Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[C:6]#[N:7])[CH3:2].F[C:13]1[N:18]=[CH:17][C:16]([N:19]2[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[NH:21][C:20]2=[O:27])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CN(C)C=O.O>[CH3:25][C:22]1([CH3:26])[C:23](=[O:24])[N:19]([C:16]2[CH:15]=[CH:14][C:13]([O:11][C:10]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=3[CH2:1][CH3:2])=[N:18][CH:17]=2)[C:20](=[O:27])[NH:21]1
Reactant: CCc1cc(C#N)ccc1O
Reactant: CC1(C)NC(=O)N(c2ccc(F)nc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCc1cc(C#N)ccc1Oc1ccc(N2C(=O)NC(C)(C)C2=O)cn1
Temperature: 120 °C
Reaction time: 96 h
Yield: 33.7 %

Procedure:
3-ethyl-4-hydroxybenzonitrile (Intermediate 115, 70 mg) was dissolved in 2 mL of dimethylformamide. 3-(6-fluoro-3-pyridinyl)-5,5-dimethyl-2,4-imidazolidinedione (Intermediate 106, 102 mg) and potassium carbonate (126 mg, 0.915 mmol) were added. The reaction mixture was stirred at 120° C. during 96 hours. Some diethyl ether (4 mL) and water (4 mL) were added. The aqueous layer was extracted 4 times with diethyl ether. The gathered organic layers were dried over sodium sulphate and evaporated giving a residue which was purified by flash chromatography on silica gel (companion system, 12 g Si cartridge) using as eluent a gradient cyclohexane/ethyl acetate 100/0, then from 100/0 to 55/45. Evaporation afforded the title compound (54 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]3[CH:26]=2)[CH2:12][CH2:11]1)[C:5]#[N:6].[OH-].[Na+].C([OH:33])(C)(C)C.CO>OO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]3[CH:26]=2)[CH2:12][CH2:11]1)[C:5]([NH2:6])=[O:33]
Reactant: N#Cc1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c(Cl)c1
Reactant: CC(C)(C)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c(Cl)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 3-chloro-4-[4-[(6-chloroimidazo[1,2-a]pyridin-2-yl)methyl]-1-piperazinyl]benzonitrile (Example 29; 0.122 g), NaOH (0.063 g), 30% hydrogen peroxide (2 drops), and tert-butanol (2 mL) is stirred at 80° C. for 4 h, after which it is cooled and concentrated under reduced pressure. The residue is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. The solids remaining suspended in the aqueous layer are collected, washed with water, dried under reduced pressure, and combined with the solids obtained from concentration of the organic layers. The solids are taken up in dichloromethane and methanol with warming and filtered through a cotton plug to remove insolubles. The filtrate is then concentrated and the residue is crystallized from dichloromethane/hexane to give 0.0745 g of the title compound; mp 254-256° C.; MS m/z 403, 405; IR (mineral oil) 1413, 1235, 1597, 800, 1328 cm-1. 1H NMR (DMSOd6) δ2.64, 3.05, 3.69, 7.17, 7.25, 7.37, 7.55, 7.79, 7.84, 7.89, 7.96, 8.80.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:19][C:18]3[C:20]([C:25]4[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:32])=[CH:21][C:22]([F:24])=[CH:23][C:17]=3[CH2:16][CH:15]=[CH:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pt](=O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:19][C:18]3[C:20]([C:25]4[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:32])=[CH:21][C:22]([F:24])=[CH:23][C:17]=3[CH2:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=CCc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Yield: 86.5 %

