Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CSC.B.[F:5][C:6]([F:14])([F:13])[C:7]1([C:10](O)=[O:11])[CH2:9][CH2:8]1>C1COCC1>[F:5][C:6]([F:14])([F:13])[C:7]1([CH2:10][OH:11])[CH2:9][CH2:8]1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCC1(C(F)(F)F)CC1
Temperature: 40 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
50 mL of borane dimethylsulfide 2M in THF were added dropwise at RT via an addition funnel to a solution of 1-trifluormethyl-cyclopropanecarboxylic acid (10 g, 64.90 mmol) in 100 mL of THF. The resulting clear solution was stirred at 40° C. for 24 hours before being cooled to 0° C. and quenched by slow addition of aqueous saturated NH4Cl. The biphasic slurry was filtered through celite. The organic layer was separated, and the aqueous layer was back extracted twice with AcOEt. The combined organic layers were dried (Na2SO4), filtered, and evaporated to give 7 g of (1-trifluoromethyl-cyclopropyl)-methanol (77% yield). Used as in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([OH:18])([CH2:14][CH2:15][CH:16]=[CH2:17])[C:10]([F:13])([F:12])[F:11].[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20].C1COCC1>CCOC(C)=O>[F:12][C:10]([C:9]1([CH2:14][CH2:15][CH:16]=[CH2:17])[C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[NH:1][C:19](=[O:20])[O:18]1)([F:13])[F:11]
Reactant: C=CCCC(O)(c1cc(Cl)ccc1N)C(F)(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCCC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21
Temperature: 60 °C
Yield: 61.4 %

Procedure:
To a 200 mL round bottomed flask with a stirring bar, argon inlet and a reflux condenser was added (±) 2-(2-Amino-5-chlorophenyl)-1,1,1-trifluoro-5-hexen-2-ol (4.80 g, 17.16 mmol), 1,1'-carbonyldiimidazole (13.91 g, 85.81 mmol) and dry THF (75 mL). This mixture was heated at 60° C. for 18 h. The cooled reaction mixture was diluted with EtOAc and washed with H2O (3×200 mL) and brine (250 mL). Drying (MgSO4), filtration, removal of the solvent in vacuo, followed by recrystallization from boiling EtOAc-hexane gave 3.22 g of (±) 4-(1,1,1,-trifluoromethyl)-4(1-buten-4-yl)-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white crystalline solid, mp: 165°-166° C. 1H NMR (CDCl3): δ1.99 (m, 1H), 2.09-2.40 (m, 3H), 5.00 (d, 1H, J=1.4 Hz), 5.03 (dd, 1H, J=1.4, 7.9), 5.78 (m, 1H), 6.85 (d, 1H, J=8.6 Hz), 7.21 (br s, 1H), 7.35 (dd, 1H, J=2.2, 8.6 Hz), 9.63 (br s, 1H).
Reaction SMILES: [H-].[Na+].C[C:4](P(OC)(O)=O)([C:6]([O-:8])=[O:7])[CH3:5].[O:14]1[CH2:19][CH2:18]C(=O)[CH2:16][CH2:15]1.[OH-].[Na+]>O1CCCC1.CO>[C:6]([CH:4]=[C:5]1[CH2:18][CH2:19][O:14][CH2:15][CH2:16]1)([OH:8])=[O:7]
Reactant: O=C1CCOCC1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C=C1CCOCC1
Reaction time: 0.17 h
Yield: 97.6 %

