Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[I:10]N1C(=O)CCC1=O.[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:10])=[CH:4][N:3]=1
Reactant: COc1ccnc(Cl)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(Cl)ncc1I
Temperature: 55 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
To a solution of 2-chloro-4-methoxypyridine (0.5 g, 3.48 mmol) in sulfuric acid (2.5 mL) was added N-iodosuccinimide (0.825 g, 3.48 mmol) portionwise at room temperature. The mixture was stirred at 55° C. for 2 hours. The reaction mixture was poured into ice water (10 mL) and 8 M NaOH (20 mL) was added slowly, after which the dark brown solution turned pale yellow. The aqueous layer was extracted with CH2Cl2 (2×20 mL). The organic layers were washed with brine (10 mL) and concentrated in vacuo onto silica gel. Dry flash chromatography, eluting with 25% EtOAc:c-Hex, gave 2-chloro-5-iodo-4-methoxypyridine as a white crystalline solid (0.169 g, 0.760 mmol, 22% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][C:16]=1[O:23][CH2:24][O:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:5]1[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][C:16]=2[O:23][CH2:24][O:25][CH3:26])[N:4]=1
Reactant: Cc1oc(-c2ccco2)nc1CCl
Reactant: COCOc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc(C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (13.12 g), 4-hydroxy-3-methoxymethoxybenzaldehyde (11.0 g), potassium carbonate (8.35 g) and N,N-dimethylformamide (200 mL) was stirred at 90° C. for 3 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration and dried to give 4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-(methoxymethoxy)benzaldehyde as pale-brown crystals (16.11 g, yield 78%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 102-103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].S(Cl)(Cl)=O.Cl[C:17](SCl)=[O:18]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]=[C:17]=[O:18])(=[O:10])=[O:9]
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: O=C(Cl)SCl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C=NS(=O)(=O)c1ccccc1Cl

Procedure:
In a flask equipped with a stirrer, reflux condenser and nitrogen bubbling apparatus, were mixed 5 g (0.03 mole) o-chlorobenzenesulfonamide, 50 ml (0.686 mole) thionyl chloride and 2 drops of pyridine. Then 3.9 g (0.03 mole) chlorocarbonylsulfenyl chloride was slowly added.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=O)[N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][N:3]=1.C(OCC)(OCC)OCC.CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][N:3]=1
Reactant: CCC(CC)n1c(=O)[nH]c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: CN(C)C=O
Product: CCC(CC)n1cnc2cnc(Cl)nc21
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a solution of 2-chloro-9-(1-ethyl-propyl)-7,9-dihydro-purin-8-one (0.5 g, 2.3 mmol) in DMF (5 mL) is added triethyl orthoformate (3.8 mL, 23 mmol) and TsOH (0.88 g, 2.6 mmol). The reaction is stirred overnight. The reaction mixture is quenched with ice water and extracted with EtOAc. The extracts are dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (SiO2, EtOAC/Hexane 1:3) gives 0.39 g of 2-chloro-9-(1-ethyl-propyl)-9H-purine.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([CH2:15][CH2:16][NH:17][CH2:18][C:19]1O[CH:21]=[CH:22][CH:23]=1)(=[O:14])=[O:13].ClC1C2C(=CC=CC=2)C=CC=1SC[CH2:37][NH:38]CC1N(C)C=CC=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([CH2:15][CH2:16][NH:17][CH2:18][C:19]1[N:38]([CH3:37])[CH:21]=[CH:22][CH:23]=1)(=[O:14])=[O:13]
Reactant: O=S(=O)(CCNCc1ccco1)c1ccc2ccccc2c1Cl
Reactant: Cn1cccc1CNCCSc1ccc2ccccc2c1Cl
Product: Cn1cccc1CNCCS(=O)(=O)c1ccc2ccccc2c1Cl
Yield: 76 %

Procedure:
Prepared as described for compound 25 from 2-[(1-chloronaphthalen-2-yl)sulfanyl]-N-[(1-methyl-1H-pyrrol-2-yl)methyl]ethanamine and in 76% yield as yellow oil.
Reaction SMILES: CCOCC.[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13]1([C:19]2[O:20][CH2:21][CH2:22][N:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[C:13]1([C:19]([NH:23][CH2:22][CH2:21][O:12][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccccc1
Reactant: c1ccc(C2=NCCO2)cc1
Solvent: O
Solvent: CCOCC
Product: O=C(NCCOc1ccccc1)c1ccccc1

