Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[C:15]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])#[CH:16]>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:20]([C:19]3[CH:21]=[CH:22][CH:23]=[C:17]([C:15]#[CH:16])[CH:18]=3)[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: C#Cc1cccc(N)c1
Solvent: CC(=O)O
Product: C#Cc1cccc(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)c1
Yield: 87.9 %

Procedure:
To a solution of 10.7 g (0.10 mole) of 4-nitrophthalic anhydride in 150 ml of glacial acetic acid was added 12.9 g (0.11 mole) of 3-ethynylaniline. A white precipitate formed immediately. The mixture was heated to reflux for 1 hour, then cooled and filtered. The precipitate was washed with water and methanol. Recrystallization from toluene gave 25.7 g (87% yield) of 4-nitro-N-(3-ethynylphenyl)phthalimide, m.p. 257°-259° C.
Reaction SMILES: O[CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9](CO)[OH:10])O)O)=[O:4].[CH2:13]([OH:18])[CH2:14][CH:15]([CH3:17])[CH3:16]>OS(O)(=O)=O>[C:9]([O:18][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:10])[CH2:7][CH2:5][C:3]([CH3:2])=[O:4]
Reactant: CC(C)CCO
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)O
Product: CC(=O)CCC(=O)OCCC(C)C
Temperature: 200 °C
Reaction time: 0.05 h
Yield: 18 %

Procedure:
In a first experiment, a mixture of crystalline fructose (10 g) in isoamyl alcohol (40 mL) and concentrated H2SO4 (0.10 mL) was placed in sealed a Teflon-lined reaction vessel inside a high-density rotor for treatment in a MicroSYNTH Microwave Labstation. The sample was heated from room temperature via microwaves to 200° C. in 3 min., and kept there for 3 min. using an irradiation power of 1000 Watts. The vessel was cooled. Analysis indicates a 59% molar yield of isoamyl HMF and 18% yield of isoamyl levulinate from fructose.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH2:12][CH2:13][CH3:14])[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>O>[CH3:11][N:10]1[C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]([CH2:12][CH2:13][CH3:14])=[N:9]1
Reactant: CCCc1cc(C(=O)OCC)n(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCc1cc(C(=O)O)n(C)n1
Temperature: 80 °C
Yield: 73.1 %

Procedure:
1-Methyl-3-n-propylpyrazole-5-carboxylic acid ethyl ester (20.2 g, 0.10 mol) was suspended in 6N aqueous sodium hydroxide solution (50 ml, 0.30 mol). The mixture was heated to 80° C. for 2 hours then diluted with water (50 ml) and acidified with concentrated hydrochloric acid (25 ml). Filtration gave the carboxylic acid as pale brown crystals (12.3 g, 71%), m.p. 150°-154° C. Found: C,56.99; H,7.25; N,16.90. C8H12N2O2 requires C,57.13; H,7.19; N,16.66%.
Reaction SMILES: [Cl:1][C:2]1[C:33]([C:34]2([C:37]#[N:38])[CH2:36][CH2:35]2)=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[N:19]=[C:18]3[S:20][C:21]([NH:23][C:24]([CH:26]4[CH2:28][CH2:27]4)=[O:25])=[N:22][C:17]3=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:8]=1[F:29])=[O:5].[C:39](OC(=O)C)(=[O:41])[CH3:40].O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:39]([N:6]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[N:19]=[C:18]3[S:20][C:21]([NH:23][C:24]([CH:26]4[CH2:28][CH2:27]4)=[O:25])=[N:22][C:17]3=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:8]=1[F:29])[C:4](=[O:5])[C:3]1[CH:30]=[CH:31][CH:32]=[C:33]([C:34]2([C:37]#[N:38])[CH2:36][CH2:35]2)[C:2]=1[Cl:1])(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(NC(=O)C6CC6)sc5n4)ccc3F)c2Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N(C(=O)c1cccc(C2(C#N)CC2)c1Cl)c1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)-N-[5-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-fluorophenyl]benzamide (180 mg, 0.328 mmol) in pyridine (2 mL) were added N,N-dimethylpyridine-4-amine (18.0 mg, 0.147 mmol) and acetic anhydride (138 μL, 1.46 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added water (5 mL), and the mixture was extracted with ethyl acetate (5mL×4). The organic layers were combined, washed successively with water (5 mL) and saturated brine (5 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5→20/80) and, preparative liquid chromatography (0.1% trifluoroacetic acid-containing acetonitrile/0.1% trifluoroacetic acid-containing water=45/55→60/40). The obtained residue was triturated with diisopropyl ether/acetone to give the title compound (68.5 mg, 35%) as a white powder.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=O)([CH3:3])[CH3:2].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C:16]1=[O:24]>>[CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=[C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:15][C:16]1=[O:24])([CH3:3])[CH3:2]
Reactant: O=C1Cc2ccccc2N1
Reactant: COc1cc(C)c(C=O)cc1C(C)C
Product: COc1cc(C)c(C=C2C(=O)Nc3ccccc32)cc1C(C)C

