Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)CCC2C=CC=CC=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].Br[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:44][O:43][C:37]1[CH:36]=[C:35]([CH2:34][CH2:33][N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]([CH3:6])([CH3:1])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH3:42]
Reactant: COc1ccc(CCBr)cc1OC
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: COc1ccc(CCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1OC

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-(2-bromo-ethyl)-3,4-dimethoxy-benzene and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([O:17]CC2C=CC=CC=2)=[CH:12][C:11]=1[Cl:25])(=[O:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([Cl:25])=[CH:12][C:13]([OH:17])=[CH:14][C:15]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)OCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OCCCCOc1c(Cl)cc(O)cc1Cl
Yield: 100.8 %

Procedure:
A mixture of 33.0 grams (0.086 mole) of 4-[2,6-dichloro-4-(phenylmethoxy)phenoxy]butyl acetate and 0.05 gram (catalyst) of 10% palladium on carbon in 350 mL of ethanol was subjected to hydrogenation conditions using a Parr hydrogenator. After the theoretical uptake of hydrogen, gas chromatographic (GC) analysis of the reaction mixture indicated the reaction was about 50% complete. Additional catalyst was added and the reaction mixture was again subjected to hydrogenation conditions using the Parr hydrogenator. GC analysis of the reaction mixture indicated the reaction was now complete. The reaction mixture was filtered and concentrated under reduced pressure, yielding 25.4 grams of the subject compound as a residue. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)([CH3:5])[C:3]#[CH:4].C([Li])CCC.[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][C@@H:25]1[C@@:55]2([CH3:56])[C:29](=[CH:30][CH2:31][C@@H:32]3[C@@H:54]2[CH2:53][CH2:52][C@@:51]2([CH3:57])[C@H:33]3[CH2:34][CH2:35][C@@H:36]2[C@H:37]([CH3:50])[CH2:38]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:28][C@@H:27]([O:58][CH:59]2[CH2:64][CH2:63][CH2:62][CH2:61][O:60]2)[CH2:26]1.N1C=CC=CC=1>O1CCOCC1.CCCCCC>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][C@@H:25]1[C@@:55]2([CH3:56])[C:29](=[CH:30][CH2:31][C@@H:32]3[C@@H:54]2[CH2:53][CH2:52][C@@:51]2([CH3:57])[C@H:33]3[CH2:34][CH2:35][C@@H:36]2[C@H:37]([CH3:50])[CH2:38][C:4]#[C:3][C:2]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)([CH3:1])[CH3:5])[CH2:28][C@@H:27]([O:58][CH:59]2[CH2:64][CH2:63][CH2:62][CH2:61][O:60]2)[CH2:26]1
Reactant: C#CC(C)(C)OC1CCCCO1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](C)[C@H]2CC[C@H]3[C@@H]4CC=C5C[C@@H](OC6CCCCO6)C[C@H](OC6CCCCO6)[C@]5(C)[C@H]4CC[C@]23C)cc1
Agent: [Li]CCCC
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: CCCCCC
Product: C[C@H](CC#CC(C)(C)OC1CCCCO1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
In a 1.5 l 4-neck flask equipped with stirrer, 100 ml dropping funnel with pressure equalizer, 30-cm Dimroth condenser, thermometer and argon-supply, a solution of 16.85 g (0.1 mol) of 3-methyl-3[(tetrahydro-2H-pyran-2-yl)oxy]-but-1-yne (prepared from 3-hydroxy-3-methylbut-1-yne and 3,4-dihydro-2H-pyran) in 300 ml of dioxane with constant stirring and under argon for 30 min. at 9°, was added drop by drop 50 ml (approximately 0.1 ml) of approximately 2 M n-butyl lithium in hexane. The solution was stirred for 2 hr. at 9° and for a further 2 hr. at room temperature. To the light yellow mixture was then added, in one portion, a solution of 22.4 g of crude (20S)-1α,3β-bis[(tetrahydro-2H-pyran-2-yl)oxy]-20-methyl-21-p-toluenesulfonyloxypregn-5-ene (corresponding to approximately 0.033 mol), in 40 ml of dioxane and stirred for 64 hr. at 105° under argon. The mixture, which became dark yellow and cloudy, was cooled to room temperature, poured onto 500 g of ice, and the emulsion was extracted 3 times with 200 ml of ether. The ether extracts were washed successively 2 times with 200 ml of water, combined, dried over sodium sulfate and concentrated under vacuum at 40°. The residue was dissolved in 200 ml of toluene and concentrated under vacuum at 40°. The residue was treated twice more in the same way to remove dioxane and excess 3-methyl-3[(tetrahydro-2H-pyran-2-yl)oxy]-but-1-yne). After drying for 1 hr. under vacuum at room temperature, the remaining light brown oil, 34.1 g (which contained some 3-methyl-3[(tetrahydro-2H-pyran-2-yl)oxy]-but-1-yne and ditetrahydropyranyloxytosylate), was dissolved in ether and added to a column prepared with hexane--ether (9:1), containing 4 ml of pyridine/1, and 1 kg of silica gel. Elution with hexane--ether (4:1) mixtures (without the addition of pyridine) yielded 19.6 g (88%) of 1α,3β,25-tris[(tetrahydro-2H-pyran-2-yl)oxy]-cholest-5-en-23-yne.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:16]([NH:23][CH2:24][CH2:25][CH2:26]Br)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[I-].[K+]>CN(C=O)C>[C:19]([O:18][C:16]([NH:23][CH2:24][CH2:25][CH2:26][O:15][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1O
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(C)(C)C)cc1OCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
Methyl 4-tert-butyl-2-hydroxybenzoate (2.41 g, 11.6 mmol) was dissolved in DMF (15 mL) and K2 CO3 (2.39 g, 17.4 mmol) and N-Boc-3-bromopropylamine (4.14 g, 17.4 mmol) was added using DMF (10 mL) to aid the transfer. Potassium iodide (0.30 g) was added, and the reaction stirred at room temperature under nitrogen for 18 hr. The DMF was removed in vacuo and the residue taken up in ethyl acetate and washed with water and brine, dried, and the solvent removed in vacuo to give a viscous brown oil. Purification by chromaotgraphy over silica on a preparative scale apparatus, eluting with a gradient of hexane to hexane:ethyl acetate (70:30) gave 1.91 g (45.2%) of a viscous yellow oil.
Reaction SMILES: CO[C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[N:31]1([C:3]([C:4]2[CH:5]=[N:6][C:7]([N:10]3[CH:14]=[C:13]([C:15]4[C:16]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:17][O:18][C:19]=4[C:20]([F:23])([F:21])[F:22])[N:12]=[CH:11]3)=[CH:8][CH:9]=2)=[O:30])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Product: O=C(c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1)N1CCOCC1
Yield: 28 %