Procedure:
In German Pat. No. 1,062,253, A. Jager describes the preparation of various ether and carboxamide compounds by treating certain substituted oxazolines with certain phenols, with the exclusion of water. A mixture of phenol and 2-phenyloxazoline refluxed for 7 hours yielded PhCONHCH2CH2OPh as a product. Similarly, p-bis(oxazolinyl)benzene and phenol gave N,N'-bis(β-phenoxyethyl)terephthalamide. Finally, Jager found that a mixture of 2-phenyl-2-oxazoline and hydroquinone produced 1,4-bis(β-benzamidoethoxy)benzene.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[O:5]1[CH2:9][CH2:8][CH2:7][S:6]1(=[O:11])=[O:10]>C1COCC1>[CH2:1]([NH:4][CH2:9][CH2:8][CH2:7][S:6]([OH:11])(=[O:10])=[O:5])[C:2]#[CH:3]
Reactant: O=S1(=O)CCCO1
Reactant: C#CCN
Solvent: C1CCOC1
Product: C#CCNCCCS(=O)(=O)O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
4 g (71.2 mmol) prop-2-yn-1-amine were dissolved in 75 ml THF and cooled to 0° C. To this mixture 8.87 g (71.2 mmol) 1,2-oxathiolane 2,2-dioxide dissolved in 25 ml THF were added drop wise at 0° to 5° C. After addition the reaction mixture was heated to room temperature and stirred for 12 hours.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([F:26])[CH:16]=3)[CH2:12][N:11]([C:27]([N:29]3[CH2:34][CH2:33][S:32][CH2:31][CH2:30]3)=[O:28])[CH2:10]2)[O:6][N:5]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:43])C=1>>[CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:24])([F:25])[F:23])=[C:17]([F:26])[CH:16]=3)[CH2:12][N:11]([C:27]([N:29]3[CH2:34][CH2:33][S:32](=[O:43])[CH2:31][CH2:30]3)=[O:28])[CH2:10]2)[O:6][N:5]=1)[CH3:2]
Reactant: CCOc1noc(C2CC(c3ccc(CC(F)(F)F)c(F)c3)CN(C(=O)N3CCSCC3)C2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCOc1noc(C2CC(c3ccc(CC(F)(F)F)c(F)c3)CN(C(=O)N3CCS(=O)CC3)C2)n1

Procedure:
76.0 mg (0.151 mmol) of the compound from Example 77 were reacted according to General Method 2 with 47.0 mg (0.136 mmol) of meta-chloroperbenzoic acid. Yield: 60.5 mg (77% of theory)
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:34]=[CH:33][C:27]2[O:28][C:29]([F:32])([F:31])[O:30][C:26]=2[CH:25]=1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.C(OCC)(=O)C>CS(C)=O>[F:32][C:29]1([F:31])[O:28][C:27]2[CH:33]=[CH:34][C:24]([CH:11]([C:12]3[C:20]4[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=4)[NH:14][CH:13]=3)[CH2:10][CH2:9][C:1]#[N:2])=[CH:25][C:26]=2[O:30]1
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc4c(c3)OC(F)(F)O4)c[nH]c12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc4c(c3)OC(F)(F)O4)c[nH]c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
0.37 g (5.76 mmol) of potassium cyanide was added to 1.35 g (2.88 mmol) of the compound from Example 112A in 26 ml of DMSO. The mixture was stirred at 80° C. for 3 h, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The combined organic phases were freed of solvent, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 0.90 g (78% of theory) of the target compound was obtained.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[N+:9]([O-])([OH:11])=[O:10]>CCOCC>[N+:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:1]([OH:2])[C:3]=1[OH:4])([O-:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccccc1O
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc(O)c1O
Temperature: 25 °C

