Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH:13]=O)=[CH:8]2.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].N1CCCCC1.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH:13]=[CH:16][C:17]([OH:19])=[O:18])=[CH:8]2
Reactant: COc1cccc2cc(C=O)ccc12
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1cccc2cc(C=CC(=O)O)ccc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5-Methoxynaphthalene-2-aldehyde (0.1 mole), malonic acid (0.2 moles), and dry pyridine (175 ml) are placed in a 1 1 round-bottom flask. The malonic acid is dissolved by shaking on a steam bath and piperidine (0.5 ml) is added. The reaction is allowed to take place on the steam bath for 4 hours. After standing at room temperature overnight, the mixture is refluxed for 1 hour and cooled. The reaction mixture is poured into 250 ml of ice water and acidified with concentrated hydrochloric acid (80 ml) with stirring. The product is collected by filtration, washed with water (4 × 150 ml) and air dried to give β-(5-methoxynaphth-2-yl)propenoic acid.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=O)=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][NH2:28])[CH3:24]>O>[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][NH:28][C:17](=[O:19])[C:16]1[CH:21]=[CH:22][C:13]([C:3]2[C:4]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[NH:1][N:2]=2)=[CH:14][CH:15]=1)[CH3:24]
Reactant: CCN(CC)CCN
Reactant: COC(=O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Solvent: O
Product: CCN(CC)CCNC(=O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzoate (0.3 g) and N,N-diethylethylenediamine (1 ml) was heated at 150° C. for 3.5 hours and then at 180° C. for 2 hours. The mixture was cooled and dissolved in industrial methylated spirit and this solution was preabsorbed onto silica which was applied to the top of a flash column. The column was eluted with dichloromethane/industrial methylated spirit/triethylamine (25:2:1) to give a solid which was stirred with water for 1 hour, filtered and dried under vacuum at 60° C. to give N-(2-diethylaminoethyl)-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, m.p. 172-174° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1)=[O:28]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: Cn1ccnc1C(=O)CBr
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2nccn2C)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-1-methylimidazole hydrobromide (Preparation is described in Example 241).
Reaction SMILES: CSCCC(Cl)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][CH:14]=[C:13]2[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.[CH3:30][S:31][CH2:32][CH2:33][C:34]([N:36]=[C:37]=[S:38])=[O:35]>C1(C)C=CC=CC=1.C(O)C>[CH3:30][S:31][CH2:32][CH2:33][C:34]([N:36]=[C:37]=[S:38])=[O:35].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][CH:14]=[C:13]2[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:37]([NH:36][C:34](=[O:35])[CH2:33][CH2:32][S:31][CH3:30])=[S:38])=[CH:25][CH:24]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CSCCC(=O)Cl
Agent: CSCCC(=O)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCSC)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
3-(Methylsulphenyl)propanoyl isothiocyanate was prepared using commercially available 3-(methylsulphenyl)propanoyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-(methylsulphenyl)propanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (41 mg, yield 56%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:22].O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(OCC)(=O)C>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:22])=[C:2]([Br:1])[CH:7]=1
Reactant: O=c1[nH]c2ccccc2c(=O)n1-c1ccc([N+](=O)[O-])cc1Br
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)c(Br)c1
Temperature: 70 °C
Yield: 93.3 %

