Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][C:7](=[O:10])[CH2:8][NH2:9])=[O:5].Cl[C:16]([O:18][CH2:19][CH2:20][Br:21])=[O:17]>CN(C)C(=O)C>[Br:21][CH2:20][CH2:19][O:18][C:16]([S:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][C:7](=[O:10])[CH2:8][NH2:9])=[O:5])=[O:17]
Reactant: O=C(Cl)OCCBr
Reactant: NCC(=O)NC(=O)c1ccccc1S
Solvent: CC(=O)N(C)C
Product: NCC(=O)NC(=O)c1ccccc1SC(=O)OCCBr
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of N-(2-mercaptobenzoyl)glycinamide (1.05 g, 5.0 mmol) in N,N-dimethylacetamide (DMA, 25 ml) was added 2-bromoethyl chloroformate (1.22 g, 6.5 mmol). The reaction mixture was stirred for 8 h, the solvent was evaporated to dryness, and the residue was triturated with ethyl ether (25 ml. The resulting precipitate was filtered, washed with water and dried over CaCO2, Yield: 89%. 1H NMR (DMSO-d6): 3.71 (t, 1H, CH2), 3.78 (d, 2H, CH2), 3.86 (t, 1H, CH2), 4.45 (t, 1H, CH2), 4.51 (t, 1H, CH2), 7.11 (brs, 1H, NH2), 7.30 (brs, 1H, NH2), 7.36-7.58 (m, 5H, Ar—H, NH2), 8.26 (t, 2H, Py-H), 8.36 (t, 1H, NH), 8.52 (t, 1H, NH), 8.66 (t, 1H, Py-H), 9.12 (d, 21, Py-H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:16][CH3:17])[CH:9]=[CH:8][CH:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.O.Cl>C1COCC1>[CH2:16]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:6]([CH2:4][OH:3])=[CH:7][CH:8]=[CH:9]2)[CH3:17]
Reactant: CCOC(=O)c1cccc2cccc(CC)c12
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cccc2cccc(CO)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
A solution of 8-ethyl-naphthalene-1-carboxylic acid ethyl ester (1.04 g) in THF (30 ml) was cooled to 0° C. and treated with diisobutyl aluminium hydride solution (11.4 ml; 1.2 M in toluene). The reaction mixture was stirred for 2 hrs at r.t., then again cooled to 0° C. and treated with H2O (50 ml) and 0.1N HCl (50 ml). The mixture was extracted with EtOAc. The organics were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient cyclohexane→cyclohexane/EtOAc 4:1) to give (8-ethyl-naphthalen-1-yl)-methanol (769 mg) as white solid. MS (ISP): 187.3 ((M+H)+).
Reaction SMILES: CO[CH:3]1[C:17](=C=O)[C:16]([N+:20]([O-])=O)=[CH:15][CH:14]=[C:4]1[O:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>C1COCC1.[C].[Pd]>[NH2:20][C:16]1[CH:15]=[CH:14][C:4]([O:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:3]([C:9]([O:11][CH3:12])=[O:10])[CH:17]=1
Reactant: CCOC(=O)CCCOC1=CC=C([N+](=O)[O-])C(=C=O)C1OC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCCOc1ccc(N)cc1C(=O)OC
Reaction time: 4 h
Yield: 205.5 %