Procedure:
To a solution containing 2.5 g of catechol in 125 ml of ether 1.0 ml of conc. nitric acid (d-1.52) was gradually added. The solution was stirred over night at room temperature and washed with water. The solvent was evaporated and the residue was treated with boiling petroleum ether (b.p. 60°-80° C). The insoluble 4-nitrocatechol was filtered and the filtrate concentrated in vacuo. After cooling the 3-nitrocatechol was filtered. Yield 0.85 g (24%), m.p. 82°-85° C.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:5]=1[O:6][CH2:7][C:8]([O:10]C)=[O:9])(=[O:3])[CH3:2].O.[OH-].[Na+]>O1CCCC1>[C:1]([C:4]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: COC(=O)COc1cc(Br)ccc1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Br)cc1OCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a solution of methyl 2-(2-acetyl-5-bromophenoxy)acetate (1.35 g, 4.5 mmol) in tetrahydrofuran:water=3:1 (20 mL) was added sodium hydroxide (400 mg, 10 mmol). The mixture was stirred at room temperature for 2 hours. The suspension was concentrated in vacuum and quenched with aqueous 1N hydrochloric acid (5 mL). The residue was taken up with water (50 mL) and extracted with dichloromethane (50 mL). The combined extract was dried over sodium sulphate, evaporated and purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give the product 2-(2-acetyl-5-bromophenoxy)acetic acid (1.14 g, 91%) as pale solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:10]=2)[CH:3]=1.N1C=CC=CC=1.[Cl:33][CH2:34][C:35](Cl)=[O:36]>CN(C=O)C>[Cl:33][CH2:34][C:35]([NH:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH:10]=2)[CH:3]=[C:2]([Cl:1])[N:7]=1)=[O:36]
Reactant: Nc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cc(Cl)n1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(CCl)Nc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cc(Cl)n1
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of Example 150b (0.262 g, 0.681 mmol) in DMF (6 mL) was added pyridine (0.11 mL, 1.36 mmol) and 2-chloroacetyl chloride (0.060 mL, 0.749 mmol). After 2 hours, the suspension was filtered. The filtrate was treated with water slowly. The precipitate formed was filtered, washed with water, and oven-dried to give 0.289 g of the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=2)[NH:12][N:11]=1.[CH:20]([O-])=[O:21].[Na+]>CN(C=O)C.CCOC(C)=O.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>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH:20]=[O:21])[CH:17]=2)[NH:12][N:11]=1
Reactant: Ic1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1
Reactant: O=C[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1
Temperature: 90 °C
Yield: 37 %

Procedure:
3-(1H-benzimidazol-2-yl)-5-iodo-1H-indazole (500 mg, 1.39 mmol) was dissolved in DMF (5 mL), then Pd(PPh3)2Cl2 (24 mg, 0.034 mmol) and sodium formate (142 mg, 2.1 mmol) were added. The reaction mixture was put under vacuum and recharged with CO three times, then heated up to 90° C. for 4 hr. The mixture was diluted with EtOAc, washed with brine, dried and concentrated. The crude product was purified by flash chromatography to afford 3-(1H-benzimidazol-2-yl)-1H-indazole-5-carboxaldehyde (135 mg, 37%) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[C:10]([CH:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)O)[CH:9]=2)=[CH:4][CH:3]=1.CC(C)=[O:24]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[C:10]([CH:15]3[C:17](=[O:24])[CH:21]=[CH:20][CH:19]3[OH:18])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCc1sc(-c2ccc(Cl)cc2)cc1C(O)c1ccco1
Reactant: CC(C)=O
Solvent: O
Product: CCc1sc(-c2ccc(Cl)cc2)cc1C1C(=O)C=CC1O
Temperature: 60 °C