Procedure:
A solution (R)-(9-(2,6-dichlorophenyl)-7-fluoro-2,5-dihydrobenzo[b]oxepin-2-yl)methyl 4-methylbenzene-sulfonate (0.7 g, 1.4 mmol) in ethyl acetate/ethanol (10/10 mL) was added platinum (IV) oxide (0.2 g) and the mixture hydrogenated at 45 psi of hydrogen for 14 hours. The reaction mixture was then filtered through celite and the filtrate concentrated under reduced pressure. Chromatography with 10–30% ethyl acetate in hexanes afforded 0.60 g (85%) of (R)-(9-(2,6-dichlorophenyl)-7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepin-2-yl)methyl 4-methylbenzene-sulfonate as a colorless oil. [α]D25=+24.81° (c=6.6 mg/0.7 mL MeOH); MS (ES) m/z 512.1 ([M+NH4]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:7][C:6]=2[CH:17]=1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>ClCCl>[Cl:25][CH2:26][C:27]([N:14]1[CH2:13][CH2:12][N:11]([CH2:10][CH:8]2[CH2:7][C:6]3[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:9]2)[CH2:16][CH2:15]1)=[O:28]
Reactant: O=C(Cl)CCl
Reactant: Clc1ccc2c(c1)CC(CN1CCNCC1)O2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCN(CC2Cc3cc(Cl)ccc3O2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
To a solution of 1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine (1.3 g, 5.1 mmol) in dichloromethane (50 ml) was added triethylamine (782 mg, 7.73 mmol, 1.5 eq) and 2-chloroacetyl chloride (758 mg, 6.71 mmol, 1.3 eq) dropwise with stirring at 0° C. for 1 hour at room temperature. The reaction mixture was quenched by the addition of water (80 ml) and extracted with dichloromethane (3×50 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 3% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford 2-chloro-1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]ethan-1-one as yellow oil (1.0 g, 59%); (ES, m/z): [M+H]+ 329; 1H NMR (300 MHz, CDCl3): δ 7.04-7.12 (m, 2H), 6.69 (d, J=8.4 Hz, 1H), 4.95-5.08 (m, 1H), 4.11 (s, 2H), 3.56-3.73 (m, 5H), 3.23-3.32 (dd, J=9.3 Hz, 15.9 Hz, 1H), 2.91-2.99 (dd, J=7.8 Hz, 15.9 Hz, 1H), 2.77-2.84 (dd, J=7.8 Hz, 13.5 Hz, 1H), 2.48-2.75 (m, 4H).
Reaction SMILES: I.[CH3:2][NH:3][C:4](=[NH:7])[S:5][CH3:6].Br[C:9](=[CH:12][O:13]C(C)C)[CH:10]=[O:11].CC#N.C([O-])([O-])=O.[K+].[K+]>O>[CH3:2][N:3]1[C:9]([CH:10]=[O:11])=[CH:12][N:7]=[C:4]1[S:5][CH3:6].[CH3:2][N:3]1[CH:10]=[C:9]([CH:12]=[O:13])[N:7]=[C:4]1[S:5][CH3:6]
Reactant: CC(C)OC=C(Br)C=O
Reactant: CNC(=N)SC
Agent: I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CSc1nc(C=O)cn1C
Product: CSc1ncc(C=O)n1C
Temperature: 35 °C
Reaction time: 16 h

Procedure:
To a mixture of 2.65 g (11.4 mmol) of 1,2-dimethyl-isothiourea hydroiodide and 1.00 g (10.4 mmol) of 2-bromo-3-isopropoxy-propenal 8 mL of MeCN was added 1.58 g (11.4 mmol) of K2CO3 (Shilcrat, S. C. et al. J. Org. Chem., 1997, 62, 8449–8454). The mixture was stirred at 35° C. under N2 for 16 h, water (20 ml) was added, and the mixture was extracted with CH2Cl2 (200 mL). The extract was dried over MgSO4, filtered, concentrated, and chromatographed (0 to 100% EtOAc in hexanes) to provide 1.09 g of 3-methyl-2-methylsulfanyl-3H-imidazole-4-carbaldehyde and 284 mg of 1-methyl-2-methylsulfanyl-1H-imidazole-4-carbaldehyde.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:21])[NH:5][C:6]1[CH:7]=[C:8]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:9]=[CH:10][C:11]=1O)[CH3:2].C(OCC)(=O)C.[ClH:28].C(=O)([O-])[O-].[K+].[K+]>O>[ClH:28].[ClH:28].[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13][C:8]1[CH:9]=[CH:10][C:11]2[O:21][C:4]([NH:3][CH2:1][CH3:2])=[N:5][C:6]=2[CH:7]=1
Reactant: CCNC(=O)Nc1cc(CCc2ccccn2)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCNc1nc2cc(CCc3ccccn3)ccc2o1
Reaction time: 1 h