Procedure:
Methanol (204 ml) was slowly added to a suspension of sodium hydride (5.48 g, 228.2 mmol) in tetrahydrofuran (204 ml) at 0° C. When addition was complete, trimethylphosphonoacetate (34.22 ml, 211.4 mmol) was added to the mixture at such a rate as to maintain the temperature below 12° C. Stirring was continued for a further 10 minutes. To this reaction mixture was added a solution of 2,3,5,6-tetrahydropyran-4-one (16.28 g, 163.0 mmol) in tetrahydrofuran (20 ml), keeping the temperature below 30° C. After the addition was complete, stirring was continued for 30 minutes at room temperature, then methanol (100 ml) and 2M sodium hydroxide (326 ml) was added, and the mixture stirred overnight at room temperature. The resulting solution was concentrated to one half of the original volume, and acidified to pH 1.2 with 6M hydrochloric acid (108 ml). The reaction mixture was partitioned between ethyl acetate and water, the combined organic extracts dried over magnesium sulfate, and solvent removed under reduced pressure to give 4-(carboxymethylene)-2,3,5,6-tetrahydropyran (22.62 g), which was used with no further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:22])(=[O:21])[N:11]([CH2:18][O:19][CH3:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[OH-].[Na+]>CO.O>[CH3:20][O:19][CH2:18][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[S:10]([C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([OH:4])=[O:2])(=[O:22])=[O:21]
Reactant: COCN(c1ccccc1)S(=O)(=O)c1ccsc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCN(c1ccccc1)S(=O)(=O)c1ccsc1C(=O)O
Yield: 76.8 %

Procedure:
To a homogenous mixture of 3-(N-methoxymethyl-N-phenylsulfamoyl)thiophene-2-carboxylic acid methyl ester (3 g, 8.75 mmol) in methanol and water was added aqueous, sodium hydroxide solution (2N, excess) at room temperature. Upon completion of the reaction, the mixture was cooled and extracted once with diethyl ether. The aqueous layer will then acidified with aqueous, HCl (2N, excess) before re-extracting twice with ethyl acetate. The organic layer was washed once with brine solution and dried over anhydrous sodium sulfate. The ethyl acetate solution was decanted and evaporated under reduced pressure to give the desired 3-(N-methoxymethyl-N-phenylsulfamoyl)thiophene-2-carboxylic acid (2.2 g, 79%).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[N:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+]>CO>[CH3:23][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][NH:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(C)CCCOc1ccccc1C=NCCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)CCCOc1ccccc1CNCCc1ccccc1
Temperature: 35 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
A stirred solution of 36.0 g of N-[[2-[3-(dimethylamino)propoxy]phenyl]methylene]benzeneethanamine in 200 ml of methanol is treated portionwise with 13.0 g of sodium borohydride. The temperature is maintained at 35° C using a cold water bath. After 3 hours, the solvent is evaporated and the semi-solid residue is treated with 300 ml of water. The product is extracted twice with 100 ml portions of ether. The solvent fractions are combined, treated with water, dried and concentrated to give 33.8 g of an oily product. Distillation yields 19.9 g of the title compound, boiling point 165°-170° C at 0.15 mm of Hg.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:27])[C:21]([CH2:25][CH3:26])([CH3:24])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:45])[C@@H:15]2[CH2:28][CH2:29][C@H:30]2[O:35][C:34](=[O:36])[CH2:33][C@H:32]([O:37][Si](C(C)(C)C)(C)C)[CH2:31]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:27])[C:21]([CH2:25][CH3:26])([CH3:24])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:45])[C@@H:15]2[CH2:28][CH2:29][C@H:30]2[O:35][C:34](=[O:36])[CH2:33][C@H:32]([OH:37])[CH2:31]2)=[CH:10]1
Reactant: CCC(C)(CC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC(C)(CC)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.9 %

