Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[CH:5]2.[Cu][C:18]#[N:19]>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([C:18]#[N:19])=[CH:10][CH:9]=3)[CH:12]=1
Reactant: N#C[Cu]
Reactant: Brc1ccc2[nH]c(-c3cccnc3)cc2c1
Product: N#Cc1ccc2[nH]c(-c3cccnc3)cc2c1
Temperature: 160 °C
Reaction time: 8 h

Procedure:
5-Bromo-2-pyridin-3-yl-1H-indole (7.0 g, 21.8 mmol) and copper (I) cyanide (2.3 g, 26.1 mmol) are placed in a round bottom flask which is flushed with N2. N-Methylpyrrolidinone (40 mL) is added via syringe. The resulting mixture is heated to 160° C. under N2 with vigorous stirring overnight. The mixture is cooled to room temperature and poured into 10% aqueous ammonia in saturated aqueous ammonium chloride (300 mL). The aqueous phase is extracted with dichloromethane (100 mL) five times. The combined organic phase is dried over sodium sulfate and concentrated. The residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:0) to give 2-pyridin-3-yl-1H-indole-5-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.20 (s, 1H), 7.48 (dd, J=8.3, 1.5 Hz, 1H), 7.51-7.55 (m, 1H), 7.59 (d, J=8.6 Hz, 1H), 8.12 (s, 1H), 8.25-8.29 (m, 1H), 8.56 (dd, J=4.8, 1.5 Hz, 1H), 9.14 (d, J=1.8 Hz, 1H), 12.27 (s, 1H). HRMS (ESI) m/z 220.0869 [(M+H)+ Calcd for C14H9N3, 220.0875].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:50]=[CH:49][C:16]([C:17]([N:19]([CH2:45][C:46](O)=[O:47])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[N:31]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([C:38]6[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=6)=[CH:34][CH:33]=5)[O:29][N:28]=4)=[CH:23][CH:22]=3)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[C:5]([C:51]([F:54])([F:53])[F:52])[CH:4]=1.[CH3:55][S:56]([NH2:59])(=[O:58])=[O:57].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]4[N:31]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([C:38]6[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][CH:43]=6)=[CH:34][CH:33]=5)[O:29][N:28]=4)=[CH:25][CH:26]=3)[CH2:45][C:46]([NH:59][S:56]([CH3:55])(=[O:58])=[O:57])=[O:47])=[O:18])=[CH:49][CH:50]=2)=[O:11])=[C:5]([C:51]([F:53])([F:54])[F:52])[CH:4]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4noc(-c5ccc(-c6ccc(C)cc6)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Reactant: CS(N)(=O)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)NS(C)(=O)=O)Cc3ccc(-c4noc(-c5ccc(-c6ccc(C)cc6)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetic acid 354 (15 mg, 0.02 mmol), methanesulfonamide (2.9 mg, 0.03 mmol) and N,N-dimethylaminopyridine (5 mg, 0.04 mmol) in anhydrous DCM (1 mL) was added dicylcohexylcarbodiimide (6.3 mg). The reaction mixture was stirred at room temperature for 12 h. The reaction was diluted with DCM (2 mL) and washed with saturated NaHCO3 solution (5 mL), brine (5 mL), dried over (MgSO4) then concentrated. The crude product was isolated by HPLC to afford 4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)-N-(2-(methylsulfonamido)-2-oxoethyl)benzamide 493. LCMS-ESI (m/z) calculated for C42H36F3N5O7S: 812; no ion observed, tR=11.03 min (Method 2).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>O1CCCC1.[Pt]=O>[CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc(-c2ccc(C=CC(=O)OC)cc2)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: C1CCOC1
Product: CCCCCOc1ccc(-c2ccc(CCC(=O)OC)cc2)cc1
Yield: 99.4 %

Procedure:
A mixture of Methyl 3-[4-(4-pentyloxyphenyl)phenyl]acrylate (2.70 g) and platinum oxide (0.41 g) in tetrahydrofuran (40 ml) was stirred for 8 hours under 3 atom of hydrogen at ambient temperature. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give Methyl 3-[4-(4-pentyloxyphenyl)phenyl]propionate (2.70 g).
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:6][CH2:5][C@@H:4]([C:7]([O:9]CC2C=CC=CC=2)=[O:8])[CH2:3]1.[Li+].[OH-].O>CO>[F:1][C:2]1([F:17])[CH2:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCC(F)(F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1CCC(F)(F)C1
Yield: 81 %

