Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:11]1[CH:15]=[C:14]([CH:16]2[O:21][C:20](=[O:22])[CH2:19][C:18](=[O:23])[CH2:17]2)[O:13][N:12]=1)([CH3:10])[CH3:9].[C:24](Cl)(=[O:28])[CH2:25][CH2:26][CH3:27]>C1COCC1>[C:24]([CH:19]1[C:18](=[O:23])[CH2:17][CH:16]([C:14]2[O:13][N:12]=[C:11]([CH:8]([CH3:10])[CH3:9])[CH:15]=2)[O:21][C:20]1=[O:22])(=[O:28])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC(=O)Cl
Reactant: CC(C)c1cc(C2CC(=O)CC(=O)O2)on1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)C1C(=O)CC(c2cc(C(C)C)no2)OC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.5 %

Procedure:
12.6 g of triethylamine was added to 27.9 g of 6-(3-isopropylisoxazol-5-yl)-tetrahydropyran-2,4-dione in 200 ml of THF. At 0° C., 13.3 g of butyryl chloride was dripped in and the mixture was stirred for one hour at 0° C. The mixture was evaporated, followed by partitioning between methylene chloride and water. The organic phase was worked up, i.e., extracted with water, 10% strength sodium carbonate solution and again with water, dried with sodium sulfate and evaporated again. The residue was dissolved in anhydrous methylene chloride and stirred for 48 hours with 1.3 g of 4-(N,N-dimethylamino)-pyridine. Removal of the solvent was followed by chromatography over silica gel with methylene chloride and methanol (98.5:1.5). The isolated compound was recrystallized from a small amount of cyclohexane. There was obtained 13 g of product.
Reaction SMILES: [Cl:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1>CCOCC>[Cl:1][C:2]([F:8])([F:9])[C:3](=[O:5])[CH2:21][C:20]([C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)=[O:22]
Reactant: CCOC(=O)C(F)(F)Cl
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CC(=O)C(F)(F)Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.4 %

Procedure:
38 g of ethyl chlorodifluoroacetate was added to 22.7 g of sodium methoxide and 300 ml of dry ether under cooling with ice. 31 g of p-chloroacetophenone was gradually added thereto under cooling with ice. The mixture was stirred at room temperature for 12 hours. The solvent was distilled off. 150 ml of 6N hydrochloric acid was added under cooling with ice, and extraction with ethyl acetate was carried out. The extract layer was washed with water, and the solvent was distilled off. The resulting crude product was purified by silica gel column chromatography (developing solvent: chloroform), and thereby 49.5 g of the desired product was obtained as a pale yellow viscous liquid. m.p. 50°-51° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[S:13]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)(=[O:16])(=[O:15])[NH2:14]>>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:21][C:20]2[CH:22]=[CH:23][C:17]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:18][CH:19]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CCCOc1ccc(C=O)cc1
Product: CCCOc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-propoxybenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a pale yellow powder (yield 84%)
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([Cl:12])=[C:9]([Cl:11])[CH:10]=1)=[O:5])C>C(O)C.O1CCCC1.[OH-].[Na+]>[Cl:11][C:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]=1[Cl:12]
Reactant: CCOC(=O)c1cc(Cl)c(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cc(Cl)c(Cl)s1
Temperature: 60 °C
Reaction time: 15 h
Yield: 39.4 %

Procedure:
5-Chloro-2-thiophenecarboxylic acid (6.50 g) was dissolved in N,N-dimethylformamide (30 ml), and ethyl iodide (3.2 ml) and potassium carbonate (5.52 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-chloro-2-thiophenecarboxylic acid ethyl ester (5.27 g). 5-Chloro-2-thiophenecarboxylic acid ethyl ester (2.23 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (1.4 ml) in acetonitrile (20 ml) was added dropwise. The mixture was stirred at room temperature for 48 hours, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography. The desired fractions were concentrated under reduced pressure to give 4,5-dichloro-2-thiophenecarboxylic acid ethyl ester (6.21 g). 4,5-Dichloro-2-thiophenecarboxylic acid ethyl ester (6.21 g) was dissolved in a mixture of ethanol (25 ml) and tetrahydrofuran (25 ml), and 1N aqueous sodium hydroxide (50 ml) was added. The mixture was stirred at 60° C. for 15 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4,5-dichloro-2-thiophenecarboxylic acid (2.14 g) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:27](O)[CH2:28][OH:29].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:7]=[CH:6][C:3]=1[CH:4]1[O:29][CH2:28][CH2:27][O:5]1
Reactant: OCCO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C=O)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C2OCCO2)c(F)c1
Temperature: 25 °C

