Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH2:13][CH2:12][C:11](=O)[CH:10]=1.Cl.[NH2:16][OH:17].C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH:10]=1
Reactant: NO
Reactant: O=C1C=C(c2ccc(O)cc2O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: ON=C1C=C(c2ccc(O)cc2O)CC1

Procedure:
3-[2,4-Bis(methoxymethoxy)phenyl]-2-cyclopenten-1-one (20 mg) was heated at 50° C. in MeOH (4 ml) containing acidic ion exchange resin (100 mg) for 3 hr. The reaction mixture was filtered and the resin washed with ethyl acetate (20 ml). The filtrate was concentrated in vacuo and the residue purified by flash column chromatography (SiO2, ethyl acetate/petrol, 7:3 v/v) to furnish 3-(2,4-dihydroxyphenyl)-2-cyclopenten-1-one (11 mg, 79%). 3-(2,4-Dihydroxyphenyl)-2-cyclopenten-1-one (6 mg), hydroxylamine hydrochloride (3.3 mg) and triethylamine (6.6 μl) were heated in ethanol (3 ml) under reflux for 3 hr. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous phase was extracted with ethyl acetate (10 ml), and the combined organic phases were washed with brine (10 ml), dried over magnesium sulfate, and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:1 v/v) to furnish the title compound as a yellow solid and as one major isomer (4 mg, 62%). Data reported for the major isomer: δH (d4-MeOH) 2.74-2.77 (2H, m), 2.96-2.99 (2H, m), 6.34 (1H, dd), 6.38 (1H, d), 6.96 (1H, t), 7.22 (1H, d); m/z (ES−) 204 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11](C(OCC)=O)=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.Cl.NO>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccn(-c2ccc(OC)cc2)n1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: NO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-1H-pyrazole-5-[(4-(N-pyrrolidinocarbonyl) phenyl)carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile was added triethylamine (0.064 mL, 0.46 mmol) and iso-butyl chloroformate (0.030 mL, 0.23 mmol). After stirring at ambient temperature for 30 min, there was added hydroxylamine hydrochloride (16 mg, 0.23 mmol). The reaction was stirred for 1 h and then the volatiles were removed. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and lyophilized to afford 28 mg (27%) of the title compound as a white powder. LRMS (ES-): 562.1 (M-H+TFA)-.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH2:15]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[CH2:24]O)[CH3:16]>>[CH2:15]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[CH2:24][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CCc1cc(C)ccc1CO
Product: CCc1cc(C)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-ethyl-4-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.20 (3H, t, J=7.6 Hz), 2.35 (3H, s), 2.68 (2H, q, J=7.6 Hz), 5.21 (2H, s), 5.79 (1H, d, J=1.6 Hz), 7.03 (1H, d, J=7.6 Hz), 7.07 (1H, s), 7.27 (1H, d, J=8.4 Hz), 7.36 (1H, dd, J=1.2 Hz, 4.8 Hz), 7.58 (1H, d, J=1.6 Hz), 7.96-7.97 (1H, s), 8.66 (1H, dd, J=0.8 Hz, 5.2 Hz). [M+H] Calc'd for C19H18N4O, 319. Found, 319.
Reaction SMILES: [O:1]1[C:6]2([CH2:10][CH2:9][NH:8][CH2:7]2)[O:5][CH2:4][CH2:3][CH2:2]1.[CH2:11]([O:13][C:14]([C:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][C:21](F)=[C:22]([F:27])[CH:23]=2)[N:18]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH:17]=1)=[O:15])[CH3:12].C(N(CC)CC)C>N1C=CC=CC=1>[CH2:11]([O:13][C:14]([C:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][C:21]([N:8]3[CH2:9][CH2:10][C:6]4([O:5][CH2:4][CH2:3][CH2:2][O:1]4)[CH2:7]3)=[C:22]([F:27])[CH:23]=2)[N:18]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH:17]=1)=[O:15])[CH3:12]
Reactant: C1COC2(CCNC2)OC1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2cc(F)c(F)cc2c1=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2cc(N3CCC4(C3)OCCCO4)c(F)cc2c1=O
Temperature: 45 °C