Procedure:
A mixture of 2-[2-{3-(3-ethylureido)-4-hydroxyphenyl}ethyl]pyridine (3.3 g) and polyphosphate ester (30 g) was stirred at 110° to 115° C. for one hour. To a reaction mixture was added a mixture of ethyl acetate and water and the resultant mixture was acidified to pH 1.0 with 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 8.0 with aqueous 20% potassium carbonate and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to column chromatography on silica gel. The fraction eluted with a mixture of chloroform and methanol (19:1 V/V) was collected and the solvent was evaporated in vacuo. The oily residue was crystallized from 15% hydrogen chloride-ethanol and tetrahydrofuran to give 5-[2-(2-pyridyl)ethyl]-2-ethylaminobenzoxazole dihydrochloride (0.97 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1.C(N(CC)CC)C.Cl.[CH2:18]([O:20][C:21]([NH:23][C:24]1([CH2:30][N:31]2[CH2:36][CH2:35][N:34]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH:46]=[CH2:47])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[CH2:33][C:32]2=[O:48])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:22])[CH3:19]>C(O)C>[CH2:18]([O:20][C:21]([NH:23][C:24]1([CH2:30][N:31]2[CH2:36][CH2:35][N:34]([S:37]([C:40]3[CH:41]=[CH:42][C:43]([CH:46]=[CH2:47])=[CH:44][CH:45]=3)(=[O:38])=[O:39])[CH2:33][C:32]2=[O:48])[CH2:25][CH2:26][N:27]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=2)[CH2:28][CH2:29]1)=[O:22])[CH3:19]
Reactant: OCc1cc(Cl)ccn1
Reactant: C=Cc1ccc(S(=O)(=O)N2CCN(CC3(NC(=O)OCC)CCNCC3)C(=O)C2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=Cc1ccc(S(=O)(=O)N2CCN(CC3(NC(=O)OCC)CCN(c4ccnc(CO)c4)CC3)C(=O)C2)cc1
Yield: 17.5 %

Procedure:
4-Chloro-2-(hydroxymethyl)pyridine (118 mg), triethylamine (500 mg) and ethanol (15 ml) were added to 1-{1-{[4-ethoxycarbonylamino-4-piperidinyl]methyl}-4-(4-vinylbenzenesulfonyl)-2-piperazinone hydrochloride (200 mg), to react at 150° C. for 15 hours in a sealed tube. The reaction solution was concentrated, a 10% aqueous sodium carbonate solution was added to the residue, the mixture was extracted with dichloromethane, dried, and concentrated. The resulting residue was dried, concentrated, purified by column chromatography (dichloromethane:10% aqueous ammonia-containing methanol=20:1), and crystallized from ether to obtain the title compound (40 mg) as pale yellow crystals.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:8]=1[CH:15]=[O:16])(=O)=O.[CH2:19](C([SnH3])=C(CCCC)CCCC)[CH2:20]CC>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>[CH:15]([C:8]1[CH:9]=[CH:10][C:11]([C:13]#[N:14])=[CH:12][C:7]=1[CH:19]=[CH2:20])=[O:16]
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Reactant: N#Cc1ccc(C=O)c(OS(=O)(=O)C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=Cc1cc(C#N)ccc1C=O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
125 mg (0.18 mmol) of bis(triphenylphosphine)palladium(II) chloride are added to a solution of 1 g (3.58 mmol) of 5-cyano-2-formylphenyl trifluoromethanesulfonate and 1.15 ml (3.94 mmol) of tri-n-butylvinylstannane in 6 ml of anhydrous and degassed DMF under an argon atmosphere. The reaction mixture is then stirred at 80° C. for 90 min. Subsequently, 100 ml of 10% strength potassium fluoride solution are added, and the mixture is stirred at RT for 1 h. The suspension is extracted three times with 20 ml of ethyl acetate each time, and the combined organic phases are washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic solution is dried over magnesium sulfate and concentrated. The residue (0.6 g) is employed without further purification in the next stage.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9](O)(=O)[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.B(O)(O)O>C1(C)C(C)=CC=CC=1>[O:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1ccccc1O
Agent: OB(O)O
Solvent: Cc1ccccc1C
Product: c1ccc2oc(-c3ccncc3)nc2c1
Temperature: 25 °C

