Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[C:28]([C:32]([NH2:34])=O)=[CH:27][CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:35]([CH3:37])[CH3:36])[O:11][N:10]=1.C(N(CC)CC)C.O(Cl)Cl.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[NH4+]>C(Cl)Cl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[C:28]([C:32]#[N:34])=[CH:27][CH:26]=[CH:25]4)=[CH:20][CH:21]=2)=[C:12]([CH:35]([CH3:37])[CH3:36])[O:11][N:10]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(N)=O)cccc3c2)cc1
Agent: ClOCl
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C#N)cccc3c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.3 %

Procedure:
To a solution of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxamide (94 mg, 0.18 mmol) and triethylamine (0.111 mL, 0.80 mmol) in methylene chloride (2 mL) at ambient temperature under nitrogen was added phosphrous oxychloride (0.068 mL, 0.71 mmol). The mixture was stirred at ambient temperature for four hours, at which time an additional equivalent of phosphorous oxychloride (0.027 mL) was added. Ammonium hydrogen carbonate (25 mg, 0.273 mmol) was then added to the mixture and the reaction was stirred at ambient temperature for 48 hours. The solvent was then removed on a rotary evaporator and the crude residue was dissolved in ethyl acetate. The organic solution was then washed with water three times, followed by saturated sodium bicarbonate, and then brine. The crude organic extract was then dried over magnesium sulfate, filtered, and then evaporated to dryness to give the title compound (89 mg, 98%).
Reaction SMILES: [SH:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][C:13]([CH3:16])([SH:15])[CH3:14].Br[CH2:20][CH2:21][CH2:22][CH3:23].[H-].[Na+].CCCCCC>O1CCCC1.C(OCC)(=O)C>[CH2:20]([S:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][C:13]([SH:15])([CH3:16])[CH3:14])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCBr
Reactant: CC(C)(S)CNc1ccccc1NCC(C)(C)S
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCSC(C)(C)CNc1ccccc1NCC(C)(C)S
Temperature: 25 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
1,2-Bis (2-mercapto-2-methylpropylamino)benzene (0.17 g, 6.1×10-4 mol, 120 M%) and 0.07 g (5.1×10-4 mol, 100 M%) 1- bromobutane were dissolved in 25 ml tetrahydrofuran (freshly distilled over Na). Sodium hydride (0.03 g, 6.25×10-4 mol, 102 M%) was then added. The mixture was stirred at room temperature under nitrogen for 3 hours. The reaction mixture was worked up as in Example 40. The product was isolated by radial chromatography on 1 mm silica plate, using hexane: ethyl acetate as the eluting solvent, giving 40 mg (23% yield) 2-(2-butylthio-2-methylpropylamino]-1-(2-mercapto-2-methylpropylamino)benzene as a yellow oil.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[N+:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][N:14]=[CH:15]2)([O-:9])=[O:8].ClCC(OCC)=O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH3:1][C:19]1[C:10]([N+:7]([O-:9])=[O:8])=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[N:14][CH:13]=[CH:12]2
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])c1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(=O)CCl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2cnccc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of potassium tert-butoxide (4.25 g, 37.9 mmol) in 13 mL of THF at −10° C. under an atmosphere of nitrogen was added a solution of 5-nitroisoquinoline (3.00 g, 17.2 mmol) and ethyl chloroacetate (2.32 g, 18.9 mmol) in 18 mL of THF dropwise. After 3 h, water (30 mL) was added and the reaction was stirred at rt for 3 d. Potassium carbonate (5.95 g, 43.1 mmol) was added, and after 24 h, the mixture was heated to 40° C. After 24 h, additional potassium carbonate (1.19 g, 8.62 mmol) was added, and the reaction was heated to 50° C. for another 3 h, then cooled to rt. The mixture was concentrated in vacuo, azeotroped 3× with toluene, and redissolved in dichloromethane. The organic solution was washed 3× with water, then with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 6-methyl-5-nitroisoquinoline that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 189.2 for [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH:20](Cl)Cl>CC(C)=O>[OH:10][C:9]1[CH:8]=[C:7]([O:11][CH2:18][O:19][CH3:20])[CH:6]=[CH:5][C:4]=1[C:2](=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: COC(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1ccc(C(C)=O)c(O)c1
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
A mixture of 2,4-dihydroxy acetophenone (2.0 g, 13.2 mmol) and oven-dried potassium carbonate (4.0 g, 30.0 mmol) in dry acetone (30 mL) was stirred for 10 min. Methoxymethylene chloride (MOMCl) (1.62 mL, 17.2 mmol) was added dropwise to the reaction mixture and the mixture was stirred at room temperature for 24 h. Solvent was evaporated under reduced pressure and water (25 mL) was added. The mixture was extracted with chloroform (3×100 mL) and the organic phase was dried over Na2SO4 and evaporated under reduced pressure. The residue was column chromatographed on silica gel eluting with 20% ethyl acetate in hexanes to afford acetophenone 6a (2.2 g, 87% yield) as a very low melting solid. Rf=0.51 (25% EtOAc-hexanes): mp 38-39° C. IR (KBr) 2959, 2829, 1632, 1579, 1504, 1367, 1262, 1142 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J=8.7 Hz, 1H), 6.51 (m, 2H), 5.15 (s, 2H), 3.42 (s, 3H), 2.51 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 202.6, 164.7, 163.4, 132.3, 114.6, 108.0, 103.6, 93.8, 56.2, 26.1; EIMS (m/z, rel intensity) 196 (M+, 100), 181 (6), 164 (9), 151 (32), 137 (24).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH2:20][CH:21]=[CH2:22])[C:12]=3[C:13]=2[CH3:14])=O)=[CH:5][CH:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH2:20][CH2:21][CH3:22])[C:12]=3[C:13]=2[CH3:14])=[CH:23][CH:24]=1
Reactant: C=CCc1c(O)ccc2oc(C(=O)c3ccc(OC)cc3)c(C)c12
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(O)ccc2oc(Cc3ccc(OC)cc3)c(C)c12
Yield: 38.1 %

