Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].C(N)CN>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O.C(OCC)C>[Si:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]ccc12
Reactant: O=C(Cl)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: NCCN
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2c1ccn2C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 100 %

Procedure:
A stirred, ice-cold mixture of 9 (18.56 g, 75 mmol), tetrabutylammonium bromide (2.42 g, 7.5 mmol) and powdered sodium hydroxide (4.0 g, 75 mmol) in dichloromethane (375 mL) was treated dropwise with benzyl chloroformate (95% purity; 20.20 g, 112.5 mmol). The reaction mixture was stirred at room temperature and the progress of the reaction was followed by TLC [ethyl acetate-hexanes (1:9)]. Further aliquots of benzyl chloroformate (each 20.20 g) were added after 1 h and 2 h, and the mixture was stirred at room temperature for a total of 18 h, diluted with water and extracted with dichloromethane. The combined organic phases were washed with brine, dried and evaporated. The residual oil was dissolved in dry diethyl ether (250 mL), cooled in ice and treated dropwise with a solution of ethylenediamine (47 mL, 355 mmol) in dry diethyl ether (150 mL) and stirred at room temperature for 0.5 h. The mixture was washed with 0.5 M aq. hydrochloric acid and brine and the organic phase was dried and evaporated. After trituration with diethyl ether and cooling in ice, some precipitated N,N-di-(benzyloxycarbonyl)ethylenediamine was removed by filtration and 10 was isolated as a pale oil (28.62 g, 100%) which was used in the next step without further purification; 1H NMR (90 MHz) δ 7.78 (d, J=7.2 Hz, 1H), 7.00-7.56 (m, 7H), 6.58-6.72 (m, 2H), 5.42 (s, 2H), 1.03 (s, 9H), 0.22 (s, 6H).
Reaction SMILES: [C:1]1([N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH3:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1.O>CS(C)=O>[C:27]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([CH2:11][C:14]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=5)[CH2:35][C:36]5[CH:43]=[CH:42][C:39]([CH3:40])=[CH:38][CH:37]=5)[N:21]=4)=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: Nc1nccc(-c2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(CN(Cc2ccc(C)cc2)c2nccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)cc3)n2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 175.3 %

Procedure:
4-(4′-Diphenylaminobiphenyl-4-yl)pyrimidine-2-amine (100 mg, 0.24 mmol) and sodium hydroxide (38 mg, 0.96 mmol) were added in dimethylsulfoxide (1 mL), and stirred at 100° C. for 30 minutes. This solution was added with a solution of 4-methylbenzyl bromide (71.6 μL, 0.53 mmol) in dimethylsulfoxide (1 mL) at 100° C. for 30 minutes, and stirred for 5 hours. This solution was cooled and added with water (100 mL) and a saturated saline solution, and allowed to stand for 24 hours. The precipitated crystalline material was purified by column chromatogram (silica gel, hexane:EtOAc=8:1) to obtain the title compound (131 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15]2[O:17][CH2:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]([NH2:30])([CH3:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>>[OH:17][CH:15]([CH2:14][O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:16][NH:30][C:19]([CH3:29])([CH3:18])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: c1ccc(CCCCCCOCC2CO2)cc1
Product: COc1ccc(CC(C)(C)NCC(O)COCCCCCCc2ccccc2)cc1

Procedure:
Using the method of Example 9, supra, 6-phenylhexylglycidyl ether (337 mg, 1.44 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (180 mg, 1 mmol) were used to prepare the title compound. Preparative TLC (20 cm×20 cm×2 mm silica, eluted with 1% MeOH/CHCl3) was used to purify the material and yielded 275 mg of free base: GC/El-MS, m/z (rel. int.) 398 (M+ -15,0.1), 293 (21), 292 (100), 163 (10), 121 (19), 114 (9), 91 (5), 90 (45), 71 (13), 70 (14), 58 (9).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]#[C:21][C:22]3[CH:23]=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=3)=[C:18]([CH2:29][CH3:30])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl>[NH2:28][C:25]1[N:24]=[CH:23][C:22]([C:21]#[C:20][C:19]2[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=[N:17][C:18]=2[CH2:29][CH3:30])=[CH:27][CH:26]=1
Reactant: CCc1ncnc(N2CCN(C(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Agent: Cl
Product: CCc1ncnc(N2CCNCC2)c1C#Cc1ccc(N)nc1

