Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:13][S:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)(=[O:11])=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc2cc[nH]c2c1
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccc2cc[nH]c2c1
Yield: 51.6 %

Procedure:
To a solution of 4-chloro-3-nitrophenyl-sulfonamide (12 g, 51 mmol) dissolved in 50 ml of anhydrous dimethylformamide, was added 13.1 g (116 mmol) of ethylcyanoacetate and 10.5 g (76 mmol) of anhydrous potassium carbonate. This mixture was heated at 110° C. for 3 hours, cooled to room temperature, and added to ice water containing 8 ml of concentrated sulfuric acid. The mixture was extracted with ethyl acetate (3×200 ml), and the combined organic layer was back extracted with 200 ml of water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by a preparative high pressure liquid chromatogram (Waters Prep 500 A) with 55% ethyl acetate in hexanes on a silica gel cartridge. The product was added to 45 ml of 50% aqueous acetic acid containing 3 ml of concentrated sulfuric acid and refluxed for 12 hours. The reaction was cooled to room temperature and added to 400 ml water. This mixture was extracted with ethyl acetate (3×100 ml). The combined organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was crystallized from 40 ml of ethyl acetate, 3 ml of ethanol and 1 ml of hexanes to obtain 6.9 g of 3-nitro-4-(2-acetonitrile)phenyl sulfonamide. This material was dissolved in 40 ml of ethanol containing 3 g of 5% palladium on activated carbon. This mixture was placed in a Parr Hydrogenation apparatus with 60 p.s.i. of hydrogen at 40° C. for 3 hours. This mixture was filtered, the filtrate concentrated under vacuum, and the residue recrystallized from 20 ml of ethyl acetate and 10 ml of ethanol to obtain 2.4 g of 6-indolesulfonamide. The sulfonamide (6.1 mmol) was reacted with 4-chlorophenyl-isocyanate (6.1 mmol) as described in Preparation 2 supra to obtain 1.1 g of the title product as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1)=[O:12])[CH3:9]>CC(N(C)C)=O.C(N(CC)CC)C.[Cu]Br>[CH2:8]([O:10][C:11]([N:13]1[CH2:14][CH2:15][CH:16]([NH:19][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:18]1)=[O:12])[CH3:9]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: Clc1ncccn1
Agent: [Cu]Br
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1CCC(Nc2ncccn2)CC1
Temperature: 200 °C

Procedure:
A mixture of 2-chloro-pyrimidine (2.00 g, 17.46 mmol, 1.0 equiv), 4-amino-piperidine-1-carboxylic acid ethyl ester (3.61 g, 20.95 mmol, 1.2 equiv) and copper(I) bromide (0.25 g, 1.75 mmol, 0.1 equiv) in anhydrous DMAc (5 mL) and triethylamine (5 mL) was heated by microwave irradiation to 200° C. for 20 min. The organic phase was concentrated under reduced pressure and the residue extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over MgSO4 and the product purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of dichloromethane (+1% triethylamine)/methanol providing 1.07 g (25%) of the title compound. MS (ISP): 251.4 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:7][N:6]=[CH:5]2.C([O-])(=O)C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:44]1[CH:45]=[C:46]([CH:53]=[CH:54][C:55]=1[CH3:56])[C:47]([NH:49][CH:50]1[CH2:52][CH2:51]1)=[O:48].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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.C(O)C>[CH:50]1([NH:49][C:47](=[O:48])[C:46]2[CH:53]=[CH:54][C:55]([CH3:56])=[C:44]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([NH:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:7][N:6]=[CH:5]4)[CH:45]=2)[CH2:51][CH2:52]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1Br
Reactant: CCN(CC)CCNc1nncc2cc(Br)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: CCN(CC)CCNc1nncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc12
Temperature: 160 °C