Procedure:
Into oven-dried glassware under a N2 atmosphere were placed 0.176 g (1.23 mmol) of 1,5-dioxa-8-azaspiro[5.4]decane, from Step 2, then 0.300 g (0.82 mmol) of 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (preparation described by H. Narita, et al., Yakugaku Zasshi, 106(9), 795-801, 1986; CA106:196218) dissolved in 10 mL of pyridine, and 0.46 mL (3.28 mmol) of triethylamine. The solution was then heated at 45° C. for 24 hours. The solvent was removed by evaporation to afford the title product which was purified by column chromatography over silica gel (0.5% methanol/chloroform increasing to 2.0% methanol/chloroform). The ester was not further purified, but was taken directly to the next step.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1.[CH:19]([N:22](CC)C(C)C)(C)C.N#CBr>C(Cl)Cl>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][CH2:7][CH:6]2[C:2]2[N:3]([C:19]#[N:22])[CH2:4][CH2:5][N:1]=2)=[CH:11][C:12]=1[CH3:18]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc2c(cc1C)CCCC2C1=NCCN1
Agent: N#CBr
Solvent: ClCCl
Product: COc1cc2c(cc1C)CCCC2C1=NCCN1C#N
Temperature: 0 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
In a 9.5 dram screw cap vial was placed 0.20 gram (0.0008 mole) of Compound 50 (prepared as set forth in Example 2), 0.11 gram (0.0008 mole) of N,N-diisopropylethylamine, and 25 mL of methylene chloride; followed by 2.4 mL (0.0008 mole) of a stock solution of 1 mL of cyanogen bromide in 30 mL of methylene chloride. The reaction mixture was then gently shaken during an 18 hour period using a mechanical shaker. After this time the reaction mixture was poured into ice water in a separatory funnel, and the mixture was extracted with three portions of methylene chloride. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The residual oil was purified by column chromatography on Grade II alumina (basic-3% water) using methylene chloride as an eluant. The appropriate fractions of eluate were combined and concentrated under reduced pressure, yielding 0.19 gram of Compound 201. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:10]=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=2)[CH:14]=O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].[NH2:19][C@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:21]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(OC(N1CCC[C@H](NCC2C=C(C(C#N)C)C=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:29]([O:28][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:20]([NH:19][CH2:14][C:13]2[CH:16]=[C:9]([C:3]3([C:1]#[N:2])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]3)[CH:10]=[CH:11][C:12]=2[O:17][CH3:18])[C@@H:21]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COc1ccc(C2(C#N)CCOCC2)cc1C=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Agent: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: COc1ccc(C2(C#N)CCOCC2)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 89 and Compound 17 in the same manner of Compound 18.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[F:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14]
Reactant: N#C[S-]
Reactant: O=C(CBr)c1ccccc1F
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1ccccc1F
Temperature: 25 °C
Yield: 95.5 %

Procedure:
A solution of 2-bromo-1-(2-fluorophenyl)ethanone (5.00 g, 23.0 mmol) and potassium thiocyanate (2.24 g, 23.0 mmol) in ethanol (50 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (60 ml) was poured into the reaction solution, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the desired product (4.29 g, 95.5%) as a solid.
Reaction SMILES: [C:1]([CH2:4][C:5]([O:7][CH2:8][CH2:9][O:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][CH:13]=1)=[O:6])(=O)[CH3:2].[NH2:23]/[C:24](/[CH3:31])=[CH:25]\[C:26]([O:28][CH2:29][CH3:30])=[O:27].[N+:32]([C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=O)([O-:34])=[O:33]>C(O)C>[CH3:2][C:1]1[NH:23][C:24]([CH3:31])=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:38]([C:37]2[CH:40]=[CH:41][CH:42]=[C:35]([N+:32]([O-:34])=[O:33])[CH:36]=2)[C:4]=1[C:5]([O:7][CH2:8][CH2:9][O:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][CH:13]=1)=[O:6]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCOC(=O)c1ccc(NC(C)=O)cc1
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCOC(=O)c2ccc(NC(C)=O)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: -5 °C
Yield: 46 %