Procedure:
A solution of 7.2 g (17.7 mmol) 4-[5-(6-Amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester in 50 mL 4 M HCl (in dioxane) ist stirred for 3 hours at room temperature. The reaction mixture is evaporated and the residue is taken up in 50 ml DCM and washed with saturated aqueous NaHCO3 solution. After phase separation the organic solvent is removed under reduced pressure. The residue is taken up in methanol dried over Na2SO4. After 15 hours the suspension is filtered off, the residue is washed with methanol and the solvent is removed under reduced pressure. After drying 5.5 g (100%) of crude product are obtained, which are used without further purification in the next step.
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:14]=[C:15]([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[CH:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[CH:24]=[CH:23]5)[CH:16]=[CH:17][C:18]=3[OH:19])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.Br[CH:35]([OH:38])[CH2:36][CH3:37].Cl>CN(C=O)C.O>[C:3]12([C:13]3[CH:14]=[C:15]([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[CH:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[CH:24]=[CH:23]5)[CH:16]=[CH:17][C:18]=3[O:19][CH2:37][CH2:36][CH2:35][OH:38])[CH2:10][CH:9]3[CH2:11][CH:5]([CH2:6][CH:7]([CH2:8]3)[CH2:12]1)[CH2:4]2
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Reactant: CCC(O)Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(-c3ccc(OCCCO)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Reaction time: 0.5 h

Procedure:
77 mg (2.55 retool) of 80% sodium hydride in oil are added to 1 g (2.42 mmol) of methyl 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoate in solution in 10 ml of DMF. After 1 h 30 min of stirring, 230 ml (2.42 mmol) of bromopropanol are added to this reaction medium which is left stirring for 12 hours at room temperature, under nitrogen. The reaction medium is poured into water, acidified to pH=1 with concentrated HCl and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate, filtered and evaporated. The residue is chromatographed on silica in dichloromethane, and crystallized from the dichloromethane/hexane mixture to give 600 mg (53%) of the expected derivative which melts at 201.9° C.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][C@H:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])[CH2:18]2)[C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>CCCCCCC>[CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][C@H:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=4)[O:28][C:29]=3[CH3:30])[CH2:18]2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(-c2nc(CO[C@H]3CCC[C@@H](OCc4cccc(C)c4C(=O)OC(C)(C)C)C3)c(C)o2)cc1
Solvent: CCCCCCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2nc(CO[C@H]3CCC[C@@H](OCc4cccc(C)c4C(=O)O)C3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
from tert-butyl methyl-6-[(1R,3S)-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)-cyclohexyloxymethyl]benzoate: 200 g (396 mmol) of tert-butyl methyl-6-[(1R,3S)-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]benzoate are dissolved in n-heptane. 300 g (2.6 mol) of trifluoroacetic acid are added. The reaction is stirred at RT for 24 hours and subsequently concentrated fully by evaporation. The residue is taken up in 1.0 l of diisopropyl ether and washed four time with 500 ml each time of water. Subsequently, 1.0 l of water is added and a basic pH is established by addition of sodium hydroxide solution (4 M). After phase separation, the aqueous phase is washed twice with 400 ml each time of diisopropyl ether. After addition of 1.6 l of diisopropyl ether, the mixture is acidified with hydrochloric acid (2 M). After phase separation, the organic phase is washed four times with 500 ml each time of water and subsequently concentrated to about a third of the volume. 2-methyl-6-[(1R,3S)-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]benzoic acid precipitates out as a crystalline solid and is filtered off. After drying under reduced pressure, 2-methyl-6-[(1R,3S)-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]benzoic acid is obtained in 66% yield.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[C:20](=O)[CH:19]([C:22](OC)=[O:23])[CH2:18][O:17][CH2:16][CH:15]1[CH3:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]1[CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][O:17][CH2:16][CH:15]1[CH3:26])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)C1COCC(C)N(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1COCC(CO)CN1Cc1ccccc1
Temperature: 23 °C
Reaction time: 60 h