Procedure:
A suspension of 3-(2-bromo-4-nitrophenyl)-1,3-dihydroquinazoline-2,4-dione (0.18 g, 0.5 mmol) and tin (II) chloride dihydrate (0.45 g, 2.0 mmol) in ethyl acetate (5 mL) was heated at 70° C. for 4 hr. The reaction mixture was then cooled, mixed with Celite, made basic with 4N NaOH (3 mL), filtered through Celite, and concentrated in vacuo to give the desired compound (0.155 g, 94%). ES-MS (M+H)+=332, 334 (Br).
Reaction SMILES: [CH2:1]([C:4]1[C:12]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:20])=[C:6]([CH3:21])[C:5]=1[CH2:22][CH3:23])[CH:2]=C.NC(N)=S.C[OH:29]>C(Cl)Cl.N1C=CC=CC=1>[CH2:22]([C:5]1[C:6]([CH3:21])=[C:7]2[C:11]([C:10](=[O:20])[O:9][CH2:8]2)=[C:12]([O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:19])[CH3:17])[C:4]=1[CH2:1][CH:2]=[O:29])[CH3:23]
Reactant: C=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Reactant: CO
Agent: NC(N)=S
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=O)C(=O)OC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
A solution of 6-allyl-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (261 mg, 0.788 mmol) in MeOH (5 mL), CH2Cl2 (5 mL) and pyridine (50 μL) was cooled to −78° C. using a dry ice/acetone bath according to the procedure of Smith, D. B. et al., J. Org. Chem., 1996, 61, 6, 2236. A stream of ozone was bubbled through the reaction via a gas dispersion tube until the reaction became blue in color (15 minutes). The ozone line was replaced with a stream of nitrogen and bubbling continued for another 15 minutes, by which time the blue color had disappeared. To this solution, at −78° C., was added thiourea (59.9 mg, 0.788 mmol) in one portion, and the cooling bath was removed. The reaction was allowed to warm to room temperature and stirred for 15 hours. The reaction mixture was filtered and then partitioned between CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2 one more time and the organic extracts were combined, washed with aqueous 1N HCl, saturated NaHCO3 and brine and dried over sodium sulfate. Filtration and evaporation of solvents in vacuo yielded the crude product, which was purified by silica gel chromatography to afford 181 mg (69%) of the product as a white solid. 1H NMR (300 MHz, CDCl3): δ=0.04 (s, 9H), 1.11 (t, J=7.5 Hz, 3H), 1.19 (m, 2H), 2.21 (s, 3H), 2.66 (q, J=7.5 Hz, 2H), 3.90 (s, 2H), 4.36 (m, 2H), 5.18 (s, 2H), 9.71 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10])=O.[CH3:20][NH:21][NH2:22].O>C1(C)C=CC=CC=1>[CH3:20][N:21]1[N:22]=[C:5]([C:4]2[CH:16]=[CH:17][C:18]([Cl:19])=[C:2]([Cl:1])[CH:3]=2)[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]1=[O:10]
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)c(Cl)c1
Reactant: CNN
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1nc(-c2ccc(Cl)c(Cl)c2)c2ccccc2c1=O
Yield: 84 %

Procedure:
To a solution of 2-(3,4-dichlorobenzoyl)benzoic acid (29.4 g, 0.1 mol) in toluene (100 mL) was added methyl hydrazine (5.8 mL). The mixture was brought to reflux for 3 hours, with the removal of water via a Dean Stark trap. The mixture was cooled, and the product was collected by filtration to afford 25.54 g (84%) of 2-Methyl-4-(3,4-dichlorophenyl)-1-(2H)-phthalazinone, m.p. 179°-181° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1.[C:18]1([S-:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Na+]>CS(C)=O>[C:18]1([S:24][CH2:2][CH2:3][N:4]2[C:16]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=[C:8]([NH2:17])[C:7]=3[N:6]=[CH:5]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [S-]c1ccccc1
Reactant: Nc1nc2ccccc2c2c1ncn2CCCl
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1nc2ccccc2c2c1ncn2CCSc1ccccc1
Temperature: 100 °C
Yield: 80 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 1-(2-chloroethyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 8.11 mmol), sodium benzenethiolate (1.79 g, 12.16 mmol), and anhydrous dimethyl sulfoxide (40 mL) under a nitrogen atmosphere. The reaction mixture was heated to 100° C. to give a homogeneous solution that was maintained at 100° C. for 30 minutes at which time the starting material was completely consumed. The hot solution was poured into rapidly stirred water (300 mL) which caused a solid to precipitate out of solution. The solid was collected by filtration to afford an off-white solid. The material was triturated with acetonitrile and collected by filtration to give 1-[2-(phenylthio)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (2.08 g, 6.49 mmol) as an off-white powder, m. p. 233-235° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].N1C=CC=CC=1.Cl[C:12]([O:14][CH:15]=[CH2:16])=[O:13]>CCOCC>[C:12](=[O:13])([O:14][CH:15]=[CH2:16])[O:4][CH2:3][CH2:2][Br:1]
Reactant: OCCBr
Reactant: C=COC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=COC(=O)OCCBr
Temperature: 25 °C
Reaction time: 27 h
Yield: 78.8 %

