Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:8]([CH3:17])=[CH:7][C:6]=1[NH:18][C:19]1[N:24]=[C:23]2[NH:25][N:26]=[CH:27][C:22]2=[C:21]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[N:20]=1)([CH3:3])[CH3:2].Cl.[CH3:42][N:43]([CH3:48])[CH2:44][C:45](Cl)=[O:46].C(N(CC)CC)C>ClCCl>[CH3:42][N:43]([CH3:48])[CH2:44][C:45]([N:14]1[CH2:15][CH2:16][CH:11]([C:9]2[CH:10]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[C:6]([NH:18][C:19]3[N:24]=[C:23]4[NH:25][N:26]=[CH:27][C:22]4=[C:21]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[S:35]([CH:38]([CH3:40])[CH3:39])(=[O:36])=[O:37])[N:20]=3)=[CH:7][C:8]=2[CH3:17])[CH2:12][CH2:13]1)=[O:46]
Reactant: CN(C)CC(=O)Cl
Reactant: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3cn[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3cn[nH]c3n2)c(OC(C)C)cc1C1CCN(C(=O)CN(C)C)CC1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
N6-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (56 mg) was dissolved in 3 mL of dichloromethane. The solution was cooled to 5° C. and 2-(dimethylamino)acetyl chloride hydrochloride (24 mg) was added to the solution followed by triethylamine (15 mg). The solution was stirred at room temperature for approximately 30 minutes. After Prep-LC-MS, the final product is obtained. MS (ES+): 649.32 (M+1)+.
Reaction SMILES: [CH2:1]([C:7]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:19]2[CH:18]=[C:17]3[CH:20](O)[CH:21]([CH3:23])[CH2:22][C:16]3=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:25]([C:7]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:19]2[CH:18]=[C:17]3[CH:20]=[C:21]([CH3:23])[CH2:22][C:16]3=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c(cc21)C(O)C(C)C3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c(cc21)C=C(C)C3
Temperature: 25 °C
Yield: 96.8 %

Procedure:
In a 500 mL round flask, 9,9-dihexyl-2-methyl-1,2,3,9-tetrahydrocyclopenta[b]fluoren-1-ol (80 g, 197.7 mmol) and p-toluene sulfonic acid (0.2 g) were dissolved in 320 mL of toluene, and then water was completely removed under reflux with Dean-Stark. The resultant material was cooled to room temperature, and then an ammonium chloride aqueous solution (150 mL) and 200 mL of diethyl ether were injected thereto, followed by separation of the organic layer. The organic layer collected by extracting the residue with diethyl ether was dried over magnesium sulfate, followed by removal of volatile materials, and then purified by using silica gel column chromatography, thereby obtaining 74.0 g of 9,9-dihexyl-2-methyl-3,9-dihydrocyclopenta[b]fluorene (yield: 96.8%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:18]([CH2:23][CH2:24][CH2:25][Br:26])[C:19]([O:21][CH3:22])=[O:20]>CN(C)C=O>[Br:26][CH2:25][CH2:24][CH2:23][CH:18]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C(Br)CCCBr
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCCBr)Oc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-nitrophenol (0.7 g), powdery potassium carbonate (0.7 g), methyl 2,5-dibromovalerate (1.37 g) and dimethylformamide (10 ml) was stirred at room temperature for 4 hours, to which was added ice-water, followed by extraction with ether. The ether layer was washed with water and dried (MgSO4), then the solvent was distilled off. The residue was purified by means of silica gel chromatography [eluted with hexane-ethyl acetate (1:4)] to obtain methyl 5-bromo-2-(2-nitrophenoxy)valerate as an oily product. The yield was 1.30 g (77.8%).
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].BrCCCCCCO.Cl>CC(CC)=O.O>[C:4]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: OCCCCCCBr
Solvent: O
Solvent: CCC(C)=O
Product: c1ccc(-c2ccccc2)cc1
Yield: 50 %