Procedure:
2-Fluoro-4-(hexadecylamino)benzaldehyde (1.7 g.) is dissolved in toluene (20 ml), and ethylene glycol (2.5 ml.) and p-toluenesulfonic acid (10 mg.) are added. The reaction mixture is heated under reflux for 16 hours while water is removed using a Dean-Stark trap. The reaction mixture is then cooled to room temperature, diluted with toluene (70 ml.), washed with aqueous sodium bicarbonate and then with water. The organic layer is separated dried over mangnesium sulfate, decolorized with charcoal and filtered through anhydrous magnesium silicate. Removal of the solvent in vacuo gives a light yellow solid which is recrystallized from hexane to yield 2-[2-fluoro-4-(hexadecylamino)phenyl]-1,3-dioxolane.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:14])[C:5]2[N:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][C:6]=2[N:7]=1.P(Br)(Br)[Br:16]>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([NH2:14])[C:5]2[N:11]=[C:10]([CH2:12][Br:16])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N)c2nc(CO)ccc2n1
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: Nc1nc(N)c2nc(CBr)ccc2n1

Procedure:
A suspension of 0.72 g (3.77 mmol) of 6 in 12 mL dry THF was stirred for 8 hours with 1 mL of phosphorus tribromide. The precipitated solid was filtered, washed with cold 50% THF-Ether, and dried to give 7. Because of the instability, this compound was not purified further. The 1HNMR showed that the majority of the solid was the desired compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C@@H:17]([CH2:32][OH:33])[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=2)=[O:19])(=[O:15])=[O:14])=[CH:9][CH:8]=1>N1C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH:16][C@@H:17]([CH2:32][O:33][S:2]([CH3:1])(=[O:4])=[O:3])[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=2)=[O:19])(=[O:14])=[O:15])=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc(NC(=O)[C@H](CO)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NC(=O)[C@H](COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (hereinafter referred to as mesyl chloride) (96 μl) was added to a solution of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-hydroxypropanamide (132 mg) in pyridine (2.5 ml) and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into a saturated saline solution and extracted with ethyl acetate. The combined ethyl acetate layers were washed with saturated saline solution, 1N HCl, and a saturated saline solution, and dried over Na2SO4. Then, the solvent was evaporated under reduced pressure to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (133 mg).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].BrBr.[C:15]([NH2:18])(=[S:17])[CH3:16]>C(OCC)C.CCOC(C)=O>[CH3:16][C:15]1[S:17][C:7]2[CH2:6][CH2:5][CH2:4][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]=2[N:18]=1
