Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)=O.[ClH:4].C([N:12]1[CH2:16][C:15](=[O:17])[NH:14][CH:13]1[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])C1C=CC=CC=1.O>[Pd].CO>[ClH:4].[O:17]=[C:15]1[NH:14][CH:13]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])[NH:12][CH2:16]1
Reactant: CC(C)COC(=O)CCC1NC(=O)CN1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O=CO
Solvent: CO
Solvent: O
Product: CC(C)COC(=O)CCC1NCC(=O)N1
Reaction time: 6 h
Yield: 40.8 %

Procedure:
To a mixture of 10% palladium on charcoal (1 g) and 99% formic acid (1 ml) in methanol (2ml), under nitrogen, was added a solution of isobutyl 3-benzyl-5-oxo-2-imidazolidinepropanoate hydrochloride (1 g, 2.93 mmol) and 99% formic acid (1.25 ml) in methanol (25 ml). The mixture was stirred under nitrogen for 6 hours. After addition of water (15 ml) and removal of the catalyst, the solvent was evaporated and the residue was triturated with ethanol to give 0.3 g (41%) of the title compound, m.p. 136°-140° C. The same compound was obtained also by the following procedure: into a mixture of isobutyl 3-benzyl-5-oxo-2-imidazolidinepropanoate hydrochloride (2.2 g, 6.4 mmol), and 10% palladium on charcoal (1.1 g) in water-methanol 2:1 (150 ml) hydrogen was bubbled at room temperature and at atmospheric pressure for 2 hours. Removal of the catalyst and evaporation of the solvent under reduced pressure gave a residue which was triturated with ethanol to afford 1.4 g (90%) of the title compound, m.p.136°-140° C. NMR (DMSO-d6): deltaH =11.1-9.50 (b.s., 2H, NH2+); 9.20 (b.s., 1H, CONH); 4.95 (t, J=6.2 Hz, 1H, NHCHNH); 3.84 (d, J=6.7 Hz, 2H, COOCH2); 3.65 (s, 2H, NCH2CO); 2.70-2.30 (c.a., 2H, CH2CH2COO); 2.25-1.60 (c.a., 3H, CH2CH2COO, CH(CH3)2); 0.87 (d, J=6.7 Hz, 6H, CH(CH3)2. MS (E.I., 70 eV, 1.5 mA) m/z=214 (M+), 141 (M--OC4H9)+, 85 (C3H5N2O)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[Na].NC1C=C(O)C(=CC=1)C([O-])=O.[K].NC1C=C(O)C(=CC=1)C([O-])=O.[Li].NC1C=C(O)C(=CC=1)C([O-])=O.CCl.[CH:50]1([CH3:60])[CH2:55][CH2:54][CH:53]([CH:56]([CH3:58])[CH3:57])[CH:52](Br)[CH2:51]1.C1(C)CCC(C(C)C)C(I)C1>[OH-].[Ag+]>[CH:50]1([CH3:60])[CH2:55][CH2:54][CH:53]([CH:56]([CH3:58])[CH3:57])[CH:52]([O:7][C:6](=[O:8])[C:5]2[C:4](=[CH:3][C:2]([NH2:1])=[CH:10][CH:9]=2)[OH:11])[CH2:51]1
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: CC1CCC(C(C)C)C(Br)C1
Agent: [Ag+]
Agent: CC1CCC(C(C)C)C(I)C1
Agent: CCl
Product: CC1CCC(C(C)C)C(OC(=O)c2ccc(N)cc2O)C1
Temperature: 50 °C