Procedure:
To a solution of 3 g of 4,4′-biphenol and 18 g of K2CO3 in methylethylketone (MEK), 0.02 g of Kl was put, and 6.9 g of 6-bromo-1-hexanol was slowly added dropwise thereto for reaction at 80° C. for 24 hours. 100 ml of distilled water was added thereto to complete the reaction, the mixture was cooled to normal temperature, and a 10% aqueous HCl solution was added thereto. The obtained precipitants were filtered to obtain 3.8 g of 4,4′-(di(6-hydroxyhexyl)oxy))biphenyl. (Yield: 50%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:6]([O:8][CH3:9])=[O:7].[H][H]>CO.C1COCC1.[C].[Pd]>[NH2:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: [H][H]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(N)c(OC)c1
Temperature: 25 °C
Yield: 104.1 %

Procedure:
10% palladium-carbon (containing 50% water, 15 g) was added to a solution of methyl 3-methoxy-4-nitrobenzoate (150 g) in methanol (600 mL) and THF (300 mL), and the reaction solution was stirred at a hydrogen pressure of 0.9 MPa at 50° C. to 64° C. for 6.5 hours. The reaction solution was left to cool to room temperature and then filtered through celite. The resulting filtrate was concentrated under reduced pressure to obtain 134 g of the title compound. The property values corresponded to the reported values (CAS #41608-64-4).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[N:15][C:16]([CH3:20])=[CH:17][CH:18]=3)[N:13]([CH2:21][CH3:22])[C:12](=[O:23])[C:11]=2[CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH:7]=[CH:8][CH:9]=1.Cl>C1COCC1.CO>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[N:15][C:16]([CH3:20])=[CH:17][CH:18]=3)[N:13]([CH2:21][CH3:22])[C:12](=[O:23])[C:11]=2[CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCc1c(-c2cccc(Cl)c2)c2ccc(C)nc2n(CC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCn1c(=O)c(CCC(=O)O)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 80 °C
Yield: 50.6 %

Procedure:
A 15 ml portion of a 1M sodium hydroxide aqueous solution was added to 15 ml of a THF-methanol (1:1) solution containing 2.70 g of ethyl 3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoate, followed by stirring under heating at an oil bath temperature of 80° C. for 2 hours. After cooling to room temperature, the whole was adjusted to pH 3 with 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and then the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography (chloroform-methanol) and further recrystallized from diisopropyl ether-ethyl acetate to obtain 1.27 g of 3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoic acid as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-])=O)[CH:10]=1)[C:5]([OH:7])=[O:6]>[OH-].[OH-].[Pd+2].CO>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH2:11])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(F)cc([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Nc1cc(F)cc(C(=O)O)c1
Reaction time: 8 h

Procedure:
Into a Parr pressure reactor were added 3-fluoro-5-nitrobenzoic acid (667, 5.0 g, 0.027 mol), methanol (50.0 mL), 20% Pd(OH)2 on carbon (300 mg). The reaction was shaken under an atmosphere of hydrogen at 50 psi overnight. The reaction was filtered through celite and was concentrated to dryness to provide a white solid (668, 4.0 g, 95.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=3)[C:11]([CH2:20][C:21]([NH2:23])=[O:22])=[C:10]2[CH2:24][CH3:25])[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11]([CH2:20][C:21]([NH2:23])=[O:22])=[C:10]2[CH2:24][CH3:25])[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(CC(N)=O)c2cc(OC)ccc2n1Cc1cccc(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1c(CC(N)=O)c2cc(O)ccc2n1Cc1cccc(Cl)c1
Yield: 80.6 %

Procedure:
A solution of 226 mg (0.63 mmol) of 1-[(3-chlorophenyl)methyl]-2-ethyl-5-methoxy-1H-indole-3-acetamide and 2.5 mL of 1M BBr3/methylene chloride in 15 mL of methylene chloride was stirred for 6 hours. The mixture was concentrated at reduced pressure, the residue dissolved in ethyl acetate, washed with water, brine and dried(MgSO4). After concentrating at reduced pressure, the residue was chromatographed on silica gel and eluted with EtOAc to give 174 mg (81% yield) of 1-[(3-chlorophenyl)methyl]-2-ethyl-5-hydroxy-1H-indole-3-acetamide.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]=[CH:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:5])C.[OH-].[Na+]>CCO>[CH2:11]([N:8]1[CH:9]=[N:10][C:6]([C:4]([OH:5])=[O:3])=[N:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ncn(Cc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ncn(Cc2ccccc2)n1
Reaction time: 16 h
Yield: 90.2 %