Procedure:
A solution of 600 mg (0.9 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-(2-ethyl-2-methylbutyryloxy)-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 5, above] in 2 ml of tetrahydrofuran was added to a mixture of 12.7 ml of a 1M tetrahydrofuran solution of tetrabutylammonium fluoride and 1.27 ml of acetic acid, and the resulting mixture was stirred at room temperature for 15 hours. At the end of this time, the tetrahydrofuran was removed from the reaction mixture by distillation under reduced pressure. The residue was then diluted with 50 ml of ethyl acetate and the diluted solution was washed twice with 50 ml each time of water, three times with 30 ml each time of a saturated aqueous solution of sodium hydrogencarbonate and once with a saturated aqueous solution of sodium chloride, in that order. The organic layer was then dried over anhydrous magnesium sulfate and removed from the mixture by filtration, after which the solvent was removed by distillation under reduced pressure. The residue was purified by flash column chromatography through silica gel, using ethyl acetate as the eluent, to give 387 mg (98% yield) of the title compound as a colorless solid. This compound was recrystallized from a mixture of hexane and ethyl acetate to produce the title compound as colorless prisms, melting at between 152° and 154° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[N:22]=[CH:23][N:24]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[CH:25]=3)=[CH:18][CH:19]=2)[C@H:14]([NH:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH2:13][C@@H:12]1[CH3:41])(=[O:10])[CH3:9]>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[N:22]=[CH:23][N:24]([CH2:26][C:27]([OH:29])=[O:28])[CH:25]=3)=[CH:18][CH:19]=2)[C@H:14]([NH:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH2:13][C@@H:12]1[CH3:41])(=[O:10])[CH3:9]
Reactant: CC(=O)N1c2ccc(-c3cn(CC(=O)OC(C)(C)C)cn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1c2ccc(-c3cn(CC(=O)O)cn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 16 h
Yield: 84 %

Procedure:
Trifluoracetic acid (1 mL) was added at room temperature to a solution of 1,1-dimethylethyl {(cis)-4-[1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazol-1-yl}acetate (for a preparation see Example 91) (1.26 g, 2.68 mmol) in DCM (5 mL). The reaction mixture was allowed to stand at room temperature for 16 h then concentrated in vacuo. The residue was co-evaporated twice with toluene then triturated with Et2O to give {4-[(cis)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazol-1-yl}acetic acid trifluoroacetate (1.19 g, 2.252 mmol, 84%) as an off-white solid.
Reaction SMILES: CS(O[C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH2:9]3)[CH2:7]1)[CH2:13]2)(=O)=O.[NH2:24][C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[C:20]([O:19][C:17](=[O:18])[NH:16][C:8]12[CH2:14][CH:12]3[CH2:11][CH:10]([CH2:15][C:6]([NH:24][C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)([CH2:13]3)[CH2:7]1)[CH2:9]2)([CH3:23])([CH3:22])[CH3:21]
Reactant: Nc1ncccn1
Reactant: CC(C)(C)OC(=O)NC12CC3CC(C1)CC(OS(C)(=O)=O)(C3)C2
Product: CC(C)(C)OC(=O)NC12CC3CC(C1)CC(Nc1ncccn1)(C3)C2
Reaction time: 0.25 h

Procedure:
The mixture of 1.04 g (3 mmole) of 3-[(tert-butoxycarbonyl)amino]-1-adamantyl methanesulphonate and 1.0 g (10.5 mmole) 2-aminopyrimidine are melted at 140° C. After 15 minutes of stirring the melt is cooled down and purified by column chromatography (n-hexane—ethyl acetate—chloroform 2:1: 1). The product is white crystalline material, 0.7 g (68%). Mp.: 163-165° C. 1H-NMR (DMSO-d6): 1.36 (s, 9H), 1.52 (s, 2H), 1.71 (d, 2H), 1.86 (d, 4H), 2.07 (m, 4H), 2.25 (m, 2H), 6.38 (s, 1H), 6.49 (t, 3H), 6.58 (s, 1H), 8.22 (d, 2H).
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:9][C:8]=3[C:7]=2[C:26]#[N:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].C1C[O:33]CC1>>[O:33]=[C:9]1[C:8]2[C:7]([C:26]#[N:27])=[C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: Cc1ccc(-c2cc(N3CCCC3)c(C#N)c3c2-c2ccccc2C3)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(-c2cc(N3CCCC3)c(C#N)c3c2-c2ccccc2C3=O)cc1
Temperature: 2.5 °C
Yield: 76 %

