Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C1COCC1.O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]([S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[CH:9]=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cnc3cc([N+](=O)[O-])ccc32)cc1
Reaction time: 16 h

Procedure:
To a stirring solution of 5-nitrobenzimidazole (7.5 g, 46 mmol) in THF (300 mL) and water (150 mL) was added K2CO3 (15.9 g, 115 mmol), followed by p-toluenesulfonyl chloride (11.4 g, 46 mmol). After stirring for 16 h, solvents were removed in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed with brine, then dried with MgSO4, filtered and concentrated in vacuo. The crude solid was dissolved in choloroform and chromatographed over a silica gel column with a gradient of chloroform through 10% methanol/chloroform. The product containing fractions were combined and concentrated in vacuo to give 11.4 g (79%) of light yellow solid.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:68])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH2:66][CH3:67])[N:64]=[CH:65][C:52]3=[CH:51][CH:50]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:77]>CO.O>[ClH:77].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:68])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH2:66][CH3:67])[N:64]=[CH:65][C:52]3=[CH:51][CH:50]=4)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CCn1ncc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCn1ncc2ccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc3c21
Yield: 85 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(1-ethyl-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (1.5 mL), water (3.5 mL) and 1 M HCl (0.2 mL) and chromatographed on a 5 g C18 cartridge {gradient 30 to 70% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound (33 mg, 85%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.46 (br s, 3H), 8.30 (s, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.54-7.38 (m, 7H), 7.32 (d, J=8.3 Hz, 2H), 4.77 (q, J=7.2 Hz, 2H), 2.62-2.49 (m, 4H), 2.23-2.12 (m, 1H), 1.86-1.75 (m, 1H), 1.47 (t, J=7.2 Hz, 3H). LCMS (Method E): RT=3.58 min, [M+H]+=436.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][C@H:21]([CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+].[Cl:28][CH2:29][C:30](O)=O>>[Cl:28][CH2:29][CH2:30][N:22]1[C:10]2[C:11](=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[C:13]3[C:15]([F:18])([F:17])[F:16])[O:19][CH2:20][C@H:21]1[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](C(C)C)CO3
Reactant: O=C(O)CCl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N(CCCl)[C@H](C(C)C)CO3
Yield: 52.8 %