Procedure:
A solution of 2-(p-methoxybenzoyl)-3-methyl-4-allyl-5-hydroxybenzofuran (3 gm, 9.3 mmoles) in ethanol (150 mL) was hydrogenated in a Parr hydrogenator in the presence of 10% palladium on charcoal at 40 psi for a period of 3 hours. The catalyst was filtered off, washed with some ethanol, and the filtrate was concentrated in vacuo. The residue was recrystallized from hexane to yield (1.1 gm, 38%) of 2-(p-methoxybenzyl)-3-methyl-4-propyl-5-hydroxybenzofuran, mp. 91°-93° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH3:22])[N:13]=2)=[O:11])[CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH3:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Cl>C(C(C)=O)C>[CH3:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][N:5]1[CH2:6][CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH3:22])[N:13]=2)=[O:11])[CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: Cc1cccc(CCl)c1
Reactant: CCn1nc(C(=O)NC2CNCCN(C)C2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCn1nc(C(=O)NC2CN(C)CCN(Cc3cccc(C)c3)C2)c2ccccc21
Reaction time: 6 h
Yield: 78.4 %

Procedure:
A mixture of N-(1-methylhexahydro-1H-1,4-diazepin-6-yl)-1-ethyl-1H-indazole-3-carboxamide (1.8 g), potassium carbonate (4.1 g), sodium iodide (0.9 g), 3-methylbenzyl chloride (0.85 g) and methyl ethyl ketone (100 ml) is refluxed with stirring for 6 hours. After cooling, the reaction mixture is filtered, and the filtrate is concentrated under reduced pressure. The residue is chromatographed on silica gel with elution of chloroformmethanol (20:1). Fractions containing the title compound are pooled and evaporated under reduced pressure to give the title compound (1.9 g) as an oil. The free base thus obtained is converted to the fumarate of the title compound in a usual manner, m.p. 135-137° C. (recrystallized from ethanol-diethyl ether).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]1[C:4]([CH3:10])=[N+:5]([O-:9])[CH:6]=[CH:7][CH:8]=1.O.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[F:11][CH:2]([F:1])[C:3]1[C:4]([CH3:10])=[N+:5]([O-:9])[CH:6]=[CH:7][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: Cc1c(C(F)F)ccc[n+]1[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C(F)F)c([N+](=O)[O-])cc[n+]1[O-]
Temperature: 95 °C