Procedure:
6-Bromo-N-(2-(diethylamino)ethyl)phthalazin-1-amine (140 mg, 430 μmol), potassium acetate (60 mg, 610 μmol), bis(pinacolato)diboron (150 mg, 610 μmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (32 mg, 40 μmol) were suspended in dioxane (4 mL) and heated in the microwave for 10 min at 160° C. The reaction was added to a mixture of 3-bromo-N-cyclopropyl-4-methylbenzamide (110mg, 430 μmol), sodium carbonate-2 M in water (0.33 mL, 0.65 mmol), tetrakis(triphenylphosphine)palladium (50 mg, 40 μmol), and ethyl alcohol (5 mL), the combination of which was heated in the microwave for 10 min at 160° C. The reaction mixture was diluted with 20 mL of EtOAc, added to an addition funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was washed 3 times with 20 mL of sodium bicarbonate (saturated, aqueous), dried over sodium sulfate, and concentrated via rotovap to give crude product. The crude was purified by chromatography to obtain the title compound. Found MS (ES+): 418(M+H)+.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[C:8]=2[C:7]([C:17]([OH:19])=[O:18])=[CH:6][CH:5]=1.[CH:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[C:23](O)[CH:22]=1.CCN=C=NCCCN(C)C.Cl.CC1(C)C=CN=C(N)C1>CN(C=O)C>[F:20][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[C:8]=2[C:7]([C:17]([O:19][C:23]2[CH:22]=[CH:21][C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=2)=[O:18])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)c1ccc(OC(F)F)c2oc3ccncc3c12
Agent: CC1(C)C=CN=C(N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC(F)F)c2oc3ccncc3c12
Temperature: 72.5 °C

Procedure:
A mixture of 6-Difluoromethyloxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylic acid (5.5 g, 0.0197 moles), p-nitro phenol (4.1 g, 0.0295 moles), EDCl (5.7 g, 0.295 moles), 4,4-dimethyl amino pyridine (250 mg, 0.00197 moles) in DMF (603.0 mL) was heated to 70-75° C. for 4-5 hours. The residue obtained after removal of solvent under vacuo was triturated with water (50.0 mL) to give intermediate-18 (6.0 mg) as yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])/[CH:5]=[CH:6]/[C:7]1[N:8]=[CH:9][C:10]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20](OC(C)(C)C)=O)[CH2:15]2)=[N:11][CH:12]=1)[CH3:2].Cl>O1CCOCC1.CO.C(OCC)(=O)C.O>[CH:18]1([CH2:17][N:16]2[CH2:20][CH2:19][C@@H:14]([NH:13][C:10]3[N:11]=[CH:12][C:7](/[CH:6]=[CH:5]/[C:4]([O:3][CH2:1][CH3:2])=[O:27])=[N:8][CH:9]=3)[CH2:15]2)[CH2:12][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(CC3CCCCC3)C2)cn1

Procedure:
To a solution of tert-butyl (3R)-3-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyrazinyl}amino)-1-piperidinecarboxylate (6.26 g) in a mixture of 1,4-dioxane (25 mL) and MeOH (5 mL) was added 4N hydrogen chloride solution in ethyl acetate (30 mL) in water bath.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])([OH:3])=O.[Cl-].[Na+].[Cl-].[Al+3].[Cl-].[Cl-].Cl>O>[O:3]=[C:1]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)CCc1ccccc1C(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(O)c1cccc2c1CCC2=O
Temperature: 160 °C

Procedure:
A mixture of 2-(2-carboxyethyl)benzoic acid (1.0 g, 5.15 mmol), sodium chloride (320 mg, 5.41 mmol) and aluminum chloride (3.43 g, 25.75 mmol) was heated to about 160° C. for about 2 hours. The mixture was cooled with an acetone/dry ice bath and a mixture of ice and water was slowly added, followed by concentrated hydrochloric acid (AMOUNT). The mixture was filtered and the obtained solid was purified by flash chromatography on silica gel using dichloromethane/methanol (50:1) as eluent. The product was further recrystallized from methanol to provide the desired product. MS (ESI): m/z 175 (M−H)−.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[OH:6][C:7]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].ClCCl>CCOCC>[C:9]([C:8]1[CH:12]=[C:13]([S:1]([OH:3])(=[O:5])=[O:2])[CH:14]=[C:15]([OH:16])[C:7]=1[OH:6])([OH:11])=[O:10]
Reactant: O=S(=O)(O)O
Reactant: O=C(O)c1cccc(O)c1O
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)c1cc(S(=O)(=O)O)cc(O)c1O