Procedure:
In THF (25 ml) was dissolved ethyl 4-(2-methoxy-carbonyl-4-nitrophenoxy)butyrate (2.37 g, 7.61 mmol), and to the mixture was added 10% palladium-carbon (containing 50% water, 0.94 g). The mixture was subjected to catalytic reduction at room temperature for 4 hours. Insoluble materials were filtered off, and the filtrate was dried with anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl 4-(4-amino-2-methoxycarbonylphenoxy)butyrate (2.20 g). IR (KBr): 1730 cm−1.
Reaction SMILES: [CH3:1][CH2:2][C:3]([N:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:4].[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26]Br)=[CH:23][CH:22]=1)([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)CC(=O)C>[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][N:9]2[CH2:8][CH2:7][CH:6]([N:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:3](=[O:4])[CH2:2][CH3:1])[CH2:11][CH2:10]2)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: CCC(=O)N(c1ccccc1)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCC(=O)N(c1ccccc1)C1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A suspension of norfentanyl of Example 4 (6.71 g, 0.029 mol), p-nitrophenethylbromide (7.178 g, 0.0372 mol), potassium carbonate (19 g, 0.14 mol) and a few crystals of sodium iodide in 4-methyl-2-pentanone (200 ml) was stirred overnight at reflux, under nitrogen. After cooling to room temperature, the precipitate was removed by filtration and the solution concentrated under reduced pressure. The dark residue was dissolved in ethyl acetate (200 ml) and washed with water (2×100 ml), dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica gel, 10% MeOH/90% CHCl3 v/v) to give the title compound as a yellow solid (5.33 g, 56% yield).
Reaction SMILES: [I-].C[S+](C)(C)=O.[H-].[Na+].[Cl:9][C:10]1[C:18]2[N:17]=[CH:16][N:15]([CH2:19][C@H:20]3[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[CH2:21]3)[C:14]=2[CH:13]=[C:12]([C:27]#[N:28])[CH:11]=1.Br[C:30]1C=C(Cl)C2N=CN(C[C@H]3CCCC(=O)C3)C=2C=1.[OH-].[Na+]>CS(C)=O.[Cl-].[Na+].O>[O:26]1[C@:22]2([CH2:23][CH2:24][CH2:25][C@H:20]([CH2:19][N:15]3[C:14]4[CH:13]=[C:12]([C:27]#[N:28])[CH:11]=[C:10]([Cl:9])[C:18]=4[N:17]=[CH:16]3)[CH2:21]2)[CH2:30]1
Reactant: N#Cc1cc(Cl)c2ncn(C[C@H]3CCCC(=O)C3)c2c1
Reactant: O=C1CCC[C@H](Cn2cnc3c(Cl)cc(Br)cc32)C1
Agent: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(Cl)c2ncn(C[C@H]3CCC[C@@]4(CO4)C3)c2c1
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a yellow solution of trimethylsulfoxonium iodide (1.31 g, 5.97 mmol) in DMSO (31.8 mL) under nitrogen at rt was added sodium hydride (0.239 g, 5.97 mmol). The color disappeared and bubbling occurred. Stirring was continued at rt for 30 min, and then a solution containing a mixture of 4-chloro-1-{[(1S)-3-oxocyclohexyl]methyl}-1H-benzimidazole-6-carbonitrile (1.15 g, 3.98 mmol) and (3S)-3-[(6-bromo-4-chloro-1H-benzimidazol-1-yl)methyl]cyclohexanone (1.36 g, 3.98 mmol) dissolved in DMSO (7.96 mL) was slowly added. After stirring 16 h, brine solution (25 mL) was added followed by 2 N NaOH (25 mL) to pH 13. The product was extracted into EtOAc (3×75 mL). The combined organics were washed with water (2×150 mL), dried over Na2SO4, filtered, and concentrated onto florisil for purification on a 12 g silica gel column (0-2% MeOH/DCM, 20 min gradient; 30 mL/min elution; 254 nm detection) to afford the title compound (0.735 g, 55% yield). MS (m/z) 302.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:32]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:14]=[CH:15][C:16]=3[CH3:17])=[CH:9][N:4]2[N:3]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39](Cl)=[O:40])[CH:34]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([C:19]([NH:18][C:13]2[CH:14]=[CH:15][C:16]([CH3:17])=[C:11]([CH:12]=2)[O:10][C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[C:2]([NH:1][C:39]([C:35]4[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=4)=[O:40])[N:32]=3)[CH:9]=2)=[O:31])[CH:25]=[CH:24][CH:23]=1)([CH3:28])[CH3:27])#[N:30]
Reactant: O=C(Cl)c1cccnc1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)nn2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)c3cccnc3)nn2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
To a solution of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.469 mmol) in pyridine (5 mL) was added pyridine-3-carbonyl hydrochloride (212 mg, 1.19 mmol), and the mixture was stirred at room temperature for 3 hr. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue. The obtained precipitate was collected by filtration and dried to give the title compound (245 mg, 97%) as a colorless powder.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:16](Br)[C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:13][C:14]=1[Cl:15].[C:22]([O-])(=[S:24])[CH3:23].[K+]>CO>[C:22]([CH:16]([C:11]1[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([Cl:8])[CH:10]=1)[C:17]([O:19][CH3:20])=[O:18])(=[S:24])[CH3:23]
Reactant: COC(=O)C(Br)c1ccc(Cl)c(Cl)c1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C(C(C)=S)c1ccc(Cl)c(Cl)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
A toluene (403 mL) solution of methyl 2-(3,4-dichlorophenyl)-2-bromoacetate (134 g, 0.451 mol) was dropwise added to a methanol (403 mL) solution of potassium thioacetate (67.7 g, 0.586 mol, 1.3 equivalent amounts based on the starting material) at 5° C. over a period of 15 minutes, followed by stirring at 5° C. for 1 hour. The formed solid was subjected to filtration, and the filtrate was mixed with toluene (403 mL), sequentially washed with water, a saturated sodium hydrogencarbonate aqueous solution, a saturated ammonium chloride aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to give the desired product as a yellow oil (136 g, yield: 103%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10](Cl)[CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].P(C1CCCCC1)(C1CCCCC1)C1CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=1[C:10]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CO
Reactant: COc1cccc(OC)c1B(O)O
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cccc(OC)c1-c1ccc(CO)c([N+](=O)[O-])c1

