Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.Br[CH2:11][C:12]([C:14]1[O:15][C:16]([Br:19])=[CH:17][CH:18]=1)=O>>[Br:19][C:16]1[O:15][C:14]([C:12]2[N:1]=[C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]3[CH:11]=2)=[CH:18][CH:17]=1
Reactant: O=C(CBr)c1ccc(Br)o1
Reactant: N#Cc1ccc(N)nc1
Product: N#Cc1ccc2nc(-c3ccc(Br)o3)cn2c1

Procedure:
Referring now to Scheme 2, the acetate salt of 2-[5-(4-Amidinophenyl)-furan-2-yl]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-6-carboxamidine (7) was synthesized from 2-[5-(4-Cyanophenyl)-furan-2-yl]-imidazo[1,2-a]pyridine-6-carbonitrile (4a), through the bis-O-acetoxyamidoxime followed by hydrogenation in glacial acetic acid. Compound 4a was obtained in four steps starting with two successive brominations of 2-acetylfuran first with N-bromosuccinimide, and second with bromine to form 2-Bromo-1-(5-bromofuran-2-yl)-ethanone (2) in a moderate yield. A condensation reaction between 6-Amino-nicotinonitrile and compound 2 gave 2-(5-Bromofuran-2-yl)-imidazo[1,2-a]pyridine-6-carbonitrile (3a). A subsequent Suzuki coupling of 3a with 4-Cyanophenyl boronic acid furnished 4a in good yield. Interestingly, 2-[5-(4-Amidinophenyl)-furan-2-y]-imidazo[1,2-a]pyridine-6-carbox-amidine acetate salt (8a) was obtained from 4a, through the bis-O-acetoxyamidoxime followed by hydrogenation in a mixture of ethanol/ethylacetate. Thus, by choice of hydrogenation solvent the saturated or unsaturated imidazo[1,2-a]pyridine can be obtained.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14]CC3C=CC=CC=3)[CH:9]=2)[CH2:5][C:4](=[O:22])[CH:3]=1>C(O)C.[Pd]>[OH:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=2)[CH2:5][C:4](=[O:22])[CH:3]=1
Reactant: O=C1C=C(O)CC(c2cccc(OCc3ccccc3)c2)C1
Agent: [Pd]
Solvent: CCO
Product: O=C1C=C(O)CC(c2cccc(O)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 20 g (0.068 mol) of 3-hydroxy-5-(3-benzyloxyphenyl)cyclohex-2-en-1-one in 250 mL of absolute ethanol was treated with 7.5 g of 5.0 percent palladium on carbon and shaken in a Parr® hydrogenator under 50 pounds of hydrogen pressure for 2 hours at room temperature. The reaction mixture was filtered through diatomaceous earth, diluted with 1 L of water and extracted thrice with 100 mL portions of ethyl acetate. The combined extracts were washed with an aqueous saturated NaCl solution, dried over MgSO4, filtered, concentrated and cooled to precipitate the desired above named product as a greyish-white solid in a yield of 9.8 g (71 percent of theoretical). The product melted at 140°-150° C./dec.
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[C:11](O)([CH3:14])([CH3:13])[CH3:12].OS(O)(=O)=O>C1C=CC=CC=1.O>[C:11]([C:3]1[CH:2]=[CH:10][C:6]2[CH2:7][CH2:8][S:9][C:5]=2[CH:4]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)O
Reactant: Oc1ccc2c(c1)CCS2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)c1ccc2c(c1)SCC2
Temperature: 60 °C
Yield: 19.8 %