Procedure:
One-tenth mol of an alkali metal salt of para-aminosalicylic acid as for example, sodium-p-aminosalicylate, potassium-p-aminosalicylate or lithium-p-aminosalicylate, is dissolved in 300 ml. of alcohol and to this is added exactly one-tenth mol of a menthyl halogen salt as for example, methyl chloride, menthyl bromide or menthyl iodide. The mixture is stirred and 0.5 gms. of freshly precipitated silver hydroxide is added as a catalyst. The mixture is warmed to 50° C. for a period of at least two hours, cooled to room temperature and filtered. The filtrate is set aside to crystallize in an ice-chest and menthyl-para-aminosalicylate is obtained as a white crystalline substance melting at 187° C. to 189° C. The compound is insoluble in water but soluble in alcohol, benzene and chloroform.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH2:4][CH2:3]1.Br[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([NH:26][C:27]2[N:32]=[C:31]([C:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]([CH3:42])[CH:34]=3)[CH:30]=[CH:29][N:28]=2)=[CH:20][C:19]=1[NH2:43].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=2)[C:19]([NH2:43])=[CH:20][C:21]=1[NH:26][C:27]1[N:32]=[C:31]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]([CH3:42])[CH:34]=2)[CH:30]=[CH:29][N:28]=1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1cc(Br)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 100 °C
Yield: 83.4 %

Procedure:
1,1 Bis(di-tert-butylphosphino)ferrocene palladium dichloride (16.74 mg, 0.03 mmol) was added to a solution containing 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (139 mg, 0.62 mmol), 4-bromo-6-methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 144, 220 mg, 0.52 mmol), and K3PO4 (220 mg, 1.04 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL, degassed for 20 minutes prior to use). The mixture was heated at 100° C. for 1 h and then concentrated in vacuo. The resulting residue was dissolved in EtOAc. This solution was washed with water (×3), brine, and was then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-10% methanolic ammonia in CH2Cl2 gave the title compound (191 mg, 84%) as a tan solid after trituration with diethyl ether; 1H NMR: 2.31 (3H, s), 2.37-2.43 (2H, m), 2.61 (2H, t), 3.01-3.04 (2H, m), 3.76 (3H, s), 3.89 (3H, s), 4.37 (2H, br s), 5.70-5.73 (1H, m), 6.63 (1H, s), 7.18-7.22 (2H, m), 7.25-7.29 (1H, m), 7.54 (1H, d), 7.63 (1H, s), 7.81 (1H, s), 8.31 (1H, d), 8.34 (1H, s), 8.46 (1H, d); m/z: ES+ MH+ 441.57.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].N1C=CC=CC=1.[CH2:14]([CH:17]1[CH2:22][CH2:21]C(CO)[CH2:19][CH2:18]1)[C:15]#[CH:16].O>CCOCC>[C:5]([O:4][CH2:1][CH:2]1[CH2:21][CH2:22][CH:17]([CH2:14][C:15]#[CH:16])[CH2:18][CH2:19]1)(=[O:7])[CH3:6]
Reactant: C#CCC1CCC(CO)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: C#CCC1CCC(COC(C)=O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
Acetic anhydride (0.92 mL, 8.25 mmol) and pyridine (0.2 mL, 2.5 mmol) were added to a solution of 5.3 (250 mg, 1.65 mmol) in 25 mL ether. The reaction was allowed to stir at ambient temperature for 24 hours. Water was added to the reaction and the organic was further extracted with 10% NaHCO3. The organic layer was dried with MgSO4 and evaporated. The residue was chromatographed on silica gel with EtOAc-Hexanes (5:95) to yield 5.6 (47%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11](C(OCC)=O)(C(OCC)=O)[CH2:12][C:13]#[N:14])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[OH-].[Na+].Cl>CO>[N+:8]([C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([CH2:11][CH2:12][C:13]#[N:14])=[N:4][CH:5]=1)([O-:10])=[O:9]
Reactant: CCOC(=O)C(CC#N)(C(=O)OCC)c1ncc([N+](=O)[O-])cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc([N+](=O)[O-])cnc1CCC#N
Reaction time: 0.92 h
Yield: 61.4 %

