Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:20])[N:4]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH:5]=[C:6]([CH3:11])[C:7]=1[C:8]([OH:10])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52](=[O:59])[NH:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl>[CH3:57][C:56]1[CH:55]=[C:54]([CH3:58])[NH:53][C:52](=[O:59])[C:51]=1[CH2:50][NH:49][C:8]([C:7]1[C:6]([CH3:11])=[CH:5][N:4]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:3](=[O:20])[C:2]=1[CH3:1])=[O:10]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1cn(C(C)c2ccccc2)c(=O)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2c(C)cn(C(C)c3ccccc3)c(=O)c2C)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 7.1 %

Procedure:
To a solution of 3,5-dimethyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylic acid (0.07 g, 0.26 mmol) in dichloromethane (10 mL) was added EDCI (0.06 g, 0.39 mmol), HOBt (0.05 g, 0.38 mmol) and triethylamine (0.078 g, 0.77 mmol). After stirred for 30 min, 3-(aminomethyl)-4,6-dimethyl pyridin-2(1H)-one (0.058 g, 0.39 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The solution was concentrated under vacuum. The residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The extractions were combined, washed with H2O, dried over Na2SO4, and concentrated under vacuum. The residue was purified by prep. HPLC (Condition: Column: YMC C18 150*30 mm*5 um; Mobile phase A: water with 0.05% ammonia solution Mobile phase B: MeCN; column temperature: 30° C.; Gradient: A/B, 35-65%) to give N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,5-dimethyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxamide as yellow solid. (7.5 mg, yield 7.1%)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]([CH3:23])[CH2:14][CH2:15][CH2:16][N:17]([CH2:21][CH3:22])[CH2:18][CH2:19][OH:20])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:24](Cl)(=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]/[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].CO>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]([CH3:23])[CH2:14][CH2:15][CH2:16][N:17]([CH2:21][CH3:22])[CH2:18][CH2:19][O:20][C:24](=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]/[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCCCCCCC/C=C/CCCCCCCC(=O)Cl
Reactant: CCN(CCO)CCCC(C)Nc1ccnc2cc(Cl)ccc12
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCC/C=C/CCCCCCCC(=O)OCCN(CC)CCCC(C)Nc1ccnc2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.9 %