Procedure:
To a 1L 4-neck round bottom flask fitted with a mechanical stirrer, thermometer, condenser, dropping funnel and nitrogen blanket was added 31.2 g (250 mmol) of 2-bromoethanol, 21.4 g (270 mmol) of pyridine and 400 mL of ether. The reaction was cooled with an ice-water bath to less than 10° C. then 28.8 g (270 mmol) of vinyl chloroformate was added so that the temperature remained below 10° C. The reaction was stirred to room temperature for 27 hours. Then the organics were washed twice with 2N HCl, twice with 2N NaOH, then dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the resulting oil was passed through a short silica gel column, to remove most of the color, to give 38.4 g (197 mmol, 78.8% yield). FTIR (neat, capillary) 3672.76, 3469.03, 3096.75, 2972.97, 2155.40, 2057.14, 1754.37, 1648.44, 1563.96, 1455.87, 1443.36, 1427.17, 1388.17, 1299.17,.1285.60, 1244.29, 1221.29, 1152.23, 1095.86, 1049.38, 988.10, 940.93, 897.08, 875.78, 828.81, 778.74, 738.01, 694.54, 663.28. NMR (CDCl3) 6.85-7.23 (1H,q), 4.40-5.10 (4H,m), 3.42-3.59(2H,t).
Reaction SMILES: C([Mg]Cl)(C)C.[CH:6]1([NH:9][C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18](I)[C:13]=3[O:12][N:11]=2)[CH2:8][CH2:7]1.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.Cl>O1CCCC1.O>[CH:6]1([NH:9][C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([B:20]([OH:25])[OH:21])[C:13]=3[O:12][N:11]=2)[CH2:8][CH2:7]1
Reactant: Ic1cccc2c(NC3CC3)noc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: OB(O)c1cccc2c(NC3CC3)noc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
Isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 2.83 mL, 5.7 mmol) was added dropwise over 20 minutes to a stirred solution of N-cyclopropyl-7-iodobenzo[d]isoxazol-3-amine (preparation 22 g, 0.50 g, 1.7 mmol) in tetrahydrofuran (10 mL) at −10° C. The mixture was stirred for 1 hour at 0° C. then triisopropyl borate (1.15 mL, 5.0 mmol) was added dropwise over 10 minutes and the mixture was stirred for 1 hour at 0° C. Then, the mixture was warmed to room temperature and stirred overnight. Water was then added, the mixture was cooled by means of an ice-water bath and the pH was adjusted to 1 with 2M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was triturated with diethyl ether and the solid was filtered and dried to give the title compound (140 mg, 39%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[Cl:7][C:8]1[CH:21]=[CH:20][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>C(O)C.O>[Cl:7][C:8]1[CH:21]=[CH:20][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(C)(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(O)COc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 36.7 %

Procedure:
A solution of 8.15 g (0.075 mol) of 1-chloro-2-methyl-2-propanol in 20 ml of ethanol is run over the course of 25 minutes into a solution, kept at about 60° C., of 15 g (0.068 mol) of p-(p-chlorophenoxy)phenol and of 3 g (0.075 mol) of sodium hydroxide pellets in 20 ml of water and 20 ml of ethanol. The mixture is heated to the reflux temperature for 2 hours and the ethanol is driven off under reduced pressure. The residue is extracted with diethyl ether and after drying and evaporation of the solvent gives 7.3 g of a yellow oil. This oil is purified by crystallisation from a mixture of cyclohexane and petroleum ether (1:2 by volume) followed by washing with 2 N NaOH. 4 g of a white powder which is insoluble in water are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH:8]=[O:9])=[C:4]([CH3:12])[CH:3]=1.[C:13]([NH2:17])(=[O:16])[CH2:14]O>O1CCCC1.CCOCC>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH:8]2[NH:17][C:13](=[O:16])[CH2:14][O:9]2)=[C:4]([CH3:12])[CH:3]=1
Reactant: NC(=O)CO
Reactant: Cc1cc(Cl)ccc1OCC=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(Cl)ccc1OCC1NC(=O)CO1
Reaction time: 24 h
Yield: 18.2 %