Procedure:
3-(3-Methyl-5-nitropyrid-2-yl)-3,3-bis(carbethoxy)propionitrile (29.8 g) was dissolved in methanol (1120 ml), molar sodium hydroxide solution (355 ml) was added, the reaction was cooled from 28° C. to room temperature and stirred for 55 minutes. The pH was lowered to 4 by the addition of concentrated hydrochloric acid, the reaction was stirred for 2.75 hr., the pH was then raised to 7 and the methanol was distilled off. The aqueous phase was extracted with chloroform, extracts were dried, filtered and concentrated. The residue was crystallised from chloroform/petroleum ether 40°-60° C. The crude product was treated with charcoal in ethanol and recrystallised from ethanol to give the title compound 10.44 g, m.p. 73°-74° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]3N=N[N:16]=[C:6]3[C:5]=2[N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].O>ClC1C=CC=CC=1Cl.ClCCl.CCOCC>[CH3:1][C:2]1[N:3]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:16])[C:5]=2[N:17]=1
Reactant: Cc1nc2c(c3ccccc3n3nnnc23)n1CCOCCCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOCCCc1cccnc1
Temperature: 25 °C
Yield: 23.4 %

Procedure:
Under an atmosphere of nitrogen, 5-methyl-6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline (0.73 g, 1.89 mmol) and triphenylphosphine (0.64 g, 2.84 mmol) were dissolved in 1,2-dichlorobenzene (15 ml). The reaction was heated at reflux for 18 hours. After cooling to ambient temperature, the solvent was removed in vacuo. The resulting residue was treated with 1N HCl/water (30 ml) and vigorous stirring produced an off white suspension. The solid was removed by filtration leaving a yellow filtrate. The filtrate was treated with 10% sodium hydroxide/water until pH 11 was reached. The filtrate was extracted with dichloromethane (3×25 ml). The combined organic fractions were washed with brine (25 ml), dried (Na2SO4), filtered and concentrated in vaeuo to yield an orange oil. The oil was dissolved in a minimum amount of dichloromethane and diluted with ether to produce a precipitate. The solid was recrystallized from n-propyl acetate to yield 0.16 g of 2-methyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinoline-4-amine as a tan solid, m.p. 145.0-146.0.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[OH:17])[CH:13]([C:18]([OH:20])=[O:19])[CH2:12][CH2:11]2)=[O:7].[CH3:25]O>>[CH3:25][O:19][C:18]([CH:13]1[C:14]2[C:10](=[CH:9][C:8]([C:6](=[O:7])[C:5]3[CH:21]=[CH:22][CH:23]=[CH:24][C:4]=3[Cl:3])=[C:16]([OH:17])[CH:15]=2)[CH2:11][CH2:12]1)=[O:20]
Reactant: CO
Reactant: O=C(c1cc2c(cc1O)C(C(=O)O)CC2)c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C1CCc2cc(C(=O)c3ccccc3Cl)c(O)cc21

Procedure:
Analogously to the description in Example 2, 8.7 g of 5-(o-chlorobenzoyl)-6-hydroxy-indane-1-carboxylic acid methyl ester and 27 ml of 2 N sodium hydroxide solution in 100 ml of methanol give 5-(o-chlorobenzoyl)-6-hydroxy-indane-1-carboxylic acid of melting point 188°-190° C. (from ethyl acetate-petroleum ether).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[F:18])#[N:8].I[C:20]1[CH:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:37]=[CH:36][C:35]([C@@H:38]([NH:40][C:41](=[O:43])[CH3:42])[CH3:39])=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)=[N:24][CH:25]=1>O1CCOCC1.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:20]2[CH:25]=[N:24][C:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][C:35]([C@@H:38]([NH:40][C:41](=[O:43])[CH3:42])[CH3:39])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[N:22][CH:21]=2)=[CH:11][C:10]=1[F:18])#[N:8]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ncc(I)cn3)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ncc(-c4ccc(C#N)c(F)c4)cn3)CC2)cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
Under argon atmosphere 0.1 mL sat. Na2CO3-solution and 3 mg (0.004 mmol) bis(triphenylphosphine)-palladium(II) chloride are added to a mixture of 16 mg (0.10 mmol) 4-cyano-3-fluorophenylboronic acid and 45 mg (0.10 mmol) (S)—N-(1-{4-[1-(5-iodopyrimidin-2-yl)-piperidin-4-yl]-phenyl}-ethyl)-acetamide (compound 4.43) in 2 mL dioxane/1 mL MeOH. The mixture was stirred at 70° C. for 6 h. After that time, the mixture was diluted with DMF and filtered. The filtrate was purified using reversed phase HPLC (water/MeOH, 0.1% TFA) to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[C:12](O)(=O)[CH3:13]>Cl>[CH3:12][C:13]1[NH:11][C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: CC(=O)O
Agent: Cl
Product: Cc1nc2cc(C(=O)O)ccc2[nH]1