Procedure:
To a solution of 5-hydroxy-2,3-dihydrobenzothiophene (500 mg, 3.28 mmoles) in 20 mL benzene in a sealable tube was added t-butanol (729 mg, 9.84 mmoles, 3.0 eq) and 0.4 mL concentrated H2SO4. The tube was sealed and the reaction mixture heated at 60° C. for 24 hours. The reaction mixture was cooled, diluted with water (50 mL) and extracted 2×25 mL ether. The combined extracts were washed with sodium bicarbonate (1×25 mL), H2O (1×25 mL) and brine (1×25 mL). The organic layer was then dried over Na2SO4, filtered and concentrated to give 220 mg crude product. Purification by flash chromatography (90/10, hexane/EtOAc) afforded 125 mg pure product (18%) mp 90°-93° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][N:13]3[C:21]4[C:16](=[CH:17][C:18]([C:22](O)=[O:23])=[CH:19][CH:20]=4)[C:15]([CH3:25])=[C:14]3[CH3:26])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[Br:29][C:30]1[CH:31]=[C:32]([C@@H:36]([NH2:38])[CH3:37])[CH:33]=[CH:34][CH:35]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[Br:29][C:30]1[CH:31]=[C:32]([C@@H:36]([NH:38][C:22]([C:18]2[CH:17]=[C:16]3[C:21](=[CH:20][CH:19]=2)[N:13]([CH2:12][C:11]2[CH:27]=[CH:28][C:8]([C:5]4([C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH2:6]4)=[CH:9][CH:10]=2)[C:14]([CH3:26])=[C:15]3[CH3:25])=[O:23])[CH3:37])[CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)C1(c2ccc(Cn3c(C)c(C)c4cc(C(=O)O)ccc43)cc2)CC1
Reactant: C[C@H](N)c1cccc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(c2ccc(Cn3c(C)c(C)c4cc(C(=O)N[C@@H](C)c5cccc(Br)c5)ccc43)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-(1-(methoxycarbonyl)cyclopropyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid (50 mg, 0.13 mmol) in DMF (1 mL) was added (S)-1-(3-bromophenyl)ethylamine (21 μL), DIEA (45 μL) and HATU (54 mg). The reaction mixture was allowed to stir at rt for 30 min, and then was diluted by ethyl acetate. The resulting mixture was washed with a 0.5 N HCl solution, a saturated solution of NaHCO3, and brine, dried on MgSO4, and concentrated to afford a yellow oil (73 mg) which was directly used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:18]O>S(=O)(=O)(O)O>[CH3:18][O:10][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CO
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)C(CC1CCCC1)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid (1.37 g, 4.61 mmol) in methanol (23 mL) was treated slowly with 5 drops of concentrated sulfuric acid. The resulting reaction mixture was heated under reflux for 42 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The residue was diluted with ethyl acetate (200 mL). The organic phase was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL), washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 19/1 hexanes/ethyl acetate) afforded 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.40 g, 97%) as a light yellow oil: EI-HRMS m/e calcd for C15H19BrO2 (M+) 310.0568, found 310.0569.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][C@@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1>>[CH3:12][C@H:13]1[NH:14][CH2:15][CH2:16][N:17]([C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:18]1
Reactant: C[C@@H]1CNCCN1
Reactant: FC(F)(F)c1cccnc1Cl
Product: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1

Procedure:
A mixture of 2-chloro-3-trifluoromethylpyridine (1.45 g, 8 mmol, Aldrich) and (R)-(−)-2-methylpiperazine (1.0 g. 10 mmol, Aldrich) was reacted under the conditions of Example 43a to give the title compound as a off-white solid. MS (ESI, pos. ion) m/z: 246 (M+1).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[C:27]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br)#[N:28]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:32][C:31]5[CH:30]=[C:29]([CH:36]=[CH:35][CH:34]=5)[C:27]#[N:28])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: N#Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(Cc3cccc(C#N)c3)C2=O)CC1
Yield: 66 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 3-cyanobenzyl bromide, to give the desired product as a white foam (66%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[3H][3H]>C(OCC)(=O)C.[OH-].[Na+].[Rh]>[CH:12]1([CH:10]([OH:11])[CH:3]2[CH2:4][CH2:5][CH:6]([O:8][CH3:9])[CH2:7][CH:2]2[OH:1])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1ccc(C(=O)c2ccccc2)c(O)c1
Agent: [Rh]
Agent: [3H][3H]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC1CCC(C(O)C2CCCCC2)C(O)C1
Yield: 73.5 %