Procedure:
Concentrated sulphuric acid (1 ml) and 2,3-dihydroxybenzoic acid (0.5 g) were heated at 60° C. for 1 hour. The mixture was cooled, taken up in ether (20 ml), poured into dichloromethane (200 ml) and cooled to give as crystals, 3-carboxy-4,5-dihydroxybenzenesulphonic acid (0.31 g); δ(DMSO-d6); 7.34(d,1H); 7.61(d,1H). To a suspension of this acid (1 g) in acetonitrile (10 ml) was added triethylamine (2.4 ml), followed by isobutyryl chloride (1.5 ml). The solution was stirred at room temperature for 1 hour, the solvent was evaporated and the residue purified by chromatography on Diaion HP 20 SS resin (aqueous methanol containing 1% acetic acid) to give 3-carboxy-4,5-di-isobutyroxybenzene sulphonic acid (1.2 g); δ(DMSO-d6): 1.19(s,6H); 1.27(s,6H); 2.90-3.15(m,2H); 7.63(d,1H); 8.04(d,1H).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7]([NH2:9])=[O:8])=[CH:3][CH:2]=1.N1C=CC=CC=1.[S:17](Cl)(Cl)=[O:18]>CCOCC>[S:17](=[N:9][C:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)=[O:8])=[O:18]
Reactant: Cc1ccc(C(N)=O)cc1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)N=S=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
p-Toluamide (76 g) and pyridine (95.5 ml) were initially charged in dry ether (600 ml) and, while cooling with ice, thionyl chloride (70.2 g) in ether (200 ml) was added dropwise. The mixture was stirred at room temperature overnight. With exclusion of moisture, the pyridine hydrochloride was then filtered off and washed with ether (100 ml). The solution was concentrated under reduced pressure and the residue (83.5 g) was used without further purification.
Reaction SMILES: NC1C=CC=CC=1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[Br-:16].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.FC1C=CC(N)=CC=1>>[Br:16][C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[NH2:8]
Reactant: [Br-]
Reactant: Cc1ccc(N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Nc1ccc(F)cc1
Solvent: Nc1ccccc1
Product: Cc1ccc(N)c(Br)c1
Yield: 66 %

Procedure:
To show that selectivity is still obtained using a highly activated aniline, bromination of p-toluidine using tetrabutylammonium tribromide was carried out as generally described in Example 4, but substituting p-toluidine for 4-fluoroaniline, on a 0.75 mole reaction. The desired product 2-bromo-4-methylaniline was obtained in 66% yield on the 0.75 mole reaction.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([C:13]2[C:21]([Cl:22])=[C:20]([Cl:23])[C:19]([Cl:24])=[C:18]([Cl:25])[C:14]=2[C:15]([OH:17])=O)=[O:12])=[C:3]1[CH3:26].[CH3:27][N:28]([CH3:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:37])[CH3:36])[CH:30]=1.C(OC(=O)C)(=O)C.[OH-].[NH4+]>Cl>[CH3:36][N:35]([CH3:37])[C:31]1[CH:30]=[C:29]([N:28]([CH3:38])[CH3:27])[CH:34]=[CH:33][C:32]=1[C:11]1([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[C:3]=2[CH3:26])[C:13]2[C:14](=[C:18]([Cl:25])[C:19]([Cl:24])=[C:20]([Cl:23])[C:21]=2[Cl:22])[C:15](=[O:17])[O:12]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: Cc1c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc2n1C
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: Cc1c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c2ccccc2n1C
Temperature: 25 °C

Procedure:
A mixture of 1.55 g (0.0036 mole) of 2-[(1,2-dimethyl-3-indolyl)carbonyl]-3,4,5,6-tetrachlorobenzoic acid prepared in a manner similar to part A of Example 2, 0.58 g (0.0035 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and ten ml of acetic anhydride was heated to reflux for approximately one hour. After cooling to room temperature, the reaction mixture was poured into 20 ml of 10 percent hydrochloric acid and the mixture then rendered alkaline by the addition of concentrated ammonium hydroxide. The purple solid which separated was collected by filtration, dried, and recrystallized twice from isopropyl acetate to obtain 3-[2,4-bis(dimethylamino)phenyl]-3-(1,2-dimethyl-3-indolyl)-4,5,6,7-tetrachlorophthalide (Formula III: R0 =R1 =R2 =R3 =Cl; R=R5 =R6 =CH3 ; R4 =N(CH3)2 ; Y1 =H) which decomposed at 228°-229° C. The mass spectrum showed an m/e at 575 (M+, 4 Cl). A toluene solution of the product spotted on silica gel developed an intense purple-colored image.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[Cl:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>O1CCOCC1.O>[Cl:12][CH2:13][CH2:14][CH2:15][C:16]([NH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:17]
Reactant: NC(C(=O)O)c1ccccc1
Reactant: O=C(Cl)CCCCl
Solvent: O
Solvent: C1COCCO1
Product: O=C(CCCCl)NC(C(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
2-Amino-2-phenylacetic acid (1.00 g, 6.62 mmol) and TEA (2.77 ml, 19.8 mmol) were dissolved in a mixture of dioxane (13.2 ml) and water (13.2 ml). The mixture was cooled at 0° C. with an ice-bath and 4-chlorobutanoyl chloride (814 μl, 7.28 mmol) was added dropwise. The mixture was stirred at the same temperature for 1 hour and then dioxane was evaporated. The aqueous solution was acidified with 1N HCl and then was extracted three times with EtOAc (20 ml×3). The organic phase was dried (Na2SO4) and evaporated. The crude pale yellow oil was purified by flash chromatography (DCM/MeOH=9/1) and the collected compound was triturated with Et2O (about 15 ml) to obtain the title compound (658 mg, 38.9% yield) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[O:7][CH:8]1[CH2:11][N:10]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[O:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1.[S:32]1[CH2:36][C:35](=[O:37])[NH:34][C:33]1=[O:38].C(O)(=O)C>CCO.C(OCC)(=O)C>[C:1]([C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[O:7][CH:8]1[CH2:11][N:10]([C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH:18]=[C:36]3[S:32][C:33](=[O:38])[NH:34][C:35]3=[O:37])=[CH:20][CH:21]=2)=[O:13])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)(C)c1ccccc1OC1CN(C(=O)c2ccc(C=O)cc2)C1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccccc1OC1CN(C(=O)c2ccc(C=C3SC(=O)NC3=O)cc2)C1
Yield: 49.7 %

