Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][C@@H:58]([CH2:72][C:73]1[CH:78]=[C:77]([F:79])[CH:76]=[C:75]([F:80])[CH:74]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[CH:10]=[C:11]([C:14]([NH:57][C@@H:58]([CH2:72][C:73]3[CH:74]=[C:75]([F:80])[CH:76]=[C:77]([F:79])[CH:78]=3)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=3)=[O:16])[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ccc2c(N(C)S(C)(=O)=O)cc(C(=O)O)cc21
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCn1ccc2c(N(C)S(C)(=O)=O)cc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Temperature: 40 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
To a mixture of 1-Butyl-4-[methyl(methylsulfonyl)amino]-1H-indole-6-carboxylic acid (0.2 g) in methylene chloride (15 mL) was added triethylamine (0.156 g), HOBT (0.105 g), and HATU (0.293 g). The mixture was stirred at 39° C. for 10 minutes at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.293 g) was added. The mixture was stirred at 40° C. for 4 h then poured into methylene chloride (50 mL), washed with water followed by brine then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 5% methanol in methylene chloride as eluent to give 0.21 g of the title compound: MS (ESI+) for C34H42F2N4O4S1 m/z 640.8 (M+H).
Reaction SMILES: [CH2:1]=[O:2].[C:3]1([N:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][S:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:18])[C:11](=[O:25])[N:10]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[C:26]1([N:10]2[C:11](=[O:25])[C:12]([CH2:15][CH2:16][S:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:18])([CH2:1][OH:2])[C:13](=[O:14])[N:9]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1C(CCS(=O)c2ccccc2)C(=O)N(c2ccccc2)N1c1ccccc1
Reactant: C=O
Solvent: CO
Product: O=C1N(c2ccccc2)N(c2ccccc2)C(=O)C1(CO)CCS(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
40% Formaline (25 ml) is added to a solution of 20 grams of 1,2-diphenyl-4-[2-(phenylsulfinyl)-ethyl]-pyrazolidine-3,5-dione in 120 ml of methanol. The solution, under magnetic stirring, is heated up to 50° C. for one hour and kept, always under a magnetic stirring, at room temperature for 12 hours. At the end the solvent is evaporated under reduced pressure, the residue is washed with water and extracted with dichloromethane.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([O:6][C:7]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]2[C:8]=1[C:9]([O:35][CH:36]([F:38])[F:37])=[C:10]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:28])=[CH:23][C:22]=1[Cl:34])[C:11]([CH2:18][CH3:19])=[N:12]2)[CH3:5].O1CCCC1.[OH-].[Li+]>O>[Cl:34][C:22]1[CH:23]=[C:24]([C:27]([N:29]2[CH2:30][CH2:31][CH2:32][CH2:33]2)=[O:28])[CH:25]=[CH:26][C:21]=1[CH2:20][C:10]1[C:11]([CH2:18][CH3:19])=[N:12][C:13]2[C:8]([C:9]=1[O:35][CH:36]([F:38])[F:37])=[C:7]([O:6][C@@H:4]([CH3:5])[C:3]([OH:39])=[O:2])[CH:16]=[CH:15][C:14]=2[F:17]
Reactant: CCc1nc2c(F)ccc(O[C@@H](C)C(=O)OC)c2c(OC(F)F)c1Cc1ccc(C(=O)N2CCCC2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2c(F)ccc(O[C@@H](C)C(=O)O)c2c(OC(F)F)c1Cc1ccc(C(=O)N2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of (S)-2-{3-[2-chloro-4-(pyrrolidine-1-carbonyl)benzyl]-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy}propionic acid methyl ester (0.75 g), tetrahydrofuran (20 mL), water (20 mL) and lithium hydroxide (0.11 g) was stirred at room temperature for 20 minutes. The mixture was washed with ethyl acetate and the aqueous phase acidified by the addition of 1.0 M aqueous hydrochloric acid and then extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. Purification of the residue by column chromatography on C-18 column, eluting with a mixture of water and methanol (4:1 to 0:1 by volume) gave title compound as an off-white solid, 0.20 g.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](O)[CH:11]=[CH2:12].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[C:1]([O:9][CH2:12][CH:11]=[CH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: C=CCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
To a 250 mL round bottom flask equipped with a reflux condensor was added 25 g of benzoic acid, 51 g of allyl alcohol, and 2.5 g of sulfuric acid. The mixture was heated at reflux for 17 hr, allowed to cool to room temperature, and 50 g of toluene was added. Using a 1 L separatory funnel, the mixture was washed once with 100 mL of water, once with 50 mL of 5 wt % Na2CO3 in water, and once more with 100 mL of water. The organic phase was dried over Na2SO4, filtered and distilled to yield allyl benzoate. The allyl benzoate distilled at a boiling point of 135° C. at about 60 mm Hg.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].Cl[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:24])([CH3:23])[CH3:22]>>[CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:24])([CH3:23])[CH3:22])[C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(C)(O)CCCCCl
Product: C=CCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2C