Procedure:
To 1.2 g (6 mmol) of 1-benzyl-1H-[1,2,4]triazole-3-carboxylic acid ethyl ester in 10 ml of EtOH was added 1.4 ml (8 mmol) of 6 M sodium hydroxide solution. The mixture was stirred for 16 h after which time it was concentrated; then, 1 M hydrochloric acid solution was added and the resulting precipitate filtered affording 1.1 g (99%) of the title compound. MS: 204.1 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:23])=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:23])=[C:17]([CH:22]=2)[C:18]([O:20][CH3:21])=[O:19])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1cc(N)ccc1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)c2ccc(C#N)cc2)ccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
4-Cyanobenzoyl chloride (4.50 g) was added to a stirred suspension of methyl 5-amino-2-methylbenzoate (J. Med. Chem., 1991, 34, 2176-2186; 3 g), triethylamine (2.54 ml) and methylene chloride (100 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The mixture was acidified by the addition of 1N aqueous hydrochloric acid solution and the mixture was stirred at ambient temperature for 30 minutes. The resultant solid was isolated and dried under vacuum at 40° C. to give methyl 5-(4-cyanobenzamido)-2-methylbenzoate (5.32 g); NMR Spectrum: (DMSOd6) 2.47 (s, 3H), 3.83 (s, 3H), 7.31 (d, 1H), 7.88 (d, 1H), 8.0 (d, 2H), 8.1 (d, 2H), 8.27 (s, 1H), 10.57 (s, 1H); Mass Spectrum: M+H+ 295.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[CH2:21][C:20]([CH3:23])=[CH:19]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:24]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH3:24][N:11]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[CH2:21][C:20]([CH3:23])=[CH:19]2)[S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9]
Reactant: CC1=Cc2cccc(CCNS(=O)(=O)c3ccc(C)cc3)c2C1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC1=Cc2cccc(CCN(C)S(=O)(=O)c3ccc(C)cc3)c2C1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 15.0 g (45.8 mmol) of 4-methyl-N-[2-(2-methyl-1H-inden-7-yl)ethyl]-benzenesulfonamide in 100 mL of dry DMF at room temperature, 22.4 g (68.7 mmol) of Cs2CO3 was added, followed by the dropwise addition of 10.0 g (70.4 mmol) of MeI over a 10 minute period. This mixture was stirred for 24 hours at 50° C. and then evaporated under vacuum. To the residue, 200 mL of water and 200 mL of dichloromethane were added. The organic layer was separated, and the aqueous layer was washed with 200 mL of dichloromethane. The combined organic extract was evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um, eluent—dichloromethane). Yield, 14.1 g (90%) of white solid. This product was further used without an additional purification. 1H NMR (CDCl3): δ 7.50-7.55 (m, 2H, 2,6-H in p-tolyl), 7.15-7.20 (m, 2H, 3,5-H in p-tolyl), 7.04 (m, 1H, 5-H in indenyl), 7.01 (m, 1H, 6-H in indenyl), 6.78 (m, 1H, 4-H in indenyl), 6.36 (m, 1H, 3-H in indenyl), 3.08-3.18 (m, 6H, 1,1′-H in indenyl and CH2CH2), 2.69 (s, 3H, NMe), 2.67 (s, 3H, 4-Me in p-tolyl), 2.05 (s, 3H, 2-Me in indenyl). Anal. Calc. for C20H23NO2S: C, 70.35; H, 6.79; N, 4.10%. Found: C, 70.95; H, 7.13; N, 3.78%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([CH:23]([OH:25])[CH3:24])=[CH:21][N:22]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:38].[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:13]2[NH:38][C:16]([C:18]3[S:19][C:20]([CH:23]([OH:25])[CH3:24])=[CH:21][N:22]=3)=[CH:15][CH:14]=2)[CH2:27][CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CC(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)s1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)[nH]2)s1
Temperature: 90 °C
Reaction time: 3 h
Yield: 29.9 %