Procedure:
A solution of 2-(pyrrolidin-1-yl)-4-p-tolyl-9H-fluorene-1-carbonitrile (350 mg) in THF was added sodium hydride (42 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Red solid; yield 76%; mp 162-164° C.; ESMS 365 (M++1); IR (KBr) 1716 cm−1 (CO) 2214 (CN).
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[CH:4][C:5](I)=[C:6]([CH:8]=1)[NH2:7].[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15]>C(N(CC)CC)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.[Cu]I>[F:1][C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[CH:4][CH:5]=[C:6]([NH:7][C:15]#[C:14][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1cc(F)c(C(F)(F)F)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#CNc1ccc(C(F)(F)F)c(F)c1
Yield: 96.1 %

Procedure:
To a solution of 3.27 g of 5-fluoro-2-iodo-4-trifluoromethyl-aniline (10.7 mmol) in 20 ml triethylamine were added 3763 mg of Pd(PPh3)2Cl2 (0.5 mmol), 102 mg of CuI (0.5 mmol) and 1.63 ml of ethinyltrimethylsilane (11.8 mmol). The reaction mixture was stirred over night at rt before most of the triethylamine was removed under reduced pressure. Then DCM was added and the resulting suspension was filtered. The filtrate was then concentrated and the residue purified by chromatography (silica gel; cyclohexane/EtOAc 9:1) to yield 2.83 g (96%) of 5-fluoro-4-trifluoromethyl-2-trimethylsilanylethynyl-phenylamine contaminated with triethylamine as a dark red liquid. 1H-NMR (CDCl3, 300 MHz): δ 0.26 (s, 9H), 4.68 (br s, 2H), 6.44 (d, J=12 Hz, 1H), 7.51 (d, J=8 Hz, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC.[Si:27]([O:34][C@@H:35]([CH3:63])[C@@H:36]([NH:51][C:52]1[C:60]2[CH:59]=[CH:58][S:57][C:56]=2[C:55]([C:61]#[N:62])=[CH:54][CH:53]=1)[C:37]([NH:39][NH:40][C:41](=O)[C:42]1[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=1)=[O:38])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C(Cl)Cl>[Si:27]([O:34][C@@H:35]([CH3:63])[C@@H:36]([NH:51][C:52]1[C:60]2[CH:59]=[CH:58][S:57][C:56]=2[C:55]([C:61]#[N:62])=[CH:54][CH:53]=1)[C:37]1[O:38][C:41]([C:42]2[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=2)=[N:40][N:39]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c2sccc12)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
To a solution of triphenylphosphine (275 mg, 1.43 mmol) in DCM (24 mL) was added 12 (363 mg, 1.43 mmol) at 0° C. After 12 was dissolved completely, Et3N (0.40 mL, 2.87 mmol) was added, followed by a solution of N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(7-cyanobenzo[b]thiophen-4-ylamino)butanoyl)-4-cyanobenzohydrazide (380 mg, 0.71 mmol) in DCM (12 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for additional 10 min. The reaction was quenched with saturated sodium thiosulfate (3 mL) and diluted with DCM (100 mL). The organic layer was separated and washed with water, brine and dried over Na2SO4. Removal of the solvent gave a residue, which was purified by flash chromatography to provide the title compound 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)benzo[b]thiophene-7-carbonitrile (360 mg, 98%). 1H NMR (400 MHz, CDCl3, δ in ppm) 8.22 (d, J=8.4 Hz, 2H), 7.93 (d, J=8.4 Hz, 2H), 7.73 (d, J=5.5 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.55 (d, J=5.5 Hz, 1H), 6.63 (d, J=8.2 Hz, 1H), 5.89 (d, J=8.6 Hz, 1H), 5.12 (m, 1H), 4.74 (m, 1H), 1.61 (d, J=6.2 Hz, 3H), 1.05 (s, 9H), 0.26 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]=1[OH:15].C(N(CC)C(C)C)(C)C.Cl[CH2:26][O:27][CH3:28]>C1COCC1>[Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]=1[O:15][CH2:26][O:27][CH3:28]
Reactant: COc1ccc2c(O)c(Br)c(C)cc2c1
Reactant: COCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(Br)c(C)cc2cc(OC)ccc12
Temperature: 0 °C
Yield: 79.6 %

