Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[O:14]=[C:15]1[N:21]2[CH2:22][CH2:23][C@H:20]2[C:19]2=[C:24]([C:27]([NH2:29])=O)[N:25]=[CH:26][N:18]2[C:17]2[CH:30]=[CH:31][S:32][C:16]1=2>O1CCOCC1.N1C=CC=CC=1>[O:14]=[C:15]1[N:21]2[CH2:22][CH2:23][C@H:20]2[C:19]2=[C:24]([C:27]#[N:29])[N:25]=[CH:26][N:18]2[C:17]2[CH:30]=[CH:31][S:32][C:16]1=2
Reactant: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 1658.3 %

Procedure:
5.75 ml (41.3 mmol) of trifluoroacetic anhydride were added dropwise at 5°-8° to a suspension of 11.05 g (40.:2 mmol) of (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carboxamide in 55 ml of dioxan and 7 ml of pyridine. The beige solution obtained was stirred at 50° for 2.5 hours and subsequently poured into 50 ml of ice-water. Extraction with methylene chloride (four times), drying over sodium sulfate, filtration and evaporation yielded a pale brown residue which was chromatographed (silica gel, methylene chloride/methanol 10:1). There were obtained 8.5 g (82%) of (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carbonitrile as a white powder of m.p. 211°-213°.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[O:6][C:5](=[O:10])[CH:4]=1.[ClH:11].[C:12]1(C)[CH:17]=[CH:16][C:15]([S:18](O)=O)=[CH:14][CH:13]=1>C(O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:4]2[C:5](=[O:10])[O:6][C:7]([CH3:9])=[CH:8][C:3]=2[OH:2])=[CH:14][CH:13]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: Cl
Reactant: Cc1ccc(S(=O)O)cc1
Agent: [Na]
Solvent: CCO
Product: Cc1cc(O)c(Sc2ccc(Cl)cc2)c(=O)o1
Reaction time: 6.5 h
Yield: 70 %

Procedure:
A mixture of the monosodium salt of 4-hydroxy-6-methyl-2-pyrone (29.6 g., 0.200 mol), p-chlorophenyl p-toluenethiolsulfonate (59.8 g., 0.200 mol), and 2B absolute ethanol (500 ml.) was heated at reflux with stirring for 6.5 hours. The ethanol was removed by distillation in vacuo and the residue triturated with water (300 ml.). The crude product was removed by filtration, 53.0 g. (m. 166°-177°C., 91% yield); after recrystallization from ethanol, 36.4 g., m. 175°-180°C., 68% yield. A second recrystallization produced the pure product, 18.0 g., m 181°-182°C., 34 percent yield. The aqueous filtrate was acidified with dilute HCl producing 21.8 g. (70 percent yield) of the by-product p-toluenesulfinic acid, m. 87°-89°C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1/[C:11](/[C:14]1[C:19](F)=[C:18]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[CH:17]=[CH:16][N:15]=1)=[N:12]/[OH:13]>C1COCC1.CN(C=O)C.C(Cl)Cl>[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[C:19]2[O:13][N:12]=1
Reactant: O/N=C(/c1ccc(F)cc1Cl)c1nccc(-c2cncnc2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Fc1ccc(-c2noc3c(-c4cncnc4)ccnc23)c(Cl)c1
Temperature: 70 °C
Yield: 33.3 %

Procedure:
To a suspension of sodium hydride (5.69 mg, 0.142 mmol) in THF (Ratio: 1.8, Volume: 1.075 ml) was added dropwise (Z)-(2-chloro-4-fluorophenyl)(3-fluoro-4-(pyrimidin-5-yl)pyridin-2-yl)methanone oxime (0.029 g, 0.084 mmol) in DMF (Ratio: 1.0, Volume: 0.597 ml) slowly. The reaction mixture was heated at 70° C. for 3 hr, and then allowed to cool to room temperature. The reaction was quenched with H2O. The reaction mixture was extracted with EtOAc (3×). The organic phases were combined, dried over Na2SO4, filtered, concentrated, and further dried under high vacuum to afford a brown residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (4 g column, 18 mL/min, 0-80% EtOAc in hexanes over 15 min, tr=3 min) gave the title compound (10.3 mg, 0.028 mmol, 33.9% yield) as a yellow solid. ESI MS (M+H)+=327.0.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=O.[C:6]1(=[O:11])C[CH2:9][CH:8]=[CH:7]1.[C:12]1(N=C=O)C=CC=CC=1>CCOCC.C(N(CC)CC)C>[CH3:12][C:4]1[CH:5]2[C:6](=[O:11])[CH2:7][CH2:8][CH:9]2[O:3][N:1]=1
Reactant: O=C1C=CCC1
Reactant: O=C=Nc1ccccc1
Reactant: CC[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC1=NOC2CCC(=O)C12
Temperature: 25 °C
Yield: 70.2 %