Procedure:
A mixture of 5-[3-chloro-4-(methylsulfonyl)phenyl]-1-[5-(1-hydroxyethyl)-1,3-thiazol-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (0.66 g), ammonium acetate (0.50 g) and acetic acid (5 mL) was stirred at 90° C. for 3 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was concentrated, 2M aqueous sodium hydroxide solution (1.5 mL), tetrahydrofuran (4 mL) and methanol (4 mL) were added to the residue, and the mixture was stirred with heating under reflux for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (0.19 g, yield 34%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate. MS: 495 (MH+).
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:41]1[S:45][C:44]([S:46]([NH2:49])(=[O:48])=[O:47])=[CH:43][CH:42]=1>>[Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([C:41]2[S:45][C:44]([S:46]([NH2:49])(=[O:48])=[O:47])=[CH:43][CH:42]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Product: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2ccc(S(N)(=O)=O)s2)o1
Yield: 75 %

Procedure:
The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (54 mg, 0.081 mmol) and 5-bromothiophene-2-sulfonamide following General Procedure A. Flash chromatography (10-20% EtOAc/hexanes) yielded the title compound as a white solid (33 mg, 75%): 1H NMR (CDCl3, 500 MHz) δ 7.68 (d, 1H, J=4.0 Hz), 7.36-7.33 (m, 3H), 7.29 (d, 1H, J=3.5 Hz), 7.26-7.23 (m, 3H), 5.29 (s, 2H), 4.89 (t, 1H, J=6.0 Hz), 2.67 (t, 2H, J=7.5 Hz), 2.02-1.95 (m, 2H), 1.74-1.59 (m, 2H), 1.40-1.38 (m, 6H), 0.97 (s, 9H), 0.17 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 166.2, 145.2, 143.2, 142.5, 136.4, 132.7, 128.8, 128.7, 126.0, 124.2, 123.8, 68.9, 36.7, 36.3, 31.8, 29.6, 26.1, 26.1, 25.5, 18.6, −4.5, −4.7.
Reaction SMILES: [C:1]([C:5]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH+]1C=CC=CC=1>O>[C:1]([C:5]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Oc2cc(C)ccc2C(C)(C)C)cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Product: Cc1ccc(C(C)(C)C)c(Oc2ccc(O)cc2)c1

Procedure:
7.1 g (0.026 mol) of 4-(2-t-Butyl-5-methylphenoxy)-methoxybenzene are heated with 15.0 g (0.13 mol) pyridinium hydrochloride to 180° C. for 6 h. After cooling water is added and the reaction mass is extracted with xylene. The product is distilled after evaporation of xylene at 130° C./0.01 Torr and recrystallized from petrol ether (80–110 to yield colourless crystals (mp 102° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[CH3:30]>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)=[CH:23][C:22]=1[CH3:30]
Reactant: COc1ccc(B(O)O)cc1C
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: COc1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cc1C

Procedure:
The title compound was prepared from the product of Example 65A and 4-methoxy-3-methylphenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 350.0 (M+H)+, retention time 1.42 minutes.
Reaction SMILES: CN(C)C=O.[Cl-].[Al+3].[Cl-].[Cl-].[Se:10]1(=[O:19])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1.Cl.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1>>[C:21]([C:16]1[CH:17]=[CH:18][C:13]2[N:12]=[CH:11][Se:10](=[O:19])[C:14]=2[CH:15]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=[Se]1C=Nc2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(c1cccnc1)c1ccc2c(c1)[Se](=O)C=N2
Temperature: 45 °C

