Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11](O[C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=[O:12])[CH:10]=1.[NH3:16]>O>[CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11]([NH:16][C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=[O:12])[CH:10]=1
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Reactant: N
Solvent: O
Product: O=C1NC(=O)c2cccc3cccc1c23
Temperature: 70 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
1,8-naphthalic anhydride (50.00 g, 0.252 mol, 1.0 eq), 32.8 ml of 29% aqueous ammonia (29.52% g, or 8.56 g dry, 0.504 mol, 2.0 eq) and water (115 g) were mixed to form a yellow slurry. The yellow slurry was heated with stirring to 70° C. then held at that temperature for 90 minutes for a total heating time of about 2 hours. After the heating period, the mixture was cooled to room temperature and filtered. The product was then washed with 500 to 600 ml of water until the pH of the wash water was neutral (pH 7). The product (i.e. 1,8-naphthalimide) was isolated as a wet filtercake (59.67 g, dry content=82.28%, representing 49.10 g of dry 1,8-naphthalimide, 99% yield), which was suitable for converting to 3, 4, 9, 10-perylenetetracarboxylic diimide. The purity of 1,8-naphthalimide was above 99% as determined by Gas Chromatography with a melting point of about 301-303° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])=[N+]=[N-].[H][H]>[Pd].C(O)C>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:13])=[O:14]
Reactant: [H][H]
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: CN(C)S(=O)(=O)c1cc(F)ccc1CN

Procedure:
A mixture of 2-(azidomethyl)-5-fluoro-N,N-dimethylbenzenesulfonamide (3.57 g, 13.8 mmol) and 5% palladium on carbon (0.89 g, 25% w/w) in absolute ethanol (100 mL) was stirred under a balloon of hydrogen gas for one hour. The reaction was filtered through a small pack of celite and the filtrate was concentrated in vacuo to a yellow oil. The crude material was purified by preparative HPLC. (Gilson semi preparative HPLC system using a Waters Delta pak column (3(10×40 mm I.D.)cartridges, C18, 15 μm pore size) eluting with 5-95% acetonitrile/water (0.1% TFA) at 30 ml/min) to afford the desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[O:6][CH2:7][C:8]1[N:12]([CH3:13])[N:11]=[C:10]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2C(OC(C)(C)C)=O)[CH:9]=1.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[O:6][CH2:7][C:8]1[N:12]([CH3:13])[N:11]=[C:10]([C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[CH:9]=1
Reactant: COc1ccc(OCc2cc([C@@H]3CCCN3C(=O)OC(C)(C)C)nn2C)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(OCc2cc([C@@H]3CCCN3)nn2C)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
To a CHCl3 (1.0 mL) solution of the compound (365 mg) obtained in Example 13-(2), TFA (5.0 mL) was added at 0° C. and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction mixture, saturated aqueous sodium bicarbonate (50 mL) was added and the organic layer extracted with CHCl3 (50 mL×2) was dried (Na2SO4), filtered and concentrated to give the titled compound (283 mg, pale brown oil.)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]1C=CC=CC=1.C(OC(OCCCC)=O)(OCCCC)=O.C(=O)(O)[O-].[NH4+]>O1CCOCC1>[NH2:18][C:15]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:17]
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCOCC1
Agent: CCCCOC(=O)OC(=O)OCCCC
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(C(N)=O)CCOCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of the commercially available 4-[(tert-butoxycarbonyl)amino]tetrahydro-2H-pyran-4-carboxylic acid in dioxane, pyridine (0.6 eq.), di-butyl dicarbonate (1.3 eq) and ammonium bicarbonate (1.26 eq) were added and the mixture was stirred at room temperature for 20 hours. Dioxane was concentrated and the residue dissolved in ethyl acetate and washed with HCl 1N, saturated aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered and evaporated in vacuo to obtain the solid compound (C-25).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:22][CH3:23])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[Se:27][C:26]=1[C:36]([NH2:38])=[O:37].CN(C=O)C.[OH-].[Na+]>>[O:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][O:12][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][C:8]=2[O:22][CH3:23])[N:5]=[CH:4][N:3]=[C:2]3[NH:24][C:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[Se:27][C:26]=2[C:36]([NH2:38])=[O:37])[CH2:17][CH2:18]1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1
