CC)CC)C.[NH:24]([C:26]1[N:27]=[N:28][C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:30]([CH3:32])[N:31]=1)[NH2:25]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:7]([O:9][C:10]([NH:12][CH2:13][C:14]([NH:25][NH:24][C:26]1[N:27]=[N:28][C:29]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:30]([CH3:32])[N:31]=1)=[O:16])=[O:11])[CH3:8]
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Reactant: CCOC(=O)NCC(=O)O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCC(=O)NNc1nnc(-c2ccccc2)c(C)n1
Reaction time: 0.08 h
Yield: 33.4 %

Procedure:
A solution of ethyl chloroformate (3.689 g) in methylene chloride (10 ml) was added dropwise to a stirred solution of N-ethoxycarbonylglycine (4.998 g) and triethylamine (3.434 g) in methylene chloride (60 ml) under cooling in 5 minutes, and the stirring was continued for 5 minutes under cooling. To the solution of the mixed anhydride was added a solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3.417 g) in chloroform (40 ml) and reacted in a similar manner to that of Example 17-(1). The reaction mixture was washed with water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in ethanol (50 ml) and a solution of sodium hydroxide (1.6 g) in water (10 ml) was added dropwise to the solution with stirring under ice cooling in 5 minutes. After stirring for 30 minutes at room temperature, the solution was evaporated, and the residue was dissolved in a small amount of water. The solution was salted out and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and evaporated. The residue was dissolved in chloroform containing a small amount of ethanol and the solution was chromatographed on silica gel (50 g). The eluent with a mixture of chloroform and ethanol (30:1) gave a colorless solid of 3-[2-(N-ethoxycarbonylglycyl)hydrazino]-5-methyl-6-phenyl-1,2,4-triazine (1.872 g).
Reaction SMILES: C[N:2]1[CH2:11][C:10](C)(C)C2[C:4](=[CH:5]C(N)=CC=2)[CH2:3]1.Cl[C:16]1[N:21]=[C:20]2[N:22]([CH3:36])[C:23](=[O:35])[N:24]([C:27]3[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:34])[C:25](=[NH:26])[C:19]2=[CH:18][N:17]=1.ClC1N=C2NC(=O)[N:46]([C:49]3[C:54](Cl)=[CH:53][CH:52]=[CH:51][C:50]=3Cl)C(=N)C2=CN=1>>[Cl:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:34])[C:27]=1[N:24]1[C:25](=[NH:26])[C:19]2[C:20](=[N:21][C:16]([NH:46][C:49]3[CH:50]=[C:51]4[C:52](=[CH:53][CH:54]=3)[CH:3]([CH2:4][CH3:5])[NH:2][CH2:11][CH2:10]4)=[N:17][CH:18]=2)[N:22]([CH3:36])[C:23]1=[O:35]
Reactant: Cn1c(=O)n(-c2c(Cl)cccc2Cl)c(=N)c2cnc(Cl)nc21
Reactant: CN1Cc2cc(N)ccc2C(C)(C)C1
Reactant: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cccc1Cl
Product: CCC1NCCc2cc(Nc3ncc4c(=N)n(-c5c(Cl)cccc5Cl)c(=O)n(C)c4n3)ccc21

Procedure:
14 mg of 3-(2,6-dichlorophenyl)-7-(3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-isoquinolin]-6′-ylamino)-4-imino-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one was obtained as a white solid according to the same method as in Example 2, for which, however, tert-butyl 6′-amino-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-isoquinoline]-2′-carboxylate obtained in the reaction of Production Example 19-5) was used in place of 2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine in Example 2, and 7-chloro-3-(2,6-dichlorophenyl)-4-imino-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one obtained in Production Example 7 was used in place of 7-chloro-3-(2,6-dichlorophenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one. In addition, as a by-product, 30 mg of 3-(2,6-dichlorophenyl)-7-[(1-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]-4-imino-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one was obtained as a white solid. 3-(2,6-Dichlorophenyl)-7-(3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-isoquinolin]-6′-ylamino)-4-imino-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one:
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([NH2:17])[S:15][CH:16]=1.Br[CH2:19][CH2:20][F:21].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN1C(=O)CCC1>[F:21][CH2:20][CH2:19][NH:17][C:14]1[S:15][CH:16]=[C:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:2]=2)[N:13]=1
Reactant: FCCBr
Reactant: Nc1nc(-c2ccc3ccccc3c2)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: FCCNc1nc(-c2ccc3ccccc3c2)cs1
Temperature: 25 °C
Yield: 7.3 %