Procedure:
To an ice-water cooled solution of 2-bromo-3-methyl-6-(methyloxy)-1-naphthalenol (13) (6.8 g, 25.5 mmol) in THF (70 mL) was slowly added N,N-diisopropylethylamine (7 mL, 5.19 g, 40 mmol, 1.58 eq) followed by the slow addition of chloromethylmethyl ether (3.2 mL, 3.39 g, 42.1 mmol, 1.65 eq) between 0-5° C. with stirring under N2. The ice-water bath was removed and the reaction mixture was allowed to stir at RT overnight. The reaction mixture was diluted with Et2O (400 mL), washed with H2O (2×250 mL) followed by 1 N HCl (2×250 mL), dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product as a dark orange oil. The crude product was partially purified by flash chromatography over SiO2 with hexanes:EtOAc (12:1 to 9:1) to give 6.32 g of the impure title compound. The impure compound was purified by flash chromatography over SiO2 with hexanes:EtOAc (15:1) to give 4.8 g (60%) of compound 14 as a pale yellow oil. 1H NMR (400 MHz; DMSO-d6): δ 3.59 (s, 3H), 3.85 (s, 3H), 5.18 (s, 2H), 7.17 (dd, J=2.5 Hz, 9.3 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.60 (s, 1H), 7.95 (d, J=9.2 Hz, 1H). 1H NMR (400 MHz; CDCl3): δ 2.54 (s, 3H), 3.72 (s, 3H), 3.90 (s, 3H), 5.24 (s, 2H), 7.02 (d, J=2.4 Hz, 1H), 7.12 (dd, J=2.6 Hz, 9.2 Hz, 1H), 7.42 (s, 1H), 8.03 (d, J=9.1 Hz, 1H). (Note: In DMSO-d6, the 3-methyl group is coincident with the DMSO peak.) HRMS (EI+) calcd for C14H15BrO3: 310.0205 (M•+). Found: 310.0196.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[CH3:11][S:12]([NH:15][CH2:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)(=[O:14])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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.O>[I:10][C:9]1[N:4]2[C:5]([S:6][C:2]([C:21]3[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=3)[CH2:16][NH:15][S:12]([CH3:11])(=[O:14])=[O:13])=[N:3]2)=[N:7][CH:8]=1
Reactant: Brc1nn2c(I)cnc2s1
Reactant: CS(=O)(=O)NCc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)NCc1cccc(-c2nn3c(I)cnc3s2)c1
Temperature: 115 °C
Yield: 23.4 %

Procedure:
A mixture of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (0.25 g, 0.757 mmol, 1 eq), (3-methanesulfonylaminomethylphenyl)boronic acid (0.208 g, 0.908 mmol, 1.2 eq), cesium carbonate (0.493 g, 1.514 mmol, 2 eq), Pd(PPh3)2Cl2 (0.053 g, 0.075 mmol, 0.1 eq), 1,4-dioxane (6 mL) and water (6 mL) was heated in a pressure tube at 115° C. for 4 h. Solvents were removed and the slurry obtained was partitioned between water and 10% MeOH in DCM. The organic layer was dried, filtered and evaporated. The residue was purified in an Isolute Flash Si II column (EtOAc) to give the desired product (77 mg, 23%). HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=4.04 min, [M+H]+ m/z 435.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1.BrC[C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:1][O:2][C:3](=[O:13])[C:4]2[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(C(=O)OCC(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 25 ml round flask, 2.0 g (11.1 mmol) of isophtalic acid monomethyl ester and 2.6 g (11.1 mmol) 2-bromo-1-(4-chloro-phenyl)-ethanone are dissolved in 10 ml of DMF followed by addition of 3.1 g (22.2 mmol, 2.0 eq.) of K2CO3. After stirring the suspension 2 h at room temperature, the solvent is removed in vacuo and the residue taken up in CH2Cl2. The organic phase is washed with aqueous NaHCO3 (5%) and the phases separated. The organic layer is dried (Na2SO4) and concentrated to yield the title compound which is used for the next step without further purification. Mass spectrum: m/z (M+H+NH3)+: 198.0
Reaction SMILES: [CH:1]1[N:5]([CH:6]2[O:10][CH:9]([CH2:11][OH:12])[CH:8]([OH:13])[CH:7]2[OH:14])[C:4]2[N:15]=[C:16]([NH2:20])[N:17]=[C:18](Cl)[C:3]=2[N:2]=1.Cl.[I:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27].C(N(CC)CC)C>C(O)C>[NH2:20][C:16]1[N:15]=[C:4]2[C:3]([N:2]=[CH:1][N:5]2[C@@H:6]2[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:13])[C@H:7]2[OH:14])=[C:18]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([I:22])[CH:24]=2)[N:17]=1
Reactant: Nc1nc(Cl)c2ncn(C3OC(CO)C(O)C3O)c2n1
Reactant: NCc1cccc(I)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc(NCc2cccc(I)c2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 80 °C
Yield: 76.4 %