Procedure:
(R)-benzyl 3,3-difluorocyclopentanecarboxylate (13 g, 54.1 mmol) was dissolved in MeOH (200 mL) at room temperature with stirring then 0.5 M LiOH (216 mL, 108 mmol) was added. After stirring for 2 h, water was added to the reaction mixture and concentrated to remove volatile solvents. The aqueous layer was rinsed with Et2O (2×) then acidified to pH 3 with 1N HCl. The aqueous layer was extracted with methylene chloride (2×) and the organic layers were combined, dried (Na2SO4), and concentrated to give (R)-3,3-difluorocyclopentanecarboxylic acid (6.58 g, 43.8 mmol, 81% yield) as an oil. 1H NMR (MeOD3, 400 MHz) δ 3.03 (m, 1H), 2.33 (m, 2H), 1.95-2.20 (m, 4H); m/z=149.2 (M−H).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O>CO.O1CCCC1>[CH:1]1([CH:6]([C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)C2CCCC2)oc2ccc(F)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(C(O)C2CCCC2)oc2ccc(F)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.9 %

Procedure:
Cyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methanone (27.15 g) synthesized above was dissolved in a mixed solvent of methanol (40 mL)-tetrahydrofuran (240 mL), and sodium tetrahydroborate (90%, 5.5 g) was added at 0° C. The reaction mixture was stirred at 0° C. for 2 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (29.26 g, 100%) as a yellow oil.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:8]=1[C:9]([NH:11][C:12]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][C:13]=1[C:14]([O:16]C)=[O:15])=[O:10])(=O)C.Cl>O1CCOCC1>[OH:6][C:7]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:8]=1[C:9]([NH:11][C:12]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][C:13]=1[C:14]([OH:16])=[O:15])=[O:10]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(C)cc1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
Dioxane (3 mL) and a 2 mol/L aqueous solution of sodium hydroxide (1.7 mL) were added to the obtained methyl 2-(2-acetoxy-4-methylbenzamido)-4-phenylbenzoate (0.14 g), followed by stirring at room temperature for 2 hours and 30 minutes. The reaction mixture was adjusted to a pH of 3.0 with 6 mol/L hydrochloric acid. The solid substance was collected by filtration to obtain 0.042 g of 2-(2-hydroxy-4-methylbenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [CH2:1]=O.[CH2:3]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:21])=[C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:13]=2)[C:8](=[O:22])[C:7]([C:23]([OH:25])=[O:24])=[CH:6]1)[CH3:4]>C(O)=O>[CH2:3]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:21])=[C:12]([N:15]3[CH2:16][CH2:17][N:18]([CH3:1])[CH2:19][CH2:20]3)[N:13]=2)[C:8](=[O:22])[C:7]([C:23]([OH:25])=[O:24])=[CH:6]1)[CH3:4]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)nc21
Reactant: C=O
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)CC3)nc21

Procedure:
To a solution of 37% formalin (12 ml) and formic acid (18 ml) was added 6.0 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid, and the mixture was heated at 120°-125° C. for 4 hours with stirring. The mixture was then concentrated to dryness under reduced pressure. The residue was adjusted to pH 8 by addition of aqueous 7% sodium bicarbonate, and extracted with chloroform. The extract was dried and the solvent was evaported. The crystalline residue was recrystallized from a mixture of dichloromethane and ethanol to give 5.0 g of 1-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 228°-230° C.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(C(C)=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][Cl:26]>>[CH3:11][O:10][C:1](=[O:9])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH2:24][CH2:25][Cl:26]
Reactant: COC(=O)c1ccccc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccccc1OCCCl