Procedure:
Compound 152 was prepared according to General Method 5 (EXAMPLE 2) from (3R)-3,4-dihydro-8-isopropoxy-3-isopropyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (16 mg, 0.05 mmol) and NaBH4 pellets (>10 equiv) in 0.5 g chloroacetic acid to afford 11 mg (58%) of (3R)-4-(2-chloroethyl)-3,4-dihydro-8-isopropoxy-3-isopropyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. This material (11 mg, 0.03 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with 4 mL of 1:1 acetic acid:concentrated HCl (0.02M) heated at 90° C. for 4 h to afford Compound 152. 1H NMR (500 MHz, CDCl3) 12.06 (bs, 1H), 7.13 (s, 1H), 7.12 (d, J=8.8, 1H), 6.98 (d, J=8.8, 1H), 4.53 (dd, J=10.7, 1.5, 1H), 3.88 (dd, J=10.7, 2.4, 1H), 3.82 (m, 1H), 3.71 (m, 1H), 3.63 (m, 1H), 3.49 (m, 1H), 2.93 (m, 1H), 1.82 (m, 1H), 0.99 (d, J=10.3, 3H), 0.98 (d, J=10.3, 3H).
Reaction SMILES: CS(C)=O.[H-].[Na+].[N+:7]([CH3:10])([O-:9])=[O:8].C([C:13]([O:15][CH2:16][CH3:17])=[O:14])#N>C(O)(=O)C>[N+:7]([CH2:10][C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-:9])=[O:8]
Reactant: CCOC(=O)C#N
Reactant: C[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a 100 ml three-neck round bottom flask, equipped with an addition funnel, a thermometer and a condenser topped with a nitrogen gas inlet tube, was added 20 ml of dimethylsulfoxide, 0.196 g (0.00815 mole) sodium hydride and then 0.5 g (0.00815 mole) of nitromethane was added dropwise at ambient temperature to give a slurry. 1.6 ml (0.0163 mole) of ethyl cyanoformate was then added dropwise forming a homogeneous solution and was then stirred for 2 hours at ambient temperature. The solution was made acidic by adding 30 ml of 1 Normal acetic acid with stirring. The product was extracted with ethyl acetate and dried over magnesium sulfate. Ethyl nitroacetate was formed in 83% yield as determined by gas chromatography.
Reaction SMILES: [C:1]1([C:7]2[C:12]3[O:13][CH:14]=[CH:15][C:11]=3[C:10](=O)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>ClC(Cl)C>[Cl:19][C:10]1[N:9]=[N:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:12]2[O:13][CH:14]=[CH:15][C:11]=12
Reactant: O=c1[nH]nc(-c2ccccc2)c2occc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: Clc1nnc(-c2ccccc2)c2occc12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
0.15 g of 7-phenyl-furano[2,3-d]pyridazine-4-(5H)-one and 10 ml of phosphorus oxychloride were dissolved in 10 ml of dichloroethane, and the solution was stirred at 100° C. for 3 hours. The reaction solution was concentrated, and a 1-N aqueous KOH solution was added thereto under cooling with ice. The solution was extracted with chloroform and dried. The solvent was distilled off, thereby obtaining 0.10 g of 4-chloro-7-phenyl-furano[2,3-d]pyridazine.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:41][C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]5[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=5)=[O:32])=[CH:26][CH:25]=4)[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.O1CCCC1>FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1>[F:40][C:36]1[CH:35]=[C:34]([NH:33][C:31]([NH:30][C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]3[C:17]4[CH:16]=[C:15]([C:12]5[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=5)[NH:41][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:29][CH:28]=2)=[O:32])[CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Nc1ccc(Oc2ncnc3[nH]c(-c4ccc(OCc5ccccc5)cc4)cc23)cc1)Nc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CSc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Oc2ncnc3[nH]c(-c4ccc(O)cc4)cc23)cc1)Nc1cccc(F)c1
Temperature: 45 °C
Reaction time: 0.67 h
Yield: 98.5 %

Procedure:
After dissolving 377 mg of 1-{4-[6-(4-benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-(3-fluorophenyl)urea in 4 ml of trifluoroacetic acid and 0.4 ml of thioanisole, the solution was stirred at 45° C. for 40 minutes. It was then returned to room temperature, potassium carbonate was added to alkalinity, and liquid separation and extraction were performed with an ethyl acetate-tetrahydrofuran (5:1) mixed solvent. The organic layer was concentrated to dryness to obtain 310 mg of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][CH:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]([C:18](=[O:38])[CH2:19][C:20]1[CH:36]=[C:35]([CH3:37])[C:23]3[N:24]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])[O:26][C:22]=3[CH:21]=1)[NH:13][CH2:12][CH2:11]2)[CH3:7])C.[OH-].[Na+]>C(O)C>[CH3:37][C:35]1[C:23]2[N:24]=[C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[O:26][C:22]=2[CH:21]=[C:20]([CH2:19][C:18]([CH:14]2[C:15]3[C:10](=[CH:9][C:8]([CH:6]([CH3:7])[CH2:5][C:4]([OH:39])=[O:3])=[CH:17][CH:16]=3)[CH2:11][CH2:12][NH:13]2)=[O:38])[CH:36]=1
Reactant: CCOC(=O)CC(C)c1ccc2c(c1)CCNC2C(=O)Cc1cc(C)c2nc(Nc3ccccc3C)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1Nc1nc2c(C)cc(CC(=O)C3NCCc4cc(C(C)CC(=O)O)ccc43)cc2o1