Procedure:
Under an inert atmosphere a solution of nitroethane (4.66 g, 4.44 ml, 62.1 mmol) in ether (15 ml) was treated at room temperature with a solution of cyclopent-2-enone (5 g, 5.1 ml, 60.9 mmol) in ether (90 ml) followed by the addition of triethylamine (70.8 mg, 97.6 μl, 700 μmol) and the dropwise addition of phenyl isocyanate (14.8 g, 13.6 ml, 124 mmol). The light yellow solution was stirred at 25° C. during the weekend. For the workup, the off-white suspension was filtered and washed three times with ether. The filtrate was evaporated, then the crude product was triturated in dichloromethane (15 ml), the solid was filtered off and washed with dichloromethane. After evaporation of the orange-colored filtrate the crude product was purified by flash chromatography on silica gel using a gradient of heptane and ethyl acetate=2:1 to 1:2 as the eluent. The rac-(3aR,6aR)-3-methyl-3a,5,6,6a-tetrahydro-cyclopenta[d]isoxazol-4-one (5.95 g, 70% yield) was obtained as yellow liquid. MS: m/z=139 [M]+. In addition, the rac-(3aR,6aS)-3-methyl-3a,4,5,6a-tetrahydro-cyclopenta[d]isoxazol-6-one (0.37 g, 4.3% yield) was obtained as a yellow oil. MS: m/z=139 [M]+.
Reaction SMILES: [C:1]1([CH2:11][OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[N:19]=[C:18](Cl)[N:17]=1>C1COCC1>[NH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[N:19]=[C:18]([O:12][CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:17]=1
Reactant: OCc1cccc2ccccc12
Reactant: Nc1cc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cc(Cl)nc(OCc2cccc3ccccc23)n1
Reaction time: 0.5 h

Procedure:
1-Naphthalenemethanol (227 mg, 1.44 mmol) is added to a slurry of 50% sodium hydride (69 mg, 1.44 mmol) in dry THF (4 ml) at 0° C. After stirring for 30 minutes, 4-amino-2,6-dichloropyrimidine (157 mg, 0.96 mmol) is added and stirred at 22° C. for 72 hours. The solution is quenched with saturated NH4Cl and concentrated in vacuo. The residue is dissolved in methylene chloride and washed 3× saturated NaHCO3, dried with MgSO4, filtered, and concentrated in vacuo. The sample is purified by chromatography using 1:2 ethyl acetate/hexanes and recrystallization from heptane/toluene, mp 160-161° C.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=3[O:29][CH3:30])[C:14]([S:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:46])=O>ClCCl>[C:1]12([C:11]3[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=3[O:29][CH3:30])[C:14]([S:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([Cl:46])=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)Sc2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: COc1ccc(C(=O)Sc2ccc(C(=O)Cl)cc2)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 1 h
Yield: 100 %

Procedure:
Into a round bottom flask there are introduced 3.80 g (9 mmoles) of 4-[3-(1-adamantyl)4-methoxybenzoylthio] benzoic acid, 40 ml of dichloromethane and 1.8 ml (9 mmoles) of dicyclohexylamine. The reaction mixture is stirred for one hour. To the resulting solution 720 μl (9.9 mmoles) of thionylchloride are added and the mixture is stirred at ambient temperature for 2 hours. It is then evaporated to dryness, and taken up in 500 ml of ethyl ether. The dicyclohexylammonium chloride is filtered and the solvent is evaporated. 3.97 g (100% yield) of crude 4-[3-(1-adamantyl)-4-methoxybenzoylthio] benzoic acid chloride which is used as such for the following synthesis are obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])(=[O:4])=[O:3].O>C(O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH2:8][OH:9])[CH:10]=[CH:11][CH:12]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(C=O)c1
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaBH is added to a solution of 750 mg (4.08 mmol) 3-methanesulphonyl-benzaldehyde in 20 ml ethanol (see P. L. Ornstein, T. J. Bleisch, M. B. Arnold, R. A. Wright, B. G. Johnson, J. P. Tizzano, D. R. Helton, M. J. Kallman, D. D. Schoepp, M. Herin, J. Med. Chem. 1998, 41(3), 358-378 or B. Eistert, W. Schade, H. Selzer, Ber. 1964, 97(5), 1470-81). The reaction mixture is stirred at room temperature for 1 h. The reaction mixture is poured into water and extracted three times with ethyl acetate. The combined organic layers are washed with water and brine, dried, filtered and concentrated in vacuo to afford the title compound, used in the next step without further purification.
Reaction SMILES: O[N:2]=[C:3](C(C)=O)C(OCC)=O.[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=O.S(=O)(=O)(O)O.C=O.[NH3:28]>>[CH3:16][C:14]1[NH:2][CH:3]=[N:28][C:13]=1[C:12]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: CCOC(=O)CC(C)=O
Reactant: N
Agent: C=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1nc[nH]c1C
Reaction time: 4 h
Yield: 50 %