Procedure:
A mixture of 4-(naphthalen-2-yl)thiazol-2-amine hydrochloride (113 mg, 0.5 mmol), 1-bromo-2-fluoroethane (127 mg, 1 mmol), Cs2CO3 (326 mg, 1 mmol), and 15 mg KI in 2 mL of NMP was heated at 80 C for 20 min in a microwave reactor. After cooling to rt, the mixture was taken up to 50 mL EtOAc and washed with water (3×80 mL) and dried over MgSO4 and concentrated. The residue was chromatographed (hexane/EtOAc) to afford N-(2-fluoroethyl)-4-(naphthalen-2-yl)thiazol-2-amine as a white solid (10 mg, 18%). 1H NMR (400 MHz, CDCl3) δ 12.32 (s, 1 H), 8.29 (d, J=1.6 Hz, 1 H), 7.95-7.91 (m, 2 H), 7.86-7.83 (m, 1 H), 7.67 (dd, J=8.4, 2.0 Hz, 1 H), 7.57-7.54 (m, 2 H), 6.70 (s, 1 H), 4.79 (t, J=4.8 Hz, 1 H), 4.67 (t, J=4.8 Hz, 1 H), 3.71 (m, 1 H), 3.65 (m, 1 H); MS (ESI) m/z 273 (M+H+).
Reaction SMILES: [CH2:1]([C@@:3]1([C:13]([O:15][CH3:16])=[O:14])[CH2:7][C:6]2[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:5]=2[O:4]1)[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH3:16][O:15][C:13]([C@:3]1([CH2:1][CH3:2])[CH2:7][C:6]2[CH:8]=[C:9]([O:12][CH2:7][CH2:3][CH:1]=[CH2:2])[CH:10]=[CH:11][C:5]=2[O:4]1)=[O:14]
Reactant: CC[C@@]1(C(=O)OC)Cc2cc(O)ccc2O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCCOc1ccc2c(c1)C[C@@](CC)(C(=O)OC)O2
Temperature: 50 °C
Reaction time: 16 h
Yield: 101.3 %

Procedure:
A mixture of methyl (2S)-2-ethyl-5-hydroxy-2,3-dihydro-benzofuran-2-carboxylate (0.22 g, 1.0 mmol), prepared in Example 10, Step 2,4-bromo-1-butene (1.35 g, 10 mmol) and Cs2CO3 (1.63 g, 5.0 mmol) in DMF (20 mL) was stirred at 50° C. for 16 hrs. The reaction was diluted with ethyl acetate and washed with water. After removal of the solvent, the reisdue was purified by preparative TLC to give 0.14 g (2S)-5-But-3-enyloxy-2-ethyl-2,3-dihydro-benzofuran-2Carboxylic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7]([O:9]CC)=O.Cl[C:14]1[N:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:12][C:4]1[S:3][C:2]2[N:1]=[C:14]3[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][N:19]3[C:7](=[O:9])[C:6]=2[CH:5]=1
Reactant: CCOC(=O)c1cc(C)sc1N
Reactant: O=C(O)c1ccc(Cl)nc1
Product: Cc1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1

Procedure:
A mixture of 2-amino-5-methyl-3-thiophenecarboxylic acid, ethyl ester (Chemische Berichte, Vol. 99, pages 94-100, 1966), 18.5 g (0.1 mol) and 6-chloro-3-pyridinecarboxylic acid (Aldrich Chemical Company), 15.7 g (0.1 mol) is heated in an oil bath at 170°-190° C. for 20 hours. The mixture is cooled, extracted with hot chloroform and the residue is dissolved in hot pyridine, cooled and 0.4 g of 2-methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid is collected; mp 312°-315° C. after recrystallization from methanol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][CH3:12])=[O:10].[N+](C1C=C(S(O[CH2:26][C@@H:27]2[CH2:29][O:28]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.O>[CH3:12][NH:11][C:9](=[O:10])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:26][C@@H:27]1[CH2:29][O:28]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: CNC(=O)Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CNC(=O)Cc1ccccc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
A mixture of 2-(2-hydroxyphenyl)-N-methylacetamide (1.00 g, 6.1 mmol) prepared according to a known procedure (Bernd, Peschke, Eur. J. Med. Chem., 2000, 35, 599-618), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (1.58 g, 6.1 mmol) and cesium carbonate (2.37 g, 7.3 mmol) in 1-methylpyrrolidin-2-one (15 ml) was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate, the combined organic layers were dried with sodium sulphate, volatiles were removed in vacuo. The residue was purified by recrystillaziation from ethyl acetate/heptane; (390 mg) of the subtitle compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].Br[CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[C:19]([O:25][CH3:26])[CH:18]=1.[CH2:27]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.FC(F)(F)C(O)=O>CC(O)C>[CH2:27]([N:34]1[CH2:39][CH2:38][N:37]([CH2:14][CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[N:8][NH:7][C:5](=[O:6])[C:4]3[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([Cl:1])[CH:3]=3)=[C:19]([O:25][CH3:26])[CH:18]=2)[CH2:36][CH2:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc(OCCBr)ccc1C=O
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: COc1cc(OCCN2CCN(Cc3ccccc3)CC2)ccc1C=NNC(=O)c1ccc(O)c(Cl)c1
Reaction time: 1 h

Procedure:
This compound was prepared analogously to the compound described in the previous example starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin—[building block 1]) (2 g, ˜2 mmoles), 4-(2-bromoethoxy)-2-methoxybenzaldehyde ([building block 2]) (0.73 g, 1.5 equivs.), and 1-benzylpiperazine ([building block 3]) (3.3 g, 10 equivs.). After cleavage with 50% trifluoroacetic acid, the residue (1.4 g) was dissolved in 2-propanol (50 ml) and concentrated to 20 ml. The mixture was allowed to stand at 5° C. for 1 h and filtered. The mother liquor was concentrated in vacuo and the residue was purified by column chromatography on silica gel (20 g) eluting with a mixture of methanol and dichloromethane (1:9). This afforded 0.98 g of the title compound.