Procedure:
5-Isopropyl-4-methoxy-2-methylbenzaldehyde was condensed with 2-oxindole to give 0.25 g of 3-(5-Isopropyl-4-methoxy-2-methylbenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.CC(C)(O)[C:36]#[N:37].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][C:36]#[N:37])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(CO)cn3)[nH]2)cc1)C1CC1
Reactant: CC(C)(O)C#N
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CCc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 22.8 %

Procedure:
To a solution of [6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]methanol (0.500 g) in tetrahydrofuran (10 mL) were added acetone cyanohydrin (202 mg), tributylphosphine (466 mg) and 1,1′-(azodicarbonyl)dipiperidine (540 mg), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was suspended in ethyl acetate and filtered to remove the precipitate, and the filtrate, and the suspension was concentrated under reduced pressure. The residue was successively purified by silica gel column chromatography (ethyl acetate:hexane=20:80-100:0, volume ratio) and basic silica gel column chromatography (ethyl acetate:hexane=20:80-100:0, volume ratio), and recrystallized from hexane-ethyl acetate to give the title compound (0.116 g, yield 23%) as colorless crystals. MS: 476 (MH+). melting point 139-141° C.
Reaction SMILES: [CH3:1][CH:2]([C:4](=[O:7])[CH2:5][CH3:6])[CH3:3].Cl.[N:9](OCCC(C)C)=[O:10]>COC(C)(C)C.COCCOC>[CH3:1][CH:2]([CH3:3])[C:4](=[O:7])[C:5](=[N:9][OH:10])[CH3:6]
Reactant: CCC(=O)C(C)C
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: COC(C)(C)C
Solvent: COCCOC
Product: CC(=NO)C(=O)C(C)C

Procedure:
100 g (948 mmol) of 2-methylpentan-3-one were dissolved in 400 ml of tert-butyl methyl ether. 50 g (274 mmol) of solution of hydrochloride in ethylene glycol dimethyl ether (20%) were added. Subsequently, a solution of 117 g (949 mmol) isoamyl nitrite in 150 ml of tert-butyl methyl ether was added dropwise within 60 minutes. The solvent was removed fully under reduced pressure. The residue was taken up in 300 ml of n-heptane and concentrated again under reduced pressure. After 200 ml of n-heptane had been added, extraction was effected with 522 ml of sodium hydroxide solution (2 molar). After phase separation, the aqueous phase was washed with n-heptane. The aqueous phase was acidified by adding conc. hydrochloric acid. The product was isolated by filtration with suction, washed with water and dried at elevated temperature under reduced pressure.
Reaction SMILES: C(S[N:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[S:6]1(=[O:15])=[O:14])CC.[OH2:16].ClCl>C(O)(=O)C>[CH2:9]([N:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([S:6]([NH2:5])(=[O:14])=[O:16])[C:7]=2[S:6]1(=[O:14])=[O:15])[CH2:8][CH2:7][CH2:13][CH3:12]
Reactant: O
Reactant: CCCSN1Cc2ccccc2S1(=O)=O
Agent: ClCl
Solvent: CC(=O)O
Product: CCCCCN1Cc2cccc(S(N)(=O)=O)c2S1(=O)=O
Temperature: 25 °C