Procedure:
To a solution of 7-chloro-4-[4-[ethyl(2-hydroxyethyl)amino]1-methylbutylamino]-quinoline (hydroxychloroquine) (3.17 g, 9.4 mmol) in 30 ml dichloromethane was added elaidic acid chloride (2.82 g, 9.4 mmol) and the reaction mixturewas stirred at ambient temperature for 48 hours. A small amount of methanol was added, and the solvents were evaporated at high vacuum. The residue was repeatedly purified on a column of silica gel (first run: chloroform/methanol 9:1, second run: chloroform/methanol 95:5). Homogenous fractions were evaporated to give 1.18 g (21%) of the title compound.
Reaction SMILES: [OH-].[CH2:2]([N+:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].C([O:21][Si:22]([O:29]CC)([O:26]CC)[O:23]CC)C>O>[Si:22]([O-:29])([O-:26])([O-:23])[O-:21].[CH2:15]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18].[CH2:15]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18].[CH2:15]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18].[CH2:15]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: CCO[Si](OCC)(OCC)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Product: [O-][Si]([O-])([O-])[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
About 490 g (500 ml) of 40 percent aqueous tetra-n-butylammonium hydroxide solution (Fluka, D-7910 Neu-Ulm) were diluted with 700 ml of water, and 223.2 g (238.7 ml=1.07 mol of Si) of tetraethoxysilane were slowly added. The mixture was then stirred at room temperature for 24 hours. Thereafter, it was concentrated by distillation to 64.9 percent of the original total amount and the solution was crystallized at 4° C.
Reaction SMILES: O.O.C(O)(=O)C(O)=O.C[O:10][CH:11]=[C:12]1[CH2:15][CH:14]([C:16]([OH:19])([CH3:18])[CH3:17])[CH2:13]1.C([O-])(O)=O.[Na+]>C1COCC1.O>[OH:19][C:16]([CH:14]1[CH2:15][CH:12]([CH:11]=[O:10])[CH2:13]1)([CH3:18])[CH3:17]
Reactant: COC=C1CC(C(C)(C)O)C1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)C1CC(C=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalic acid dihydrate (68 g, 0.54 mol) was added to a solution of 2-[3-(methoxymethylidene)cyclobutyl]propan-2-ol (70 g, 0.45 mol) in THF:H2O (1:1, 700 mL) at 0° C. and stirred at ambient temperature for 1 hour. Then, 10% aqueous NaHCO3 solution was added to the reaction mixture and extracted with EtOAc (500 mL×4). The combined organic layer was then washed with water (200 mL×2), brine (200 mL) dried over anhydrous Na2SO4 and concentrated in vacuo to afford the title compound as a pale yellow liquid (mixture of cis and trans isomers). 1H NMR (400 MHz, CDCl3, mixture of cis and trans): δ 1.09-1.11 (2 s, 6H), 2.07-2.26 (m, 4H), 2.31-2.39 (m, 1H), 2.95-2.99 (m, 1H), 9.75 & 9.84 (2 s, 1H). 13C NMR (100 MHz, CDCl3, mixture of cis and trans): δ 21.8, 26.1, 39.4, 40.7, 41.8, 70.3, 202.6. 1H NMR (400 MHz, DMSO-d6, mixture of cis and trans): δ 0.96 (s, 3H), 0.98 (s, 3H), 1.88-2.29 (m, 5H), 2.87-2.92 (m, 1H), 4.13 & 4.21 (2 s, 1H), 9.56 & 9.74 (2 s, 1H). 13C NMR (100 MHz, DMSO-d6, mixture of cis and trans): 22.1, 22.7, 26.8, 40.9, 41.9, 42.4, 68.8, 69.1, 203.8, 204.1. 1H NMR (400 MHz, DMSO-d6-D2O exchange, mixture of cis and trans): δ 0.94 (s, 3H), 0.96 (s, 3H), 1.85-2.22 (m, 5H), 2.86-2.90 (m, 1H), 9.53 & 9.71 (2 s, 1H).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[Cl:11][P:12]1(Cl)[N:17]=[P:16](Cl)(Cl)[N:15]=[P:14](Cl)(Cl)[N:13]=1>C1COCC1>[CH:7]([C:6]1[CH:9]=[CH:10][C:3]([O:2][P:16]2([O:2][C:3]3[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=3)[N:17]=[P:12]([O:2][C:3]3[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=3)([Cl:11])[N:13]=[P:14]([O:2][C:3]3[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=3)([O:2][C:3]3[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=3)[N:15]=2)=[CH:4][CH:5]=1)=[O:8]
Reactant: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Reactant: O=Cc1ccc(O)cc1
Agent: [Na]
Solvent: C1CCOC1
Product: O=Cc1ccc(OP2(Cl)=NP(Oc3ccc(C=O)cc3)(Oc3ccc(C=O)cc3)=NP(Oc3ccc(C=O)cc3)(Oc3ccc(C=O)cc3)=N2)cc1
Reaction time: 12 h
Yield: 70 %

Procedure:
2591 mg of 4-hydroxybenzaldehyde sodium salt (18 mmol) are added at 0° C. and under an inert atmosphere to a solution containing 1.2 g of hexachlorocyclotriphosphazene (3.45 mmol) in THF (300 mL). The reaction medium is stirred for 12 hours while the temperature is allowed to gradually return to room temperature. The crude reaction product is evaporated to dryness then purified by “flash” chromatography on a silica column. The product is isolated in the form of a translucent oil with a yield of 70%.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([CH2:15][O:16]C(=O)C2C=CC=CC=2)[O:13][C@H:12]([N:25]2[CH:32]=[C:31]([F:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:11]1)(=O)C1C=CC=CC=1>CO.O>[C@H:12]1([N:25]2[CH:32]=[C:31]([F:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[O:13][C@@H:14]([CH2:15][OH:16])[C@@H:10]([OH:9])[CH2:11]1
Reactant: O=C(OC[C@@H]1O[C@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: CO
Product: O=c1[nH]c(=O)n([C@@H]2C[C@H](O)[C@H](CO)O2)cc1F
Yield: 85 %