Procedure:
31.38 g of 3-difluoromethyl-2-methylpyridine N-oxide (XVII) was dissolved in 64 ml of concentrated sulfuric acid, to which a mixed solution of 93 ml of concentrated sulfuric acid and 107 ml of 65% nitric acid were added, and the resulting mixture was heated at 95° C. for 20 hours. The reaction solution was poured into iced water and the precipitated crystal was separated by filtering to obtain 17.79 g of 3-difluoromethyl-2-methyl-4-nitropyridine N-oxide (XVIII).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:12]=2)[C:7]1=[O:24])[CH3:2].Br[CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=3)[CH:12]=2)[C:7]1=[O:24])[CH3:2]
Reactant: CCCBr
Reactant: CCOC(=O)CN1C(=O)c2ccc(Oc3ccc(O)cc3)cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc(Oc2ccc3c(c2)C(=O)N(CC(=O)OCC)C3=O)cc1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
A mixture of [5-(4-hydroxy-phenoxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetic acid ethyl ester (2.479 g, 7.26 mmol), 1-bromopropane (1.32 mL, 14.52 mmol), potassium carbonate (2.01 g, 14.52 mmol), and acetone (25 mL) was refluxed overnight. After cooling to ambient temperature the mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water. The organic phase was washed with saturated NaCl, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (2.485 g). 1H NMR (200 MHz, CDCl3): δ (ppm)=7.77 (q, 1H, J=8.1 Hz), 7.3-6.8 (m, 6H), 4.38 (s, 2H), 4.20 (q, 2H, J=7.0 Hz), 3.93 (t, 2H, J=6.4 Hz), 1.82 (q, 2H, 6.6 Hz), 1.28 (t, 3H, J=7.0 Hz), 1.06 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[NH:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27](O)=[O:28])=[CH:26][C:21]=2[N:20]=[CH:19]1.N(CCCC)(CCCC)CCCC.[I-].ClC1C=CC=C[N+]=1C>CN(C)C=O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:27]([C:25]3[CH:24]=[CH:23][C:22]4[NH:18][CH:19]=[N:20][C:21]=4[CH:26]=3)=[O:28])=[CH:8][CH:9]=2)[N:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Cc1nn(-c2ccccc2)c2cc(N)ccc12
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccc2)c2cc(NC(=O)c3ccc4[nH]cnc4c3)ccc12
Temperature: 100 °C
Reaction time: 48 h

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of 3-methyl-1-phenyl-1H-indazol-6-amine (520 mg, 2.33 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL), 1H-benzo[d]imidazole-5-carboxylic acid (324 mg, 2.00 mmol, 0.86 equiv), NBu3 (925 mg, 5.00 mmol, 2.14 equiv). To the resulting mixture was then added 2-chloro-1-methylpyridiniumiodide (612 mg, 2.40 mmol, 1.03 equiv) at 50° C. The resulting solution was stirred for 2 days at 100° C. in an oil bath, then concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (50:1). The resulting mixture was washed with methanol (1×10 mL) and diethyl ether (1×10 mL) to yield N-(3-methyl-1-phenyl-1H-indazol-6-yl)-1H-benzo[d]imidazole-5-carboxamide as a yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH2:12][O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:9]=[C:8]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:22]([O:32][CH3:33])[CH:21]=2)[N:7]=1)=[CH2:5])C.Cl.C(=O)(O)[O-].[Na+]>>[CH3:33][O:32][C:22]1[CH:21]=[C:20]([NH:19][C:8]2[N:7]=[C:6]([C:4](=[O:3])[CH3:5])[CH:11]=[C:10]([CH2:12][O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[N:9]=2)[CH:25]=[CH:24][C:23]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1
Reactant: C=C(OCC)c1cc(COCC(F)(F)F)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)=O)n2)ccc1-n1cnc(C)c1
Temperature: 60 °C
Yield: 99.5 %