Procedure:
A solution of 9.5 g of 2-pentyl-7-(propylthio-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide in 40 ml of acetic acid containing 1.3 ml of water was contacted with 7.0 ml of liquified chlorine at 10° to 15° C. and allowed to warm to 25° C. The excess chlorine was removed via a stream of nitrogen gas and the solution was poured onto ice. The resulting solid was filtered, washed with water and hexane, dried, dissolved in CH2Cl2 and contacted with 2.0 ml of liquified ammonia at -78° C. to 25° C. The mixture was added to 100 ml of 1N HCl and extracted with CH2Cl2. The extract was washed with water and brine, dried over MgSO4, concentrated and slurried in ether to give 6.35 g of the title compound as a white powder, m.p. 156°-160° C.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:22]([O:21][C:17](=[O:20])[CH:18]=[CH:19][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Brc1ccc2c(c1)CCc1ccccc1N2
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C=Cc1ccc2c(c1)CCc1ccccc1N2
Temperature: 100 °C
Yield: 33.6 %

Procedure:
A mixture of 2-bromo-10,11-Dihydro-5H-dibenzo[b,f]azepin (4.11 g, 15 mmol, prepared as described in Tetrahedron (1992), 48, 4779) tert-butyl acrylate (2.91 g, 22.5 mmol), palladium acetate (40 mg, 0.2 mmol), tri-o-tolylphosphine (183 mg, 0.6 mmol) and triethylamine (20 ml) in an screw cap ampoule was heated at 100° C. for 20 h. The cooled reaction mixture was diluted with ethyl acetate (50 ml), washed with water (3×20 ml), dried (MgSO4), filtered and evaporated in vacuo. The residue (3.9 g) was purified by column chromatography on silicagel (600 ml) using a mixture of ethyl acetate and heptane (1:6) as eluent which afforded 1.62 g (34%) of 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-2-yl)acrylic acid tert-butyl ester as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1.Cl.[NH2:14][OH:15].C(=O)([O-])O.[Na+].O>CO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:11][O:15][NH2:14])=[CH:6][CH:5]=1
Reactant: NO
Reactant: COC(=O)c1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C=NON)cc1
Yield: 81 %

Procedure:
In 200 ml of methanol were dissolved 16.5 g of 4-cyanobenzoic acid methyl ester and 7.2 g of hydroxylamine hydrochloride. To the solution was added 8.82 g of sodium hydrogencarbonate at room temperature. The mixture was heated for 3 hours under reflux. The reaction mixture was cooled, to which was added 400 ml of water. Resulting crystalline precipitate was collected by filtration, which was washed with water and ether, followed by drying under reduced pressure to afford 16.1 g of the titled compound as colorless needles.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:9]([O:20][CH3:21])=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2].C=O.[C:24](O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CO>[N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([CH3:24])[CH2:18][CH2:19]2)[C:9]([O:20][CH3:21])=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2]
Reactant: CC(=O)O
Reactant: COc1cc(C#N)c([N+](=O)[O-])cc1OCC1CCNCC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C#N)c([N+](=O)[O-])cc1OCC1CCN(C)CC1
Yield: 86.3 %