Procedure:
10 g of (2-hydroxy-4-methoxyphenyl)phenylmethanone (Eusolex® 4360, Merck) are dissolved in 5550 ml of ethyl acetate containing 1 g of 1N NaOH. 10 g of 5% Rh/C catalyst (50% of water) are subsequently added. The hydrogenation is carried out using hydrogen 3.0 at 40° C. and a pressure of 5 bar. When the hydrogenation is complete, the catalyst is separated off by filtration. The solution obtained is transferred into the separating funnel, and the phases are separated. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water, subsequently dried over sodium sulfate, filtered and evaporated in a rotary evaporator, giving 7.8 g of product as white solid (cis and trans isomer mixture).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]=[C:8]1[CH2:17][CH:16]([C:18](OCC)=[O:19])[CH2:15][C:14]2[N:13]=[N:12][C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)=[CH:10][C:9]1=2.Cl>C(OCC)(=O)C>[OH:19][CH2:18][CH:16]1[CH2:15][C:14]2[N:13]=[N:12][C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)=[CH:10][C:9]=2[CH:8]([OH:7])[CH2:17]1
Reactant: CCOC(=O)C1CC(=O)c2cc(-c3cccc(C(F)(F)F)c3)nnc2C1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Product: OCC1Cc2nnc(-c3cccc(C(F)(F)F)c3)cc2C(O)C1
Reaction time: 1 h
Yield: 36.9 %

Procedure:
To a suspension of lithium aluminum hydride (14.5 mg, 0.38 mmol) in tetrahydrofran (1 mL) was added ethyl 5-oxo-3-(3-trifluoromethylphenyl)-7,8-dihydro-6H-cinnoline-7-carboxylate (92.8 mg, 0.25 mmol) obtained in Example 2 at −40° C., followed by stirring as it is for 1 hour and gradually elevating temperature up to room temperature. Ethyl acetate (3 mL) and a 1N HCl solution (0.5 mL) were added to quench the reaction, followed by further adding distilled water (2 mL) for extraction. An organic layer obtained by washing with a saturated saline solution was dried with sodium sulfate anhydride, followed by filtering the drying agent, concentrating the organic layer under reduced pressure and purification of thus obtained residue using silica gel column chromatography (methylene chloride/methanol=10/1) to obtain an objective compound (29.9 mg, 36.3%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.S([O-])([O-])(=O)=O.[N+:16]([O-])([O-:18])=[O:17].[K+].[NH4+]>S(=O)(=O)(O)O>[N+:16]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][NH:2][CH2:1]2)=[CH:6][CH:7]=1)([O-:18])=[O:17]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1ccc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 27 h
Yield: 41.9 %

Procedure:
1,2,3,4-Tetrahydroisoquinoline (4.0 g, 30.0 mmol) was dissolved in 10 N of sulfuric acid (6 mL, 30.0 mmol) and then evaporated to dryness to afford a solid residual. This sulfate was added slowly to a solution of potassium nitrate (3.34 g, 33.0 mmol) in sulfuric acid (15 mL), taking care that the temperature of the reaction mixture did not rise above 5° C. After being stirred at room temperature for a further 27 h, the reaction mixture was slowly poured into a con. ammonium solution (ca. 100 mL) under ice cooling. The resulted solution was extracted with dichloromethane (100 mL×3). The combined organic phase was washed with brine (150 mL), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (DCM:MeOH=100:1) to afford 31-2 as a brown solid (2.24 g, yield 41%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]([O:14]CC)(=S)[C:10]([NH2:12])=O>C(O)C>[NH2:12][C:10]1[C:9](=[O:14])[NH:7][C:2]2[C:1]([N:8]=1)=[CH:6][CH:5]=[CH:4][CH:3]=2
Reactant: Nc1ccccc1N
Reactant: CCOC(=S)C(N)=O
Solvent: CCO
Product: Nc1nc2ccccc2[nH]c1=O
Temperature: 25 °C
Yield: 17.6 %