Reactant: NC(=O)c1[se]c(-c2ccccc2)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cc(-c4ccccc4)[se]c3C(N)=O)c2cc1OCCCN1CCOCC1

Procedure:
The reaction of 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline with 3-amino-5-phenylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as a yellow color solid, mp 236-240° C. IR (KBr) vmax 34369, 3158, 2935, 1635, 1579, 1387, 1321, 1238, 1216, 1145, 1113, 902, 846 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 12.50 (1H, s), 9.16 (1H, s), 8.65 (1H, s), 7.77 (2H, br s), 7.68-7.70 (2H, m), 7.44-7.52 (3H, m), 7.39 (1H, s), 7.26 (1H, s), 4.20 (2H, br s), 3.96 (3H, s), 3.58 (4H, br s), 2.50 (2H, br s), 2.40 (4H, br s), 2.00 (2H, pentet, J=6.5 Hz); LC-MS (positive ion mode): m/z 566, 568 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[CH:11][C:10]=1[C:26]#[N:27])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:31]I.[Cl-].[NH4+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH3:31])=[CH:11][C:10]=1[C:26]#[N:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)COc1ccc(NC(=O)OCc2ccccc2)cc1C#N
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(C(=O)OCc1ccccc1)c1ccc(OCC(=O)OC(C)(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
t-Butyl(4-benzyloxycarbonylamino-2-cyanophenoxy)acetate (100 mg) obtained in Reference Example 50(2) is dissolved in N,N-dimethylformamide (3 ml) and thereto is added 60% oleaginous sodium hydride (12.5 mg). After the mixture is stirred for 20 minutes at room temperature, methyl iodide (24.4 μl) is added thereto dropwise and the mixture is further stirred for one hour. To the reaction solution is poured saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate and evaporated to remove the solvent. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1 followed by 3/1) to give t-butyl[4-(N-benzyloxycarbonyl-N-methylamino)-2-cyanophenoxy]acetate (91 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].CO[CH2:24][CH2:25]OC>O>[CH:24]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15])=[CH2:25]
Reactant: COCCOC
Reactant: COc1ccc2ncc(C#N)c(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1c(C#N)cnc2ccc(OC)cc12
Temperature: 85 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
To a solution of 4-chloro-6-(methyloxy)-3-quinolinecarbonitrile (1.1 g, 5.03 mmol), potassium carbonate (0.76 g, 5.53 mmol), tetrakis-triphenylphosphine (120 mg, 0.10 mmol) in DME (30 mL) and H2O (10 mL) was added 2,4,6-trivinylcycloborane-pyridine complex (1.33 g, 5.53 mmol). After stirring for 5 hours at 85° C. the reaction contents was concentrated and the product purified by chromatography on silica gel (hexanes/EtOAc, 4:1) to give a light brown solid (0.9 g, 86%): LC/MS (ES) m/e 211 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:11][CH:12]=[CH2:13])[C@@H:5]1[CH2:9][O:8][CH2:7][C@H:6]1O)[CH:2]=[CH2:3].C([N:16](CC)CC)C.CS(Cl)(=O)=O.[OH-].[NH4+]>C(OC)(C)(C)C>[CH2:1]([N:4]([CH2:11][CH:12]=[CH2:13])[C@H:5]1[C@H:6]([NH2:16])[CH2:7][O:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: CCN(CC)CC
Reactant: C=CCN(CC=C)[C@@H]1COC[C@H]1O
Agent: CS(=O)(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: C=CCN(CC=C)[C@@H]1COC[C@H]1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of trans-4-(diprop-2-en-1-ylamino)tetrahydrofuran-3-ol (50.0 g, 0.273 mol) in methyl tert-butyl ether was added triethylamine (44.0 g, 0.437 mol) at 5° C. Methanesulfonyl chloride (25.4 mL, 0.327 mol) was added using an addition funnel over a period of 15 min at 5° C. After 30 minutes, triethylamine (55.0 g, 0.546 mol) was added and the reaction was allowed to warm to ambient temperature. Ammonium hydroxide (29% aqueous solution, 700 mL) was then added. After 16 hours, the organic layer was separated, and the aqueous layer was washed with methyl tert-butyl ether (3×250 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to afford adduct trans-N,N-di(prop-2-en-1-yl)tetrahydrofuran-3,4-diamine. The material was used without further purification.