Procedure:
To a solution of [5-(4-chloro-phenyl)-2-ethyl-thiophen-3-yl]-furan-2-yl-methanol (2.52 g, 7.9 mmol) in acetone (30 ml) and water (5 ml) is added polyphosphoric acid (0.5 ml) and the resulting solution heated at 60° C. for 5 hours. The resulting black solution is concentrated in vacuo and purified by flash chromatography on silica gel to give 5-[5-(4-chloro-phenyl)-2-ethyl-thiophen-3-yl]-4-hydroxy-cyclopent-2-enone as a clear gum (320 mg)
Reaction SMILES: I[C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.C(=O)(O)[O-].[Na+].[CH3:14][O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19](B(O)O)=[CH:18][N:17]=1>COCCOC.C(Cl)Cl.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>[CH3:7][C:5]1[N:6]=[C:2]([C:19]2[C:20]([O:22][CH3:23])=[N:21][C:16]([O:15][CH3:14])=[N:17][CH:18]=2)[S:3][C:4]=1[CH3:8]
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Cc1nc(I)sc1C
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: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1ncc(-c2nc(C)c(C)s2)c(OC)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-iodo-4,5-dimethyl-1,3-thiazole (prepared in a similar manner to that described in JACS 123 (6), 1017-1022, (2001), 250 mg, 1.046 mmol) was dissolved in 1,2-Dimethoxyethane (DME) (4.357 ml). Tetrakis(triphenylphosphine)palladium(0) (60.4 mg, 0.052 mmol) was added and the mixture was stirred at room temperature for 10 minutes. Sodium bicarbonate (4.183 ml, 4.18 mmol) and [2,4-bis(methyloxy)-5-pyrimidinyl]boronic acid (385 mg, 2.091 mmol) were added and the resulting mixture was stirred at 85° C. for 2 hours. The mixture was allowed to cool to rt and left standing at rt over the week end. The mixture was diluted with DCM (5 mL), the aqueous phases was separated and extracted with DCM (2×5 mL). The organics were combined and dried over sodium sulphate to give a yellow solid that was purified by silica chromatography, eluting with DCM:MeOH from 100:0 to 95:5 to afford the title compound as a pale yellow solid (143 mg).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:13]([NH2:15])=[O:14].C(N(CC)CC)C.[Br:23][CH:24]([CH3:28])[C:25](Br)=[O:26]>CN(C=O)C>[Br:23][CH:24]([CH3:28])[C:25]([NH:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:13]([NH2:15])=[O:14])=[O:26]
Reactant: CC(Br)C(=O)Br
Reactant: NC(=O)c1cnn(C2CCOCC2)c1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)Nc1c(C(N)=O)cnn1C1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of C2 (5.0 g, 23.8 mmol) and triethylamine (3.65 mL, 26.2 mmol) in anhydrous DMF (50 mL) was cooled in an ice bath and treated drop-wise with 2-bromopropanoyl bromide (5.4 g, 25 mmol). The mixture was stirred at 0° C. for 30 mins, warmed to room temperature and stirred at ambient temperature for an additional 2 h. The reaction was partitioned between EtOAc (200 mL) and aqueous 2N hydrochloric acid (500 mL); the organic phase was washed with saturated aqueous sodium bicarbonate solution (400 mL), saturated aqueous sodium chloride solution (200 mL) and dried over sodium sulfate. Filtration and concentration of the filtrate provided crude C24 as an orange residue, which was used in the next step without purification,
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]([CH3:18])([CH3:17])[C@@H:12]2[C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:23](O)[C:24]#[C:25][CH2:26][OH:27]>>[OH:27][CH2:26][C:25]#[C:24][CH2:23][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]([CH3:17])([CH3:18])[C@@H:12]2[C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OCC#CCO
Reactant: COC(=O)[C@@H]1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Product: COC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#CCO)cc2)CCSC1(C)C
Yield: 65.2 %

Procedure:
According to the procedure of Step 2 of Example 248, Mitsunobu coupling of 0.10 g (0.288 mmoL) of methyl(3S)-4-[(4-hydroxyphenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholinecarboxylate and 0.031 g (0.363 mmol) of 2-butyne-1,4-diol gave 0.078 g of methyl(3S)-4-({4-[(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxylate as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:14])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[C:3]([F:6])([F:5])[F:4].N1C=CC=CC=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.Cl>O>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:2]([F:14])([F:1])[C:3]([F:5])([F:4])[F:6])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: OCCCCCCC(F)(F)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCCCCC(F)(F)C(F)(F)F)cc1
Yield: 73.3 %