Reactant: CC(N)=S
Reactant: CCOC(=O)C1CCCCC1=O
Agent: BrBr
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCCc2sc(C)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution of ethyl 2-oxocyclohexanecarboxylate (15 g, 88 mmol) in anhydrous diethyl ether (40 mL) cooled at 0° C. was added bromine (4.5 mL, 88 mmol) dropwise over 15 mins. After complete addition mixture allowed to warm to room temp over 90 min. Mixture diluted with EtOAc (100 mL) and washed with sat. NaHCO3, sat. NaCl, dried over MgSO4, filtered and evaporated. Residue taken up in ethanol (100 mL) and thioacetamide (6.6 g, 88 mmol) added. Mixture stirred at room temp for 1 h then at reflux overnight. Mixture evaporated and residue partitioned between sat. NaHCO3 and DCM. Organic layer dried over MgSO4, filtered and evaporated. Residue purified by MPLC (Biotage Horizon: FLASH 65i) eluent: 100% Hexanes (500 mL), gradient 0 to 25% EtOAc in Hexanes (1200 mL) then 25% EtOAc in Hexanes (1200 mL) to give the title compound (6.14 g, 31%) as a pale orange oil. 1HNMR (500 MHz, CDCl3) δ: 4.22 (q, J=7.1, 2H), 3.84 (t, J=5.5, 1H), 2.80 (m, 1H), 2.73 (m, 1H), 2.65 (s, 3H), 2.18 (m, 1H), 2.11-1.95 (m, 2H), 1.85 (m, 1H), 1.29 (t, J=7.1, 3H).
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[I:14]CI.N(OC(C)(C)C)=O>C(#N)C.CCOCC>[I:14][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(C(F)(F)F)ccc1N
Reactant: ICI
Agent: CC(C)(C)ON=O
Solvent: CCOCC
Solvent: CC#N
Product: N#Cc1cc(C(F)(F)F)ccc1I
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-5-(trifluoromethyl)benzonitrile (Intermediate 7, 15.1 g) and diiodomethane (24 mL) in acetonitrile (150 mL) at 35° C. was added t-butyl nitrite (21 mL) dropwise. The reaction was maintained at approximately 35° C. during the addition. The reaction was aged for 30 min and then heated to 60° C. for 30 minutes. The reaction mixture was cooled, diluted with ether and washed twice with water, twice with aqueous sodium bisulfite, water and then brine. The solution was dried over anhydrous MgSO4, filtered through a silica gel plug and then concentrated giving afford a red oil. The product was purified by silica gel chromatography eluting sequentially with hexanes, 3:1 hexanes/CH2Cl2 and 1:1 hexanes/CH2Cl2 to afford 2-iodo-5-(trifluoromethyl)benzonitrile. 1H NMR (CDCl3, 500 MHz) δ 8.10 (d, J=8.5 Hz, 1H), 7.85 (d, J=1.8 Hz, 1H), 7.52 (dd, J=8.5, 1.8 Hz, 1H).
Reaction SMILES: B(Br)(Br)Br.[C:5]([C:7]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[CH:9][C:8]=1[F:22])#[N:6].O>ClCCl>[C:5]([C:7]1[C:8]([F:22])=[CH:9][C:10]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[CH:11][C:12]=1[F:13])#[N:6]
Reactant: COc1ccc(-c2cc(F)c(C#N)c(F)c2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: N#Cc1c(F)cc(-c2ccc(O)cc2)cc1F
Temperature: 25 °C