Procedure:
To 25 g (0.16 mol) of methyl salicylate in 250 ml of methyl ethyl ketone 34 g (0.25 mol) of potassium carbonate were added. This mixture was refluxed for 1 h and 27.3 ml (0.35 mol) of 1-bromo-2-chloro-ethane were added and taken to reflux again. Four hours later, 34 g (0.25 mol) more of potassium carbonate and 16.3 ml (0.2 mol) more of 1-bromo-2-chloro-ethane were added. This operation was repeated until the reaction was completed. Then the inorganic salts were filtered and the liquid phase was diluted with the same volume of hexane. This organic phase was washed twice with water and worked-up as usual. The yield in this step was quantitative and the product was pure enough for the next synthetic step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:20]([O-])=O>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20]
Reactant: COc1c([N+](=O)[O-])ccc2c1CCCC(N1CCOCC1)C2
Agent: [Pd]
Solvent: CCO
Product: COc1c(N)ccc2c1CCCC(N1CCOCC1)C2
Yield: 60.8 %

Procedure:
The latter nitro isomer, 4-(1-Methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-morpholine (1.51 g, 4.939 mmol) was dissolved in ethanol (100 mL) and hydrogenated over 10% palladium on carbon (151 mg) at 50 psi using a Parr shaker for 3 hours. The palladium was removed by filtration and the ethanol was concentrated to afford a brown foam which was purified via ISCO chromatography (gradient elution: 2 to 8% methanol: dichloromethane) to afford 1-methoxy-6-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (830 mg, 61%) as a brown solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([C:15]1[N:19]3[CH:20]=[C:21]([CH:24]([N:26]4[CH2:30][CH2:29][C@H:28]([NH:31]C(=O)OC(C)(C)C)[CH2:27]4)[CH3:25])[CH:22]=[CH:23][C:18]3=[N:17][N:16]=1)[CH:11]=[CH:10]2)([CH3:4])([CH3:3])[CH3:2].[ClH:39]>C(Cl)Cl.CC(O)C>[ClH:39].[ClH:39].[ClH:39].[C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([C:15]1[N:19]3[CH:20]=[C:21]([CH:24]([N:26]4[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]4)[CH3:25])[CH:22]=[CH:23][C:18]3=[N:17][N:16]=1)[CH:11]=[CH:10]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(c1ccc2nnc(-c3ccc4cccc(C(C)(C)C)c4n3)n2c1)N1CC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(c1ccc2nnc(-c3ccc4cccc(C(C)(C)C)c4n3)n2c1)N1CC[C@H](N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of tert-butyl (3S)-1-(1-(3-(8-tert-butylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.028 g, 0.0544 mmol) in DCM (2 mL) was added 5 N HCl (0.33 ml, 1.63 mmol) in IPA. The mixture was stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure to give (3S)-1-(1-(3-(8-tert-butylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-amine tri-HCl salt (0.027 g, 94.7%) as solid. LCMS APCI (+) m/z 415 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.C(Cl)Cl.O>[CH2:23]([NH:30][C:13]([C:12]1[C:7]([NH:6][CH2:5][C:4]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:2]([Cl:1])[CH:3]=2)=[N:8][C:9]([S:16][CH3:17])=[N:10][CH:11]=1)=[O:15])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(CNc2nc(SC)ncc2C(=O)O)cc1Cl
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CNc2nc(SC)ncc2C(=O)NCc2ccccc2)cc1Cl
Reaction time: 8 h
Yield: 63.2 %

Procedure:
In THF (60 mL) were dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio) pyrimidine-5-carboxylic acid (1.0 g, 2.95 mmol), benzylamine (379 mg, 3.54 mmol) and HATU (1.35 g, 3.54 mmol). DIEA (1 mL, 5.9 mmol) was added dropwisely. The reaction was conducted at ambient temperature for 8 h, followed by addition of water and extraction with DCM. The organic phase was dried over sodium sulfate. Then the solvent was removed by rotary evaporation. The obtained solid was purified by silica gel column chromatography (DCM/methanol=50/1). The product was N-benzyl-4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-formamide as a faint yellow solid (800 mg, yield 63%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([OH:9])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:37]1([CH2:40][N:41]2[C:49]3[N:48]=[C:47]([CH2:50][C:51]4[CH:56]=[CH:55][C:54]([NH:57][CH3:58])=[CH:53][CH:52]=4)[NH:46][C:45]=3[C:44](=[O:59])[N:43]([CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[F:67])[C:42]2=[O:68])[CH2:39][CH2:38]1>ClCCl>[CH:37]1([CH2:40][N:41]2[C:49]3[N:48]=[C:47]([CH2:50][C:51]4[CH:52]=[CH:53][C:54]([N:57]([CH3:58])[C:7]([C:3]5[CH:4]=[N:5][O:6][C:2]=5[CH3:1])=[O:9])=[CH:55][CH:56]=4)[NH:46][C:45]=3[C:44](=[O:59])[N:43]([CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[F:67])[C:42]2=[O:68])[CH2:39][CH2:38]1
Reactant: Cc1oncc1C(=O)O
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1oncc1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 28 %