Procedure:
A mixture of 2-aminophenol (10.9 g, 100 mmol), isonicotinic acid (12.3 g, 100 mmol) and boric acid (6.1 g, 100 mmol) in xylene (500 ml) was heated at reflux, under a nitrogen atmosphere, for 17 hours. The mixture was cooled to room temperature and the orange suspension partitioned between sodium hydroxide solution (4N, 500 ml) and ethyl acetate (500 ml), the phases were separated and the organic layer washed with sodium hydroxide solution (2N, 2×300 ml), water (100 ml) and brine (100 ml).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])=[CH:9][C:8]2=[O:22])([O:3]C)=[O:2].[O:23]1[CH:25]([CH2:26][CH3:27])[CH2:24]1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:24][CH:25]([OH:23])[CH2:26][CH3:27])=[CH:9][C:8]2=[O:22])([OH:3])=[O:2]
Reactant: COC(=O)c1ccc2oc(-c3ccccc3O)cc(=O)c2c1
Reactant: CCC1CO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CCC(O)COc1ccccc1-c1cc(=O)c2cc(C(=O)O)ccc2o1
Yield: 39.3 %

Procedure:
A mixture consisting of 6-carbomethoxy-2'-hydroxy-flavone (10 g), obtained according to the method described in Example 2, and 1,2-epoxy-butane (6 g) and benzyl-trimethylammonium hydroxide (0.5 ml) in dioxane (40 ml) was kept at reflux temperature for 48 hours. After cooling, dilution with water, and extraction with ethylacetate, the organic phase was washed with potassium carbonate 5% and water. The solution was evaporated to dryness, and the resulting product was treated with the stoichiometric quantitity of a solution of potassium hydroxide 1% in ethanol 95% at reflux temperature for an hour. After acidification with acetic acid, concentration under vacuum, dilution with water, filtration and double crystallisation from ethanol, 6-carboxy-2'-(2-hydroxy-butoxy)-flavone (4.7 g) was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][C:10]2[N:11]=[N:12][NH:13][N:14]=2)=[O:8])=[CH:5][CH:4]=1)=O.[CH:17]1([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CN(C=O)C.CO>[CH:17]1([C:23]2[CH:24]=[CH:25][C:26]([NH:27][CH2:1][C:3]3[CH:16]=[CH:15][C:6]([C:7]([NH:9][C:10]4[N:11]=[N:12][NH:13][N:14]=4)=[O:8])=[CH:5][CH:4]=3)=[CH:28][CH:29]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: O=Cc1ccc(C(=O)Nc2nn[nH]n2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(Nc1nn[nH]n1)c1ccc(CNc2ccc(C3CCCCC3)cc2)cc1
Temperature: 70 °C
Yield: 83.4 %