Procedure:
A solution containing 4.6 g (0.025 mole) of (4-chloro-2-methylphenoxy)acetaldehyde and 2.1 g (0.028 mole) of glycolamide in 25 ml of tetrahydrofuran and 25 ml of ether was allowed to stand at ambient temperature for 24 hours. The resulting product was washed with 5% sodium carbonate and water, dried and purified by silica chromatography to give 1.1 g of 2-(4-chloro-2-methylphenoxymethyl)-4-oxazolidinone as a white crystalline solid melting at 109°-112°.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[CH2:1]([O:5][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][O:23]1)[CH2:2][C:3]#[CH:4]
Reactant: C1=COCCC1
Reactant: C=CCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C#CCCOC1CCCCO1
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of 3-butyn-1-ol 1 (1.00 g, 14.3 mmol) and PPTS (0.72 g, 2.9 mmol) in CH2Cl2 (20 mL) was treated dropwise with dihydropyran (1.7 mL, 19 mmol) and the resulting mixture was stirred for overnight. The reaction mixture was diluted with CH2Cl2 (80 mL) and washed with 0.02 N NaOH (50 mL) and brine (100 mL). The organic layer was dried over MgSO4 and concentrated and the residue was purified with 3-5% EtOAc in hexane on silica gel to give 1.90 g of compound 2 (12.3 mmol, 86% yield): 1H NMR (CDCl3) δ 4.63 (t, J=3.4 Hz, 1H), 3.92˜3.77 (m, 2H), 3.59˜3.45 (m, 2H), 2.47 (td, J=7.1, 2.8 Hz, 2H), 1.96 (t, J=2.5 Hz, 1H), 1.90˜1.44 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:10]2[C:5](=[CH:6][C:7]([C:11]([C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=[O:16])=[O:12])=[CH:8][CH:9]=2)[C:4]([CH3:23])([CH3:22])[CH:3]1[CH3:24].S(=O)(=O)(O)O.[CH2:31](O)[CH3:32]>>[CH3:1][C:2]1([CH3:25])[C:10]2[C:5](=[CH:6][C:7]([C:11]([C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([O:17][CH2:31][CH3:32])=[O:16])=[O:12])=[CH:8][CH:9]=2)[C:4]([CH3:23])([CH3:22])[CH:3]1[CH3:24]
Reactant: CCO
Reactant: CC1C(C)(C)c2ccc(C(=O)c3ccccc3C(=O)O)cc2C1(C)C
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccccc1C(=O)c1ccc2c(c1)C(C)(C)C(C)C2(C)C

Procedure:
A solution of 2.4 g (7.1 mmoles) of 2-[(1,1,2,3,3-pentamethyl-5-indanyl)carbonyl]benzoic acid, described in Example II, in 80 cm3 of ethyl alcohol containing 0.1 cm3 of 98% sulfuric acid, is heated for 12 hours at reflux. The solution is then concentrated under reduced pressure. The crude ester is dissolved in 100 cm3 of ethyl ether. The etherified solution is washed with sodium bicarbonate and then with water, dried on sodium sulfate and finally evaporated to dryness. After drying, 2.5 g of ethyl 2-[(1,1,2,3,3-pentamethyl-5-indanyl)carbonyl]benzoate in the form of a colorless oil are obtained which slowly crystallizes at ambient temperature to give a white solid whose melting point is 56-57° C. The NMR1H 80 MHz and IR spectra conform to the expected structure.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[C:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=O)[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:55][NH:56][C:57](=[NH:59])[CH3:58]>C(Cl)Cl>[O:23]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([NH:59]/[C:57](=[N:56]\[OH:55])/[CH3:58])=[O:19])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][NH:3]1
Reactant: O=C(O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)NCCO3)c1
Reactant: CC(=N)NO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C/C(=N/O)NC(=O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)NCCO3)c1
Reaction time: 0.33 h