Procedure:
As described for Example 18, 6-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-nicotinic acid methyl ester (90 mg, 0.22 mmol), was converted, using morpholine instead of cyclopropanemethylamine, to the title compound (28 mg, 28%) which was obtained as a yellow oil. MS: m/e=470.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[C:4]([C:16]#[C:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)[CH:3]=1.CC([O-])(C)C.[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:16]=[C:17]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[NH:8][C:5]2=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C#CC1CCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc2cc(C3CCC3)[nH]c2cn1
Temperature: 90 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
To the solution of tert-butyl 6-chloro-4-(cyclobutylethynyl)pyridin-3-ylcarbamate (2.6 g, 8.5 mmol) in DMF (50 mL) was added t-BuOK (1.9 g, 16 mmol). The reaction mixture was stirred at 90° C. for 2 h. The mixture was diluted with water and extracted with dichloromethane (3×50 mL). The extract was washed with brine, dried, concentrated in vacuo and purified by chromatography on silica gel (5-10% ethyl acetate in petroleum ether as eluant) to afford the pure product of 5-chloro-2-cyclobutyl-1H-pyrrolo[2,3-c]pyridine (0.9 g, 53% yield). 1H NMR (300 MHz, CDCl3) δ: 8.66 (br, s, 1H), 8.45 (s, 1H), 7.44 (s 1H), 6.27 (s, 1H), 3.75-3.52 (m, 1H), 2.52-1.90 (m, 6H).
Reaction SMILES: B1([C:7]2[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)OCCCO1.Br[C:16]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][C:17]=1[NH2:18].C(=O)([O-])[O-].[K+].[K+].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>[CH:23]([C:21]1[CH:20]=[CH:19][C:17]2[C:16](=[C:7]3[C:12](=[C:13]([NH2:14])[N:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:22]=1)([CH3:25])[CH3:24]
Reactant: CC(C)c1ccc(N)c(Br)c1
Reactant: N#Cc1ccccc1B1OCCCO1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)c1ccc2nc(N)c3ccccc3c2c1
Temperature: 25 °C