Procedure:
A solution of boron tribromide (25.0 ml, 61.5 g, 0.25 mol) in dry dichloromethane (140 ml) was added dropwise to a stirred, cooled (-78° C.) solution of compound 8 (12.22 g, 0.05 mol) in dry dichloromethane (250 ml) under dry nitrogen. The stirred mixture was allowed to warm to room temperature over 9 h (i.e., until glc analysis revealed absence of starting material). The mixture was cooled to -10° C., water was added slowly (exothermic) and cooled to 2° C. The product was filtered off, washed with water and dried (CaCl2) in vacuo to give a pale-yellow powder.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[C:13]([O:17][C:18](=[O:29])[NH:19][C@H:20]([CH2:27]O)[CH2:21][C:22]([CH3:26])([CH3:25])[CH:23]=[CH2:24])([CH3:16])([CH3:15])[CH3:14].[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:13]([O:17][C:18](=[O:29])[NH:19][C@H:20]([CH2:27][N:34]1[C:30](=[O:40])[C:31]2[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:33]1=[O:35])[CH2:21][C:22]([CH3:26])([CH3:25])[CH:23]=[CH2:24])([CH3:16])([CH3:15])[CH3:14]
Reactant: C=CC(C)(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC(C)(C)C[C@@H](CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DEAD (0.63 ml, 4 mmol) is added to a suspension of ((S)-1-Hydroxymethyl-3,3-dimethyl-pent-4-enyl)-carbamic acid tert-butyl ester (1 g, 4 mmol), phthalimide (588 mg, 4 mmol) and PS-triphenylphosphine (3.72 g, 8 mmol) in THF (50 ml) and the resulting solution is stirred at room temperature overnight. The resin is removed by filtration, and the filtrate concentrated in vacuo. Purification by flash chromatography (SiO2, EtOAc/iso-hexane) yields [(S)-1-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3,3-dimethyl-pent-4-enyl]-carbamic acid tert-butyl ester as a white solid; [M+H−BOC]+ 273.
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][OH:25].[CH2:26](Br)[CH:27]=[CH2:28]>O>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH:27]=[CH2:28]
Reactant: C=CCBr
Reactant: COCCOCCOCCOCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOCCOCCOCCOCCOC
Temperature: 0 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
An oven-dried 100 mL round bottom flask was charged with t-BuOK (13 mmol), dry THF (30 mL), purged with argon and cooled to 0° C. in an ice bath. Tetraethyleneglycol monomethyl ether (10 mmol) was then added dropwise to the solution and the reaction stirred at 0° C. for 1 h under argon. Allyl bromide (13 mmol) was added dropwise, and the solution was warmed to R.T. and allowed to stir for 24 h under argon. Deionized water (2 mL) was then added and the reaction stirred for 10 min. All liquid were then removed in vacuo and the residue redissolved in ethyl acetate (50 mL). The organic was washed three times with water (20 mL), dried over Na2SO4, filtered over Celite and then concentrated in vacuo to yield clear/light yellow oil (47%). 1HNMR (400 MHz, CDCl3): δ=5.90 (m, 1H), 5.23 (dd, 1H, 3JHHtrans=17.3 Hz, 2JHHgem=1.7 Hz), 5.15 (dd, 1H, 3JHH=10.4 Hz, 2JHHgem=1.5 Hz), 4.00 (dd, 2H, 3JHH=5.89 Hz, 4JHH=1.5 Hz), 3.65 (m, 12H), 3.59 (m, 2H), 3.53 (m, 2H), 3.36 (s 3H) ppm. 13CNMR (400 MHz, CDCl3): δ=134.8, 117.0, 72.2, 71.9, 70.6, 70.6, 70.6, 70.5, 69.4, 59.0 ppm. HRMS-ESI: Calculated [M+Na]+: 271.1516. found: 271.1516.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:17]=[C:14]([CH:15]=[O:16])[C:13]([OH:18])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:18][C:13]1[CH:12]=[CH:11][C:10]([Br:9])=[CH:17][C:14]=1[CH:15]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
A mixture of benzyl bromide (2.04 g, 11.926 mmol), 5-bromosalicylaldehyde (1.844 g, 9.174 mmol), potassium carbonate (5.07 g, 36.696 mmol) and dimethylformamide (15 ml) was stirred at 50° C. for 2 hours under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was washed with methanol to give the title compound (1.2 g, 44.9%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)[N:4]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[N:4]=1
Reactant: COc1cc(OC)nc(Cc2ccccc2[N+](=O)[O-])n1
Solvent: CCO
Product: COc1cc(OC)nc(Cc2ccccc2N)n1
Temperature: 0 °C
Yield: 83.7 %