Procedure:
100 g (0.657 mol) of 3,4-diaminobenzoic acid are boiled under reflux with 47.3 g (0.788 mol) of glacial acetic acid and 600 ml of 4N HCl in analogy to Example 14a.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([NH:12][CH2:13][CH2:14][OH:15])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[OH:15][CH2:14][CH2:13][N:12]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:10][CH3:11]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCN(CCO)c1ccc(C=O)cc1
Temperature: 95 °C

Procedure:
To a three neck flask fitted with a mechanical stirrer, a thermometer, and a condenser, is added 124 g (1 mole) of 4-fluorobenzaldehyde, 89.1 g (1 mole) of 2-(N-ethylamino)ethanol, 138.2 g (1 mole) of anhydrous potassium carbonate, and dimethylsulfoxide. The mixture is heated at 95° C. for 3 hours. After cooling to room temperature, the solution is poured into a four-fold excess of ice water, and the solid product is collected by filtration and recrystallized from water.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[O:23])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH:22]([OH:23])[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(O)c2ccncc2)cc1

Procedure:
The title compound was prepared by the reduction of 4-tert-Butyl-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide with NaBH4 according to the procedure described in the preceding example. MS: (M+H)=431.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].C(C1C(CCCOCCC(OC(C)(C)C)=O)=CC=CN=1)#N.[C:33]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[CH:37][N:36]=1)#[N:34].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:33]([C:35]2[N:36]=[CH:37][C:38]([CH2:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[CH:39][CH:40]=2)=[N:34]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)CCOCCCc1ccc(C#N)nc1
Agent: CC(C)(C)OC(=O)CCOCCCc1cccnc1C#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCOCCCc1ccc(-c2nc(=O)c3ccccc3s2)nc1
Yield: 16.4 %