Procedure:
A solution of 1-(3,5-di-O-benzoyl-2-deoxy-β-L-xylofuranosyl)-5-fluorouracil (6b) (0.25 g, 0.55 mmol) in ammoniacal methanol (25 ml) is stirred overnight at room temperature. The solution is evaporated under reduced pressure and the residue is evaporated several times with methanol. The crude material obtained is dissolved in water and the resulting solution is washed several times with chloroform. The aqueous phase is evaporated and the residue is directly crystallized from methanol to give 115 mg (yield 85%) of pure 7b: m.p.=198-200° C.; UV [EtOH 95] λmax 267 nm (ε, 8500), λmin 233 nm (ε, 2100); 1H NMR (DMSO-d6) δ ppm=11.79 (s, 1H, 3-NH), 8.16 (d, 1H, H-6; J=7.4 Hz), 6.05 (dd, 1H, H-1′; J=1.8 and 6.5 Hz), 5.38 (d, 1H, OH-3′; J=3.3 Hz), 4.73 (t, 1H, OH-5′; J=5.4 Hz), 4.30-4.20 (m, 1H, H-3′), 3.85-3.60 (m, 3H, H-4′,5′ and 5″), 2.60-2.50 (m, 1H, H-2′ partially obscured by DMSO-d5), 1.90 (dd, 1H H-2″; J=1.8 and 14.7 Hz); mass spectra (matrix: glycerol-thioglycerol, 50:50, v/v): FAB>0 339 [M+glycerol+H]+, 247 [M+H]+, 131 [BH2]+ and 115 [s]+; FAB<0 245 [M−H]− and 129 [B]−.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:5]2=[CH:4][CH:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1)#[N:14].C(=O)(O)[O-].[Na+]>CO.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:12][N:8]1[C:6]2=[N:7][C:2]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:13]#[N:14])=[CH:3][CH:4]=[C:5]2[NH:10][C:9]1=[O:11]
Reactant: CC1(C)OB(c2ccccc2C#N)OC1(C)C
Reactant: Cn1c(=O)[nH]c2ccc(Cl)nc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cn1c(=O)[nH]c2ccc(-c3ccccc3C#N)nc21
Temperature: 100 °C

Procedure:
5-chloro-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1-3) (74 mg, 0.4 mmol), 2-cyanophenylboronic acid pinacol ester (179 mg, 1.2 mmol), sodium bicarbonate (200 mg, 2.4 mmol), and bis(tri-t-butylphosphine)palladium(0) (61 mg, 0.12 mmol) were added to a microwave vial and purged with nitrogen. Dioxane (1.2 mL) was added, the vessel was sealed and the suspension was heated at 100° C. for 12 minutes in a microwave reactor. The cooled reaction was diluted with methanol, and passed through a syringe filter. The solution was purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile) and the desired fractions were collected and concentrated to produce 2-(3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)benzonitrile (4-1). MS (M+H)+: observed=251.1, calculated=251.3.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([OH:15])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[N+]=[N-].Cl>CC(O)C>[NH2:1][CH2:4][C@@H:5]([OH:15])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1
Reactant: [N-]=[N+]=NC[C@@H](O)COc1ccc(F)cc1
Agent: Cl
Solvent: CC(C)O
Product: NC[C@@H](O)COc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of (R)-1-azido-3-(4-fluoro-phenoxy)-propan-2-ol (4.83 g, 22.9 mmol) NaBH4 (1.73 g, 45.8 mmol) in iPrOH (100 mL) was stirred at 80° C. for 24 h. After cooling to RT, aq. HCl (200 mL, 0.25 M) was added, washed with CH2Cl2 (100 mL). Saturated aq. K2CO3 (150 mL) was added to the aqueous phase. The product was extracted with CH2Cl2 (2×100 mL), extracts were dried over Na2SO4 and evaporated. The residue was dried under vacuum. White solid, 2.20 g (11.9 mmol, 52%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4]([C:7]2[N:8]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=3)=[CH:3][CH2:2]1>[C].[Pd].C(O)C>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:8]2[C:9]3[C:14](=[CH:13][C:12]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:11][CH:10]=3)[CH:15]=[C:7]2[CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(C1=CCOCC1)n2Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)c1ccc2c(c1)cc(C1CCOCC1)n2Cc1ccc(F)cc1
Temperature: 22.5 °C
Reaction time: 24 h
Yield: 47.9 %

Procedure:
A mixture of 2-(5,6-dihydro-2H-4-pyranyl)-1-(4-fluorobenzyl)-5-methanesulfonyl-indole (83 mg), 10% palladium carbon (15 mg) and ethanol (5 ml) was stirred at 15 to 30° C. for 24 hours under hydrogen atmosphere. The mixture was filtered and the mother liquid was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 40 mg of the desired product as a white crystal.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.CN1CCOCC1.[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[C:22]([F:29])[CH:21]=1>ClCCl>[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:25])=[C:22]([F:29])[CH:21]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: C1CN[C@H](CN2CCCC2)C1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(c1ccc(Br)cc1F)N1CCCC1CN1CCCC1