Procedure:
2-nitro-4-(1-piperidin-4-ylmethoxy)5-methoxybenzonitrile (771 mg, 2.65 mmol) in CH2Cl2 (8 ml) and MeOH (4 ml) was reacted for 0.5 hour with formaldehyde (13.3 M, 300 μl, 4 mmol), acetic acid (191 mg, 3.18 mmol) and NaBH(OAc)3 (674 mg, 3.18 mmol) slowly added over 15 minutes. The solution was evaporated, the oily residue was taken up in a mixture of Na2CO3 and ethylacetate, extracted with ethylacetate. The organic phase was dried over MgSO4, evaporated to give title compound as a yellow solid (698 mg, 86%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[CH2:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=1)C1C=CC=CC=1.[N+:24]([C:27]1[CH:32]=[CH:31][C:30](ON)=[CH:29][CH:28]=1)([O-:26])=[O:25]>Br.C(O)(=O)C>[CH2:18]([C:17]1[O:22][C:30]2[CH:31]=[CH:32][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][C:29]=2[C:16]=1[C:15](=[O:23])[C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1)[CH2:19][CH2:20][CH3:21]
Reactant: NOc1ccc([N+](=O)[O-])cc1
Reactant: CCCCC(=O)CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
1-(4-Benzyloxyphenyl)-heptane-1,3-dione (191 mg; see Example 1 (a)), was suspended in 1 ml HBr/acetic acid and O-4-nitrophenylhydroxylamine, 100 mg, was added. The mixture was stirred at room temperature for 6 h. After quenching with water and extraction to EtOAc followed by evaporation of the solvent, a crude material containing approximately 125 mg of the title compound was obtained. Yield ca. 59%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([Br:16])=[N:11][NH:10][C:9]2=[O:17])=[O:5])[CH3:2].[H-].[Na+].Br[CH:21]([CH3:24])[CH2:22]O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([Br:16])=[N:11][N:10]([CH:21]([CH3:24])[CH3:22])[C:9]2=[O:17])=[O:5])[CH3:2]
Reactant: CC(Br)CO
Reactant: CCOC(=O)c1ccc2c(Br)n[nH]c(=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
Bromo-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid ethyl ester (6 g, 0.02 mol) was dissolved in dimethylformamide (DMF) (60 ml). To this was added NaH (60%, 0.97 g, 0.024 mol) as a DMF suspension (5 ml). The mixture was stirred at room temperature for 30 minutes then 2-bromo-propanol (3.7 g, 0.03 mol) was added in one portion as a solution in DMF (5 ml). The reaction mixture was stirred for 48 hours whereupon LC-MS showed complete consumption of starting material. The DMF was removed under vacuum and the resulting residue was partitioned between DCM (100 ml) and water (100 ml), the organic layer was dried (MgSO4), filtered and concentrated under vacuum. The resulting yellow oil was recrystallised from methanol to give the title compound (2.3 g, 34% yield) as a white solid. MS (ESI+)=(M+H)+ 339 & 341
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8](Cl)=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].Cl.[NH2:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[OH:22].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[OH:22])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1ccc2nc(Cl)sc2c1Br
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1Br
Temperature: 125 °C
Reaction time: 12 h

Procedure:
To the solution of 7-bromo-2-chloro-6-methoxybenzo[d]thiazole (150 mg, 0.539 mmol, 1.0 eq) in 1 mL of NMP was added (1R,2R)-2-aminocyclohexanol hydrochloride (0.123 mg, 0.809 mmol, 1.5 eq) and DIPEA (263 μL, 1.503 mmol, 2.8 eq) at room temperature. The reaction mixture was stirred at 125° C. for 12 hours, thereafter the mixture was diluted with saturated sodium bicarbonate solution (ca. 100 mL) and aqueous layer extracted with ethyl acetate (ca. 200 mL×3). Combined organic layers were dried over sodium sulfate, filtered and condensed under reduced pressure to give crude product as brown oil which was sufficiently pure and was carried to next step without further purification. LC/MS (m/z) [359.0] (MH+)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([C:25]2[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1>CN(C=O)C.O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([C:25]2[CH:32]=[CH:31][C:28]([CH2:29][N:6]3[C:5]4[C:9](=[N:10][C:2]([Cl:1])=[N:3][C:4]=4[Cl:11])[N:8]=[CH:7]3)=[CH:27][CH:26]=2)=[O:24])=[CH:33][CH:34]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)c1ccc(Cn2cnc3nc(Cl)nc(Cl)c32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.1 %