Procedure:
A solution of LAH in THF (2.0 M, 3.25 mL, 6.49 mmol, 3.00 equiv) was added to a solution of methyl 4-benzyl-3-methyl-5-oxo-1,4-oxazepane-6-carboxylate (4-4, diastereomeric mixture, 600 mg, 2.16 mmol, 1 equiv) in THF (30 mL) at −78° C. and the resulting mixture was warmed to 23° C. and stirred for 60 h. Additional LAH solution (2.0 M, 3.25 mL, 6.49 mmol, 3.00 equiv) was added and the mixture was heated at 60° C. for 4 h. The mixture was cooled to 0° C. and excess LAH was quenched with 100 uL of H2O, followed by 100 uL of 15% aqueous sodium hydroxide solution, and lastly 300 uL of H2O. The mixture was diluted with EtOAc (100 mL) and filtered. The filtrate was concentrated and the residue purified by reverse phase liquid chromatography (H2O/CH3CN gradient w/0.1% TFA present) to afford (4-benzyl-3-methyl-1,4-oxazepan-6-yl)methanol (4-5) as a mixture of diastereomers (TFA salts). 1H NMR (300 MHz, CD3OD) δ 7.62-7.45 (m, 5H), 4.70-4.30 (br m, 2H), 4.10-3.75 (br m, 3H), 3.65-3.30 (br m, 6 H), 2.45 (m, 1H), 1.45 (d, 3H,J=7.3 Hz). LRMS m/z (M+H) 236.3 found, 236.2 required. The TFA salts were free based by elution through an ion exchange column (Strata™ X-C, water loading, washing with CH3OH followed by elution of free base with 5% NH4OH in methanol).
Reaction SMILES: CC(C)CN[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].[C:17](=[S:19])=[S:18].C(O)C>[OH-].[Na+]>[S:18]1[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=[C:17]1[SH:19]
Reactant: S=C=S
Reactant: CC(C)CNc1c(N)cnc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Sc1nc2cnc3ccccc3c2s1