Procedure:
Into a reaction vessel, 5.00 g (22.7 mmol) of 6-(perfluoroethyl)hexanol (1) and 6.3 ml of pyridine were placed, and 5.21 g (27.3 mmol) of p-toluene-sulfonyl chloride was added little by little thereto under stirring and cooling with ice. After the addition, the system was stirred for 6 hours. The reaction product was poured into iced water, acidified by addition of 6 ml of hydrochloric acid and then extracted with chloroform. The organic layer was washed with salt water and dried with sodium sulfate, followed by solidification by removal of the solvent under a reduced pressure. The residue was purified by silica gel column chromatography with eluents of hexane/toluene=2/1, toluene, and toluene/ethyl acetate=5/1, successively, having increasing polarity, thereby obtaining 6.23 g (yield=73.3%) of 6-(perfluoroethyl)hexyl p-toluenesulfonate (2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH2:9][OH:10])[CH:3]=1.[O-:11][Mn](=O)(=O)=O.[K+:16]>CC(C)=O>[K+:16].[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(CO)n1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(Br)cc(C(=O)[O-])n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 116 %

Procedure:
To a solution of (4-bromo-6-methyl-pyridin-2-yl)-methanol (1.31 g, 6.48 mmol) in acetone (150 mL), KMnO4 (2.61 g, 16.5 mmol) is added. The mixture is stirred at 40° C. for 2 h before it is filtered over a sintered glass funnel. The filtrate is evaporated to dryness, the remaining solid is washed with water and dried under HV to give 4-bromo-6-methyl-pyridine-2-carboxylic acid potassium salt (1.91 g) as a white solid; LC-MS: tR=0.45 min, [M+1]+=217.89.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.[Br:16]C1CC(C(C)C)CCC1=O>>[Br:16][CH:7]1[C:2](=[O:1])[CH2:3][CH2:4][C:5]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:8]#[N:9])[CH2:6]1
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Reactant: CC(C)C1CCC(=O)C(Br)C1
Product: N#CC1(c2ccccc2)CCC(=O)C(Br)C1

Procedure:
The bromination of 4-oxo-1-phenyl-cyclohexanecarbonitrile takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C(O[CH2:17][C:18]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[C:26]=2[CH3:35])[C:22]2[N:36]=[C:37]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[S:38][C:21]=2[C:20](=[O:45])[N:19]=1)(=O)C.[C:46]1(=[O:56])[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48](=[O:55])[NH:47]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:35][C:26]1[C:27]([C:31]([F:32])([F:33])[F:34])=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][N:23]1[C:22]2[N:36]=[C:37]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)[S:38][C:21]=2[C:20](=[O:45])[N:19]=[C:18]1[CH2:17][N:47]1[C:48](=[O:55])[C:49]2[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46]1=[O:56]
Reactant: CC(=O)OCc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(C(F)(F)F)c1C
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(Cn2c(CN3C(=O)c4ccccc4C3=O)nc(=O)c3sc(N4CCOCC4)nc32)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DEAD (0.035 mL, 0.221 mmol) was added to a solution of 5-(hydroxymethyl)-4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (Example 113, 65 mg, 0.148 mmol), 1H-isoindole-1,3(2H)-dione (26.1 mg, 0.177 mmol) and triphenylphosphine (58.1 mg, 0.221 mmol) in Tetrahydrofuran (THF) (2 mL). The reaction was stirred at RT for overnight. The mixture was partitioned between DCM and NaCl solution, the organic layer was dried over MgSO4 and was concentrated. The residue was purified on a silica column eluting with 30% EtOAc/Hexanes to give the titled product, 60 mg (60%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH3:7][O:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12](B(O)O)=[CH:11][N:10]=1.C([O-])(O)=O.[Na+]>COCCOC.O>[CH3:7][O:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:11][N:10]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Brc1nccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ncc(-c2nccs2)c(OC)n1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
2-bromo-1,3-thiazole (commercially available from Aldrich, 0.165 ml, 1.829 mmol) was dissolved in degassed 1,2-Dimethoxyethane (DME) (5 ml). Pd(Ph3)4 (106 mg, 0.091 mmol) was added. The reaction mixture was stirred at room temperature for 15 min. [2,4-bis(methyloxy)-5-pyrimidinyl]boronic acid (commercially available from Aldrich, 707 mg, 3.84 mmol) and 5 mL of degassed 1M aqueous solution of NaHCO3 were added to the reaction mixture under N2 atmosphere. After 2 h 30 min stirring at 90° C., the reaction mixture was diluted with water and extracted with DCM. The collected organic phases were evaporated. The residue was purified by flash chromatography eluting with cyclohexane/EtOAc 5:1. 294 mg of the title compound were isolated as a yellow solid.