Procedure:
This compound was obtained by reacting 7-Allyl-3-methylxanthine with 1-chloro-5-hydroxy-5-methylhexane in an analogous manner to Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[C@@H:16]([OH:17])[C:15](=[O:18])[NH:14][C:13]3[CH:19]=[CH:20][C:21]([O:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[CH:22][C:12]=3[S:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]Cl>C(C(C)=O)C>[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][N:14]1[C:13]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:22][C:12]=2[S:11][C@@H:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[C@@H:16]([OH:17])[C:15]1=[O:18]
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3cc(Oc4ccc(F)cc4)ccc3NC(=O)[C@@H]2O)cc1F
Agent: Cl
Solvent: CCC(C)=O
Product: COc1ccc([C@@H]2Sc3cc(Oc4ccc(F)cc4)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1F

Procedure:
Following a procedure similar to that described in Example 11(d), 865 mg of (2S, 3S)-2-(3-fluoro-4-methoxy- phenyl)-8-(4-fluorophenoxy)-2,3-dihydro-3-hydroxy-1,5-benzothiazepin-4(5H)-one [prepared as described in step (c) above] were alkylated with 2-dimethylaminoethyl chloride hydrochloride in 50 ml of methyl ethyl ketone to afford about 900 mg of the title compound as a syrup. The compound was used in the following reaction without further purification.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([NH:12][C:13]2([C:27]#[N:28])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-:29].[NH4+]>>[C:6]1([NH:12][C:13]2([C:27]([NH2:28])=[O:29])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CC1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reaction time: 8 h

Procedure:
To 4500 parts of sulfuric acid are added portionwise 710 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarbonitrile, while keeping the temperature below 25° C. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto a mixture of 10,000 parts of crushed ice and 3600 parts of ammonium hydroxide. The product is extracted with trichloromethane (7500 parts). The extract is dried, filtered and evaporated. The residue is stirred in 140 parts of 2,2'-oxybispropane. The product is filtered off and dried, yielding 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxamide; mp. 182.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:19](Cl)(=[O:21])[CH3:20]>>[C:19]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CC(=O)Cl
Product: CCN1CC=C(c2c[nH]c3ccc(NC(C)=O)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.062 mMol) 5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.005 mL (0.068 mMol) acetyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:8][C:7](=[O:9])[CH2:6][C:5](=[O:10])[CH2:4]1.Br[CH2:12][C:13]#[C:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].CCOCC>CN(C)C=O>[CH3:21][O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][C:14]#[C:13][CH2:12][CH:6]1[C:7](=[O:9])[CH2:8][CH2:3][CH2:4][C:5]1=[O:10]
Reactant: O=C1CCCC(=O)C1
Reactant: COC(=O)CCCC#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CCCC#CCC1C(=O)CCCC1=O
Temperature: 25 °C