Procedure:
To a stirred solution of 4-{[3-(2-tert-butylphenoxy)azetidin-1-yl]carbonyl} benzaldehyde (480 mg, 1.42 mmol) and piperidine (70 μl, 0.71 mmol) in EtOH (15.0 mL) was added 1,3-thiazolidine-2,4-dione (200 mg, 1.70 mmol) and acetic acid (17 μl) at 80° C. After 16 h the reaction mixture was diluted with ethyl acetate, washed with saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting mixture was washed with acetonitrile and diethyl ether to provided 5-(4-{[3-(2-tert-butylphenoxy)azetidin-1-yl]carbonyl}benzylidene)-1,3-thiazolidine-2,4-dione (308 mg, 56%) as a colorless solid.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.C[OH:15]>O>[C:10]([O:9][C:7]([N:1]1[CH2:2][C:3](=[O:15])[S:4][CH2:5][CH2:6]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCSCC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCSC(=O)C1
Temperature: 0 °C
Reaction time: 72 h
Yield: 97 %

Procedure:
A mechanically-stirred mixture of tert-butyl thiomorpholine-4-carboxylate (243 g, 1.19 mol), MeOH (1.5 L), and H2O (1.5 L) was cooled to 0° C. Solid NaIO4 (280 g, 1.3 mol) was added in portions over a 2 hour period. For convenience, the suspension was stirred for 3 days at room temperature. The solids were filtered, washing with MeOH (3×500 mL). The filtrate was concentrated. Residual water was saturated with solid NaCl, and the aqueous phase was extracted with EtOAc (4×200 mL). The combined organic phases were dried (MgSO4), filtered, and concentrated to obtain the product (255 g, 97%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH:17]=1)=[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:9][N:10]=2.[C-:18]#[N:19].[K+].O.O1CCOCC1>C(Cl)Cl>[C:11]1([C:8]2[O:9][N:10]=[C:6]3[CH:5]=[CH:4][C:3]([CH2:2][C:18]#[N:19])=[CH:17][C:7]=23)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [C-]#N
Reactant: BrCc1ccc2noc(-c3ccccc3)c2c1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#CCc1ccc2noc(-c3ccccc3)c2c1
Yield: 114.7 %