Procedure:
9.9 ml (0.13 mol) of dimethylformamide are introduced dropwise and with stirring into a 250-ml flask containing 61.3 g (0.46 mol) of aluminum chloride, and the flask is fitted with a reflux condenser and heated in an oil bath to a temperature in the region of 45° C. 7.9 g (0.04 mol) of benzoselenazolinone and 10.6 g (0.06 mol) of nicotinoyl chloride hydrochloride are introduced.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([N:6]1[CH2:5][CH:4]([CH3:8])[NH:3][CH:2]([CH3:1])[CH2:7]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CN(S(C)(=O)=O)CC(C)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of cis-2,6-dimethylpiperazine and triethylamine in DCM at 0° C. was added dropwise methanesulphonyl chloride and the reaction mixture stirred at room temperature overnight. After quenching with water, extraction into DCM and being washed with brine, the organics were dried and the solvent removed under reduced pressure to yield 1-methanesulfonyl-3,5-dimethylpiperazine as a pale yellow solid.
Reaction SMILES: [CH:1]([CH:3]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][C:4]1=[O:20])=[CH2:2].[BH4-].[Na+]>CO>[CH:1]([CH:3]1[C:7]2([CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)[CH2:6][CH2:5][CH:4]1[OH:20])=[CH2:2]
Reactant: C=CC1C(=O)CCC12CCN(C(=O)OC(C)(C)C)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=CC1C(O)CCC12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Yield: 104.6 %

Procedure:
A solution of tert-butyl 1-vinyl-2-oxo-8-azaspiro[4.5]decane-8-carboxylate (0.59 g, 2.11 mmol) from Procedure 17, Step B in methanol (6 mL) was cooled to −70° C. and sodium borohydride (0.022 g, 0.60 mmol) was added. The reaction was allowed to warm to room temperature for 3 h and was then quenched with the addition of 1N hydrochloric acid. The mixture was diluted with water and extracted twice with ether. The combined ether layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to afford the title compound (0.621 g). 1H NMR (400 MHz, CDCl3) indicated a mixture of isomers which was used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.[CH3:36][O:37][C:38]([C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Br)=[CH:42][CH:41]=1)=[O:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH2:44][C:43]3[CH:42]=[CH:41][C:40]([C:38]([O:37][CH3:36])=[O:39])=[CH:47][CH:46]=3)[C:22]2=[O:35])[CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Product: COC(=O)c1ccc(Cn2c(=O)n(C3CCN(c4ncnc5cc(OC)c(OC)cc45)CC3)c(=O)c3cc([N+](=O)[O-])ccc32)cc1
Yield: 26 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound 24 was used and 4-methoxycarbonylbenzyl bromide was used in place of methyl iodide. As a result, 101.2 mg (yield: 26%) of Compound 13 was obtained as pale yellow crystals.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH2:5]1[C:10](=[O:11])[O:9][CH2:8][C:6]1=O.C1(C)C=CC=CC=1.O>C(O)(=O)C>[CH:1]1([NH:4][C:6]2[CH2:8][O:9][C:10](=[O:11])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=C1COC(=O)C1
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C=C(NC2CC2)CO1
Temperature: 120 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
At 0° C., 10.5 ml of cyclopropylamine (149.9 mmol) are added dropwise to 10.0 g of tetronic acid (99.9 mmol) in 57 ml of acetic acid, and the mixture is stirred at 120° C. for 2 h. After addition of 200 ml of toluene, the mixture is heated under reflux on a water separator for 3 hours. The reaction mixture is concentrated under reduced pressure and the residue is partitioned between 2.5 N of aqueous sodium hydroxide solution and dichloromethane. The aqueous phase is extracted a few more times with dichloromethane and the combined organic phases are dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue by recrystallization from ethanol gives 5.2 g (37% of theory) of 4-(cyclopropylamino)furan-2(5H)-one.
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.O=P(Cl)(Cl)Cl.[Br:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>>[Br:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH:22][C:9]1[C:4]2[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=c1[nH]cnc2cnc(F)cc12
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Yield: 63 %

Procedure:
Reaction of 6-fluoro-3H-pyrido[3,4-d]pyrimidin-4-one (0.60 g, 3.6 mmol) with POCl3, followed by reaction of the crude 4,6-dihalo compound with 3-bromoaniline gives 4-(3-bromoanilino)-6-fluoropyrido[3,4-d]pyrimidine (0.73 g, 63%). 1H NMR (DMSO) δ 10.09 (1H, brs), 8.96 (1H, s), 8.75 (1H, s), 8.25 (2H, m), 7.90 (1H, brd, J=6.5 Hz), 7.44 -7.34 (2H, m).