Procedure:
To a solution of 4-(1-ethoxyvinyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-2-amine (0.418 g, 0.90 mmol) dioxane (60 mL) water 3 mL) and concentrated hydrochloric acid (0.228 mL, 2.71 mmol) were added. The solution was heated at 60° C. for 15 min. The mixture was treated with an excess of sodium bicarbonate and extracted twice with ethyl acetate. The combined organic phase was dried over sodium sulfate and concentrated to yield the title product as a solid 390 mg (99%).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:22][OH:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[CH:31][N:32]([CH3:34])[CH:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[Mn]([O-])(=O)(=O)=[O:36].[K+]>[OH-].[Na+]>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:36])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[CH:31][N:32]([CH3:34])[CH:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(C)cn3)cc2n1Cc1ccc(-c2ccccc2CO)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: CCCc1nc2c(C)cc(-c3cn(C)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4′-[(2-n-propyl-4-methyl-6-(1-methylimidazol-4-yl)-benzimidazol-1-yl)methyl]-2-hydroxymethylbiphenyl (0.2 g, 0.4 mmol) in 7 ml of 4 N sodium hydroxide solution, 0.252 g of potassium permanganate (1.5 mmol) is added. Reaction mixture is then stirred overnight at room temperature and finally quenched with 30 ml of saturated solution of Na2CO3. The obtained mixture is filtered, clear filtrate acidified with acetic acid to pH 4-5 and precipitated solid isolated and dried. Yield: 0.08 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C(N(C(C)C)CC)(C)C.[CH3:42][O:43][CH2:44]Cl>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH2:42][O:43][CH3:44])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reactant: COCCl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCO[C@H]1CC[C@H](N(c2cc(C3=CCCCC3)sc2C(=O)OC)C(=O)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
To a solution of 5-cyclohex-1-enyl-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (1 g, 2.18 mmol) in dichloromethane (10 mL) was added diisopropyl ethylamine (0.6 mL, 3.3 mmol), chloromethyl methyl ether (250 μL, 3.3 mmol) and DMAP (40 mg, 0.33 mmol). The reaction mixture was refluxed for 12 h. Solvents were removed and the residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:3) as eluent to obtain 5-cyclohex-1-enyl-3-[(trans-4-methoxymethoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (780 mg, 71%) as a syrup.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@H:11]([N:19]1[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:21]=[CH:20]1)[CH2:12][CH2:13]OS(C)(=O)=O)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[SH:39].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Si:1]([O:8][C@H:9]([C@H:11]([N:19]1[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:21]=[CH:20]1)[CH2:12][CH2:13][S:39][C:30]1[CH:31]=[CH:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=1)[CH3:10])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: Sc1ccc2ccccc2c1
Reactant: CCOC(=O)c1cn([C@H](CCOS(C)(=O)=O)[C@H](C)O[Si](C)(C)C(C)(C)C)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn([C@H](CCSc2ccc3ccccc3c2)[C@H](C)O[Si](C)(C)C(C)(C)C)cn1
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a mixture of ethyl 1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-methanesulfonyloxy-3-pentyl]imidazole-4-carboxylate (160 mg, 0.368 mmol) and 2-naphthalenethiol (118 mg, 0.736 mmol) in DMF (5 ml) was added potassium carbonate (102 mg, 0.736 mmol) at room temperature and the reaction mixture was stirred for 2 hours. The resulting reaction mixture was poured into water (25 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate) and evaporated in vacuo. The residue was purified by silica gel (10 g) chromatography eluting with chloroform/methanol (100:1 to 50:1) to give ethyl 1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(2-naphthylthio)-3-pentyl]imidazole-4-carboxylate (146 mg, 79.5%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:28][C:29]([F:32])([F:31])[F:30])(=O)=O>CN(C=O)C>[F:30][C:29]([F:32])([F:31])[CH2:28][O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(OCc2ccccc2)cc1
Temperature: 50 °C
Yield: 106.1 %