Procedure:
N4-(2-methylpropyl)quinoline-3,4-diamine (5.4 g, 25 mmol) was combined with carbon disulfide (9 mL, 150 mmol) and ethanol (55 mL) and then heated at reflux on a steam bath for 2 hours. The resulting precipitate was isolated by filtration, washed with ethanol and then air dried to provide 4.4 g of crude product. A portion (1 g) was dissolved in hot dilute sodium hydroxide and then reprecipitated with acetic acid. The precipitate was isolated by filtration while still hot, washed with hexane and then air dried to provide thiazolo[4,5-c]quinoline-2-thiol as a solid, m.p. 282-284° C. Analysis: Calculated for C10H6N2S2: % C, 55.02; % H, 2.77; % N, 12.83: Found: % C, 54.96; % H, 2.69; % N, 12.74.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1Nc1ccc(Cl)nc1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-amino-6-chloropyridine gave 2-chloro-N4-(6-chloropyridin-3-yl)-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.53 (d, 1H, J=3 Hz), 8.25 (dd, 1H, J=3 and 9 Hz), 8.15 (d, 1H, J=2.4 Hz), 7.39 (d, 1H, J=. 8.7 Hz), 7.00 (bs, 1H); LCMS: purity: 98%; MS (m/e): 259 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([C:14](O)=[O:15])=[C:12]([CH3:17])[O:11][N:10]=1.S(Cl)(Cl)=O.[CH3:22][NH:23][CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([C:14]([N:23]([CH3:24])[CH3:22])=[O:15])=[C:12]([CH3:17])[O:11][N:10]=1
Reactant: CNC
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)O
Solvent: O=S(Cl)Cl
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)N(C)C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
To 3-(2,6-dichlorophenyl)-5-methylisoxazol-4-carboxylic acid (25 mg, 0.10 mmol) was added thionyl chloride (1 mL) and the neat solution allowed to stir 60° C. After 30 min, excess thionyl chloride was evaporated and dimethyl amine (40 μL, 0.08 mmol, 2M in tetrahydrofuran) was added and allowed to stir overnight at ambient temperature. The residue was purified using reversed phase HPLC to afford the title compound (10 mg). HRMS (ESI, pos. ion) m/z calcd for C13H12Cl2N2O2: 298.0276, found 298.0276.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][O:13][CH3:14])=[C:6]([N:8]([CH3:10])[CH3:9])[CH:7]=1.[Li]CCCC.[CH3:20][C:21]1[CH:28]=[C:27]([O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH:26]=[C:25]([CH3:40])[C:22]=1[CH:23]=[O:24]>C1COCC1>[CH3:9][N:8]([CH3:10])[C:6]1[CH:7]=[C:2]([CH:23]([C:22]2[C:25]([CH3:40])=[CH:26][C:27]([O:29][Si:30]([CH:31]([CH3:33])[CH3:32])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])=[CH:28][C:21]=2[CH3:20])[OH:24])[CH:3]=[CH:4][C:5]=1[O:11][CH2:12][O:13][CH3:14]
Reactant: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C)c1C=O
Reactant: COCOc1ccc(Br)cc1N(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1ccc(C(O)c2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1N(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a stirring solution of N-(5-bromo-2-methoxymethoxy-phenyl)dimethylamine (3.4 g, 13.07 mmol) in THF (80 mL) at −78° C. was added n-BuLi (5.22 mL, 2.5 M in hexanes). The mixture was stirred at −78° C. for 1 hr and a solution of 2,6-dimethyl-4-triisopropylsilanyloxy-benzaldehyde (3.6 g, 11.77 mmol) was added. The reaction mixture was stirred at −78° C. for 1 hr, allowed to warm to room temperature and stirred for 1 hr. The reaction mixture was quenched with saturated NH4Cl and diluted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (30:70) to afford (3-dimethylamino-4-methoxymethoxy-phenyl)-(2,6-dimethyl-4-triisopropylsilanyloxyphenyl)methanol as a yellow oil (4 g, 63%): 1H NMR (300 MHz, DMSO-d6): δ 6.89 (d, J=8.4 Hz, 1 H), 6.79 (s, 1 H), 6.61 (m, 1 H), 6.51 (s, 2 H), 6.01 (d, J=4.0 Hz, 1 H), 5.65 (d, J=4.0 Hz, 1 H), 5.14 (s, 2 H), 3.41 (s, 3 H), 2.64 (s, 6 H), 2.17 (s, 6 H), 1.24 (m, 3 H), 1.08 (d, J=7.2 Hz, 18 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=25% ethyl acetate in hexanes; Rf=0.27.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[C@H:9]([OH:12])[CH2:10][OH:11].C(#N)CC.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:19]=[CH:18]/[C:17]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][C:3]=1[C@H:9]([OH:12])[CH2:10][OH:11]
Reactant: OC[C@@H](O)c1cc(I)ccc1Cl
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc(Cl)c([C@H](O)CO)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
(1S)-1-(2-chloro-5-iodophenyl)ethane-1,2-diol (2.60 g, 8.71 mmol), propionitrile (87 mL), ethyl acrylate (1.24 mL, 11.32 mmol), and triethylamine (3.6 mL, 26.13 mmol) were combined and N2 was flushed through the solution for 10 minutes. Then Pd(OAc)2 (587 mg, 0.871 mmol) and P(O-tol)3 (1.06 g, 3.48 mmol) were added and the solution was heated to 80° C. After 16 h, the solution was cooled to rt and then EtOAc was added. The solution was washed with 1N HCl (2×), brine, dried, concentrated, and purified by Biotage chromatography (0%-100% EtOAc/hexanes) to afford 1.90 g of product as an oil (81%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.79 (d, J=1.77 Hz, 1 H) 7.65 (d, J=16.17 Hz, 1 H) 7.34-7.40 (m, 2 H) 6.45 (d, J=15.92 Hz, 1 H) 5.24 (ddd, J=7.39, 2.84, 2.65 Hz, 1 H) 4.27 (q, J=7.24 Hz, 2 H) 3.89-3.97 (m, 1 H) 3.57 (ddd, J=11.49, 7.45, 4.55 Hz, 1 H) 2.87 (d, J=3.28 Hz, 1 H) 2.18 (t, J=5.81 Hz, 1 H) 2.05 (s, 3 H) 1.34 (t, J=7.20 Hz, 2 H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:11]([Br:12])=[N:10][N:9]=[N:8]1)(=O)C.Cl>>[Br:12][C:11]1[N:7]([CH2:6][CH2:5][OH:4])[N:8]=[N:9][N:10]=1
Reactant: CC(=O)OCCn1nnnc1Br
Agent: Cl
Product: OCCn1nnnc1Br