Procedure:
Sodium hydride (4.2 g) is suspended in dimethylformamide (50 ml) and while stirring the mixture at room temperature, a solution of 3,5-cyclohexanedione (11.2 g) in dimethylformamide (50 ml) is added over a period of 10 minutes. Several minutes later the mixture is cooled to -10° C., and a solution of methyl 7-bromo-5-heptynoate, described in Example 12, in dimethylformamide (50 ml) is added. The reaction mixture is stirred overnight at -10° to -5° C., then ether is added. The mixture is extracted with sodium carbonate. The aqueous extract after acidification with 10% HCl is extracted with ethyl acetate to yield a crude product, which on crystallization from ether affords 7-(2,6-dioxocyclohexyl)5-heptynoic acid methyl ester, m.p. 108° - 110° C, εmaxEtOH 256nm (ε = 14,200).
Reaction SMILES: [OH-:1].[K+:2].[CH:3]([CH:9]1[CH2:14][C:13](=[O:15])[O:12][C:10]1=[O:11])=[CH:4][CH2:5][CH2:6][CH2:7][CH3:8]>C(O)CO>[K+:2].[K+:2].[CH:3]([CH:9]([CH2:14][C:13]([O-:12])=[O:15])[C:10]([O-:1])=[O:11])=[CH:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: [OH-]
Reactant: CCCCC=CC1CC(=O)OC1=O
Agent: [K+]
Solvent: OCCO
Product: CCCCC=CC(CC(=O)[O-])C(=O)[O-]
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Into a glass flask there were charged 16 grams of potasium hydroxide, 41.5 grams of ethyleneglycol and 25.5 grams of hexenyl succinic anhydride. The mixture was stirred for two hours at 100° C. Yield: 78.9 grams=98.0% of theoretical. The catalyst solution thus obtained is hygroscopic.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[CH:16]=[CH:15][C:14](=[CH:17][C:18]#[N:19])[CH2:13][C:7]32[CH2:11][N:10]([CH3:12])[CH2:9][C:8]=13.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CN(C)C=O>[C:18]([CH:17]=[C:14]1[CH2:13][C:7]23[CH2:11][N:10]([CH3:12])[CH2:9][C:8]2=[C:2]([N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[CH:3]=[CH:4][N:5]=[C:6]3[CH:16]=[CH:15]1)#[N:19]
Reactant: CN1CCNCC1
Reactant: CN1CC2=C(Cl)C=CN=C3C=CC(=CC#N)CC32C1
Solvent: CN(C)C=O
Product: CN1CCN(C2=C3CN(C)CC34CC(=CC#N)C=CC4=NC=C2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
5.8 g (22 mmol) of 4-chloro-10-cyanomethylene-2-methylpyrrolo[4,3-e]benzazepine were dissolved in 50 ml of dimethylformamide, 6.6 ml (60 mmol) of N-methylpiperazine were added (strongly exothermic reaction) and the mixture was stirred at 80° C. under nitrogen for 1 h. After removal of the solvent under reduced pressure the residue was taken up in about 200 ml of ice/water, the mixture was make alkaline with a little 10% strength sodium hydroxide solution and then stirred while cooling for 1 h and the pale brown crude product was filtered off with suction, washing copiously with water. The crude product was purified by column chromatography (silica gel, mobile phase 95/5 methylene chloride/methanol). 5.3 g (73%) of yellowish 10-cyanomethylene-2-methyl-4-(4-methyl-1-piperazinyl)pyrrolo-[4,3-e]benzazepine were obtained in the form of a mixture of the (E) and (Z) isomers, which was recrystallized from isopropanol: melting point 178°-180° C.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>O1CCCC1>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[O:35])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reactant: O=C=Nc1ccccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1F)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (805 mg, 3.36 mM) and triethylamine (0.6 mL) in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 2-fluorophenyl isocyanate (565 mg/ml, 5.04 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chloroform-hexane (1:9) to give 8c as oil. Yield: 1.02 g, 80.56%.
Reaction SMILES: Br[C:2]1[C:6](Br)=[CH:5][O:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:13]([O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([C:2]2[C:6]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:22]=3)=[CH:5][O:4][C:3]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:24]=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1occ(Br)c1Br
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Product: CCOC(=O)c1occ(-c2cccc(OCc3ccccc3)c2)c1-c1cccc(OCc2ccccc2)c1
Yield: 13.1 %