Procedure:
Procedure DD: To a stirring solution of (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (11.0 mmol) and n-methylmorpholine (11.0 mmol) in dichloromethane (0.10M), slowly add 4-Bromo-2-fluorobenzoic acid chloride (1.0 mmol) diluted in dichloromethane. Stir reaction at room temperature for one hour. After this time wash the reaction with saturated aqueous sodium bicarbonate while extracting with dichloromethane. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo to give the title compound. MS (m/e): 355.1/357.1 (M+1)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][C:2]=1[OH:1]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(N)c(O)c1
Temperature: 50 °C
Yield: 76.1 %

Procedure:
A solution of ethyl 3-hydroxy-4-nitrophenylacetate (5.0 g, Reference Example 4) was dissolved in ethanol (approximately 200 mL) was treated with ammonium formate (approximately 20 g). The mixture was warmed to 50° C. and then treated cautiously with palladium on charcoal (approximately 1 g, 5%)—effervescence was observed. After 30 minutes the mixture was filtered hot through a pad of celite and the filtrate was concentrated to give the title compound (3.3 g) as a black solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-:23].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.[OH-].[Na+]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]([I:23])=[CH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C#Cc2ccncc2)cc1OC1CCCC1
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(I)=Cc2ccncc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.9 %

Procedure:
To a solution of acetylene from step 1 (8.79 g, 30 mmol) in dichloromethane (600 mL) at room temperature there was added a solid mixture of sodium iodide (18 g, 120 mmol) and p-toluenesulfonic acid monohydrate (11.4 g, 60 mmol). The mixture was stirred at room temperature for 18 h. The mixture was diluted with aqueous 1N NaOH (600 mL) and stirred vigorously for 15 min. The organic phase was collected and washed 3 times with water, dried and evaporated to a residue which was stirred in a 2:1 mixture of hexane and ether (100 mL) for 2 h and filtered to afford the desired vinyl iodide (8.46 g, 67%) as a beige solid, assayed by NMR to be a 4:1 mixture of Z and E isomers.
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[O:15]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[CH:18][N:17]=[CH:16]1>C(Cl)Cl.N1C=CC=CC=1.C(Cl)Cl>[O:15]1[C:19]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([CH:6]4[CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:7]4)=[CH:13][CH:12]=3)(=[O:28])=[O:27])=[CH:24][CH:25]=2)=[CH:18][N:17]=[CH:16]1
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(-c4cnco4)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.9 %

Procedure:
The crude 4-(1-propyl-azetidin-3-yl)-phenylamine (40 mg, 0.21 mmol) was dissolved in CH2Cl2/pyridine 9:1 (10 ml) and 4-oxazol-5-yl-benzenesulfonyl chloride (51 mg, 0.21 mmol) was added. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2Cl2 and washed successively with 1N aqueous HCl, saturated aqueous NaHCO3 and water. The organic layer was dried over Na2SO4 and evaporated. The residue was chromatographied on silica gel (CH2Cl2:methanol, 95:5) to afford the title compound (30 mg, 36%) as a white amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[F:18][C:19]([F:32])([F:31])[C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[NH2:23]>>[F:18][C:19]([F:31])([F:32])[C:20]1[CH:21]=[C:22]([NH:23][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:3]=2[O:2][CH3:1])[CH:24]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:26]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1cc(-c2ccccc2)ccc1C(=O)O
Product: COc1cc(-c2ccccc2)ccc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 97.5 %

Procedure:
Using 2-methoxy-4-phenylbenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: Cl[CH:2]([O:4][CH2:5][CH:6]=[CH2:7])[CH3:3].[NH:8]1[CH:12]=[N:11][CH:10]=[N:9]1>C(#N)C>[N:8]1([CH:2]([O:4][CH2:5][CH:6]=[CH2:7])[CH3:3])[CH:12]=[N:11][CH:10]=[N:9]1
Reactant: C=CCOC(C)Cl
Reactant: c1nc[nH]n1
Solvent: CC#N
Product: C=CCOC(C)n1cncn1

Procedure:
Allyl 1-chloroethyl ether (3.6 g; Black and Lander, J.C.S., 1965, 5525) and 1,2,4-triazole (6.9 g) in acetonitrile (75 ml) were refluxed for 6 hours. The solvent was removed under reduced pressure; the residual solid was heated with water and extracted with diethyl ether. The ethereal phase was washed with water and dried over magnesium sulphate, and the solvent was removed. The residual oil was purified by passing through a column of silica gel, eluting with ethyl acetate to give the title compound as a colourless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:3][O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6].[CH:21]1(C(OC)=O)CCC[CH2:22]1>>[CH2:16]([C:2]1([CH2:3][O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:10])([CH3:11])[CH3:12])=[O:6])[CH2:20][CH2:22][CH2:21][CH2:1]1)[CH2:17][CH:18]=[CH2:19]
Reactant: COC(=O)C1CCCC1
Reactant: C=CCCC(C)(C)COC(=O)N[C@H](C(=O)O)C(C)(C)C
Product: C=CCCC1(COC(=O)N[C@H](C(=O)O)C(C)(C)C)CCCC1