Procedure:
A mixture of 5-methyl-isoxazole-4-carboxylic acid (7.3 mg, 0.05 mmol) in dichloromethane (1.0 mL) at 25° C. was treated with triphenylphosphine (17 mg, 0.06 mmol). This mixture was cooled to 0° C. and then was reacted with N-chlorosuccinimide (10 mg, 0.07 mmol). This mixture was stirred at 0° C. for 15 min and then was warmed to 25° C. for 20 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (50 mg, 0.11 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was diluted with dichloromethane (50 mL) and then was washed with a saturated aqueous sodium bicarbonate solution (1×10 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3:97 methanol/dichloromethane) afforded impure product. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (25 mL). The aqueous layer was re-extracted with dichloromethane (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford 5-methyl-isoxazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (7.6 mg, 24.4%) as an off-white solid: EI-HRMS m/e calcd for C29H27N6O4F (M+) 542.2078, found 542.2083.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([Cl:11])=[C:5]([OH:10])[C:6]([CH3:9])=[CH:7][CH:8]=1.Cl.Cl.[CH2:14]([N:19]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[NH4+].OO>O.C(O)C>[NH2:2][C:3]1[C:8](=[N:26][C:23]2[CH:22]=[CH:21][C:20]([N:19]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:25][CH:24]=2)[CH:7]=[C:6]([CH3:9])[C:5](=[O:10])[C:4]=1[Cl:11]
Reactant: CCCCCN(CCCCC)c1ccc(N)cc1
Reactant: Cc1ccc(N)c(Cl)c1O
Agent: Cl
Agent: OO
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCCCCN(CCCCC)c1ccc(N=C2C=C(C)C(=O)C(Cl)=C2N)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.4 %

Procedure:
0.48 g of 3-amino-2-chloro-6-methylphenol hydrochloride is added to 0.8 g of N,N-dipentylbenzene-1,4-diamine dihydrochloride in solution in 5 ml of water and 40 ml of ethanol. The pH is adjusted to 9.5 with 20% ammonium hydroxide and then 1.7 ml of 9% aqueous hydrogen peroxide solution are added. The mixture is left stirring at ambient temperature for 5 hours and then the precipitate formed is filtered off. 0.72 g of 3-amino-2-chloro-4-{[4-(dipentylamino)phenyl]imino}-6-methylcyclohexa-2,5-dien-1-one (1o) is thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2([C:13]([F:16])([F:15])[F:14])O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH:6]=[C:7]2[C:13]([F:14])([F:15])[F:16]
Reactant: COc1cccc2c1CCC2(O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1cccc2c1CC=C2C(F)(F)F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-methoxy-1-trifluoromethyl-indan-1-ol (170 mg, 0.73 mmol) in benzene (4 mL) was added p-toluenesulfonic acid (139 mg, 0.73 mmol). The mixture was stirred overnight at 80° C., and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 4-methoxy-1-trifluoromethyl-3H-inden. The 4-methoxy-1-trifluoromethyl-3H-inden was dissolved in CH2Cl2 (2 ml) and 1M-BBr3 (in CH2Cl2, 1.46 mL, 1.46 mmol) was added dropwise. The mixture was stirred for 1 hour at room temperature, and then washed with saturated ammonium chloride, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 1-trifluoromethyl-3H-inden-4-ol (70 g, 48%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:10]([OH:21])([C:16]([O:18]CC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:22]([C@@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])=[C:23]=[O:24]>C1COCC1>[CH2:3]([C:10]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:21][C:23](=[O:24])[N:22]([C@@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[C:16]1=[O:18])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@@H](N=C=O)c1ccccc1
Reactant: CCOC(=O)C(O)(Cc1ccccc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2)OC(=O)N([C@H](C)c2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a mixture of NaOH (25 g) and 15.7 g of activated molecular sieves in 1159 mL of THF at 0° C. was added a 1159 mL THF solution of diethyl benzyl(hydroxy)propanedioate (153 g). After 5 min, to this mixture was added [(1R)-1-isocyanatoethyl]benzene (118 g). The mixture was stirred at 0° C. for 30 min and then warmed to ambient temperature and stirred for 4 h. The reaction mixture was directly purified using a Biotage silica gel chromatography system (5-30% ethyl acetate in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6](=[O:13])[NH:5][C:4]=2[C:3]=1[C:14]([O:16][CH3:17])=[O:15].[N+:18]([O-])([O-:20])=[O:19].[K+]>OS(O)(=O)=O>[CH3:17][O:16][C:14]([C:3]1[C:4]2[NH:5][C:6](=[O:13])[C:7](=[O:12])[NH:8][C:9]=2[CH:10]=[C:11]([N+:18]([O-:20])=[O:19])[C:2]=1[CH3:1])=[O:15]
Reactant: COC(=O)c1c(C)ccc2[nH]c(=O)c(=O)[nH]c12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1c(C)c([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12
Reaction time: 23 h