Procedure:
A mixture of 5.0 g (26.7 mmol) of 2-nitro-4-chlorobenzyl alcohol, 6.33 g (34.8 mmol) of 2,6-dimethoxybenzene boronic acid, 0.73 g (0.80 mmol) of Pd2dba3, 11.3 g (34.8 mmol) of Cs2CO3, and 0.45 g (1.60 mmol) of Cy3P was dissolved in 100 mL of dioxane and warmed to reflux for 18 h. The reaction mixture was cooled, filtered through a pad of silica gel which was washed with Et2O and concentrated. The residue was purified by flash column chromatography on silica gel eluted with a gradient of 25-50% Et2O in hexanes and gave 4-(2′,6′-dimethoxyphenyl)-2-nitrobenzyl alcohol as a pale yellow solid.
Reaction SMILES: [C:1]1([C:15]([OH:16])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].N(C1C=CC(O)=CC=1)=[O:18]>>[C:11]1([C:15]([OH:16])=[C:1]([N+:2]([O-:4])=[O:3])[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[CH:10]=1)[N+:12]([O-:14])=[O:13].[N+:12]([O-:14])([OH:18])=[O:13]
Reactant: O=Nc1ccc(O)cc1
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Product: O=[N+]([O-])O

Procedure:
A process for the production of picric acid comprising adding a liquid suspension containing from about 4 to about 20 percent weight/volume of mono-nitroso phenol over a period of time sufficient to form picric acid to a nitric acid solution containing between 45 and 100 percent by weight of nitric acid, said solution being maintained at a temperature in the range from about 45° to 100°C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13]([N:17]([CH3:19])[CH3:18])[CH:14]=[CH:15][CH:16]=3)=[CH:10][C:2]1=2.[Br:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([Br:32])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25].C(N(CC)CC)C>ClCCl>[Br:20][C:21]1[CH:22]=[C:23]([C:24]([N:1]2[CH2:6][CH2:5][O:4][C:3]3[N:7]=[CH:8][C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([N:17]([CH3:19])[CH3:18])[CH:12]=4)=[CH:10][C:2]2=3)=[O:25])[CH:27]=[C:28]([Br:32])[C:29]=1[O:30][CH3:31]
Reactant: CN(C)c1cccc(-c2cnc3c(c2)NCCO3)c1
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4cccc(N(C)C)c4)cc32)cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
By the same method as in the step d) of Example 2, [3-(2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-phenyl]-dimethyl-amine (102 mg, 0.39 mmol), 3,5-dibromo-4-methoxy-benzoyl chloride (197 mg, 0.59 mmol) and triethylamine (286 μl, 1.99 mmol) were dissolved in dichloromethane (5 ml) and then stirred at room temperature for 3 hours to obtain the target compound 48, i.e., (3,5-dibromo-4-methoxy-phenyl)-[7-(3-dimethylamino-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone, as white solid (135 mg, 62%).
Reaction SMILES: [CH:1]1([NH:4][CH:5]=[C:6]([C:12](=[O:30])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([CH:20]3[CH2:28][CH2:27][C:22]4([O:26][CH2:25][CH2:24][O:23]4)[CH2:21]3)=[CH:15][C:14]=2F)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[O:26]1[C:22]2([CH2:27][CH2:28][CH:20]([C:16]3[CH:15]=[C:14]4[C:13]([C:12](=[O:30])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:18][C:17]=3[F:19])[CH2:21]2)[O:23][CH2:24][CH2:25]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(C2CCC3(C2)OCCO3)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cn(C2CC2)c2cc(C3CCC4(C3)OCCO4)c(F)cc2c1=O
Reaction time: 4 h
Yield: 86.2 %