Procedure:
A stirred solution of 3-{((4-methyl-2-o-tolylamino-benzoxazol-6-yl)-acetyl)-1,2,3,4-tetrahydro-isoquinolin -6-yl}-butanoic acid ethyl ester [0.1 g, Reference Example 1(a)] in ethanol (20 mL), under argon and at room temperature, was treated with sodium hydroxide solution (1 mL, 1M) and then heated at reflux temperature for 2.5 hours. The reaction mixture was evaporated to low volume (approximately 2 mL) and then treated with water (12 mL). This mixture was acidified to pH 1 by addition of hydrochloric acid (1.75 mL, 1M) and cooled in ice. The resulting solid was filtered, then washed three times with water (3 mL) and then dried at 60° C. under vacuum to give the title compound as a white solid. LC-MS: RT=3.53 minutes; MS (ES)=498 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=2)[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:29])=[CH:23][CH:22]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: COC(=O)C(Cc1cccc(CO)c1)C(=O)OC
Product: COC(=O)C(Cc1cccc(COC(=O)Nc2ccc(OC)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)benzyl]malonate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].B(O)(O)[C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([C:2]2[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:17][CH:18]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 100 °C

Procedure:
To a 350 mL high-pressure vial was added tert-butyl 2-bromobenzoate (5.142 g, 20.0 mmol), p-tolylboronic acid (4.08 g, 30.0 mmol), Pd(PPh3)4 (3.47 g, 3.0 mmol), potassium carbonate (8.29 g, 60.0 mmol) and dioxane with water (4:1, 200 mL). The mixture was degassed for 5 min and sealed. The mixture was heated at 100° C. for 40 min wherein analytical HPLC analysis indicated the completion of the reaction. The mixture was filtered through Celite and MeOH was used to wash the Celite pad. The solvent was removed and the crude was purified by flash chromatography (AcOEt/Hexane 0→30%) to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][C:25]([CH3:27])=[CH2:26])[C:21]([OH:28])=[C:20]([C:29]([OH:31])=[O:30])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[I-].[K+].O.C(OCC)(=O)C>ClC1C=CC=CC=1Cl.II>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:19]=[C:20]([C:29]([OH:31])=[O:30])[C:21]4[O:28][C:25]([CH3:27])([CH3:26])[CH2:24][C:22]=4[CH:23]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: C=C(C)Cc1cc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)cc(C(=O)O)c1O
Agent: II
Agent: [I-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2nc(-c3cc4c(c(C(=O)O)c3)OC(C)(C)C4)cs2)cc1OCC
Yield: 50 %

Procedure:
In 40 ml of o-dichlorobenzene was dissolved, with heating, 2 g of 2-(3,4-diethoxyphenyl)-4-[3-carboxy-4-hydroxy-5-(2-methyl-2-propenyl)Phenyl]-thiazole. Thereto were added about 10 mg of iodine and 1.5 g of potassium iodide (ground in a mortar), and the mixture was refluxed for 14 hours with heating. The reaction mixture was mixed with 30 ml of water and phase separation was conducted. The organic layer was mixed with 30 ml of ethyl acetate. The mixture was washed with 20 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane) and recrystallized from diisopropyl ether to obtain 1 g of 2-(3,4-diethoxyphenyl)-4-(2,2-dimethyl-7-carboxy-2,3-dihydrobenzofuran-5-yl)thiazole as white powdery crystals.
Reaction SMILES: CS[C:3]1[N:8]=[CH:7][C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]=1.[CH2:14]([NH2:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:14]([NH:30][C:3]1[N:8]=[CH:7][C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCN
Reactant: CCOC(=O)c1cnc(SC)nc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ncc(C(=O)OCC)cn1

Procedure:
A mixture of 2.0 g of ethyl 2-methylthio-5-pyrimidinecarboxylate, 3.0 g. of hexadecylamine, and 20 ml. of hexamethylphosphoramide is heated at 110° C. for 10 hours, allowed to cool, and diluted with water. Filtration affords a solid which is crystallized from hexane to yield ethyl 2-hexadecylamino-5-pyrimidinecarboxylate as a tan solid.
Reaction SMILES: C(SC1C=C2C(C(Br)=CN=C2)=CC=1)C1C=CC=CC=1.[Br:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([S:31](Cl)(=[O:33])=[O:32])=[CH:28][CH:29]=2)[CH:24]=[N:23][CH:22]=1.[F:35][C:36]1[C:41]([F:42])=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:37]=1[OH:46].C(N(CC)CC)C>O.C(O)(=O)C.C(#N)C>[Br:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([S:31]([O:46][C:37]3[C:36]([F:35])=[C:41]([F:42])[C:40]([F:43])=[C:39]([F:44])[C:38]=3[F:45])(=[O:33])=[O:32])=[CH:28][CH:29]=2)[CH:24]=[N:23][CH:22]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=S(=O)(Cl)c1ccc2c(Br)cncc2c1
Agent: Brc1cncc2cc(SCc3ccccc3)ccc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Br)cncc2c1
Reaction time: 1 h