Procedure:
The product of stage (i) (32.6 g) was added to a stirred suspension of stannous chloride dihydrate (133 g) in ethanol (300 ml). After refluxing for 2 hours, the solution was poured into ice-water (2500 ml) and extracted with ethyl acetate (3×500 ml). The combined extracts were washed with saturated sodium chloride solution, dried and evaporated to give 24.3 g of the desired product as a brown solid, mp 82°-84° C.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH2:19][N:18]([CH:23]2[CH2:25][CH2:24]2)[CH2:17][C:16]3([CH3:27])[CH3:26])=[CH:7][CH:6]=1.CO.O.[OH-].[Li+]>O>[CH:23]1([N:18]2[CH2:17][C:16]([CH3:26])([CH3:27])[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:12]#[C:11][C:8]4[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:28])=[O:2])=[CH:10][CH:9]=4)[CH:14]=3)[CH2:19]2)[CH2:24][CH2:25]1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CN(C2CC2)C3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CN(C2CC2)Cc2ccc(C#Cc3ccc(CC(=O)O)cc3)cc21

Procedure:
Following general procedure J and using [4-(2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6ylethynyl)-phenyl]-acetic acid methyl ester (Compound 23, 0.01 g, 0.027 mmol), methanol (1 mL), tetrahydrofiuran (1 mL), water (0.5 mL) and lithium hydroxide monohydrate (0.042 g, 1 mmol) the title compound was obtained as a pale yellow solid foam (0.0065 g, 68%).
Reaction SMILES: O1CCCC1.[C:6]([C:8]1([OH:23])[C:19]([CH3:21])([CH3:20])[CH2:18][C:11]2([O:15][CH:14]([CH3:16])[CH:13]([CH3:17])[O:12]2)[CH:10]=[C:9]1[CH3:22])#[CH:7].[CH2:24]([SnH:28]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]>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>[CH3:16][CH:14]1[CH:13]([CH3:17])[O:12][C:11]2([CH2:18][C:19]([CH3:21])([CH3:20])[C:8](/[CH:6]=[CH:7]/[Sn:28]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:24][CH2:25][CH2:26][CH3:27])([OH:23])[C:9]([CH3:22])=[CH:10]2)[O:15]1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CC1(O)C(C)=CC2(CC1(C)C)OC(C)C(C)O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](/C=C/C1(O)C(C)=CC2(CC1(C)C)OC(C)C(C)O2)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.4 %

Procedure:
Under argon, tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.20 mmol) was initially charged in a round-bottom flask that had been dried by heating, and abs. tetrahydrofuran (25 ml) and 8-ethynyl-2,3,7,9,9-pentamethyl-1,4-dioxaspiro[4.5]dec-6-en-8-ol (1.0 g, 3.99 mmol) were added. Stirring at room temperature for 5 minutes was followed by the addition of tributyltin hydride (1.29 ml, 4.79 mmol). The resulting reaction mixture was stirred at room temperature for 1 h and then water was added. The aqueous phase was repeatedly extracted thoroughly with dichloromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. By final column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), it was possible to obtain 2,3,7,9,9-pentamethyl-8-[(E)-2-(tributylstannyl)vinyl]-1,4-dioxaspiro[4.5]dec-6-en-8-ol (1.50 g, 66% of theory) in the form of a colorless oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.13 (d, 1H), 5.93 (d, 1H), 5.42 (s, 1H), 4.22/3.63 (m, 2H), 1.61 (s, 3H), 1.59 (d, 1H), 1.52 (d, 1H), 1.49 (m, 6H), 1.32-1.24 (m, 12H), 1.09 (s, 3H), 0.89 (m, 18H).
Reaction SMILES: [C:1]([N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3Cl)[C@H:11](O)[C@@H:10]1O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[C:43]1([CH:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:50][NH2:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C1COCC1>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([N:8]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[CH:10]=[CH:11]2)=[C:19]([NH:51][CH2:50][CH:49]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
(1S,2R,3S,5R)-3-(Di-Boc-amino)-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol (13.0 g, 27.66 mmol) is dissolved in THF (250 mL) under an atmosphere of argon. DIPEA (4.28 g, 33.19 mmol) is added followed by 2,2-diphenylethylamine (6.0 g, 30.43 mmol) and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 18 hours. The solvent is removed in vacuo and the reaction mixture is partitioned between DCM (250 mL) and 0.1 M HCl (250 mL). The organic layer is washed with water (200 mL) and brine (200 mL), dried over MgSO4, filtered and the solvent is removed in vacuo to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH:12]1C=CC=CC=1>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])=[CH:9][N:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: c1ccccc1
Reactant: O=C(O)c1cc(Br)ncc1F
Solvent: CO
Product: COC(=O)c1cc(Br)ncc1F
Yield: 88.4 %

Procedure:
To a cooled solution of 2-bromo-5-fluoroisonicotinic acid (3.0 g, 13.6 mmol) in benzene (20 ml) and methanol (10 ml) is dropwise over a period of 15 min added under stirring and cooling (trimethylsiliyl)diazomethane (2 M in ether, 14 ml, 28 mmol). The yellow solution is stirred for 1.5 h without cooling and evaporated to dryness. Purification of the residue (3.3 g) by chromatography on a 50 g Silicycle silica cartridge using a heptane/ethyl acetate 10-50% gradient affords methyl 2-bromo-5-fluoroisonicotinate (2.82 g, 88.4%) as a light yellow solid. mp.: 43-6° C. MS: m/z=233.9 (M+H+).