Procedure:
A solution of 21.4 g (50 mmol) of α-[(cyclopropylamino) methylene]-4-(1,4-dioxaspiro[4.4]non-7-yl)-2,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester in 250 ml of dry t-butanol was treated with a slurry of 6.2 g (55 mmol) of potassium t-butoxide in 150 ml of dry t-butanol. The resulting suspension was stirred at 65° for 4 hours and then at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in methylene chloride and washed with 1.0 M hydrochloric acid. After drying (MgSO4) and evaporating the solvent in vacuo, the residue was recrystallized from ethyl acetate/hexane to give 17.3 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)[CH:20]([CH3:22])[CH3:21])C.ICCC>COCCOC>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:21][CH2:20][CH3:22])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C2CCNCC2)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: CCCI
Product: CCCN1CCC(c2ccc(C(=O)OC)cc2)CC1
Temperature: 70 °C

Procedure:
4-Piperidin-4-yl-benzoic acid methyl ester (28 mmol), ethyldiisopropylamine (31 mol) and 1-iodopropane (42 mmol) are dissolved in 1,2-dimethoxyethane (100 ml) and the mixture is heated at 70° C. overnight. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with CH2Cl2/MeOH=9:1 as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A pale brown powder with Rf=0.35 (CH2Cl2/MeOH=9:1) is obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[Na+].O>C(O)C>[CH2:25]([O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:13]1[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cccc(-c2ccccc2-c2ccccc2OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc(-c2ccccc2-c2ccccc2OCc2ccccc2)c1
Temperature: 50 °C

Procedure:
2-Benzyloxy-[1,1′;2′,1″]terphenyl-3″-carboxylic acid ethyl ester (84 mg, 0.206 mmol) was dissolved in ethanol (2 ml) and 2M sodium hydroxide (0.5 ml) added. The mixture was stirred and heated to 50° C. for 4 h. Water was added and the mixture extracted with isohexane. The aqueous layer was acidified with 2M hydrochloric acid and extracted with diethyl ether (2×10 ml). The combined organic phases were washed with water, dried (MgSO4) and evaporated. The oil was triturated with isohexane and the resulting white solid filtered, washed with isohexane and dried in vacuo. (42 mg, 54%).
Reaction SMILES: [F:1][C:2]1[C:3]([I:12])=[C:4]2[NH:10][N:9]=[C:8](N)[C:5]2=[N:6][CH:7]=1.CN(C=O)C.N(OC(C)(C)C)=O.I>O>[F:1][C:2]1[C:3]([I:12])=[C:4]2[NH:10][N:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1n[nH]c2c(I)c(F)cnc12
Agent: CC(C)(C)ON=O
Agent: I
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cnc2cn[nH]c2c1I
Temperature: 25 °C
Yield: 11.68 %

Procedure:
6-Fluoro-7-iodo-1H-pyrazolo[4,3-b]pyridin-3-amine (2.0 g, 7.19 mmol) was combined with DMF (15 mL) and cooled to 0° C. before tert-butyl nitrite (1.709 mL, 14.39 mmol) was added. The reaction mixture was then warmed to room temperature and heated at 85° C. for 4 hours. The reaction mixture was cooled to room temperature and HI solution (1.614 g, 7.19 mmol) in water (57%) was added and heated to 85° C. for another 8 hours. The mixture was cooled, concentrated, to give a residue which was purified by preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 25-45% acetonitrile (containing 10 mM NH4HCO3) in water (containing 10 mM NH4HCO3) to give the title compound. (221 mg, 0.840 mmol, 11.68% yield). MS [M+H] found 264.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:11]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])=O.[CH2:22]([O:24][CH2:25][CH2:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]1[CH3:36])[CH3:23].C(OC(=O)C)(=O)C.[OH-].[NH4+]>C1(C)C=CC=CC=1>[CH2:22]([O:24][CH2:25][CH2:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:11]2([C:3]3[CH:4]=[CH:5][C:6]([N:8]([CH3:9])[CH3:10])=[CH:7][C:2]=3[CH3:1])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15](=[O:17])[O:16]2)=[C:28]1[CH3:36])[CH3:23]
Reactant: Cc1cc(N(C)C)ccc1C(=O)c1ccccc1C(=O)O
Reactant: CCOCCn1c(C)cc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOCCn1c(C)c(C2(c3ccc(N(C)C)cc3C)OC(=O)c3ccccc32)c2ccccc21
Temperature: 70 °C
Yield: 37.1 %