Procedure:
To a vial charged with 7-(benzylthio)-4-bromoisoquinoline (0.570 g, 1.726 mmol) was added acetonitrile (16.24 ml), acetic acid (0.609 ml), water (0.406 ml). The resulting solution was cooled in an ice water bath and 1,3-dichloro-5,5-dimethyl-2-imidazolidinedione (0.453 ml, 3.45 mmol) was added. After 1 hr LC/MS of the resulting solution indicated product, 4-bromoisoquinoline-7-sulfonyl chloride, as the primary species. m/z (ESI) 306.0 (M+H)+. To the mixture was added 2,3,4,5,6-pentafluorophenol (0.361 ml, 3.45 mmol) and triethylamine (0.962 ml, 6.90 mmol) affording a yellow solution. After 45 min LC/MS indicated conversion to desired product (PFP ester). The mixture was diluted with EtOAc and extracted with H2O. The aqueous phase was extracted with EtOAc. The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. The crude material was purified with a 40 g silicycle HP column (SiliCycle, Inc. Quebec City, Canada) ramping EtOAc in heptane (0-15%) providing product as a pale yellow oil, perfluorophenyl 4-bromoisoquinoline-7-sulfonate (0.618 g, 1.361 mmol, 79% yield). m/z (ESI) 454.1 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:37])[CH:15]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=2[CH2:25][CH2:26][CH3:27])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14](=[O:37])[CH:15]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][C:18]=2[CH2:25][CH2:26][CH3:27])(=[O:11])=[O:12])=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: CCCc1cc(CO)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCc1cc(C=O)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 14 h
Yield: 26.1 %

Procedure:
To a solution of 0.573 g (1.09 mmol) of the product of Example 65 dissolved in 5.0 mL of dichloromethane was added 2.86 g (32.9 mmol) of manganese dioxide and 1.15 g of finely powdered 3A molecular sieves and the reaction mixture was magnetically stirred at room temperature for 14 hours. The reaction mixture was then filtered through a bed of celite and MgSO4 and the flitrate was evaporated in vacuo. The residue was dissolved in dichloromethane and applied to a silica gel flash chromatography column and then eluted with 3% MeOH--CH2Cl2. Evaporation of the purified fractions and drying in vacuo afforded 0.149 g (26%) of the title compound.
Reaction SMILES: Br[CH2:2][C:3](=[N:8][OH:9])[C:4]([CH3:7])([CH3:6])[CH3:5].[CH2:10]([OH:14])[C:11](=[CH2:13])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:5][C:4]([C:3]1[CH2:2][CH2:12][C:11]([CH3:13])([CH2:10][OH:14])[O:9][N:8]=1)([CH3:7])[CH3:6]
Reactant: CC(C)(C)C(CBr)=NO
Reactant: C=C(C)CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(CO)CCC(C(C)(C)C)=NO1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of 1-bromo-3,3-dimethyl-2-butanone oxime (4.5 g) (J. Org. Chem., 1979, 44, 3861) in dichloromethane (150 mL) was added methallyl alcohol (22 mL) and sodium carbonate (16 g). The reaction mixture was stirred at room temperature for 40 h and then filtered through a pad of Celite. The solvent and excess alcohol were removed at reduced pressure. The residue was chromatographed on silica gel with 2:1 hexanes/ethyl acetate to give the title compound (3.2 g) as a low melting waxy solid. NMR (200 Mhz, CDCl3) 3.5 (m, 2H, CH2OH), 2.2-1.6 (m, 4H, ring CH2 's), 1.2 (s, 12H, t-Bu and Me). IR (Nujol) 3240 cm-1 (br, OH).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH:11]1[C:24]2[S:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:16][C:15]=2[C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].O>[CH3:10][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[C:7]([CH3:8])[C:2]=1[C:14]1[C:15]2[O:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:23][C:24]=2[CH:11]=[CH:12][CH:13]=1
Reactant: OB(O)c1cccc2c1Oc1ccccc1S2
Reactant: Cc1cc(O)cc(C)c1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: Cc1cc(O)cc(C)c1-c1cccc2c1Oc1ccccc1S2
Yield: 86.5 %