Procedure:
To a 20 ml DMF solution of 4-benzyloxyphenol (3.35 g, 16.7 mmol) and cesium carbonate (6.02 g, 18.5 mmol) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.29 g, 18.4 mmol) upon cooling in an ice-water bath. The cooling bath was removed and the reaction mixture was heated to 50° C. for 1 hr. The reaction mixture was diluted with AcOEt and water. The organic layer was separated, washed with 1N hydrochloric acid, dried over anhydrous Na2SO4, filtered, and concentrated to give benzyl 4-(2,2,2-trifluoroethoxy)phenyl ether 5.0 g (quant.). This material was dissolved in 200 ml of ethanol and was hydrogenated in a Parr shaker with 10% Pd/C 222 mg under hydrogen atmosphere (50 psi) overnight. The catalyst was removed by suction filtration through a pad of celite. The filtrate was concentrated to give the title compound 2.6 g (87%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>C(O)(C)C>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[NH2:14])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: NCc1ccccc1N
Reactant: CSc1ncnc2cc(N)ncc12
Solvent: CC(C)O
Product: Nc1cc2ncnc(NCc3ccccc3N)c2cn1
Yield: 47.1 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (136 mg, 0.71 mmol) (described in a previous experimental) and 2-aminobenzylamine (1.70 g, 13.8 mmol) in isopropanol (5 mL) is stirred at reflux for 1 h, and the resulting product is chromatographed on silica gel (7-20% EtOH/EtOAc) and alumina (6-10% EtOH/CHCl3) to give 7-amino-4-(2-aminobenzylamino)pyrido[4,3-d]pyrimidine (89 mg, 47%) as a white solid. 1H NMR (DMSO) δ 9.08 (1H, s), 8.68 (1H, t, J=5.8 Hz), 8.26 (1H, s), 7.05 (1H, d, J=7.4 Hz), 6.96 (1H, t, J=7.6 Hz), 6.63 (1H, d, J=7.9 Hz), 6.51 (1H, t, J=7.4 Hz), 6.46 (2H, brs), 6.35 (1H, s), 5.20 (2H, brs), 4.56 (2H, d, J=5.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([CH2:15]O)[CH:12]=[C:11]([O:17][CH3:18])[C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].P(Br)(Br)[Br:20]>ClCCl>[Br:20][CH2:15][C:13]1[CH:12]=[C:11]([O:17][CH3:18])[C:3]([O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:2]([F:1])[CH:14]=1
Reactant: CCOC(=O)COc1c(F)cc(CO)cc1OC
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CCOC(=O)COc1c(F)cc(CBr)cc1OC
Yield: 52.2 %

Procedure:
The compound was prepared according to general procedure G with ethyl 2-(2-fluoro-4-(hydroxymethyl)-6-methoxyphenoxy)acetate (0.4 mmol) in dichloromethane (5 ml) and PBr3 (0.4 mmol). 67 mg of compound were obtained (54% yield). This compound was used without further purification. 1H NMR (250 MHz, CDCl3): δ 1.29 (t, J=7.0 Hz, 3H), 3.89 (s, 3H), 4.25 (q, J=7.0 Hz, 2H), 4.41 (s, 2H), 4.71 (s, 2H) 6.74 (m, 1H), 6.81 (m, 1H). MS (ESI): m/z 319.9 [M+H]+
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][C:23]#[N:24])[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][C:23]#[N:24])[CH2:17][CH2:16]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: N#CCC[C@H]1CC[C@H](N)CC1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 90 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.087 g, 0.41 mmol), 3-(trans-4-aminocyclohexyl)propanenitrile (0.080 g, 0.52 mmol) TFA salt and N,N-diisopropylethylamine (0.35 mL, 2.0 mmol) in isopropyl alcohol (0.89 mL) was heated at 90° C. for 2 h. The resulting mixture was concentrated and purified on silica gel (eluting with 0 to 20% EtOAc in dichloromethane) to give the desired product (63 mg, 47%). LCMS calculated for C16H19N4O2S (M+H)+: m/z=331.1. Found: 331.0.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:20](=[O:21])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.[I-].[K+]>CN(C=O)C>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[C:9]2[C:20](=[O:21])[CH:5]([CH2:4][CH2:3][CH2:2][N:46]3[CH2:47][CH2:48][N:43]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=4)[CH2:44][CH2:45]3)[CH2:6][CH2:7][C:8]=2[O:12][N:11]=1
Reactant: O=C1c2c(-c3ccccc3F)noc2CCC1CCCCl
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2c(-c3ccccc3F)noc2CCC1CCCN1CCN(c2ccccn2)CC1
Temperature: 80 °C

Procedure:
To a solution consisting of 5-(3-chloropropyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (6.4 g) and DMF (100 ml) was added anhydrous potassium carbonate (1.4 g), diisopropylethyl amine (5.4 ml), 1-(2-pyridyl)piperazine (4.8 ml) and potassium iodide (0.4 g) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80° C. for 16 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with water twice, then brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via preparative HPLC (silica gel, 3% methanol) afforded 4.2 g of 6,7-dihydro-3-(2-fluorophenyl)-5-[3-(4-(2-pyridyl)-1-piperazinyl)-propyl]-1,2-benzisoxazol-4(5H)-one, as an oil which solidified upon standing. The product was recrystallized from ether, m.p. 94°-96° C.