Procedure:
A mixture of 2-amino-6-chloropurine riboside (purchased from Aldrich Chemical Co., 80 mg, 0.26 mmol), 3-iodobenzylamine hydrochloride (71.5 mg, 0.265 mmol), and triethylamine (0.11 ml, 0.79 mmol) in ethanol (1.6 ml) was heated for 24 h at 80° C. After the reaction mixture was concentrated to dryness the residue was purified on a silica gel column chromatography (CHCl3 --MeOH, 20:1→10:1) to yield 2-amino-N6 -(3-iodobenzyl)-9-[β-D-ribofuranosyl]-adenine (99 mg, 75%) as a colorless solid: m.p. 152°-154° C.; 1H NMR (DMSO-d6) d 3.52 (m, 1H, H-5'a), 3.63 (m, 1H, H-5'b), 3.89 (m, 1H, H-4'), 4.10 (m, 1H, H-3'), 4.50 (m, 1H, H-2'), 4.60 (br s, 2H, CH2), 5.08 (d, J=4.6 Hz, 1H, exchangeable with D2O, 3'-OH), 5.35 (m, 2H, exchangeable with D2O, 5'- and 2'-OH), 5.73 (d, J=6.2 Hz, 1H, H-1'), 5.83 (br s, 2H, exchangeable with D2O, NH2), 7.11 (pseudo t, J=7.9 and 7.8 Hz, 1H, H-5"), 7.36 (d, J=7.8 Hz, 1H, H-4" or -6"), 7.58 (d, J=7.8 Hz, 1H, H-4" or -6"), 7.70 (s, 1H, H-2"), 7.94 (s, 1H, H-8).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:22]=[C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:20]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:19][C:13]=3[C:14]=2[C:15]([O:17]C)=[O:16])=[CH:6][CH:5]=1>CCO.C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]3[CH:22]=[C:21]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])[C:20]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:19][C:13]=3[C:14]=2[C:15]([OH:17])=[O:16])=[CH:8][CH:9]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(OC(C)C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)Oc1cc2c(C(=O)O)c(-c3ccc(F)cc3)oc2cc1NS(C)(=O)=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
Excess NaOH (10 mL, 1N aq) was added to a stirring solution of methyl 2-(4-fluorophenyl)-5-isopropoxy-6-(methylsulfonamido)benzofuran-3-carboxylate (3.0 g, 6.89 mmol) in EtOH (34 mL) and THF (34 mL). It was allowed to stir at 60° C. overnight. The mixture was then heated to 67° C. and allowed to stir for 4 more hours. The mixture was concentrated then diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the titled compound (2.7 g, 96%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.31-1.38 (m, 6H) 2.99 (s, 3H) 4.63-4.73 (m, 1H) 7.32-7.41 (m, 2H) 8.00-8.08 (m, 2H) 8.88 (s, 2H) 13.05 (s, 1H). LC-MS retention time: 1.03 min; m/z (MH−): 406. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.