Procedure:
A 500 ml round bottom flask was charged with 12.2 grams (65.4 mmol) of 2-cyanophenylboronic acid propanediol ester, 14.0 g (65.4 mmol) of 2-bromo-4-isopropylaniline, 2.27 (2 mmol) tetrakis(triphenylphosphine)palladium, 18.0 g (131 mmol) of potassium carbonate, 150 ml toluene, and 50 ml ethanol. The reaction was heated to reflux under N2 for 18 hours. After cooling to room temperature the reaction was extracted with ethyl acetate and water. The organic was washed with brine and then dried with magnesium sulfate. The solids were collected by filtration and the solvent removed from filtrate. The product was purified by silica gel chromatography using 94.5% dichloromethane, 5% methanol, 0.5% ammonium hydroxide as the eluent. The fractions containing the desired product were combined and the solvent removed. The product was confirmed by NMR and mass spectroscopy.
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N+:10]([CH3:13])([O-:12])=[O:11]>>[N+:10]([CH:13]=[CH:6][C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1)([O-:12])=[O:11]
Reactant: O=Cc1ccc(O)cc1
Reactant: C[N+](=O)[O-]
Product: O=[N+]([O-])C=Cc1ccccc1

Procedure:
In the present application, the Henry reaction between p-hydroxy benzaldehyde and nitromethane at 90° C. was carried out, resulting in the formation of nitrostyrene. Typically, 20 mg of a particular aminofunctionalized mesoporous sample was added into a mixture of 122 mg (1 mmol) p-hydroxybenzaldehyde and 10 mL of nitromethane. The reaction mixture was stirred at 90° C. under nitrogen and aliquots of the reaction product were taken with a filter syringe and characterized by solution 1H NMR spectroscopy and GC-MS over the course of the reactions. The percent yield and conversion were determined by using 1H NMR spectra measured in deutrated acetone.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[C:14]1([C@H:20]([CH3:23])[CH2:21][NH2:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>O>[C:14]1([C@H:20]([CH3:23])[CH2:21][NH:22][C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@H](CN)c1ccccc1
Reactant: O=C(Cl)c1cnc2ccccc2n1
Solvent: c1ccncc1
Solvent: O
Product: C[C@H](CNC(=O)c1cnc2ccccc2n1)c1ccccc1
Yield: 74.9 %

Procedure:
Prepared from 2-quinoxaloyl chloride (0.47 g, 2.4 mmol), (S)-2-phenyl-1-propylamine (0.30 g, 2.2 mmol), pyridine (5 mL), and water (50 mL) yielding 0.48 g (74%) of (173):
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:25][CH2:26][CH2:27][CH3:28])[N:18]([CH2:19][CH2:20][CH2:21][C:22](=O)[CH3:23])[C:14]=2[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1>CO>[CH3:3][O:2][N:4]=[C:22]([CH2:21][CH2:20][CH2:19][N:18]1[C:14]2[C:13]3[N:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:5])[C:15]=2[N:16]=[C:17]1[CH2:25][CH2:26][CH2:27][CH3:28])[CH3:23]
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCC(C)=O
Reactant: CON
Agent: Cl
Solvent: CO
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCC(C)=NOC
Reaction time: 8 h
Yield: 99 %

Procedure:
Methoxylamine hydrochloride (0.59 g, 21 mmol, 1.5 eq) was added to a solution of 5-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)pentan-2-one (1.54 g, 4.73 mmol, 1 eq) in methanol (20 mL) and stirred overnight. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (100 mL) and saturated aqueous sodium bicarbonate (75 mL). The aqueous layer was extracted with dichloromethane (2×25 mL) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford a yellow solid. The material was subjected to HPFC (silica gel, eluting with 0-25% CMA in chloroform), triturated with hot acetonitrile, filtered, and dried at 100° C. under vacuum for 24 hours to afford 1.66 g of 5-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)pentan-2-one O-methyloxime as a white powder with an E/Z ratio of 80:20, mp 132-134° C. Anal. calcd for C19H26N6O: C, 64.38; H, 7.39; N, 23.71. Found: C, 64.19; H, 7.42; N, 23.76.
Reaction SMILES: C(OC1N=C2C(N=C(OC)N2CCCC2CCCCN2)=C(N)N=1)CCC.[NH2:27][C:28]1[N:36]=[C:35]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])[N:34]=[C:33]2[C:29]=1[N:30]=[C:31]([O:62][CH3:63])[N:32]2[CH2:42][CH2:43][CH2:44][CH2:45][CH:46]1[CH2:51][CH2:50][N:49](C(OCC2C=CC=CC=2)=O)[CH2:48][CH2:47]1>>[CH2:38]([O:37][C:35]1[N:34]=[C:33]2[C:29]([N:30]=[C:31]([O:62][CH3:63])[N:32]2[CH2:42][CH2:43][CH2:44][CH2:45][CH:46]2[CH2:47][CH2:48][NH:49][CH2:50][CH2:51]2)=[C:28]([NH2:27])[N:36]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1