Procedure:
One mole of ethyl 2-hydroxyimino-acetoacetate, prepared from 130 g. (1 m.) of ethyl acetoacetate, was added over 75 minutes to a stirred suspension of 166 ml. (3 m.) of concentrated sulfuric acid and 105 g. (3.5 m.) of paraformaldehyde at 5°-10°. The mixture was stirred at 5°-10° for four hours and aqueous ammonia (28%) was added to pH 5 and the temperature rose to 70°. The reaction mixture was held for 30 minutes at pH 5 at 65°-70° and then neutralized with aqueous ammonia (28%). The mixture was cooled to 10°. The solid material was filtered off, washed with water and isopropanol and dried to give ethyl 5-methyl-4-imidazolecarboxylate (yield 50%).
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[N:15]([CH:30]([CH3:32])[CH3:31])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].ClC([O:36][CH2:37][CH3:38])=O.O.C(O)(=O)C[C:42](CC(O)=O)(C(O)=O)[OH:43].O>CC1C=C(C)C=C(C)N=1>[CH2:37]([O:36][O:11][C:10](=[C:42]=[O:43])[C@H:8]1[O:9][C@@H:1]([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[N:15]([CH:30]([CH3:32])[CH3:31])[N:14]=2)[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@@H:6]1[OH:7])[CH3:38]
Reactant: Cc1c(Cc2ccc(OC(C)C)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1C(C)C
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: CCOOC(=C=O)[C@H]1O[C@@H](Oc2nn(C(C)C)c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a solution of 3-(β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole (0.10 g) in 2,4,6-trimethylpyridine (1 mL) was added ethyl chloroformate (0.072 g), and the mixture was stirred at room temperature overnight. To the reaction mixture were added citric acid monohydrate (3.3 g) and water, and the resulting mixture was purified by ODS solid phase extraction (washing solvent: distilled water, eluent: methanol). Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) and recrystallization (recrystallization solvent: ethyl acetate/hexane=⅓) afforded 3-(6-O-ethoxy-carbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole (0.084 g).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[N+](=[CH2:14])=[N-].[CH3:15][OH:16]>C(OCC)C>[CH3:15][O:16][C:4]([C:3]1[CH2:7][CH2:8][CH2:9][CH2:10][C:2]=1[C:1]([O:6][CH3:14])=[O:11])=[O:5]
Reactant: C=[N+]=[N-]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CO
Solvent: CCOCC
Product: COC(=O)C1=C(C(=O)OC)CCCC1
Reaction time: 8 h
Yield: 93 %