Procedure:
20 g (0.07 moles) of 2-(4-acetylaminobenzoyloxy)ethyl acetylacetate, 8.41 g (0.07 moles) of ethyl 3-aminocrotonate and 9.84 g (0.07 moles) of 3-nitrobenzaldehyde are heated under reflux in 65 ml of ethanol for 8 hours. The solvent is then evaporated, 15 ml of boiling methanol are added to the residue, the solution is discoloured with activated charcoal and cooled to -5° C. to obtain 2-(4-acetylaminobenzoyloxy)ethyl 2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate with half a molecule of ethanol as yellow crystals melting--after recrystallisation in ethanol--at 157°-162° C. The yield is 46% of the theoretical yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[Cs+].[Cs+].IC>CO>[CH3:20][O:14][C:13](=[O:15])[C@@H:12]1[CH2:16][C@@H:17]([OH:19])[CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: [Cs+]
Solvent: CI
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-benzyloxycarbonyl-4-hydroxy-L-trans-proline 9 (47.5 g; 179 mmol) in anhydrous methanol (900 ml) is adjusted to pH=9.0-9.5 using caesium carbonate. The mixture is subsequently stirred at room temperature for 30 min., and then concentrated. After having been dried for 30 minutes under high vacuum, the residue is taken up in anhydrous N,N-dimethylformamide (900 ml). Iodomethane (28.0 g; 197 mmol) is added, and the mixture is stirred at room temperature for 21 h. The solution is concentrated, and the residue is subsequently distilled repeatedly with toluene, taken up in chloroform (1.8 l), and then extracted by shaking once with each of water and a 10% solution of sodium hydrogen carbonate, and once again with water (600 ml on each occasion). The organic phase is dried (magnesium sulphate) and concentrated. Yield: 50.0 g (quantitative).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(=O)(=O)(O)[OH:14]>>[CH3:5][CH:6]([NH:4][C:1](=[O:14])[CH:2]=[CH2:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C=CCCCCCC
Reactant: C=CC#N
Reactant: O=S(=O)(O)O
Product: C=CC(=O)NC(C)CCCCCC

Procedure:
Following a procedure analogous to that of Example 1, treat acrylonitrile with 1-octene in the presence of phenothiazene and 83% sulfuric acid to obtain the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.C1COCC1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(CN)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CNC(=O)c2ccccc2)cc1
Temperature: 7 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
To a mixture of p-methoxybenzylamine (181 g, 1.32 mol), triethylamine (185 mL, 134 g, 1.32 mol) and THF (772 mL) was added dropwise benzoyl chloride (185 g, 1.32 mol) at 16° C. or lower. The mixture was stirred at 7° C. or lower for 3 hr, water (400 mL) was added dropwise thereto at 14° C. or lower. The mixture was extracted with ethyl acetate (140 ml), and the aqueous layer was extracted with ethyl acetate (360 ml). The combined organic layers were washed successively with 20% brine (0.15 kg×2) and 20% brine (0.22 kg, once), and dried over magnesium sulfate (50 g). Silica gel (22 g) was added to the solution, and the mixture was filtered (silica gel precoat). The filtrate was concentrated to 0.67 kg under reduced pressure at 60° C. or lower, and the residue was cooled to 5° C. The resulting crystals were collected by filtration, washed with cold ethyl acetate (140 mL), and dried under reduced pressure at 50° C. to give N-(p-methoxybenzyl)benzamide (257 g, yield 80.7%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:8]([CH3:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](OC2C=CC=CC=2)=[N:19][C:20]#[N:21])=[CH:13][CH:12]=1>COCCOC>[C:20]([N:19]=[C:18]([O:17][C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1)[NH:1][C:2]1[C:3]([N:8]([CH3:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1)#[N:21]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: CN(C)c1ncccc1N
Solvent: COCCOC
Product: CN(C)c1ncccc1NC(=NC#N)Oc1ccccc1

Procedure:
According to the procedure of Example 5, Step 3, 3-amino-2-dimethylaminopyridine (1.41 g, 0.0108 mol) was allowed to react with diphenylcyanocarbonimidate (2.45 g, 0.0108 mol) in ethylene glycol dimethyl ether (20 ml), under nitrogen for 18 hours. The reaction mixture was concentrated and the residue chromatographed on silica gel with mixtures of MeOH--CHCl3 containing from 0 to 5% MeOH. The product amounted to 3.23 g.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.Cl.[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH2:32])=[NH:31])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.[OH-].[Na+]>O(CCO)C>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:32]=[C:30]([NH:29][C:26]3[CH:25]=[CH:24][C:23]([CH2:22][C:19]4[CH:18]=[CH:17][N:16]=[CH:21][CH:20]=4)=[CH:28][CH:27]=3)[N:31]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: N=C(N)Nc1ccc(Cc2ccncc2)cc1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(Cc4ccncc4)cc3)n2)s1