Procedure:
4-Formyl-N-(2H-tetrazol-5-yl)benzamide (8.94 g, 41.2 mmol) was dissolved in DMF (50 mL) by gentle heating. A solution of 4-cyclohexylaniline (7.20 g, 41.2 mmol) in methanol (100 mL) was added and a turbid suspension was formed. The suspension was heated to 70° C. for 1 hour. Acetic acid (50 mL) and sodium cyanoborohydride (2.0 g, 31.7 mmol) was then added. The turbid suspension was heated to 70° C. for an additional hour, before being cooled to 0° C. on an ice bath. The insoluble material was collected by filtration and washed twice with water, before being dried overnight in a vacuum oven to afford 12.94 g (83.5%) of 4-[(4-cyclohexylphenylamino)methyl]-N-(2H-tetrazol-5-yl)benzamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][C:9]2[N:10]=[CH:11][NH:12][C:13](=O)[C:8]=2[CH2:7]1)=[O:5])[CH3:2].C(OC(C1N(C(OC(C)(C)C)=O)CC2C(=O)NC=NC=2C1)=O)C.C(Cl)(Cl)(Cl)[Cl:48].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCCl>[CH2:1]([O:3][C:4]([CH:6]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][C:9]2[N:10]=[CH:11][N:12]=[C:13]([Cl:48])[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2c(nc[nH]c2=O)CN1C(=O)OC(C)(C)C
Reactant: ClC(Cl)(Cl)Cl
Agent: CCOC(=O)C1Cc2nc[nH]c(=O)c2CN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: CCOC(=O)C1Cc2c(Cl)ncnc2CN1C(=O)OC(C)(C)C

Procedure:
To a solution of the mixture of 4-oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylic acid 7-tert-butyl ester 6-ethyl ester and 4-Oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6,7-dicarboxylic acid 6-tert-butyl ester 7-ethyl ester (1.5 g, 4.64 mmol) in DCE (25 mL), carbon tetrachloride (1.34 mL, 13.9 mmol) and triphenylphosphine (2.43 g, 9.28 mmol) are added. The reaction is heated at reflux and after completion of reaction as judged by LCMS. The solvents are removed and the products are isolated using FCC eluting with heptane:EtOAc 80:20. At this point the two products are separated. 4-Chloro-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylic acid 7-tert-butyl ester 6-ethyl ester MS (ESI) m/z 342.1 (M+1) and 4-chloro-7,8-dihydro-5H-pyrido[4,3-a]pyrimidine-6,7-dicarboxylic acid 6-tert-butyl ester 7-ethyl ester MS (ESI) m/z 342.1 (M+1) are isolated as an almost 4:1 ratio.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[CH:14]=[C:13]1[C:12]1[C:7](=[C:8]([CH3:21])[C:9]([O:19][CH3:20])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].C(Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+].[Br:32]Br>C(Cl)Cl.O>[Br:32][C:14]1[C:15](=[O:18])[CH2:16][CH2:17][C:5]2([CH2:1][CH2:2][CH2:3][CH3:4])[C:13]=1[C:12]1[C:7](=[C:8]([CH3:21])[C:9]([O:19][CH3:20])=[CH:10][CH:11]=1)[CH2:6]2
Reactant: CCCCC12CCC(=O)C=C1c1ccc(OC)c(C)c1C2
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCCCC12CCC(=O)C(Br)=C1c1ccc(OC)c(C)c1C2
Reaction time: 0.08 h
Yield: 89 %