Procedure:
A mixture of methyl thiosalicylate (2.80 g, 16.6 mmol), a mixture of tert-butyl 3-[(2-cyanopyridin-3-yl)propoxy]propionate and tert-butyl 3-[(2-cyanopyridin-5-yl)propoxy]propionate (ca. 9:1, 4.55 g, 15.7 mmol), triethylamine (2.02 g, 20 mmol) and toluene (20 ml) was refluxed under nitrogen atmosphere for 20 hrs. The reaction mixture was concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography, eluted with ethyl acetate-hexane (2:1, v/v) to give the titled compound (1.10 g, 16%).
Reaction SMILES: [C:1]([C:5]([C:8]([C:11]([S:14]([N:17]([CH2:19][CH2:20]I)[CH3:18])(=[O:16])=[O:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].C(C(C(C(S(N(CCO)C)(=O)=O)(F)F)(F)F)(F)F)(F)(F)F.S(Cl)([Cl:45])=O>C(Cl)Cl>[C:1]([C:5]([C:8]([C:11]([S:14]([N:17]([CH2:19][CH2:20][Cl:45])[CH3:18])(=[O:16])=[O:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2]
Reactant: O=S(Cl)Cl
Reactant: CN(CCI)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CN(CCO)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: ClCCl
Product: CN(CCCl)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
CF3(CF2)3SO2N(Me)CH2CH2I was made as follows: CF3(CF2)3SO2N(Me)CH2CH2OH was reacted with an excess of thionyl chloride in methylene chloride at 25-45° C. to give CF3(CF2)3SO2N(Me)CH2CH2Cl, which (7.1 g) was mixed with a solution of 6.0 g NaI in acetone. The resulting solution was stirred at reflux, and the conversion to CF3(CF2)3SO2N(Me)CH2CH2I was followed by GC. At 24 hours, conversion was 14 percent, and 6.0 g more NaI was added; at 3 days, conversion was 46 percent; at 6 days, conversion was 72 percent, and 6.0 g NaI was added; at 13 days, 96 percent conversion was achieved. The resulting product was precipitated with water and recrystallized from hexane to provide 6.2 g white plates with a m.p. of 80-82° C. FO2S(CF2)2O(CF2)2I was obtained from Sigma-Aldrich Chemical Company, St. Louis, Mo. C3F6O(isoC3F3O)5CF(CF3) can be prepared essentially as described by Chen et. al. in J Fluorine Chem. 65, 59 (1993). I(CF2)4I was obtained from Sigma-Aldrich Chemical Company, St. Louis, Mo. CF3(CF2)7Br was obtained from 3M Company, St. Paul, Minn., and is available from Sigma-Aldrich Chemical Company, St. Louis, Mo. Sodium acetate was obtained from Sigma-Aldrich Chemical Company, St. Louis, Mo. Dimethylsulfoxide (DMSO) was obtained from Alfa Aesar, Ward Hill, Mass. Tetrahydrofuran (THF) was obtained from EMD Chemicals, Inc., Gibbstown, N.J. p-Toluenesulfonic acid was obtained from J. T. Baker, Phillipsburg, N.J. NaHCO3 was obtained from EMD Chemicals, Inc., Gibbstown, N.J.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:25]
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Reactant: CNC
Product: COc1ccc(N(C)c2nc(CN(C)C)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine and dimethylamine by a procedure similar to Example 76. 1H NMR (DMSO-d6): 7.71 (d, J=8.7 Hz, 1H), 7.60 (t, J=8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.09 (t, J=8.1 Hz, 1H), 7.00-6.96 (m, 3H), 3.78 (s, 3H), 3.63 (s, 2H), 3.50 (s, 3H), 2.33 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(N(CC)CC)C>CN(C)C=O.[Pd]>[CH:7]1[C:8]2[C:3](=[CH:2][CH:11]=[CH:10][C:9]=2[NH2:12])[CH:4]=[CH:5][N:6]=1
Reactant: O=[N+]([O-])c1ccc(Br)c2ccncc12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1cccc2ccncc12
Reaction time: 2 h
Yield: 61.2 %

Procedure:
A suspension of 5-bromo-8-nitro-isoquinoline (2.0 g, 7.93 mmol), triethylamine (1.2 g, 11.90 mmol) and Pd/C (10%; 200 mg) in dimethylformamide (10 mL) was hydrogenated at atmospheric pressure for 2 h. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated in vacuo to afford isoquinolin-8-amine (700 mg, 66%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=3[N:10]=[CH:9]2)=[CH:5][CH:4]=1.[Br:20]Br.N.CO.C(Cl)(Cl)Cl>CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([NH2:17])=[C:16]([Br:20])[C:11]=3[N:10]=[CH:9]2)=[CH:18][CH:19]=1
Reactant: COc1ccc(Cn2cnc3cc(N)ccc32)cc1
Reactant: BrBr
Agent: N
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cn2cnc3c(Br)c(N)ccc32)cc1
Yield: 95 %