Procedure:
Prepared similarly to Intermediate 32 from phenylmethyl 4-{4-[6-amino-2-(butyloxy)-8-(methyloxy)-9H-purin-9-yl]butyl}-1-piperidinecarboxylate.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][N:2]=1.C(OO)(=[O:13])C>C(O)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][N+:2]=1[O-:13]
Reactant: c1ccc2cnncc2c1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Product: [O-][n+]1cc2ccccc2cn1
Temperature: 80 °C

Procedure:
Phthalazine (0.40 moles) was dissolved in 200 ml of glacial acetic acid. Under nitrogen, 10 ml portions of a 32% solution of peracetic acid in acetic acid were added until 0.44 mole had been added and then the mixture was heated to 80° C. for 1 hour. The resulting reaction mixture was cooled to room temperature and the acetic acid was removed using a rotary evaporator. The solid residue was suspended/dissolved in 500 ml water and treated with 50 ml of 50% sodium hydroxide and extracted 5 times with 500 ml of dichloromethane. The organic extracts were combined, dried over magnesium sulfate, crystallized from dichloromethane-hexane, and vacuum-dried to yield 50.1 g of phthalazine N-oxide (0.34 mole), mp (DSC)=149° C. GC analysis showed the desired product contained less than 0.5% phthalazine.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]#[N:11])=[CH:2]1>CCO.[Pd]>[CH:3]1([C:10]#[N:11])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH2:2]1
Reactant: N#CC1=CCc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: N#CC1CCc2ccccc21
Reaction time: 8 h
Yield: 95 %

Procedure:
A suspension of 5% Pd on carbon in a solution of 1H-indene-3-carbonitrile in EtOH (200 ml) was placed under an atmosphere of hydrogen with vigorous stirring overnight. After removal of excess hydrogen from the reaction the solution as filtered through celite and concentrated to an oil. The resulting oil was re-dissolved in EtOH and filtered a second time to remove the remaining carbon and catalyst. Evaporation of solvent afforded 12.0108 g of 1-indanecarbonitrile (95% yield) as an oil.
Reaction SMILES: [CH3:1][CH:2]([C:11]([OH:13])=[O:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Br)=[CH:5][CH:4]=1.[C-:14]#[N:15].[K+]>CCO.O>[C:14]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([CH3:1])[C:11]([OH:13])=[O:12])=[CH:4][CH:5]=1)#[N:15]
Reactant: [C-]#N
Reactant: CC(C(=O)O)c1ccc(CBr)cc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1ccc(CC#N)cc1
Temperature: 80 °C