Procedure:
3,4,5,6-tetrahydrophthalic anhydride (3.04 g, 0.02 mol) was disolved in methanol (25 ml) and refluxed for 2 hours. The solution was then cooled to ice bath temperature and a solution of diazomethane in diethyl ether was added dropwise until a yellow colour persisted. The solution was then allowed to stand overnight, after which time the solvent was removed in vacuo to give the title compound In 93% yield. δH (90 MHz, CDCl3) 3.66 (s,6H), 2.20 (s,4H), 1.66 ppm (s,6H)
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4]Cl.[OH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[SH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]>[F:11][C:10]([F:13])([F:12])[C:7]1[CH:8]=[CH:9][C:2]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21][CH2:4][C:3]=2[CH:6]=1
Reactant: FC(F)(F)c1ccc(Cl)c(CCl)c1
Reactant: Oc1ccccc1S
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2c(c1)CSc1ccccc1O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
A solution of 45 g of 2-chloro-5-trifluoromethylbenzyl chloride (B. Pecherer, U.S. Pat. No. 3,465,051; Chem.Abstr. 71, 123 885, 1969) and 37.6 g of 2-hydroxythiophenol (cf.Example 18, reference given) in 800 ml of dimethylformamide is treated with 27.2 g of potassium carbonate and the mixture stirred for 3 hours in a nitrogen atmosphere at a room temperature. Further 30 g of potassium carbonate and 3 g of copper are then added and the mixture refluxed for 12 hours. Dimethylformamide is distilled off in vacuo and the residue separated between water and benzene. It is then filtered, the benzene layer of the filtrate separated, dried with potassium carbonate and processed by distillation. There are obtained 40.2 g of (73%) 2-trifluoromethyl-11H-dibenz (b,f)-1,4-oxathiepin boiling at 135°-137° C./0.1 kPa. The distillate crystallizes from petroleum ether and the pure 1,4-oxathiepin (cf. Example 16) in 30 ml of benzene was added dropwise for 1 hour to a refluxing solution of 3.9 g of ethyl chloroformate in 15 ml of benzene. The mixture was refluxed for 1.5 hours and, after cooling washed with water, with 10% sulfuric acid and again with water. It was then dried with magnesium sulfate and evaporated. The residue (the crude carbamate) was dissolved in 10 ml of ethanol and the solution treated with 9.0 g of potassium hydroxide. Then, the mixture was refluxed for 2 hours in a bath having a temperature of 130° C. It was diluted with water and extracted with benzene. From the benzene solution the basic product was reextracted by shaking with excessive 10% hydrochloric acid. The aqueous layer together with the oily hydrochloride were separated, made alkaline with aqueous ammonia and the released base extracted with benzene. The extract was dried with potassium carbonate and evaporated. There were obtained 4.0 g of an oily base which was neutralized with 1.9 g of oxalic acid in acetone. The hydrogen oxalate crystallized in a yield of 5.15 g was recrystallized from aqueous ethanol and melted at 210°-211° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>CC(C)=O>[CH2:27]([O:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:4](=[O:18])[CH:3]=1)[CH:26]=[CH2:25]
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(=O)n(-c2ccccc2)c2ncccc12

Procedure:
To a mixture of 62 g. of 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one, 39.6 g. of anhydrous potassium carbonate and 1,800 ml of acetone there is added dropwise, with stirring, 37.5 g. of allyl bromide. The reaction mixture is refluxed for 22 hours, concentrated in vacuo, and the residue extracted with 600 ml. of chloroform. The organic extract is washed with water, 1N sodium hydroxide solution and again with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude solid is triturated with 3×400 ml of boiling isopropyl ether, filtered, yielding the insoluble product, wt. 38.5 g. m.p. 171°-174°. Recrystallization from methanol produces the product as a colorless solid, m.p. 176°-177° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([N:27]=[C:28]=[O:29])[CH2:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:28]([NH:27][CH2:23][CH2:24][CH2:25][CH3:26])=[O:29])=[CH:18][CH:17]=1
Reactant: CCCCN=C=O
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: CCCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 56 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinazoline (100 mg) was dissolved in toluene (10 ml) with heat, n-butyl isocyanate (0.29 ml) was added, and the admixture was refluxed with heat for 40 minutes. After removing the solvent by distillation, the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (5/1) to obtain 75 mg of the title compound (yield: 56%).
Reaction SMILES: FC(F)(F)S(O[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH:8]1[C:23]([O:25][CH3:26])=[O:24])(=O)=O.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[C:36]([F:39])([F:38])[F:37].C([O-])([O-])=O.[Na+].[Na+].CCOCC>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:30]1[CH:31]=[C:32]([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH2:9][C:8]=2[C:23]([O:25][CH3:26])=[O:24])[CH:33]=[CH:34][C:35]=1[C:36]([F:37])([F:38])[F:39]
Reactant: OB(O)c1ccc(C(F)(F)F)c(Cl)c1
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)CCC1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(c2ccc(C(F)(F)F)c(Cl)c2)CCN(C(=O)OCc2ccccc2)C1
Temperature: 80 °C
Yield: 94.7 %