Procedure:
A reaction and treatment was carried out in the same manner as in Reference Example 5(1) using ethyl 3,4-dibromo-2-furancarboxylate (2.00 g) and 3-benzyloxyphenylboronic acid (1.80 g). The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/20), thereby giving 1.70 g of a mixture of ethyl 3-(3-benzyloxyphenyl)-4-bromo-2-furancarboxylate and ethyl 4-(3-benzyloxyphenyl)-3-bromo-2-furancarboxylate and 0.26 g of ethyl 3,4-bis(3-benzyloxyphenyl)-2-furancarboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]=[C:9]1[NH:13][C:12]([C:14](=O)[C:15]([OH:17])=[O:16])=[CH:11][S:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][N:20]1[CH2:24][CH2:23][N:22]([CH3:25])[C:21]1=[O:26]>C(O)C>[C:1]([O:5][C:6]([N:8]=[C:9]1[NH:13][C:12]([C:14](=[N:19][N:20]2[CH2:24][CH2:23][N:22]([CH3:25])[C:21]2=[O:26])[C:15]([OH:17])=[O:16])=[CH:11][S:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(N)C1=O
Reactant: CC(C)(C)OC(=O)N=c1[nH]c(C(=O)C(=O)O)cs1
Solvent: CCO
Product: CN1CCN(N=C(C(=O)O)c2csc(=NC(=O)OC(C)(C)C)[nH]2)C1=O
Reaction time: 8 h

Procedure:
13.1 g of 2-(2-tert.-butoxycarbonylimino-4-thiazolin-4-yl)-glyoxylic acid are dissolved in 160 ml of ethanol by warming for a short time. 5.5 g of 1-amino-2-oxo-3-methyl-imidazolidine are added to this solution at 20° C. After standing overnight, the reaction mixture is evaporated in a rotary evaporator, the residue is treated with water and the precipitate is filtered off. Excess NaHCO3 solution is added to this precipitate and the undissolved material is filtered off. The filtrate is acidified and the precipitate which separates out is filtered off, washed with water and dried.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([N:10]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[S:30][CH:31]=[CH:32][N:33]=3)=[CH:25][CH:24]=2)[CH2:11][CH2:12][CH2:13][C:14]2[S:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][CH:15]=2)(=[O:9])=[O:8])[CH:2]=1.Cl.N1C=CC=C(S(Cl)(=O)=O)[CH:36]=1>C(N(CC)CC)C>[CH3:36][O:20][C:19]([C:17]1[S:18][C:14]([CH2:13][CH2:12][CH2:11][N:10]([S:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:8])=[O:9])[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[S:30][CH:31]=[CH:32][N:33]=3)=[CH:27][CH:28]=2)=[CH:15][CH:16]=1)=[O:21]
Reactant: O=C(O)c1ccc(CCCN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccnc2)s1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CCCN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccnc2)s1

Procedure:
The title compound of Step B was prepared from 5-[3-(4-thiazol-2-yl-benzylamino)-propyl]-thiophene-2-carboxylic acid methyl ester of Step A and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. MS 514 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]4[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=4)[C:20]([NH:22][CH3:23])=[O:21])=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][NH:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][CH:26]=[C:17]([C:15]2[CH:14]=[N:13][N:12]3[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:7]=4)=[CH:9][N:10]=[C:11]3[CH:16]=2)[CH:18]=1
Reactant: CNC(=O)c1cccc(-c2cnn3c(-c4ccnc(Cl)c4)cnc3c2)c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1cccc(-c2cnn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)c1

Procedure:
3-[3-(2-Chloro-pyridin-4-yl)-imidazo[1,2-b]pyridazin-7-yl]-N-methyl-benzamide (1 eq, 0.110 mmol, 40 mg) and phenyl boronic acid (1.2 eq, 0.132 mmol, 16.1 mg) are dissolved in DME (1.5 ml) and water (0.5 ml) and Na2CO3 (2 eq, 0.22 mmol, 27.3 mg) is added. PdCl2(PPh3)2 (0.1 eq, 0.011 mmol, 7.7 mg) is then added and the reaction mixture is heated using microwave radiation at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield N-Methyl-3-[3-(2-phenyl-pyridin-4-yl)-imidazo[1,2-b]pyridazin-7-yl]-benzamide as a yellow solid; [M+H]+=406
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7]([CH3:10])=[N:8][O:9][C:5]=2[CH:4]=1.I[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[Li+].CC([N-]C(C)C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7]([CH2:10][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(C)noc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(CI)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(CCC3CCN(C(=O)OC(C)(C)C)CC3)noc2c1
Yield: 80.7 %