Procedure:
To a solution of 6-methyl-2,3-dioxo-1,2,3,4-tetrahydro-quinoxaline-5-carboxylic acid, methyl ester (1.11 g, 4.74 mmol) in conc. H2SO4 (15 mL) at room temperature was added in one portion with vigorous stirring potassium nitrate (0.529 g, 5.23 mmol). The reaction mixture was stirred for 23 hours and poured over ice. The precipitated product was thoroughly washed with water upon collection to give 1.28 g (97%).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]4[CH2:34][CH2:33][CH:32]([C:35]5[N:39]=[C:38]([C:40]6[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=6)[NH:37][N:36]=5)[CH2:31][CH2:30]4)=[CH:24][CH:23]=3)=[N:9][C:10]3[N:11]([N:13]=[CH:14][C:15]=3[C:16]#[C:17][Si](C)(C)C)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].ClCCl>CO>[C:16]([C:15]1[CH:14]=[N:13][N:11]2[CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]([C:22]3[CH:23]=[CH:24][C:25]([CH2:28][N:29]4[CH2:30][CH2:31][CH:32]([C:35]5[N:39]=[C:38]([C:40]6[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=6)[NH:37][N:36]=5)[CH2:33][CH2:34]4)=[CH:26][CH:27]=3)=[N:9][C:10]=12)#[CH:17]
Reactant: C[Si](C)(C)C#Cc1cnn2cc(-c3ccccc3)c(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1cnn2cc(-c3ccccc3)c(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)nc12

Procedure:
250 mg 6-phenyl-5-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-3-[(trimethylsilyl)ethynyl]pyrazolo[1,5-a]pyrimidine and 114 mg K2CO3 are stirred in 5 ml methanol and 5 ml dichloromethane for 7 h. The solvent is removed by evaporation and the residue is purified by chromatography on silica gel (dichloromethane/methanol) to yield the desired compound
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[NH2:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>O1CCCC1>[OH:18][C:14]1[CH:13]=[C:12]([NH:11][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)=[O:7])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)CCCCC(=O)Cl
Reactant: Nc1cccc(O)c1
Solvent: C1CCOC1
Product: O=C(CCCCC(=O)Nc1cccc(O)c1)Nc1cccc(O)c1
Reaction time: 0.21 h

Procedure:
A solution of adipoyl chloride (5.5 g, 0.03 mol) in dry tetrahydrofuran (THF, 50 mL) is added dropwise to a magnetically stirred solution of 3-aminophenol (13.0 g, 0.12 mol) in 150 mL of THF. A precipitate forms after 10-15 minutes and is collected by filtration, washed with water, washed with a mixture of water and tetrahydrofuran and recrystallized from an ethanol/water mixture. Analysis of the resulting 8.86 g of white solid indicates it to have the following structure: ##STR2##