Procedure:
To a solution of 1-(4-methoxybenzyl)-5-aminobenzimidazole (0.80 g, 2.2 mmol) in 20 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CHCl3) to provide 0.90 g (2.1 mmol, 95%) of the product.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:11]=[C:12]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH2:13][NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)=[O:16].O>C(Cl)Cl>[C:1]1([S:7]([N:32]2[CH2:31][CH2:30][N:29]([C:12](=[O:11])[CH2:13][NH:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:19][CH:18]=3)=[O:16])[CH2:34][CH2:33]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: O=C(NCC(=O)N1CCN(S(=O)(=O)c2ccccc2)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
TEA (62.57 mg, 062 mmol) followed by benzenesulphonyl chloride (54.6 mg, 0.31 mmol) were added at to 0° C. to biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) in DCM (4 mL). The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product extracted with DCM. The organic layer was separated, washed with 10% HCl solution, saturated NaHCO3 solution and brine, dried over sodium sulphate and concentrated. The resulting residue was purified by column chromatography (using 60-120 mesh silica gel and 30% EtOAc in hexane as eluent) to afford 45 mg (31.4% yield) of biphenyl-4-carboxylicacid {2-[4-benzene sulfonyl-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 98.75%, 1H NMR: (DMSO) δ 8.76 (t, 1H), 7.92 (d, 2H), 7.8-7.6 (m, 9H), 7.54-7.44 (t, 2H), 7.44-7.36 (t, 1H), 4.1 (d, 2H), 3.6 (s, 4H), 3.0-2.86 (d, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C:12](O)=[O:13])=[CH:5][CH:4]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:35][NH2:36]>C(Cl)Cl>[OH:35][NH:36][C:12](=[O:13])[CH2:11][CH:10]([S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(SC(CC(=O)O)Cc2ccccc2)cc1
Reactant: C[Si](C)(C)ON
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(SC(CC(=O)NO)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.9 %

Procedure:
To a solution of 1 g (3.31 mmol) of 3-(4-methoxyphenylsulfanyl)-4-phenylbutyric acid in 30 mL of CH2Cl2 at 25° C. under argon is added 0.2 mL of DMF followed by 4.1 mL (8.27 mmol) of 2 M solution of oxalyl chloride in CH2Cl2. After stirring at 25° C. for 1.5 hours, 2.1 mL (16.53 mmol) of O-trimethylsilylhydroxylamine is added and this is then stirred at 25° C. for 18 hours. The reaction is partitioned between CH2Cl2 and 1 N HCl. The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by flash silica gel chromatography affords 0.86 g (82%) of N-hydroxy-3-(4-methoxyphenylsulfanyl)-4-phenylbutyramide as a yellow crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]([CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][CH:13]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].[Li]C(C)(C)C.[CH3:32][C:33]1[CH:40]=[C:39]2[O:41][CH2:42][O:43][C:38]2=[CH:37][C:34]=1[CH:35]=[O:36]>C1COCC1>[Cl:1][C:2]1[C:3]([N:8]([CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][C:13]=2[CH:35]([OH:36])[C:34]2[CH:37]=[C:38]3[O:43][CH2:42][O:41][C:39]3=[CH:40][C:33]=2[CH3:32])(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: Cc1cc2c(cc1C=O)OCO2
Reactant: COCCOCN(c1noc(C)c1Cl)S(=O)(=O)c1csc2ncccc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COCCOCN(c1noc(C)c1Cl)S(=O)(=O)c1c(C(O)c2cc3c(cc2C)OCO3)sc2ncccc12
Yield: 35 %

Procedure:
The title compound was prepared by the method of Example 4(B) using N-(4-chloro-5-methyl-3-isoxazolyl)-N-(methoxyethoxymethyl)thieno[2,3-b]pyridine-3-sulfonamide (0.23 g, 0.54 mmoles), THF (5 ml), t-BuLi (1.7 M, 0.41 ml, 0.70 mmoles) and 2-methyl-4,5-(methylenedioxy)benzaldehyde (0.13 g, 0.81 mmoles)[Example 6(A)]. Flash chromatography (40% EtOAc/hexanes) provided 0.11 g (36%) of the title compound as a light orange oil.