Procedure:
A mixture of 9.1 g (0.032 mole) of 5-(bromomethyl)-3-phenyl-2,1-benzisoxazole, 9.8 g (0.15 mole) of potassium cyanide, 50 ml of water and 80 ml of dioxane was heated at reflux under nitrogen for 2.5 hr. The solution was cooled and diluted with 200 ml of methylene chloride. The layers were separated and the organic layer was washed twice with water (emulsion), dried over sodium sulfate and concentrated to give 8.6 g of a dark solid as residue. The solid was chromatographed on 180 g of silica gel eluting with 2% acetone in benzene and 5.8 g (80%) of solid was obtained from the eluant. An analytical sample, m.p. 107°-109° C. was prepared by recrystallizing with 2-propanol.
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(OCC)=O)N=1)CC2)=O.OCC1C=CC(B(O)O)=CC=1.Cl[C:61]1[N:66]=[CH:65][C:64]([O:67][CH2:68][CH2:69][N:70]([CH3:72])[CH3:71])=[CH:63][N:62]=1.CC1(C)C(C)(C)OB([C:81]2[CH:86]=[CH:85][C:84]([OH:87])=[CH:83][CH:82]=2)O1>>[CH3:71][N:70]([CH3:72])[CH2:69][CH2:68][O:67][C:64]1[CH:63]=[N:62][C:61]([C:81]2[CH:86]=[CH:85][C:84]([OH:87])=[CH:83][CH:82]=2)=[N:66][CH:65]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: CN(C)CCOc1cnc(Cl)nc1
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: OCc1ccc(B(O)O)cc1
Product: CN(C)CCOc1cnc(-c2ccc(O)cc2)nc1

Procedure:
Compound 112C was prepared in a similar manner to the synthesis of compound 34D by substituting compound 34C and 4-(hydroxymethyl)phenylboronic acid with compound 112B and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, respectively: 1H NMR (DMSO-d6): δ 9.80 (s, 1H), 8.56 (s, 2H), 8.12-8.15 (m, 1H), 6.83-6.86 (m, 2H), 4.23 (t, J=5.8 Hz, 2H), 2.65 (t, J=5.65 Hz, 2H), 2.22 (s, 6H); ESI (+)/MS: 259 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([NH:22][O:23][CH2:24][C@H:25]1[CH2:29][O:28]C(C)(C)[O:26]1)=[O:21].C1COCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([NH:22][O:23][CH2:24][C@H:25]([OH:26])[CH2:29][OH:28])=[O:21]
Reactant: Cn1c(Nc2ccc(I)cc2Cl)c(C(=O)NOC[C@H]2COC(C)(C)O2)c(=O)n(C)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(Nc2ccc(I)cc2Cl)c(C(=O)NOC[C@H](O)CO)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(R)-6-(2-chloro-4-iodophenylamino)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Example 26, 140 mg, 0.24 mmol, 1 eq) was dissolved in 3 ml of MeOH and 3 ml of THF then p-toluenesulfonic acid (24 mg, 0.5 eq) was added. After stirring at RT for 6 hours the reaction was complete. Evaporation in vacuo, followed by HPLC purification gave the title compound as a white solid. (31 mg, 24%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.89 (s, 3H) 3.21 (s, 3H) 3.28-3.40 (m, 2H) 3.65-3.74 (m, 2H) 3.93 (dd, J=14.15, 6.82 Hz, 1H) 4.61 (t, J=5.68 Hz, 1H) 4.99 (d, J=4.04 Hz, 1H) 7.14 (d, J=8.34 Hz, 1H) 7.70 (dd, J=8.34, 1.77 Hz, 1H) 7.98 (d, J=1.77 Hz, 1H) 12.03 (s, 1H) 12.50 (s, 1H) [M+H] calc'd for C16H18ClIN4O6, 525. found, 525.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][C:11]([CH2:21][CH2:22][CH2:23][CH:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([S:17]([CH3:20])(=[O:19])=[O:18])C(OCC)=O)=[O:4].[Cl-].[Na+].C(=O)=O>CCOCC.O.CS(C)=O>[CH3:20][S:17]([CH:11]([CH2:21][CH2:22][CH2:23][CH:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][C:9]#[C:8][CH2:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])(=[O:18])=[O:19]
Reactant: CCCCCC(CCCC(CC#CCCCC(=O)OC)(C(=O)OCC)S(C)(=O)=O)OC(C)=O
Agent: O=C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: CCCCCC(CCCC(CC#CCCCC(=O)OC)S(C)(=O)=O)OC(C)=O

Procedure:
A solution of ethyl 2-(6-methoxycarbonyl-2-hexyn-1yl)-2-(4-acetoxynonyl)-2(methylsulfonyl)-acetate (48.8 g., 0.1 mole), water (3.6 g., 0.2 mole), and sodium chloride (6.5 g., 0.11 mole) in 120 ml. of dimethyl sulfoxide is heated at 130°-150° C. for 6 hours until evolution of carbon dioxide is completed. The mixture is cooled, treated with 400 ml. of water and the oily product taken up in ether, washed with water and dried over sodium sulfate. Evaporation of the ether in vacuo leaves the title compound as a yellow viscous oil.