Procedure:
A suspension of 2-(4-bromomethyl)phenylpropionic acid (2.0 g, 8.2 mmol) and potassium cyanide (1.6 g, 24.7 mmol) in EtOH (10 mL) and water (2 mL) was heated at 80° C. in a sealed tube for 1 h. The mixture was cooled to room temperature, diluted with water (10 mL) and the EtOH was removed under reduced pressure. The remaining aqueous mixture was extracted once with EtOAc then acidified carefully with 2N HCl until pH˜3 is reached. The aqueous layer was extracted with EtOAc and the combined organic layer was dried over MgSO4, filtered, and concentrated to give 2-[4-(cyanomethyl)phenyl]propionic acid in ˜90% purity. This material was used directly in the next step. A mixture of 2-[4-(cyanomethyl)phenyl]propionic acid (1.4 g, 7.4 mmol) in MeOH (8 mL) and aqueous NaOH(SN, 8 mL, 40 mmol) was heated at 85° C. in a sealed tube for 1.5 h. The mixture was cooled to room temperature, the MeOH was removed under reduced pressure, and the remaining aqueous was extracted with once ether. The aqueous layer was acidified with 2N HCl until pH˜2 to generate a precipitate that was filtered and dried under vacuum to afford 2-[4-(carboxymethyl)phenyl]propionic acid (1.1 g, 71%) as an off-white solid; 1H NMR (400 MHz, DMSO-d6) δ 12.27 (br s, 1H), 7.15-7.22 (m, 4H), 3.61 (q, J=6.8 Hz, 1H), 3.50 (s, 2H), 1.30 (d, J=7.2 Hz, 3H); MS (Electrospray): m/z 163.1 (M-CO2H). To a suspension of (R)-1-[5-(2,2,2-trifluoroethoxy)pyridine-2-yl]ethanamine bis-HCl (0.39 g, 1.3 mmol), 2-[4-(carboxymethyl)phenyl]propionic acid (0.35 g, 1.7 mmol), EDC (0.35 g, 1.8 mmol), and 1-hydroxy-7-azabenzotriazole (0.25 g, 1.8 mmol) in DMF (5 mL) was added diisopropylethylamine (1.2 mL, 6.7 mmol). After stirring for 2 h at room temperature, the mixture was diluted with water (20 mL) and extracted with dichloromethane. The organic layer was dried over MgSO4, filtered, and concentrated to give a crude oil that was purified by preparative reversed-phase HPLC to give 2-{4-[2-oxo-2-(((1R)-1-[5-(2,2,2-trifluoroethoxy)-pyridine-2-yl]ethyl)amino)ethyl]phenyl}propionic acid mono-TFA salt as a foam; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J=7.6 Hz, 1H), 8.33 (d, J=2.8 Hz, 1H), 7.49 (dd, J=2.8 and 8.8 Hz, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.19 (s, 4H), 4.88-4.93 (m, 1H), 4.85 (q, J=8.8 Hz, 2H), 3.62 (q, J=7.2 Hz, 1H), 3.44 (s, 2H), 1.35 (d, J=8.0 Hz, 3H), 1.33 (d, J=7.6 Hz, 3H); MS (Electrospray): m/z 411.4 (M+H).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:26][C:27]1[C:31]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[C:30]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[NH:29][N:28]=1>O1CCCC1.O>[CH:1]1([CH2:7][C:8]([NH:26][C:27]2[C:31]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[C:30]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[NH:29][N:28]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: O=C(O)CC1CCCCC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(CC1CCCCC1)Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: -10 °C
Yield: 29.1 %

Procedure:
220 mg of cyclohexylacetic acid was dissolved in 10 ml of tetrahydrofuran. While this solution was being cooled at −10° C., 160 mg of N-methylmorpholine and 220 mg of isobutyl chloroformate were added thereto with stirring. The resulting mixture was stirred for 15 minutes. After the addition of 127 mg of 3-amino-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole, the mixture was stirred for 30 minutes and then stirred at room temperature for 4 days. After the addition of water, the reaction mixture was extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. After the resulting residue was dissolved in 10 ml of methanol, 1 ml of 2N sodium hydroxide was added thereto, followed by stirring at room temperature for 90 minutes. Then, the solvent was distilled off under reduced pressure. After the addition of water, this mixture was extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography using 30 g of silica gel [with an elution solvent comprising chloroform-methanol (30:1)]. Thus, 55 mg (29% yield) of the title compound was obtained as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.C([O-])(=O)C.[Na+].Cl.[CH3:31][O:32][NH2:33]>C(O)C>[CH3:1][C:2]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[N:33][O:32][CH3:31]
Reactant: CC1(COc2ccc(CC3SC(=O)NC3=O)cc2)CCCCC1=O
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CON=C1CCCCC1(C)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[[4-[(1-methyl-2-oxocyclohexyl)methoxy]phenyl]methyl]-2,4-thiazolidinedione (3 g), sodium acetate (0.78 g) and O-methylhydroxylamine hydrochloride (0.66 g) were suspended in ethanol (200 mL) and refluxed overnight. The reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate and dried over MgSO4. Filtration and concentration left 3.25 g of yellow oil which was purified by high pressure liquid chromatography. The product, 2.21 g of yellow oil, was dissolved in ethanol (100 mL) and stirred overnight at room temperature with KOH (0.35 g). The solvent was removed using a rotary evaporator, ethyl acetate was added, and the product was dried over Na2SO4. After filtration and concentration, the product was dried overnight under vacuum at room temperature to give 1.79 g of thepotassium salt of the title compound as a white solid, which fuses at 135°-138° C.