Procedure:
A mixture of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (1 mmol, 0.21 g) and N-(4-pyridin-4-ylmethyl-phenyl)-guanidine hydrochloride (2 mmol, 0.40 mg) in 2-methoxylethanol was treated with NaOH (40 mg). The reaction mixture was allowed to heat at reflux for 2 d. The solvent was evaporated and the residue was crystallised from EtOAc/MeOH to afford the title compound as an orange solid. 1H-NMR (300 MHz, d6-DMSO) δ 3.00 (s, 3H, CH3), 3.02 (s, 3H, CH3), 4.29 (s, 2H, CH2), 7.44 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.56 (m, 2H, Ph-H), 7.61 (m, 2H, Ar-H), 8.09 (m, 2H, Ph-H), 8.82 (m, 2H, Ar-H), 8.87 (d, 1H, J=5.5 Hz, pyrimidinyl-H). DE MALDI-TOF MS: {M+H}+=377.52 (C21H19N5S requires 373.48).
Reaction SMILES: C(O[C:9]([C:11]1[CH:16]=[CH:15][C:14](CO[Si](C(C)(C)C)(C)C)=[CH:13][CH:12]=1)=[CH2:10])C1C=CC=CC=1.[CH2:26]([O:33]C(C1C=CC=C(CO[Si](C(C)(C)C)(C)C)C=1)=C)C1C=CC=CC=1.ClCC=CC1C=CC=CC=1.[Si](Cl)(C(C)(C)C)(C)C.C>>[OH:33][CH2:26][CH:10]=[CH:9][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=C(OCc1ccccc1)c1cccc(CO[Si](C)(C)C(C)(C)C)c1
Reactant: C=C(OCc1ccccc1)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: C
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: ClCC=Cc1ccccc1
Product: OCC=Cc1ccccc1

Procedure:
α-Benzyloxy[4-(tert-butyldimethylsilyloxymethyl)styrene] and α-Benzyloxy[3-(tert-butyldimethylsilyloxymethyl)styrene] (Formula II, R1 =(tert-butyldimethylsilyloxymethyl)phenyl, R2 =benzyl). (Hydroxymethyl)styrene was prepared from (chloromethyl)styrene (a 2:3 mixture of para and meta isomers) by a sequence described in Polymer, 1973, 14, 330. It was treated with tert-butyldimethylsilyl chloride following the general directions found in Journal of the American Chemical Society, 1972, 94, 6190. Method C was used to convert the 25 resulting compound to the required alkoxystyrene: 1H NMR (CCl4) δ 0.70 (6H, s), 0.94 (9H, s), 4.17 (1H, d, J 2.4 Hz), 4.63 (3H, broadened s), 4.83 (2H, s), 7.0-7.6 (9H, m); MS (CH4) 355 (MH+, 4%), 91 (100%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[O-:9][CH2:10][CH3:11].[Na+].CN(C)C=O.O>C(OCC)C>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([O:9][CH2:10][CH3:11])[CH:7]=1
Reactant: CC[O-]
Reactant: Brc1cncc(Br)c1
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cncc(Br)c1
Temperature: 65 °C
Yield: 17.9 %

Procedure:
3,5-Dibromopyridine (98%) was purchased from Lancaster Chemical Company. Sodium ethoxide (96%) and N,N-dimethylformamide (DMF) (99.9+%, HPLC grade) were purchased from Aldrich Chemical Company. Under a nitrogen atmosphere, a mixture of 3,5-dibromopyridine (5.00 g, 21.1 mmol), sodium ethoxide (2.87 g, 42.2 mmol), and DMF (10 mL) was stirred and heated at 65° C. for 15 h. The mixture was poured into water (70 mL), and anhydrous diethyl ether (155 mL) was added. Because of insoluble solids, it was necessary to filter both phases. The aqueous layer was separated and extracted with ether (2×25, 3×50 mL). The combined ether extracts were dried (MgSO4), filtered, and concentrated by rotary evaporation, producing a dark-brown syrup. The brown residue was purified by vacuum distillation, affording 0.76 g (17.9%) of an oil, bp 105° C. at 5 mm Hg. 1H NMR (CDCl3): δ 9.12 (br s, 1H), 8.83 (br s, 1H), 8.42 (dd, 1H), 4.41 (q, 2H), 1.42 (t, 3H). 13C NMR (CDCl3): δ 142.72, 136.50, 123.78, 64.31, 14.57.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].[CH2:11]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]=[CH:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].Cl>C(OCC)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:17][CH2:18]2)=[CH:3][CH:4]=1
Reactant: CCCCCC1C=CC(=O)CC1
Reactant: COc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCC1=CCC(O)(c2ccc(OC)cc2)CC1