Procedure:
The general procedure described in Example 3 was used with 4-chloro-3,5-dimethyl-phenol (156 mg, 1.00 mmol), 4-phenoxathiineboronic acid (293 mg, 1.20 mmol), Pd(OAc)2 (2.2 mg, 0.010 mmol, 1 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (10.0 mg, 0.020 mmol, 2 mol %), K2CO3 (414 mg, 3.00 mmol), water (3.0 mL), 12 h, 100° C. The product was isolated as a colorless oil (277 mg, 85%), which became a white solid upon standing. Mp=116° C. 1H NMR (400 MHz, CDCl3) δ: 7.20 (m, 2H), 7.01-7.16 (m, 3H), 6.96 (d, 1H, J=7.6 Hz), 6.73 (m, 3H), 5.64 (s, 1H), 2.04 (s, 6H). 13C NMR (125 MHz, CDCl3) δ: 154.6, 152.6, 149.9, 138.3, 130.2, 129.9, 129.5, 127.8, 126.8, 126.1, 124.7, 124.6, 121.2, 121.1, 118.2, 114.2, 20.9. IR (neat, cm−1): 3367, 1593, 1471, 1419, 1311, 1265, 1223, 1154, 1026, 752. Anal. Calcd for C20H16O2S: C, 74.97; H, 5.03. Found: C, 74.88; H, 4.99.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].C[C:24]([N:26](C)C)=O>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].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.[Zn]>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:24]#[N:26])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3ccccc3)sc2c1O
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)c1nc(C#N)c2nc(-c3ccccc3)sc2c1O
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (124 mg, 0.33 mmole), tris(dibenzylideneacetone)dipalladium(0)(15 mg, 0.02 mmole), 1,1′-bis(diphenylphosphino)ferrocene (18 mg, 0.03 mmole), zinc cyanide (23 mg, 0.20 mmole) and zinc (3 mg, 0.04 mmole) in dimethylacetamide (0.65 ml) was stirred at 120° C. for 4 h and twenty minutes before it was cooled to room temperature, quenched with water, filtered. The filtrate was partitioned between chloroform/isopropanol (3:1) and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of methanol and dichloromethane to give the title compound as a white solid (41 mg). MS: (+) m/z 325.87 (M+1), MS: (−) m/z 324.00 (M−1),
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[CH2:8]1CCN2C(=NCCC2)C[CH2:9]1.ICC.O>CN(C=O)C.CCOC(C)=O>[C:1]([CH:3]([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COC(=O)CC#N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCI
Product: CCC(C#N)C(=O)OC
Temperature: 70 °C

Procedure:
To a solution of methyl 2-cyanoacetate (2.0 mL, 22.61 mmol., Acros) and DBU (3.4 mL, 22.61 mmol) in DMF (22 mL) was added iodoethane (2.0 mL, 24.90 mmol) dropwise at 0° C. The resulting mixture was heated to 70° C. for 20 hours. After cooling to room temperature, H2O (150 mL) and EtOAc (150 mL) were added. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% EtOAc/hexanes) to give the title compound in 300 mg. 1H NMR (CDCl3, 200 MHz): δ=3.82 (s, 3H), 3.48 (dd, 1H, J=5.9 Hz and 6.8 Hz), 2.08-1.92 (m, 2H), 1.12 (t, 3H, J=7.3 Hz).