Procedure:
A mixture of 14.5 g of 2-(2-methyl-4-dimethylaminophenyl)carbonylbenzoic acid, 11.5 g of 1-(2-ethoxyethyl)-2-methylindole and 40.0 ml acetic anhydride was maintained at approximately 70° C. for approximately four hours. The resulting solution was cooled to ambient temperature and slowly poured into a mixture of toluene and 5 percent aqueous ammonium hydroxide. The toluene layer was separated, washed with water and then with saturated sodium chloride solution. The toluene solution was evaporated to dryness. The residue which remained was recrystallized twice from a mixture of hexane and isopropyl alcohol to obtain 8.9 g of 3-[1-(2-ethoxyethyl)-2-methylindol-3-yl]-3-(2-methyl-4-dimethylaminophenyl)phthalide (Formula I: R=C2H5OC2H4 ; R1 =R2 =R3 =R4 =CH3 ; X=Y=H), a white-colored solid which melted at 170.5° to 171° C. Significant infrared maxima appeared at 1750 (C=O;s) and 1123 (C--O;s)cm-1. A toluene solution of the product spotted on an acid clay or a phenolic resin coated paper developed a cyan-colored image.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:37])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:36])[CH2:33][S:34][CH3:35])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:45]OS([O-])=O.[K+]>CN(C=O)C.O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:37])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:36])[CH2:33][S:34]([CH3:35])=[O:45])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSCC(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CS(C)=O)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 58.7 %

Procedure:
To a solution of N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(methylthio)acetamide (Example 19) (20 mg, 0.03 mmol) in a mixture of DMF/H2O (1:1 v/v, 1.0 mL) was added Oxone (10 mg, 0.03 mmol) and the reaction was stirred at RT for 3 days. A second portion of Oxone® (10 mg, 0.03 mmol) was added, the mixture was stirred for a further 24 hr and was then partitioned between brine (20 mL) and DCM (20 mL). The organic extract was washed with brine (20 mL), dried (MgSO4) and evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 4 g, 30-100% EtOAc in isohexane, gradient elution) and subjected to SCX capture and release to afford the title compound (Example 20) as a tan coloured solid (11 mg, 52%): m/z 625 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 2.69 (3H, s), 3.88 (2H, d), 4.04 (2H, d) 5.39 (2H, s), 6.35 (1H, s), 7.02 (1H, d), 7.31 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.58-7.64 (3H, overlapping m), 7.93 (1H, m), 8.30-8.33 (2H, overlapping m), 8.37 (1H, d), 8.59 (1H, br s), 8.79 (1H, br s), 10.85 (1H, br s).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1.[CH:50]1([SH:56])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:50]1([S:56][C:2]2[N:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:21]4[NH:25][N:24]=[N:23][N:22]=4)=[CH:13][CH:14]=3)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=2)[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: SC1CCCCC1
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCn1c(=O)cc(SC2CCCCC2)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1=O
Yield: 52 %

Procedure:
A mixture of 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.5 g), cyclohexylmercaptan (0.12 ml) and potassium carbonate (0.13 g) in acetonitrile (10 ml) was heated under reflux for 5 hours with stirring. The reaction mixture was allowed to cool and the precipitate was removed by filtration. The filtrate was concentrated to dryness. The resulting residue was dissolved in methanol (15 ml) and then 1N hydrochloric acid (1.5 ml) was added to the solution, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless amorphous powders (0.2 g, 52%).