Procedure:
To a stirred solution of 3-methyl 1-(phenylmethyl) 4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-piperidinedicarboxylate (3 g) (P38) and [3-chloro-4-(trifluoromethyl)phenyl]boronic acid (1.826 g) in dry toluene (37 mL) under N2 atmosphere at 0° C., Pd(PPh3)4 (292 mg) dissolved in absolute EtOH (26 ml), was added followed by Na2CO3 2M (21 mL). The reaction mixture was heated to 80° C. for 2 h. Et2O was then added to the solution and the organic phase was separated. The aqueous layer was extracted with Et2O and the combined organic phases were washed with saturated NaCl aqueous solution, dried and concentrated under vacuum. The crude was purified by flash-chromatography (eluting with cyclohexane/ethyl acetate from 9:1 to 8:2) to give the title compound (3.03 g).
Reaction SMILES: [CH2:1]([C@H:3]1[C:12]([CH3:14])([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[CH2:4]1)[CH3:2].[C:18](Cl)(=[O:20])[CH3:19].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[C:18]([C:8]1[CH:7]=[C:6]2[C:11]([C:12]([CH3:14])([CH3:13])[C@H:3]([CH2:1][CH3:2])[CH2:4][C:5]2([CH3:16])[CH3:17])=[CH:10][C:9]=1[CH3:15])(=[O:20])[CH3:19]
Reactant: CC[C@@H]1CC(C)(C)c2ccc(C)cc2C1(C)C
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC[C@@H]1CC(C)(C)c2cc(C(C)=O)c(C)cc2C1(C)C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a solution of (R)-3-ethyl-1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene ([α]546 +2.2° (C=0.95 in ethanol)) (36.5 g; 0.159 mol) and acetyl chloride (13.7 g; 0.174 mol) in 1,2-dichloroethane (100 ml), anhydrous aluminum chloride (25.3 g; 0.190 mol) was added at 20° C., and the resulting mixture was stirred for 1 hour. The reaction mixture was treated with dilute hydrochloric acid while cooling with ice. The organic layer was washed with dilute hydrochloric acid, saturated sodium carbonate solution and saturated sodium chloride solution in order, dried over anhydrous sodium sulfate and concentrated t give (R)-7-acetyl-3-ethyl-1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene (41.5 g; 0.153 mol; 96%). B.P., 120° C./0.1 mmHg. [α]365 -46.1° (C=0.97 in ethanol).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9]1[C:14](C(O)=O)=[CH:13][N:12]=[C:11]2[N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][C:10]=12.C([N:31]([CH2:34]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:43])C=CC=CC=1.CCOC(C)=O>O1CCOCC1.O>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:9]2=[C:10]3[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:11]3=[N:12][CH:13]=[C:14]2[NH:31][C:34]1=[O:43]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: C[C@@H]1CCCC[C@@H]1Nc1c(C(=O)O)cnc2c1ccn2COCC[Si](C)(C)C
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc3c(ccn3COCC[Si](C)(C)C)c21
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a solution of 4-{[(1S,2R)-2-methylcyclohexyl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (3.9 g) and triethylamine (5.11 mL) in dioxane (39 mL) was added diphenylphosphoryl azide (5.0 mL) and the mixture was stirred at 120° C. for 3 hours. To the mixture were added EtOAc and water. The organic layer was separated and extracted with EtOAc. The extract was washed with saturated aqueous sodium hydrogencarbonate and brine, dried over MgSO4, filtrated and evaporated. The residue was purified by column chromatography on silica gel with EtOAc and n-hexane (1:4 to 1:2) to give 1-[(1S,2R)-2-methylcyclohexyl]-6-{[2-(trimethylsilyl)ethoxy]methyl}-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (3.33 g) as a white powder.
Reaction SMILES: CS(O[CH:6]1[CH2:9][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH2:7]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>>[N:21]([CH:6]1[CH2:9][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH2:7]1)=[N+:22]=[N-:23]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(OS(C)(=O)=O)C2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC2(CC(N=[N+]=[N-])C2)C1

Procedure:
The process is performed according to the procedure described in Example 6 (step 6.3.). Starting with 1.62 g (5.30 mmol) of tert-butyl 2-methanesulfonyloxy-6-azaspiro[3.4]octane-6-carboxylate (isomer 1′), described in Example 12 (step 12.1.), and 0.68 g (10.61 mmol) of sodium azide, the product is obtained in the form of a yellow oil, which is used without further purification in the following step.