Procedure:
An adaptation of the method of Burrell et al., J. Chem. Soc. Perkin I. 2707 (1973), was used. A mixture of 1,2-phenylenediamine (324 mg, 3.00 mmol; Aldrich Co.) and ethyl thiooxamate (400 mg, 3.00 mmol; Aldrich Co.) in 7.5 mL of ethanol was heated to reflux. The resulting solution was stirred under reflux for 3 h. The resulting suspension was cool to 25° C. A pale yellow precipitate appeared. The mixture was vacuum filtered and the solid was washed with EtOH (5×2 mL) and dried in vacuum at 60° C. overnight to yield 85 mg (18%) of 3-aminoquinoxalin-2(1H)-one as a pale yellow solid (McKillop et al., Tetrahedron Lett. 23:3357 (1982)): mp dec.>320° C. 1H NMR (300 MHz, DMSO-d6) δ 7.261-7.075 (m, 4H, H-5+H-6+H-7+H-8). LRMS: 161 (M+, 100%), 133 (50%).
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.[CH3:50][N:51]([CH3:57])[C@H:52]1[CH2:56][CH2:55][NH:54][CH2:53]1>CN(C)C=O>[CH3:50][N:51]([CH3:57])[C@H:52]1[CH2:56][CH2:55][N:54]([C:8]([NH:9][C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38]([NH:39][C:40]5[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=5)=[O:47])[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)=[O:7])[CH2:53]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Solvent: CN(C)C=O
Product: CN(C)[C@H]1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)C1
Reaction time: 6 h
Yield: 81 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) was added (3S)-3-dimethylaminopyrrolidine (0.0508 ml) at room temperature, followed by stirring for 6 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (45.6 mg, 81%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([O:12][CH3:13])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.C(O)(=[O:16])C>[Cr].O>[Cl:11][C:10]1[C:2]([Cl:1])=[C:3]2[C:7]([CH2:6][CH2:5][C:4]2=[O:16])=[CH:8][C:9]=1[O:12][CH3:13]
Reactant: COc1cc2c(c(Cl)c1Cl)CCC2
Reactant: CC(=O)O
Agent: [Cr]
Solvent: O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)CC2
Reaction time: 1 h

Procedure:
4,5-Dichloro-6-methoxy-2,3-dihydro-1H-indene (21 gm., 0.097 mole) is dissolved in acetic acid (280 ml.) and chromium, trioxide (14 gm., 0.14 mole) in a mixture of water (15 ml.) and acetic acid (40 ml.) is added dropwise with stirring over a period of one hour. The mixture is poured, with stirring into cold water (1200 ml.) and the solid that separates is removed by filtration, washed with water and dried. The product, which consists of a mixture of the desired material and the isomer described in Step D, is subjected to column chromatographic separation using 225 gm. of silica gel and chloroform is used for elution. Evaporation of the solvent gives 6,7-dichloro-5-methoxy-2,3-dihydro-1H-inden-1-one, 5.2 gm., m.p. 154°-156° C.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[N:34][N:35]=2)[N:32]=1>CN(C)C=O>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([CH:33]=[N:34][N:35]=4)[N:32]=3)[CH2:12][CH2:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Clc1ccc2nncn2n1
Reactant: OCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)N2CCN(CCCOc3ccc4nncn4n3)CC2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
0.311 g of 4-(diphenylmethyl)-1-piperazinepropanol was dissolved in 5 ml of N,N-dimethylformamide; 0.048 g of 60% oily sodium hydride was added; the reaction mixture was stirred in an oil bath (60° C.) for 30 minutes. After cooling, 0.232 g of 6-chloro[1,2,4]triazolo[4,3-b]pyridazine was added; the reaction mixture was stirred in an oil bath. (bath temperature 60° C.) for 40 minutes. After cooling, ice water was added; the reaction mixture was extracted with ethyl acetate; the extract was washed with saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (90:10:1). The desired fraction was collected and concentrated; the crystal obtained was filtered, washed with ethyl ether, and dried, to yield 0.339 g of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH3:22])=[C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([Cl:19])=[C:11]2[Cl:20])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[F-].[Cs+].[C:25](B1OC(C)(C)C(C)(C)O1)([CH3:27])=[CH2:26]>COCCOC.CCOC(C)=O>[Cl:20][C:11]1[N:10]([C:4]2[C:5](=[O:9])[N:6]([CH3:8])[N:7]=[C:2]([C:25]([CH3:27])=[CH2:26])[C:3]=2[O:21][CH3:22])[C:18]2[C:13]([C:12]=1[Cl:19])=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: COc1c(Br)nn(C)c(=O)c1-n1c(Cl)c(Cl)c2ccccc21
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: C=C(C)c1nn(C)c(=O)c(-n2c(Cl)c(Cl)c3ccccc32)c1OC
Temperature: 150 °C
Yield: 92.6 %