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][C:27]=1[O:38][CH3:39].[Cl:40][C:41]1[C:42]([C:51]([F:54])([F:53])[F:52])=[N:43][N:44]([CH2:47][C:48](O)=[O:49])[C:45]=1[CH3:46]>>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:33][CH2:34][N:35]([C:48](=[O:49])[CH2:47][N:44]3[C:45]([CH3:46])=[C:41]([Cl:40])[C:42]([C:51]([F:54])([F:53])[F:52])=[N:43]3)[CH2:36][CH2:37]2)=[CH:28][C:27]=1[O:38][CH3:39]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: COc1cc(N2CCNCC2)ccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)ccc1Br

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Bromo-3-methoxyphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.34 (d,1H), 6.71 (s, 1H), 6.52 (d, 1H), 5.39 (s, 2H), 3.82 (s, 3H), 3.62 (m, 4H), 3.30 (m, 2H), 3.20 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=495.0, found=495.0.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12](OC)[CH2:13][Cl:14]>ClCCl>[CH3:10][O:11][CH:12]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][Cl:14]
Reactant: NC(=O)c1ccccc1
Reactant: COC(CCl)OC
Solvent: ClCCl
Product: COC(CCl)NC(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 41.3 %

Procedure:
9.6 g of benzamide and 49.8 g of chloroacetaldehyde dimethyl acetal, and an amount of strongly acidic ion exchanging resin having an exchange capacity corresponding to the benzamide were agitated for 3 hours at a temperature of 60° C. The reaction fluid was cooled to 40° C., and 30 ml of dichloromethane was added thereto. The ion exchanging resin was removed by filtration under reduced pressure, and the dichloromethane and excess chloroacetaldehyde dimethyl acetal were removed from the filtrate by vacuum distillation, 100 ml of hexane was added thereto and crystals were precipitated, and these were then filtered and desiccated to obtain 7.0 g of compound (1).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:3]=1.N1C=CC=CC=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:12]([N:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:7](=[O:11])[C:6]=2[C:2]([NH:1][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:3]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)n1nc(N)c2c(=O)[nH]ccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)n1nc(NC(=O)c2ccccc2)c2c(=O)[nH]ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-amino-1-tert-butyl-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (20.0 mg) obtained in Example 264 and pyridine (0.016 ml) in THF (3 ml) was added benzoyl chloride (0.023 ml), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (28.8 mg).
Reaction SMILES: C1C2C(C[O:15][C:16]([N:18]([CH2:34][C:35]3[N:39](C)[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH2:19][CH2:20][NH:21][C@@H:22]([C@@H:30]([CH3:33])[CH2:31][CH3:32])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=O)C3C(=CC=CC=3)C=2C=CC=1.[CH2:45](NCC)C.[N+](C1C=CC(OC(=O)OC2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=O>CN(C)C=O.ClCCCl>[CH3:33][C@@H:30]([CH2:31][CH3:32])[C@H:22]([N:21]1[CH2:20][CH2:19][N:18]([CH2:34][C:35]2[N:39]([CH3:45])[C:38]3[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=3[N:36]=2)[C:16]1=[O:15])[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24]
Reactant: CCNCC
Reactant: CC[C@H](C)[C@H](NCCN(Cc1nc2ccccc2n1C)C(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Agent: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CCN(Cc2nc3ccccc3n2C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A solution of the product of Example 96A (0.81 mmol) in N,N-dimethylformamide (5 mL) was treated with diethylamine (0.8 mL), stirred at 25° C. for 2 hours and concentrated. A solution of the residue in 1,2-dichloroethane (16 mL) was treated with bis-(p-nitrophenyl)carbonate (0.296 g, 0.973 mmol), stirred at 60° C. for 16 hours and concentrated. The residue was chromatographed on silica gel, eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.192 g, 59% yield).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[N:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]#[C:32][C:33](OCC)=[O:34])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>C1COCC1>[C:1]1([N:7]2[C:31]([C:28]3[CH:29]=[C:30]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][CH:22]=[C:21]4[C:18]3[CH:17]=[CH:16][N:15]=[CH:20][CH:19]=3)=[CH:32][C:33](=[O:34])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C#Cc1ccc2nccc(-c3ccncc3)c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1cc(-c2ccc3nccc(-c4ccncc4)c3c2)n(-c2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.8 %