Procedure:
The procedure described in Example 1d was followed using 6-methoxy-3-methyl-1,2-benzisoxazole (0.32 g, 1.96 mmol), 4-iodomethyl-1-piperidinecarboxylic acid, 1-(1,1-dimethylethyl) ester (0.70 g, 2.15 mmol), and 1M LDA (2.0 mL, 2.0 mmol) in dry THF (3 mL). After purification, the title compound (0.57 g, 80%) was obtained as a white solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](O)=[O:5].O.[NH4+:14]>O1CCOCC1>[NH2:2][C@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([NH2:14])=[O:5]
Reactant: N[C@@H](C(=O)O)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)[C@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.025 g (15 mmol) of (2R)-2-amino-2-phenylethanoate hydrochloride were suspended in 45 ml of dioxane and 45 ml of aqueous ammonium hydrate were added. After 8 hours at room temperature under stirring the solvent was evaporated and the residue redissolved with chloroform and washed with water. The organic layer was concentrated to afford 1.7 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[CH:6]=[C:5]([C:14]2[C:15]([CH3:27])([CH3:26])[C:16](=[O:25])[N:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:18]=2)[CH:4]=1.[CH3:28][C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[CH:6]=[C:5]([C:14]2[C:15]([CH3:27])([CH3:26])[C:16](=[O:25])[N:17]([CH:19]3[CH2:24][CH2:23][N:22]([S:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([CH3:28])[CH:30]=4)(=[O:37])=[O:36])[CH2:21][CH2:20]3)[N:18]=2)[CH:4]=1
Reactant: COc1cc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc2c1OC(C)(C)C2
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Product: COc1cc(C2=NN(C3CCN(S(=O)(=O)c4cccc(C)c4)CC3)C(=O)C2(C)C)cc2c1OC(C)(C)C2

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B12) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and crystallization of the product containing fractions from DCM and diethyl ether to yield the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([N:10]1[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[CH:12]=[CH:11]1)[CH2:6]2.I.CS[C:23]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)=[NH:24]>C(O)C>[CH3:1][N:2]1[CH:3]2[CH2:9][CH2:8][CH:7]1[CH2:6][CH:5]([N:10]1[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:23]([C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)=[NH:24])=[CH:16][CH:17]=3)[CH:12]=[CH:11]1)[CH2:4]2
Reactant: CSC(=N)c1cccs1
Reactant: CN1C2CCC1CC(n1ccc3cc(N)ccc31)C2
Agent: I
Solvent: CCO
Product: CN1C2CCC1CC(n1ccc3cc(NC(=N)c4cccs4)ccc31)C2
Temperature: 25 °C
Reaction time: 23 h
Yield: 103.8 %

Procedure:
Compound 85 (52 mg, 0.2036 mmol) is charged to a small, argon purged flask fitted with a magnetic stir bar. Anhydrous ethanol (5 mL) and thiophene-2-carboximidothioic acid methyl ester hydroiodide (87.1 mg, 0.3056 mmol) are added to the flask and the reaction was stirred under argon at ambient temperature for 23 hours, at which time the solvent was evaporated and the residue was purified via chromatography on silica gel (methanol:CH2Cl2, 1:9 to 2M NH3 in methanol:CH2Cl2, 5:95) to yield a pale yellow residue, 86 (77 mg, 100%). 1H NMR (major isomer-MeOD) δ 1.81-1.89 (m, 2H), 2.07-2.14 (m, 2H), 2.23-2.31 (m, 2H), 2.48 (s, 3H), 2.69-2.79 (m, 2H), 3.49-3.59 (m, 2H), 4.51-4.61 (m, 1H), 6.58 (d, 1H, J=3.3 Hz), 7.13 (dd, 1H, J=8.7, 1.9 Hz), 7.31-7.34 (m, 1H), 7.54-7.57 (m, 2H), 7.61 (d, 1H, J=3.5 Hz), 7.94-7.97 (m, 2H); ESI-MS (m/z, %): 365 (MH+, 15%), 183 (M++doubly charged, 100%); ESI-HRMS calculated for C21H25N4S (MH+): 365.1794, observed: 365.1784.