Procedure:
6-bromo-4-(2,3-dichloroindol-1-yl)-5-methoxy-2-methyl-pyridazin-3-one (0.600 g, 1.49 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.0608 g, 0.0744 mmol) and cesium fluoride (0.476 g, 2.98 mmol) are suspending in DME (3 mL) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (330 μL, 1.79 mmol) is added. The resulting reaction mixture is heated under microwave irradiation to 150° C. for 20 min. The resulting reaction mixture is diluted with EtOAc (50 mL) and then washed with brine (50 mL). The organic layer was dried (MgSO4) and then concentrated under reduced pressure onto silica. Purification by flash chromatography (combiflash, 0 to 20% EtOAc/isohexane) afforded the desired product 4-(2,3-dichloroindol-1-yl)-6-isopropenyl-5-methoxy-2-methyl-pyridazin-3-one (503 mg, 1.38 mmol, 93%) as a pale brown oil.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][CH:12]([CH3:14])[CH3:13])[CH2:8]2.[CH3:15][N:16]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:19]([C:27](O)=[O:28])[CH:18]=[N:17]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]([CH:12]([CH3:14])[CH3:13])[C:27]([C:19]1[CH:18]=[N:17][N:16]([CH3:15])[C:20]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:28])[CH2:8]2
Reactant: CC(C)NC1C2CC3CC(C2)CC1C3
Reactant: Cn1ncc(C(=O)O)c1-c1ccccc1
Product: CC(C)N(C(=O)c1cnn(C)c1-c1ccccc1)C1C2CC3CC(C2)CC1C3

Procedure:
Methyl-5-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-yl-isopropyl-amide is prepared from adamantan-2-yl-isopropyl-amine (of intermediate 3) and 1-methyl-5-phenyl-1H-pyrazole-4-carboxylic acid (Maybridge plc, Cornwall, UK) according to general procedure C.
Reaction SMILES: FC1C=CC=C(F)C=1C1SC=C(C(O)=O)N=1.[N:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:24][CH:25]=[C:26]([C:28]([OH:30])=O)[N:27]=2)=[CH:19][CH:18]=1.[NH2:31][C:32]1[CH:33]=[N:34][S:35][C:36]=1[N:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1>>[N:17]1[CH:18]=[CH:19][C:20]([C:23]2[S:24][CH:25]=[C:26]([C:28]([NH:31][C:32]3[CH:33]=[N:34][S:35][C:36]=3[N:37]3[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]3)=[O:30])[N:27]=2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2sncc2N)CC1
Reactant: O=C(O)c1csc(-c2ccncc2)n1
Agent: O=C(O)c1csc(-c2c(F)cccc2F)n1
Product: CC(C)(C)OC(=O)N1CCN(c2sncc2NC(=O)c2csc(-c3ccncc3)n2)CC1
Yield: 89.3 %

Procedure:
Following the procedure described in Step (3) of Example 6, and substituting Compounds 2E and 6D8 with 2-(pyridin-4-yl)thiazole-4-carboxylic acid (19E) (58 mg, 0.28 mmol) and tert-butyl 4-(4-aminoisothiazol-5-yl)piperazine-1-carboxylate (31D3) (80 mg, 0.28 mmol) respectively, Compound 31A (120 mg, 0.25 mmol) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.C([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)CCC>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([N:27]([CH:12]([CH3:13])[CH2:11][CH2:15][CH3:14])[C:24]2[CH:23]=[CH:22][CH:21]=[CH:26][CH:25]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: CCCCc1ccc(N)cc1
Solvent: CCN(CC)CC
Product: CCCC(C)N(c1ccccc1)c1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[(4-pentyl)phenylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-butylphenylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH:1]1[C:6]([C:7]([CH2:9]Br)=[O:8])=[CH:5][CH:4]=[C:3]([Cl:11])[CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@H:31]3[C@H:26]([CH2:27][CH2:28][CH2:29][CH2:30]3)[C:25](=[O:32])[NH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[Cl:11][C:3]1[CH:4]=[CH:5][C:6]([C:7](=[O:8])[CH2:9][N:24]2[N:23]=[C:22]([C:16]3[CH:15]=[C:14]([O:13][CH3:12])[C:19]([O:20][CH3:21])=[CH:18][CH:17]=3)[C@H:31]3[C@H:26]([CH2:27][CH2:28][CH2:29][CH2:30]3)[C:25]2=[O:32])=[CH:1][CH:2]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(CC(=O)c3ccc(Cl)cc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from ω-bromo-4-chloroacetophenone and compound 1 as described for compound 8. Crystallized from methanol. M.p. 142°-144° C.