Procedure:
A solution of phenylhydrazine (0.093 ml, 0.95 mmol) in anhydrous THF (4.0 ml) was treated with a 1M solution of potassium tert-butoxide in THF (1.89 ml, 1.89 mmol). The resulting solution was added to a solution of ethyl 3-[4-(4-pyridinyl)-6-quinolinyl]-2-propynoate (0.268 g, 0.95 mmol) in THF (10 ml). The resulting brown solution was stirred at room temperature for 1 hour then at 65° C. for 1 hour. The resulting orange slurry was cooled to room temperature then concentrated under reduced pressure. The resulting residue was taken into saturated aqueous NaHCO3 then extracted into methylene chloride and the extracts were dried over sodium sulfate then evaporated under reduced pressure. The resulting oil was purified by HPLC (acetonitrile/water, 5-80% gradient). The product was concentrated to a residue then recrystallized from ethanol to give the title compound (0.020 g, 6%) as a white solid. MS (ES)+ m/e 365 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1)=O.C(O)=O.C([NH2:16])=O.Cl>C(O)C>[Br:10][C:6]1[CH:5]=[C:4]([CH:2]([NH2:16])[CH3:1])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: NC=O
Agent: Cl
Solvent: CCO
Solvent: O=CO
Product: CC(N)c1cccc(Br)c1
Temperature: 220 °C

Procedure:
A mixture of commercially available 3-bromoacetophenone (30 g, 0.1508 mol), formic acid (47 ml) and formamide (70 ml) was heated to 220° C. for 5 h. The brown liquid obtained was cooled to RT, quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine and concentrated to provide a brown liquid. Ethanol (375 ml) and conc.HCl (75 ml) were added to the brown liquid and the reaction mixture refluxed over night. Ethanol was removed completely under reduced pressure and the aqueous layer was washed with ether and ethyl acetate to remove all non-basic impurities. The aqueous layer was basified with 10% sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, and concentrated to provide 26 g (86.65%) of A1.13a This compound was taken to the next step with out further purification. 1H NMR (CDCl3, 300 MHz) δ 1.38 (d, 3H), 4.1 (q, 1H), 7.2 (m, 1H), 7.27 (m, 1H), 7.37 (m, 1H), 7.51 (s, 1H). LS-MS (M−H)+=200.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:29][CH2:30][CH3:31]>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:29][CH2:30][CH3:31])[CH2:23][CH2:24]1
Reactant: CCCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCN(CCC)CC3)c2n1

Procedure:
Prepared similarly to Example 82 from 2-(butyloxy)-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purin-6-amine and 1-iodopropane.
Reaction SMILES: [CH2:1]([C:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][OH:26])[C:5]1=[O:29])[CH:2]=[CH2:3].O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([C:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=[O:26])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CCC1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)N([C@@H](CC)CO)C1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: C=CCC1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)N([C@H](C=O)CC)C1=O
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 197 mg (0.44 mmol) of (5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 121, Step L) in DCM (6 mL) was added 12 μL (0.66 mmol) of water and 280 mg (0.66 mmol) of Dess-Martin periodinane. The resulting light yellow slurry was warmed to room temperature and stirred for 50 min. The reaction was quenched with saturated aqueous sodium thiosulfate, diluted with water, and extracted with DCM (2×). The combined organic layers were washed with saturated aqueous sodium bicarbonate (1×) and saturated aqueous sodium chloride (1×), and then were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (0 to 7% MeOH/DCM, gradient elution) provided the title compound as a light yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:20][S:21][CH2:22][C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)[C:10]([S:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[C:9]([OH:18])[C:8](=[O:19])[O:7]1)=O)C.[Li+].[BH4-].O.Cl>O1CCCC1>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][S:11][C:10]1[C:6]([CH2:20][S:21][CH2:22][C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)([CH2:4][OH:3])[O:7][C:8](=[O:19])[C:9]=1[OH:18]