Procedure:
A solution of 6.5 g of p-bromoanisole in 20 ml of anhydrous diethyl ether was added dropwise under stirring at 15°-20° C. to 1 g of magnesium metal powder, followed by reaction at room temperature for 1 hour so that a Grignard reagent was formed. After 5 g of 4-pentylcyclohexenone were added under stirring at -10° to 0° C. to the thus-formed Grignard reagent, they were reacted at room temperature for additional 1 hour. After the completion of the reaction, diluted hydrochloric acid was added dropwise to the reaction mixture, followed by the extraction of the reaction mixture with diethyl ether. After the extract was washed with saturated NaCl, anhydrous sodium sulfate was added to dry the extract. The diethyl ether was distilled off under reduced pressure, whereby 4-(4-methoxyphenyl)-4-hydroxy-1-pentylcyclohexene was obtained as a crude reaction product.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([NH2:12])[NH:4][N:3]=1.CO[CH:15](OC)[CH2:16][CH:17](OC)OC.C(N(CC)CC)C>CN(C=O)C>[NH3:1].[NH2:12][C:5]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[N:1]=[CH:15][CH:16]=[CH:17][N:3]2[N:4]=1
Reactant: CCOC(=O)c1c(N)n[nH]c1N
Reactant: COC(CC(OC)OC)OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N)nn2cccnc12
Product: N
Temperature: 100 °C
Yield: 69 %

Procedure:
A mixture of ethyl 3,5-diamino-1H-pyrazole-4-carboxylate (1.0 g, 5.9 mmol), 1,1,3,3-tetramethoxypropane (2.9 mL, 18 mmol), triethylamine (2 mL, 10 mmol), and DMF (15 mL) was heated at 100° C. for 14 hrs, then a further 2 mL of 1,1,3,3-tetramethoxypropane was added. After adding the additional 1,1,3,3-tetramethoxypropane, a significant by-product was noted and heating was stopped immediately. The reaction was cooled to room temperature and the DMF was removed in vacuo. The residue was partitioned between DCM and water, then the organic layer was concentrated and the residue purified by silica chromatography, eluting with 95:5 DCM: 2M methanolic ammonia solution to afford 420 mg (35%) of ethyl 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylate. 1H NMR (500 MHz, CDCl3) δ 8.57 (dd, J=4.3, 1.6, 1H), 8.43 (dd, J=6.7, 1.6, 1H), 6.84 (dd, J=6.7, 4.4, 1H), 5.52 (s, 2H), 4.48 (q, J=7.1, 2H), 1.45 (t, J=7.1, 3H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CC#N>[Br-:23].[CH2:30]([O:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][N+:1]12[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH2:3][CH2:2]1)[CH2:7][CH2:8]2)[CH3:31]
Reactant: CCOC(=O)CCCBr
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: CCOC(=O)CCC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 56.5 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0679 g, 0.231 mmol) and ethyl 4-bromobutanoate (0.055 mL, 0.524 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0637 g, 57.9%). EI-MS m/z 408 (M+) Rt (1.80 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[CH2:5]2.N1CCCCC1.Cl[C:20]([C@@H:22]([O:24][C:25](=[O:27])[CH3:26])[CH3:23])=[O:21]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:20]([CH:22]([O:24][C:25](=[O:27])[CH3:26])[CH3:23])=[O:21])[NH:7][C:6](=[O:12])[CH2:5]2
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CC(=O)OC(C)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: -40 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
The stirred solution of 5-fluoro-6-amino-1,3-dihydro-indol-2-one (450 mg, 2.71 mmol) in 10 ml of tetrahydrofuran was added with piperidine (0.4 ml). The mixture was cooled to −40° C. in an acetone-dry ice bath and added with (S)-acetic acid 1-chlorocarbonyl-ethyl ester (423 mg, 2.71 mmol) in 10 ml of tetrahydrofuran dropwise. Upon the completion of the addition, the resulting mixture was stirred at the room temperature overnight until the precipitate was formed. The solid was filtered, washed with water and recrystallized from methanol to give acetic acid 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-ethyl ester (750 mg, 99%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](Cl)=[N:9]2)=[N:4][CH:3]=1.[NH3:13].O>O1CCOCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([NH2:13])=[N:9]2)=[N:4][CH:3]=1
Reactant: N
Reactant: Clc1ccc2ncc(Br)cc2n1
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc2ncc(Br)cc2n1
Temperature: 160 °C
Reaction time: 24 h
Yield: 79.8 %

Procedure:
In a sealed reactor, 500 mg (1.23 mmol, 1 eq) of 7-bromo-2-chloro-1,5-naphthyridine and 7 mL (41.6 mmol, 33 eq) of 20% aqueous ammonia solution were introduced in 7 mL of dioxane. The mixture was stirred at 160° C. for 24 h. The mixture was allowed to reach rt and water was added. Aqueous layer was extracted with ethyl acetate. Organic layers were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography using methylene chloride and then methylene chloride/ethanol: 98/2 as eluent. The solvent was evaporated to dryness to afford 220 mg of white powder with 80% yield.