Procedure:
A mixture of 9a-butyl-7-methoxy-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (133 mg, 0.468 mmol), CCl4 (0.94 mL), and NaHCO3 (196 mg, 2.333 mmol) was cooled in an ice bath and stirred. Bromine (0.024 mL, 0.467 mmol) was added while stirring and swirling the reaction mixture by hand. A gummy, red precipitate formed during the addition. The mixture was swirled by hand for 5 minutes in order to break up the gum, which gradually changed to a stirrable orange solid. The mixture was stirred and swirled a total of 35 minutes at 0° C. The mixture was diluted with CH2Cl2 and water and shaken. The organic phase was separated, washed with water containing Na2S2O4, washed with brine, dried over MgSO4, filtered, and evaporated under vacuum to a yellow gum (241 mg). The crude product was purified by preparative layer chromatography on two 0.1×20×20 cm silica gel GF plates, developing with 4:1 hexanes-EtOAc. The major UV visible band at Rf 0.39-0.50 was eluted with EtOAc and evaporated under vacuum to give 4-bromo-9a-butyl-7-methoxy-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (151 mg) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH2:22]1[O:30][C:29]2[CH:28]=[CH:27][C:26]([Mg]Br)=[CH:25][C:24]=2[O:23]1>C1COCC1>[OH:1][C:2]1([C:27]2[CH:26]=[CH:25][C:24]3[O:23][CH2:22][O:30][C:29]=3[CH:28]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:3]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Br[Mg]c1ccc2c(c1)OCO2
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
To a solution of ethyl 1-oxo-3-phenylindene-2-carboxylate (1.0 g, 3.6 mmol) in THF (35 ml) under an argon atmosphere at 0° C. was added a solution of freshly prepared 3,4-methylenedioxyphenyl magnesium bromide (5.4 mmol). After stirring for 30 min, the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 10% EtOAc/hexanes to afford the title compound (1.03 g, 72%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[NH:11][N:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]=1[CH2:17][CH2:18][NH2:19].C(N(C(C)C)CC)(C)C.[CH2:29]([C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)[CH2:30][CH2:31][CH2:32][CH3:33]>ClCCl>[CH2:29]([C:34]1[CH:35]=[CH:36][C:37]([S:40]([NH:19][CH2:18][CH2:17][C:8]2[C:9]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[N:10][NH:11][C:7]=2[C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)(=[O:42])=[O:41])=[CH:38][CH:39]=1)[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCc1c(-c2cccs2)n[nH]c1-c1cnccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCc1ccc(S(=O)(=O)NCCc2c(-c3cccs3)n[nH]c2-c2cnccn2)cc1
Reaction time: 3 h
Yield: 30580.7 %

Procedure:
A mixture of the 2-(5-Pyrazin-2-yl-3-thiophen-2-yl-1H-pyrazol-4-yl)-ethylamine 1D (7 mg, 25.8 μmol), diisopropylethylamine (9.0 μl, 51.6 μmol) and 4-n-pentylbenzenesulfonyl chloride (7.0 mg, 28.3 μmol) in dichloromethane (1 mL) was stirred for 3 h. The reaction mixture was concentrated under reduced pressure. The crude product dissolved in methanol (2 ml) and was purified by prep-HPLC. Removal of the solvent in vacuo provided the title compound (3.8 g mg, 41% yield). MS m/e 481; HPLC retention time 3.54 min (Method A).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([N:23]=[N+:24]=[N-:25])=[CH:11][C:10]=1[CH:26]([CH3:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([O:33][C:34](=[O:50])[N:35]([C:48]#[CH:49])[C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1)([CH3:32])([CH3:31])[CH3:30].CCOC(C)=O.O>CN(C=O)C>[C:29]([O:33][C:34](=[O:50])[N:35]([C:48]1[N:23]([C:12]2[CH:11]=[C:10]([CH:26]([CH3:28])[CH3:27])[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][C:13]=2[O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:24]=[N:25][CH:49]=1)[C:36]1[CH:37]=[CH:38][C:39]([N:42]2[CH2:43][CH2:44][O:45][CH2:46][CH2:47]2)=[CH:40][CH:41]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: C#CN(C(=O)OC(C)(C)C)c1ccc(N2CCOCC2)cc1
Reactant: CC(C)c1cc(N=[N+]=[N-])c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cc(-n2nncc2N(C(=O)OC(C)(C)C)c2ccc(N3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 1,5-bis-benzyloxy-2-isopropyl-4-azido-benzene (373 mg, 1 mmol) and ethynyl-(4-morpholin-4-yl-phenyl)-carbamic acid t-butyl ester (275 mg, 0.91 mmol) in DMF (2.5 ml) was flushed with nitrogen three times as previously described before adding [Cp*Ru]4 (49 mg, 0.045 mmol) and repeating the three cycle-degassing with nitrogen. The reaction mixture was stirred at RT until completion (i.e., monitored by TLC). AcOEt and H2O were then added. The organic phase was extracted four times with AcOEt, washed with water (three times) and brine (once) and dried over Na2SO4. The solvent was removed under reduced pressure and the reaction mixture was purified by column chromatography (PE/AcOEt:60/40). The title compound was obtained as an oil.