Procedure:
To a suspension of the product obtained in Step A above (540 mg, 1.61 mmol) in 10 ml of CH2Cl2 there are added, in succession, 516 mg (1.61 mmol) of TBTU and then 364 μl (2.09 mmol) of DIEA. After stirring for 20 minutes, 120 mg (1.61 mmol) of N-hydroxyacetamidine are added and the reaction mixture is stirred for 1.5 hours at ambient temperature. The reaction mixture is washed with water and then with saturated NaCl solution, dried (MgSO4) and evaporated to dryness. The residue is taken up in CH2Cl2; a white precipitate forms which is filtered off to yield the expected product.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]([NH2:9])=[O:8])=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)(=O)=O>C(#N)C>[Br:1][C:2]1[C:3]([C:7](=[O:8])[NH2:9])=[N:4][N:5]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: NC(=O)c1n[nH]cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c(C(N)=O)n2)CC1
Yield: 37 %

Procedure:
4-bromo-1H-pyrazole-3-carboxamide (673 mg), potassium carbonate (636 mg) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (1187 mg) in acetonitrile (20 ml) were stirred at 90° C. overnight. The mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 55 to 100% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-(4-bromo-3-carbamoyl-pyrazol-1-yl)piperidine-1-carboxylate (489 mg) as a solid. NMR Spectrum: (DMSOd6): 1.41 (s, 9H), 1.78 (dd, 1H), 1.83 (dd, 1H), 1.96-2.04 (m, 2H), 2.90 (bs, 2H), 4.03 (m, 2H), 4.33-4.41 (m, 1H), 7.30 (s, 1H), 7.44 (s, 1H), 8.14 (s, 1H)
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.C(N(CC)CC)C.[NH:19]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C@H:20]([C:24](O)=[O:25])[CH:21]([CH3:23])[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH:19]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C@H:20]([C:24]([NH:1][C@H:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:25])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 19.9 g (110 mmols) of H-Leu-OMe.HCl in 120 ml of dimethylformamide is mixed at 0° C. with 14.6 ml (105 mmols) of triethylamine. The precipitated triethylamine hydrochloride is filtered off, the filtrate added to a solution of 25.1 g (100 mmols) of Z-Val-OH in 200 ml of dimethylformamide at 0° C. and then 22.6 g (110 mmols) of dry dicyclohexylcarbodiimide are added. The batch is stirred for 1 hour at 0° C., then kept overnight in a refrigerator, filtered, and the filtrate is evaporated under a high vacuum at 40° C. The oily residue is taken up in 30 ml of ethyl acetate, the solution cooled to 0° C. and the precipitated dicyclohexylurea is filtered off. On addition of n-hexane the product crystallizes overnight out of the filtrate; it melts at 102°-105° C. Optical rotation [α]D20 =-41° (c=2.88 in methanol).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1.CC(C)([O-])C.[K+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:2][CH2:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10]1
Reactant: C1=Cc2ccccc2C1
Reactant: C=Cc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C1=C(CCc2ccccn2)c2ccccc2C1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
43 g (0.47 mol) of 2-vinylpyridine were added to a mixture of 56 ml (0.48 mol) of indene in 40 ml of toluene and 4 g (0.036 mol) of solid potassium tert-butoxide at 60-90° C. over a period of 40 minutes. The mixture was then stirred for another 2 hours at 115° C., cooled to room temperature and subsequently neutralized by means of 2 ml of glacial acetic acid. Insoluble constituents were filtered off and the filtrate was distilled under reduced-pressure. This gave 42 g of 2-[2-(1H-inden-3-yl)ethyl]pyridine (40%, b.p. 161-163° C. at 2 mm).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Brc1ccc(CN2CCOCC2)cc1
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: CCO
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCOCC2)cc1
Temperature: 120 °C
Yield: 19.6 %

Procedure:
100 mg of 4-(4-Bromo-benzyl)-morpholine was combined with 111 mg of 2-(Trifluoromethyl)phenyl boronic acid, 23 mg of tetrakis(triphenylphosphine)palladium(0), 1.3 mL of 2M sodium carbonate solution, 3.6 mL toluene and 1.7 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was purified by flash chromatography using flash chromatography followed by reverse phase HPLC. 24.6 mg of product is obtained. ES MS (+) m/z 322