Procedure:
5-Bromo-1H-tetrazole-1-ethanol acetate (ester) (40 g) and 2N hydrochloric acid (216 ml) were stirred at room temperature for 22 h.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[NH2:13][C:14]1[C:15](=[O:28])[N:16]([CH2:25][CH2:26][CH3:27])[C:17](=[O:24])[N:18]([CH2:21][CH2:22][CH3:23])[C:19]=1[NH2:20].CCOC(/N=N/C(OCC)=O)=O>C(O)C.C(O)(=O)C>[CH2:25]([N:16]1[C:15](=[O:28])[C:14]2[NH:13][C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)=[N:20][C:19]=2[N:18]([CH2:21][CH2:22][CH3:23])[C:17]1=[O:24])[CH2:26][CH3:27]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CCO
Solvent: CC(=O)O
Product: CCCn1c(=O)c2[nH]c(-c3ccc4c(c3)OCCO4)nc2n(CCC)c1=O
Temperature: 60 °C
Yield: 92.2 %

Procedure:
2.18 g (0.013 mol) of 1,4-benzodioxan-6-aldehyde, 80 ml of ethanol and 2.4 ml of glacial acetic acid are mixed together and 2.8 g (0.012 mol) of 5,6-diamino-1,3-dipropyluracil are added thereto. The clear solution is refluxed for 21/4 hours and then cooled to 60° C. At this temperature, 2.1 ml (0.013 mol) of diethylazodicarboxylate are added dropwise and the viscous suspension produced is mixed with 80 ml of ethanol and refluxed for 2 hours. After a further 20 hours at ambient temperature the mixture is cooled to 5° C., the solid matter is filtered under suction and washed with ethanol and ether. 4.1 g of the title compound are obtained in the form of a grey solid (=92% of theory), melting point 280°-282° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:9])[CH:7]=[CH2:8])=[N:2]1.[ClH:10]>CCOCC>[Cl:10][CH2:8][CH2:7][C:6]([C:3]1[CH:4]=[CH:5][O:1][N:2]=1)=[O:9]
Reactant: C=CC(=O)c1ccon1
Reactant: Cl
Solvent: CCOCC
Product: O=C(CCCl)c1ccon1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The product of step (b) was treated with 1M HCl in ether (5 ml) and stirred for 4 h at ambient temperature. The solvent was then removed under reduced pressure to leave the product as a dark gum (0.42 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C)C=O>[Br:8][C:7]1[C:2]([NH:1][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:3][CH:4]=[C:5]([Br:9])[N:6]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ncc(Br)nc1Br
Temperature: 2.5 °C
Reaction time: 18 h
Yield: 47.3 %

Procedure:
A 2000 mL 3-necked round bottomed flask was charged with 2-amino-3,5-dibromopyrazine (172 g, 680 mmol) in dimethylformamide (860 mL) and cooled to 0-5° C. Cesium carbonate (288 g, 884 mmol) was added in one portion followed by the portion-wise addition of ethyl chloroacetate (87 mL, 816 mmol). The solution was allowed to warm to 20-25° C. then heated to 55° C. (exotherm observed, max temperature observed 76° C.). Once the internal reaction temperature subsided to 65° C. the reaction was heated at 65° C. for ˜4 h. The reaction was cooled to 20-25° C. and filtered through filter paper to remove inorganic salts and the solid was washed with dimethylformamide (3 vol). The filtrate was added dropwise to 16 vol of ice-water (8 vol ice/8 vol water) and the slurry was allowed to agitate for 12-24 h. The resulting brown solid was isolated following filtration and washed with water (10 vol) and air-dried. Crude product was dissolved in methyl t-butyl ether (3.46 L, 15 vol). Charcoal (C-906 from Ecosorb, 20 wt %, 46.1 g) was added and the mixture was heated at reflux for 1 h. After cooling to rt, the charcoal was removed over a Celite bed and the filtrate was concentrated to dryness. The crude was dissolved in ethyl acetate (576 mL, 2.5 vol) and concentrated to a thick slurry. A solution of 2% ethyl acetate in heptane (1.15 L, 5 vol) was added and the mixture was stirred at rt for 30-60 min. The product was collected by filtration, washed with heptane (2-3 vol) and dried under high vacuum at 35-40° C. for 16 h to afford the desired compound as an off-white solid (109 g, 47% yield). A second crop was isolated from the mother liquor as follows: the filtrate was concentrated to give a crude oil. Ethyl acetate (1 vol.) was added. The resulting solution was seeded with previously isolated product and cooled at 0-5° C. for 1 h. The resulting solid was collected by filtration and washed with cold ethyl acetate:heptane (1:1 mixture, <1 vol). The solid was dried as described previously and combined with the first crop to provide the title compound (132 g, 57% total yield). MS (ESI) m/z 337.8 [M−1]+, 339.8 [M+1]+, 341.8 [M+3]+.