Procedure:
N-{[(1-But-3-en-1-ylcyclopentyl)methoxy]carbonyl}-3-methyl-L-valine was prepared according to the procedure for N-{[(2,2-dimethylhex-5-enyl)oxy]carbonyl}-3-methyl-L-valine by using methyl cyclopentanecarboxylate instead of ethyl isobutyrate in Step 1. LRMS (ESI) m/z 312.3 [(M+H)+; calcd for C17H30NO4: 312.2].
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11]C)[CH:7]=[C:6]([Cl:13])[C:3]=1[CH:4]=[O:5].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:9]([OH:10])=[C:8]([OH:11])[CH:7]=[C:6]([Cl:13])[C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(Cl)c(C=O)c(Cl)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1c(Cl)cc(O)c(O)c1Cl
Temperature: -65 °C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
Into an oven-dried, three-neck round bottom flask, fitted with a thermometer, 1.0 g (4.52 mmol; Aldrich, Milwaukee, Wis.) of 2,6-dichloro-3-hydroxy-4-methoxybenzaldehyde and 45 mL of dichloromethane were added under nitrogen atmosphere. The solution was cooled to −65° C. and 1.32 mL (14 mmol) of boron tribromide was added dropwise. The reaction mixture was left to warm up slowly to room temperature with stirring for 16 hours. The reaction mixture was carefully quenched with the addition of 5 mL of water, then transferred to a single-neck round bottom flask and volatiles were removed in vacuo. The residue was taken up with 50 mL of ethylacetate and washed three times with water and two times with brine. The organic layer was dried over MgSO4, then concentrated to yield 0.9 g (96%) of crude 2,6-dichloro-3,4-dihydroxybenzaldehyde, as an off-white solid, which was used without further purification. 1H-NMR δ (d6-acetone): 6.85 (1H, s), 9.1 (2H, br s), 10.2 (1H,s). Melting point=213-215° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:32]1[CH:37]=[CH:36][C:35]([CH2:38]O)=[CH:34][CH:33]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:38][C:35]2[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=2)=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Reactant: OCc1ccncc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: FC(F)(F)c1cc(Br)ccc1OCc1ccncc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 101.2 %

Procedure:
To a suspension of 4-bromo-2-(trifluoromethyl)phenol (8.00 g) in 1,4-dioxane (100 ml), triphenylphosphine (10.99 g) and 4-pyridylcarbinol (3.84 g) were added. Then diisopropyl azodicarboxylate (8.93 g) was dropwised and stirred at 20° C. for 18 h. The mixture was evaporated off the solvent, diethyl ether (100 ml) and iso-hexane (25 ml) were added and stirred at 20° C. for 2 h, stood for 3 days, filtered and washed with diethyl ether and iso-hexane. The filtrate was concentrated and purified by Biotage SNAP cartridge KP-Sil column (100 g, heptane:ethyl acetate=1:0, 2:1 to 1:1) to give 11.16 g red-orange oil as 4-((4-bromo-2-(trifluoromethyl)phenoxy)methyl)-pyridine (80% purity).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:19]C)[N:12]2[CH2:15][CH2:16][CH2:17]Cl)=[C:8]([NH2:21])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[I-].[Na+]>C1COCC1>[NH2:21][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:19])[N:12]2[CH2:15][CH2:16][CH2:17][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCCl)c2n1
Reactant: C1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCCN3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.8 %

Procedure:
A mixture of N2-butyl-9-(3-chloropropyl)-8-(methyloxy)-9H-purine-2,6-diamine (250 mg, 0.8 mmole), piperidine (340 mg, 4 mmole) and sodium iodide (360 mg, 2.4 mmole) in THF (8 ml) was heated under reflux for 48 hours. The solvent was evaporated and the residue purified by preparative TLC then dissolved in methanol (5 ml). Hydrogen chloride in methanol (0.5 ml) was added and the mixture stirred at room temperature for 16 hours. The solvent was then evaporated and the pH of the residue was adjusted to 7-8 by addition of sodium bicarbonate solution. The product was extracted into ethyl acetate and the extract was evaporated and the residue purified by preparative HPLC to give the title compound (16 mg).