Reactant: CCOC(=O)C1(CSCc2ccco2)OC(=O)C(O)=C1SCc1ccco1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1OC(CO)(CSCc2ccco2)C(SCc2ccco2)=C1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.4 %

Procedure:
To a solution of 4-hydroxy-5-oxo-3-(2-furanylmethyl sulfanyl)-2-[(2-furanylmethyl sulfanyl)-methyl]-2,5-dihydrofuran-2-carboxylic acid ethyl ester (0.5 g, 1.219 mmol) in anhydrous tetrahydrofuran (THF, 30 mL) was added a THF solution of LiBH4 (2 mL, 4 mmol) at 0-5° C. under argon atmosphere. The mixture was stirred overnight at room temperature and water (1 mL) was slowly added. The mixture was stirred for 5 min and concentrated hydrochloric acid (1 mL) was added. The solution was mixed with water (150 mL) and extracted with methylene chloride (2×100 mL). The combined organic solution was washed with water (50 mL), dried and evaporated. The residue was purified by column chromatography, eluted with a mixed solvent of hexane and ethyl acetate (3:1 to 2:1, v/v) affording 55.6 mg of 4-(furan-2-ylmethylsulfanyl)-5-(furan-2-ylmethylsulfanyl methyl)-3-hydroxy-5-hydroxymethyl-5H-furan-2-one as a cream oil. 1H NMR (CD3OD, 300.16 MHz) δ (ppm): 7.45-7.42 (m, 2H), 6.35-6.22 (m, 4H), 4.50-3.71 (m, 5H), 3.48 (d, J=12.2 Hz, 1H), 2.97 (d, J=14.8 Hz, 1H) and 2.64 (d, J=14.8 Hz, 1H). 13C NMR (CD3OD, 75.48 MHz) δ (ppm): 167.70, 151.21, 150.45, 143.03, 142.38, 142.19, 125.61, 110.33, 110.00, 108.44, 107.81, 88.79, 64.19, 34.07, 28.87 and 26.83. MS (ESI, rel. int.) m/z: 369 (M+H+, 3), 391 (M+Na+, 100).
Reaction SMILES: N1C=CN=C1.[CH2:6]1[CH2:18][O:17][C:8]([CH3:16])([CH2:9][CH2:10][CH2:11][CH:12]([CH3:15])[CH2:13][OH:14])[O:7]1.[Si:19](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[O:14]([CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10][CH2:9][C:8]1([O:7][CH2:6][CH2:18][O:17]1)[CH3:16])[Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(CO)CCCC1(C)OCCO1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(CCCC1(C)OCCO1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
Imidazole (26.5 g) is added to a solution of 6,6-ethylenedioxy-2-methyl-heptanol (33.35 g) in dimethylformamide (50 ml). A solution of t-butyldiphenylsilyl chloride (52.2 g) in dimethylformamide (200 ml) is added dropwise to the reaction mixture and allowed to stir for 3 hours at room temperature. The reaction mixture is extracted with hexane (3×300 ml) and the combined extract is washed with brine and dried (Na2SO4). The solvent is removed in vacuo to give 1-t-butyldiphenylsiloxy-6,6-ethylenedioxy-2-methyl-heptane (75.35 g, 99.6%); nmr (CDCl3,δ), 0.91 (d, 3H, CH3CH), 1.03 [s, (CH3)3C], ##STR43## 3.47 (d, CHCH2O), 3.88 (s, OCH2CH2O), 7.2-7.8 (m, 10 H, 2φ).
Reaction SMILES: [CH2:1]1[O:19][C:4]2=[CH:5][C:6]3[O:11][C:10](=[O:12])[C:9]([C:13]([O:15]CC)=[O:14])=[CH:8][C:7]=3[CH:18]=[C:3]2[O:2]1.O.Cl>CO.[OH-].[K+]>[CH2:1]1[O:19][C:4]2=[CH:5][C:6]3[O:11][C:10](=[O:12])[C:9]([C:13]([OH:15])=[O:14])=[CH:8][C:7]=3[CH:18]=[C:3]2[O:2]1
Reactant: CCOC(=O)c1cc2cc3c(cc2oc1=O)OCO3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2cc3c(cc2oc1=O)OCO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
To a suspension of ethyl 6,7-methylenedioxy-2-oxo-1-benzopyran-3-carboxylate (0.26 g) in methanol (20 ml), 2N KOH (1.5 ml) was added, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into water and acidified with hydrochloric acid; the resulting crystal was collected by filtration to yield 6,7-methylenedioxy-2-oxo-1-benzopyran-3-carboxylic acid (0.1 g, 44%), which was then recrystallized from N,N-dimethylformamide-water to yield yellow prisms having a melting point of 279°-280° C.