Procedure:
To a solution of 2,6-dichloropurine (3.25 g) in DMF (34 ml) was added potassium carbonate (2.85 g) as well as 4-(4-chlorobenzoyl)benzyl bromide (5.32 g) and the mixture was stirred at room temperature for 24 hours. This reaction mixture was diluted with water and extracted with ethyl acetate and the extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1-1:3) to provide the title compound (1.37 g, 19%) as colorless (anhydrous) powder. 1H-NMR (CDCl3) δ5.76(2H,s), 7.21-7.85(8H,m), 8.33(1H,s).
Reaction SMILES: [Li]CCCC.[CH3:6][Si:7]([CH3:14])([CH3:13])[C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>CCOCC>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])[C:10]1[S:9][C:8]([Si:7]([CH3:14])([CH3:13])[CH3:6])=[N:12][CH:11]=1)[CH2:25][CH2:26][CH3:27]
Reactant: C[Si](C)(C)c1nccs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cnc([Si](C)(C)C)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of n-BuLi (2.5M in hexane, 6.0 mL, 15 mmol) in ether (60 mL) at −78° C. is added a solution of 2-(trimethylsilyl)thiazole (2.0 mL, 12.5 mmol) in ether (20 mL) dropwise. The mixture is stirred at −78° C. for 1 h then tributyltin chloride (4.04 mL, 15 mmol) in ether (25 mL) is added dropwise and stirring is continued at −78° C. for 1 h. The reaction mixture is washed with saturated NaHCO3, dried over anhydrous MgSO4 and concentrated to afford the title compound as a yellow oil which used in the next step without further purification: 1H NMR (CDCl3) δ 0.41 (s, 9H), 0.90 (t, J=8 Hz, 9H), 1.14 (q, 6H), 1.13 (q, 6H), 1.54 (m, 6H), 8.06 (s, 1H); (M+1)+=447.
Reaction SMILES: [O:1]=[S:2]1(=[O:49])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]3[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.S(Cl)([Cl:52])=O>ClC(Cl)C>[O:1]=[S:2]1(=[O:49])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]3[CH:41]=[CH:40][C:36]([C:37]([Cl:52])=[O:38])=[CH:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)Cl)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 73.2 %

Procedure:
A mixture of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (200 mg, 0.289 mmol) and thionyl chloride (0.211 mL, 2.89 mmol) in dichloroethane (5 mL) was refluxed for 30 h. The reaction mixture was concentrated under reduced pressure to provide the title compound as a white solid (150 mg, 73%). LCMS: m/e 705.46 (M−Cl+OMe+H)+, 3.0 min (method 10).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[C:10]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:12][CH2:13][CH3:14])=[O:11]>C1(C)C=CC=CC=1>[CH2:13]([O:12][C:10](=[O:11])[CH:15]=[CH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)[CH3:14]
Reactant: Cc1cccc(C=O)n1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cccc(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A mixture of 6-methyl-pyridine-2-carbaldeyde (3.0 g, 24.8 mmol) and carbethoxymethylene triphenylphosphorane (9.5 g, 27.2 mmol) in toluene (20 ml) was stirred at room temperature overnight. The precipitate was filtered and washed with toluene. The filtrate was concentrated, and the residue was purified via flash chromatography (DCM/MeOH) affording 3-(6-Methyl-pyridin-2-yl)-acrylic acid ethyl ester CCLII in 63% yield (2.95 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[C:4]([C:10]2[N:14]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]3=[N:12][CH:11]=2)[CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=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>[Cl:19][C:17]1[CH:16]=[CH:15][N:14]2[C:10]([C:4]3[CH:3]=[C:2]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=3)=[CH:11][N:12]=[C:13]2[CH:18]=1
Reactant: CNc1cc(-c2cnc3cc(Cl)ccn23)cc(Cl)n1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CNc1cc(-c2cnc3cc(Cl)ccn23)cc(-c2ccccc2)n1

Procedure:
[6-Chloro-4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-pyridin-2-yl]-methyl-amine (1 eq, 0.19 mmol, 56 mg) and phenylboronic acid (1.1 eq, 0.21 mmol, 25.6 mg) are dissolved in DME (2 ml) and water (0.5 ml) and Na2CO3 (1.5 eq, 0.29 mmol, 35.5 mg) is added. PdCl2(PPh3)2 (0.1 eq, 0.019 mmol, 13.4 mg) is 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 [4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-6-phenyl-pyridin-2-yl]-methyl-amine as a brown solid; [M+H]+=335